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Is severity of obesity associated with diagnosis or health education practices?

To assess the association of the severity of obesity with diagnosis and health education, and to identify any differences within demographic or other subgroups. Clinician visits for 2-18 year olds from the 2005-2008 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey were combined. Descriptive, bivariate and multivariate analyses were used to compare diagnosis of obesity and health education (nutrition, exercise and weight reduction) across elevated body mass index (BMI) groups (overweight, obese and extreme or very obese, defined as>120% of the 95th percentile for age and gender), patient socio-demographic characteristics, physician specialty and type of visit (well child visits (WCV) versus non-well child visits (non-WCV). A total of 17,808 visits had a calculated BMI, of which 5.8% were extremely obese, 13% were obese and 15.2% were overweight, with the highest percentages among older children, blacks and Hispanics. Diagnosis and weight reduction education were higher among children with an extreme BMI. Nutrition and exercise education were not correlated with severity of obesity. Race, ethnicity or gender biases were not identified. Severity of obesity was significantly associated with presentation to a non-WCV rather than a WCV.

Extremely obese children have higher, but still insufficient, rates of diagnosis and health education. Nutrition and exercise education are not prevalent throughout all age groups. Providers may be relying inconsistently and insufficiently on visual cues to drive their obesity prevention practices. Furthermore, lower rates of diagnosis and education at non-WCV may result in a missed opportunity to prevent comorbidities. This is of particular concern as overweight children are less likely to be seen at WCV than non-WCV.

Do acute pancreatitis with gradient echo T2*-weighted magnetic resonance imaging?

To study gradient recalled echo (GRE) T2*-weighted imaging (T2*WI) for normal pancreas and acute pancreatitis (AP). Fifty-one patients without any pancreatic disorders (control group) and 117 patients with AP were recruited. T2* values derived from T2*WI of the pancreas were measured for the two groups. The severity of AP was graded by the magnetic resonance severity index (MRSI) and the Acute Physiology and Chronic Healthy Evaluation II (APACHE II) scoring system. Logistic regression was used to analyze the relationship between the T2* values and AP severity. The usefulness of the T2* value for diagnosing AP and the relationship between the T2* values and the severity of AP were analyzed. On GRE-T2*WI, the normal pancreas showed a well-marinated and consistently homogeneous isointensity. Edematous AP, as well as the non-necrotic area in necrotizing AP, showed ill-defined but homogeneous signal intensity. AP with pancreatic hemorrhage showed a decreased T2* value and a signal loss on the signal decay curve. The T2* value of pancreas in the AP group was higher than that of the control group (t=-8.20, P<0.05). The T2* value tended to increase along with the increase in MRSI scores but not with the APACHE II scores (P>0.05). AP was associated with a one standard deviation increment in the T2* value (OR =1.37; 95% CI: 1.216-1.532).

T2*WI demonstrates a few characteristics of the normal pancreas and AP, which could potentially be helpful for detecting hemorrhage, and contributes to diagnosing AP and its severity.

Does coadministration of carvedilol attenuate nitrate tolerance by preventing cytochrome p450 depletion?

Long-term administration of nitroglycerin (NTG) causes tolerance secondary to increased vascular formation of reactive oxygen species. Carvedilol, which has potent antioxidant activity in addition to functioning as an adrenergic blocker, prevents nitrate tolerance by a still to be elucidated mechanism. The present study investigated how carvedilol attenuates nitrate tolerance, particularly with reference to cytochrome P450 (CYP), an enzyme involved in the development of tolerance. Male Wistar rats were subjected to 48-h continuous infusion of NTG alone (0.5 mg/h) or NTG with concomitant carvedilol (20 or 100 microg/h), and then compared with vehicle-treated rats (4 groups; n=6 in each group). Following the continuous administration, nitrate tolerance, assessed by bolus NTG injections, was hemodynamically prevented by coadministration of carvedilol. Levels of CYP1A1/1A2, superoxide production, and phosphorylated vasodilator-stimulated phosphoprotein at serine 239 (P-VASP) were examined in the aortic wall and heart tissue. When NTG alone was continuously administered, vascular superoxide was produced, there was a decrease in the cardiac CYP1A1/1A2 level, and depletion of P-VASP. However, each of these changes induced by continuous NTG administration was significantly attenuated by coadministration of carvedilol and the extent of attenuation was more pronounced at the higher dose (100 microg/h).

Coadministration of carvedilol attenuates nitrate tolerance through maintenance of NO/cGMP pathway activity by preventing free radical generation and CYP depletion.

Does a new undergraduate curriculum based on Tomorrow's Doctors prepare house officers better for their first post?

In 1994 Manchester University introduced an integrated undergraduate medical course using problem-based learning (PBL) throughout. The study reported here explored whether there were any differences between the new course graduates (NCGs) and the traditional course graduates (TCGs) in the types of scenarios they recalled as 'critical incidents', or challenging cases, while working as pre-registration house officers (PRHOs). The focus is on differences rather than causal links. We used semistructured interviews to generate our data. Twenty-four traditional course graduates and 23 new course graduates were interviewed approximately 3 months after starting their first PRHO placement. We identified 4 types of critical incidents relating to: clinical practice; limitations of competence; emotional involvement; and communication. Traditional course graduates reported difficulties in making patient management decisions, whereas the NCGs were better at dealing with uncertainty, knowing their limits and asserting their rights for support. Communication difficulties and coping with emotional involvement were common across both groups of graduates and hence remain problems in relation to being prepared for the role of a PRHO.

Graduates of the new, integrated curriculum seemed to be much better at dealing with uncertainty, knowing their personal limits and asserting their rights for support when they felt these limits had been reached. Communication difficulties and emotional involvement remain major factors in the transition from student to PRHO.

Does transcriptional response of P. pastoris in fed-batch cultivations to Rhizopus oryzae lipase production reveal UPR induction?

The analysis of transcriptional levels of the genes involved in protein synthesis and secretion is a key factor to understand the host organism's responses to recombinant protein production, as well as their interaction with the cultivation conditions. Novel techniques such as the sandwich hybridization allow monitoring quantitatively the dynamic changes of specific RNAs. In this study, the transcriptional levels of some genes related to the unfolded protein response (UPR) and central metabolism of Pichia pastoris were analysed during batch and fed-batch cultivations using an X-33-derived strain expressing a Rhizopus oryzae lipase under control of the formaldehyde dehydrogenase promoter (FLD1), namely the alcohol oxidase gene AOX1, the formaldehyde dehydrogenase FLD1, the protein disulfide isomerase PDI, the KAR2 gene coding for the BiP chaperone, the 26S rRNA and the R. oryzae lipase gene ROL. The transcriptional levels of the selected set of genes were first analysed in P. pastoris cells growing in shake flask cultures containing different carbon and nitrogen sources combinations, glycerol + ammonium, methanol + methylamine and sorbitol + methylamine. The transcriptional levels of the AOX1 and FLD1 genes were coherent with the known regulatory mechanism of C1 substrates in P. pastoris, whereas ROL induction lead to the up-regulation of KAR2 and PDI transcriptional levels, thus suggesting that ROL overexpression triggers the UPR. This was further confirmed in fed-batch cultivations performed at different growth rates. Transcriptional levels of the analysed set of genes were generally higher at higher growth rates. Nevertheless, when ROL was overexpressed in a strain having the UPR constitutively activated, significantly lower relative induction levels of these marker genes were detected.

The bead-based sandwich hybridization assay has shown its potential as a reliable instrument for quantification of specific mRNA species in P. pastoris cells grown in fed-batch cultures. As a proof-of-principle, the influence of the carbon and nitrogen sources, the specific growth rate, as well as the ROL overexpression on the transcriptional levels of a reduced set of bioprocess-relevant genes has been quantitatively studied, revealing that ROL overexpression and secretion seems to trigger the UPR in P. pastoris, resulting in a physiological bottleneck for the production process.

Seroprevalence of hepatitis B before marriage: a study on marriage candidates in the Southeast of Iran; is it worthy of consideration?

Hepatitis B virus infection is one of the most common causes of acute and chronic hepatitis worldwide. Furthermore, since most people with hepatitis B virus are asymptomatic, timely diagnosis is important for prevention. This study has evaluated the prevalence of Hepatitis B seromarkers in marriage candidates. In this Cross-sectional study, 370 marriage volunteers selected by the simple sampling method were investigated in 2011 - 2012. A total of 185 men and 185 women were investigated. Mean Age of participants was 24.7 years. The prevalence rates of hepatitis B surface antigen (HBsAg), anti hepatitis B surface antibody (anti-HBs) and anti-hepatitis B core antibody (anti-HBc) were 1.1%, 47.6% and 8.9% respectively. Frequency of HBsAg was 0.5% and 1.6% in men and women respectively. The prevalence of anti-HBs was 43.8% in men and 51.45% in women. Anti-HBs was more common in young people and those with higher levels of education and positive history of vaccination. The prevalence of anti-HBc was 8.1% and 9.7% in men and women respectively.

Although Kerman is a low endemic area, due to the high risk of transmission to the spouse and offspring, screening for HBV study before marriage is recommended.

Does gadolinium attenuate regional stunning in the canine heart in vivo?

Gadolinium, a lanthanide cation, ameliorates pathophysiologic features of both heart failure and cardiac arrhythmias. We have shown, in an in vitro model, that gadolinium blocks stretch-induced contractile dysfunction in both normal and stunned myocardium. The present study tested the hypothesis that gadolinium would also attenuate regional myocardial stunning in an in vivo model. Mongrel dogs (n = 13) were subjected to regional myocardial ischemia (occlusion of the left anterior descending coronary artery) for 15 minutes, followed by reperfusion for 180 minutes. Intravenous gadolinium (500 micromol) was given to 7 dogs before ischemia; no gadolinium was given to control animals. Regional contractile function was assessed serially by means of both systolic shortening (percentage) and regional preload recruitable stroke work. Administration of gadolinium before ischemia had no effect on heart rate, arterial blood pressure, stroke volume, or regional contractile function. Ischemia resulted in paradoxical systolic bulging in both groups. After 180 minutes of reperfusion, systolic shortening was enhanced in gadolinium-treated animals compared with that in control animals (10.9% +/- 1.5% vs 2.4% +/- 1.7%, P =.003). Both the slope and x-axis intercept of regional preload recruitable stroke work returned to preischemic values in treated animals but remained abnormal in control animals.

These data confirm that gadolinium attenuates regional myocardial stunning in vivo. Gadolinium may cause peripheral vasodilatation but does not appear to exert positive inotropic effects on the normal canine heart. The mechanism underlying gadolinium-mediated effects on stunned myocardium remains undefined, but this study suggests that use of gadolinium may represent a novel adjunct to current cardioprotective strategies.

Is excessive lowering of blood pressure beneficial for progression of brain white matter hyperintensive and cognitive impairment in elderly hypertensive patients : 4-year follow-up study?

This study was designed to explore the appropriate blood pressure (BP) target required to reduce cognitive decline and brain white matter lesions (WMLs) in elderly hypertensive patients. Elderly patients (n = 294, ≥80 years of age) being treated for hypertension were enrolled in a longitudinal study examining cognitive impairment after an initial assessment and a period of 4 years. All patients underwent neurological and cognitive assessment, laboratory examination, and magnetic resonance imaging of the brain. The 4-year follow-up examination revealed that body mass index, alcohol consumption, systolic blood pressure (SBP), diastolic blood pressure, and Mini-Mental State Examination (MMSE) all showed a significant decline, whereas fasting plasma glucose, white matter hyperintensities (WMH) volume, and the WMH/total intracranial volume (TIV) ratio were significantly increased when compared with baseline observations. Interestingly, the decline in MMSE, as well as the increment of WMH and WMH/TIV ratio was smaller in patients with SBP ranging from 140 to 160 mm Hg than in those whose SBP was lower than 140 mm Hg or higher than 160 mm Hg (P < .05). Furthermore, we observed that a 15 to 35 mm Hg targeted lowering of SBP in the elderly patients was more beneficial to our cognitive analysis than treatments that achieved less than 15 mm Hg or greater than 35 mm Hg (P < .05).

In elderly hypertensive patients, there exists a beneficial target for SBP lowering beyond which treatment may not be beneficial for improving or delaying the progression of cognitive impairment and WMLs.

Does [ Emodin block voltage dependent potassium channels in rat proximal colon smooth muscle cells ]?

To investigate the effect of emodin on the voltage dependent potassium (K(V)) currents in rat proximal colon smooth muscle cells. Whole cell patch clamp technique was used to record potassium currents including fast transient outward current (I(KA)) and delayed rectifier current (I(Kdr)). Contamination of calcium-dependent potassium currents was minimized with CdCl2 in external solution and EGTA in pipette solution. Emodin (1-30 micromol x L(-1)) reversibly and dose-dependently reduced the amplitude of I(Kdr) with an K(d) value of (1.9 +/- 0.1) micromol x L(-1). I(KA) was also inhibited with 30 micromol x L(-1) emodin to a lesser extent. Although acceleration of the decay rate of the K(V) currents was observed, the block by emodin was not through open block mechanism because a steady state level of inhibition of I(Kdr) was achieved during the first pulse from holding potential -70 mV to + 50 mV after the cells were holding at -70 mV for a three minutes interval in the presence of emodin. Emodin (5 micromol x L(-1)) had no effect on the steady-state activation and inactivation kinetics of K(V) currents, but 30 micromol x L(-1) of emodin produced a positive shift of the voltage dependence of activation, and an increase in the steepness of activation gating as well as shifted the voltage dependence of inactivation to positive direction.

Emodin, not through open block mechanism, markedly reduced the amplitude of I(KA) and I(Kdr) and modulated the gating properties of K(V) channels in a reversible and dose-dependent manner.

Does over-expression of LPTS-L in hepatocellular carcinoma cell line SMMC-7721 induce crisis?

To evaluate the function of the longer transcripts LPTS-L in hepatocellular carcinoma cell line SMMC-7721. SMMC-7721 cells were transfected with LPTS-L expression construct and stably transfected cells were selected by G418. Multiple single clones formed and were checked for their phenotype. In the study of the effect on telomerase activity of LPTS-L in vitro, GST-LPTS-L fusion protein was expressed in E.coli and purified by glutathione-agarose column. Telomeric repeat amplification protocol (TRAP) assays were performed to study the influence of telomerase activity in SMMC-7721 cells. Over-expression of LPTS-L induced SMMC-7721 cells into crisis. LPTS-L could inhibit the telomerase activity in SMMC-7721 cells in vitro.

LPTS-L is a potent telomerase inhibitor. Over-expression of LPTS-L can induce hepatoma cells into crisis due to the reduction of telomerase activity.

Do an update on the cytokine network in rheumatoid arthritis?

To update the knowledge accumulated on the contribution of cytokines to rheumatoid arthritis and related animal models. Publications from the end of 2002 and 2003 period were analyzed for a selection. A better understanding of the clinical results with tumor necrosis factor-alpha inhibitors has come from studies in treated patients. The expected effect of infliximab on the apoptosis of cells expressing tumor necrosis factor-alpha was not observed in synovium biopsy specimens. The mode of action of tumor necrosis factor-alpha on bone destruction has been clarified in gene-defective mice. Tumor necrosis factor-alpha acts through osteoclasts--an effect that is inhibited with osteoprotegerin. New interleukin-1 inhibitors with a potential for increased efficacy, such as interleukin-1trap, have been manufactured and are now being tested in rheumatoid arthritis. The list of cytokines of interest for therapeutic intervention has been growing rapidly. The results with animal models have provided clues to control arthritis with natural interleukin-18 inhibitors, such as interleukin-18 BP. Additional results have been accumulated that indicate the contribution of T cell subsets in inflammation and destruction through the production of interleukin-17. Synergistic interactions with other cytokines are critical in the interleukin-17 tuning effects. Macrophage inhibitory factor was described many years ago. Its comeback is based on properties of synoviocyte activation and proliferation.

Such findings are critical for a better understanding of response heterogeneity in patients treated with the cytokine inhibitors now on the market. New therapeutic approaches are been planned from these results.

Is non-alcoholic fatty liver disease associated with late but not early atherosclerotic lesions in Chinese inpatients with type 2 diabetes?

To investigate the association between non-alcoholic fatty liver disease (NAFLD) and carotid and lower limb atherosclerotic lesions in a large group of hospitalized-based type 2 diabetic population and to assess the prevalence and characteristics of NAFLD in Chinese subjects with type 2 diabetes (T2DM). A total of 8571 patients (4804 men) with T2DM were included in this cross-sectional study. The main outcome measures were detection of NAFLD, carotid intima-media thickness (C-IMT), carotid and lower limb atherosclerotic plaque formation, and classical risk factors. The prevalence of carotid (56.5% vs. 44.5%; p<0.001) and lower limb plaque (56.2% vs. 48.7%; p<0.001), and carotid (11.2% vs. 6.8%; p<0.001) and lower limb stenosis (15.1% vs. 10.3%; p<0.001) was markedly higher in the diabetic patients with NAFLD than in those without, after controlling for age. However, there was no significant difference in C-IMT between diabetic patients with and without NAFLD (0.82±0.30mm vs. 0.85±0.39mm) after controlling for age. Fully adjusted multiple linear regression and logistic regression analyses revealed that NAFLD was significantly associated with increased prevalence of carotid and lower limb atherosclerotic plaque but not with C-IMT. NAFLD, age, sex, longer duration of diabetes and the presence of hypertension were independently associated with carotid and lower limb atherosclerotic plaque (p<0.05).

NAFLD was not associated with elevated C-IMT but was associated with carotid and lower limb atherosclerotic plaque independent of conventional cardiovascular disease risk factors and metabolic syndrome in Chinese inpatients with T2DM.

Facial rejuvenation after intradermal botulinum toxin: is it really the botulinum toxin or is it the pricks?

The use of intradermal botulinum toxin A (onabotulinumtoxinA) remains a relatively new technique and is an off-label cosmetic application for facial skin rejuvenation. There is little documented clinical evidence of the objective benefits of this therapy. To determine whether intradermal facial onabotulinumtoxinA injection has any benefits. Interventional, comparative, split face clinical trial. Informed consent was obtained from 10 physicians. One half of the physician's faces were randomly injected with onabotulinumtoxinA (2 U/0.1 mL; 30 facial injections on half of the face, each 0.1 mL) intradermally and the other half of the face with normal saline (30 facial injections on half of the face, each 0.1 mL). The injecting clinician and the subjects were blinded to the contents of the syringes. One and 4 weeks later, two neutral, blinded observers assessed the subjects in person. The patients were also photographed in ambient light surroundings and the same observers compared the halves of their faces in photographs and rated them on a scale of -4 to +4. Global improvement in skin texture and tightness was noted in the post-treatment photographs (the skin appeared to be tenser and smoother), although there was no difference between the two groups and, hence, the changes could not be clinically ascribed to the intradermal botulinum toxin injections. No other meaningful clinical difference could be demonstrated between the two sides of the face, in any of the 10 subjects, in person or in photographs. The small study sample precluded formal statistical analysis.

Intradermal botulinum toxin A injection does not appear to have any benefit in facial rejuvenation.

Does japanese lifestyle during childhood prevent the future development of obesity among Japanese-Americans?

To evaluate whether a Japanese lifestyle during childhood could protect against the future development of obesity-associated metabolic diseases by comparing native Japanese with Japanese-Americans in whom genetic factors are the same. Study subjects were 516 native Japanese and 781 Japanese-Americans who underwent medical examinations between 2007 and 2010. Japanese-Americans were divided into 444 first-generation immigrants (JA-1), who were born in Japan, and 337 second- or later-generation descendants (JA-2), who were born in the United States. The JA-2 group was then divided into the kibei subgroup (N = 79), who had moved to Japan before the age of 18 years and later returned to the United States, and the non-kibei subgroup (N = 258), who had never lived in Japan. The JA-2 group had the highest percentages of obesity, metabolic syndrome, and type 2 diabetes compared with native Japanese and JA-1. Furthermore, among JA-2, the prevalence of obesity and metabolic syndrome in the kibei subgroup was significantly lower than that in the non-kibei subgroup. The prevalence of diabetes in the kibei subgroup also tended to be lower than in the non-kibei subgroup.

The prevalence of obesity and metabolic diseases differed with residence in Japan during childhood among Japanese-Americans. These findings indicate the possibility that Japanese lifestyle during childhood could reduce the future risks for obesity-associated metabolic diseases.

Does anticancer agent 3-bromopyruvic acid form a conjugate with glutathione?

3-Bromopyruvic acid (3-BP), a glycolytic inhibitor and a promising anticancer compound, induces oxidative stress and depletes cells of glutathione (GSH). The causes of GSH loss remain unclear. The aim of this study was to ascertain whether 3-BP forms a conjugate with glutathione. GSH was incubated with various amounts of 3-BP and the extent of reaction was titrated with (1)H NMR and (1)H-(1)H NMR. The reaction outcome was identified by MS/MS. Intracellular formation of the conjugate was assessed in cells treated with 3-BP and 3-BP((13)C) and analyzed using the targeted LC-MS/MS method in negative ionization MRM mode. 3-BP was found to react with GSH in a 1:1 ratio forming an S-conjugate. The same conjugate was formed intracellularly in erythrocytes and MCF-7 cells.

3-BP reacts with GSH in the absence of cells and intracellularly. This reaction appears to be the main cause of GSH loss in 3-BP treated cells.

Does laser type impact myocardial function following transmyocardial laser revascularization?

Transmyocardial laser revascularization (TMR) is currently clinically performed with either a CO(2) or Ho:YAG laser for the treatment of severe angina. While both lasers provide symptomatic relief, there are significant differences in the laser-tissue interactions specific to each device that may impact their ability to enhance the perfusion of myocardium and thereby improve contractile function of the ischemic heart. A porcine model of chronic myocardial ischemia was employed. After collecting baseline functional data with cine magnetic resonance imaging (MRI) and dobutamine stress echo (DSE), 14 animals underwent TMR with either a CO(2) or Ho:YAG laser. Transmural channels were created with each laser in a distribution of 1/cm(2) in the ischemic zone. Six weeks post-treatment repeat MRI as well as DSE were obtained after which the animals were sacrificed. Histology was preformed to characterize the laser-tissue interaction. CO(2) TMR led to improvement in wall thickening in the ischemic area as seen with cine MRI (40.3% vs. baseline, P < 0.05) and DSE (20.2% increase vs. baseline, P < 0.05). Ho:YAG treated animals had no improvement in wall thickening by MRI (-11.6% vs. baseline, P = .67) and DSE (-16.7% vs. baseline, P = 0.08). Correlative semi-quantitative histology revealed a significantly higher fibrosis index in Ho:YAG treated myocardium versus CO(2) (1.81 vs. 0.083, P < 0.05).

In a side-by-side comparison CO(2) TMR resulted in improved function of ischemic myocardium as assessed by MRI and echocardiography. Ho:YAG TMR led to no improvement in regional function likely due to concomitant increase in fibrosis in the lasered area.

Is impaired vigilance and increased accident rate in public transport operators associated with sleep disorders?

Sleep disturbances can impair alertness and neurocognitive performance and increase the risk of falling asleep at the wheel. We investigated the prevalence of sleep disorders among public transport operators (PTOs) and assessed the interventional effects on hypersomnolence and neurocognitive function in those diagnosed with obstructive sleep apnea (OSA). Overnight polygraphy and questionnaire data from 101 volunteers (72 males, median age 48 range [22-64] years, 87 PTOs) employed at the Gothenburg Public Transportation Company were assessed. Treatment was offered in cases with newly detected OSA. Daytime sleep episodes and neurocognitive function were assessed before and after intervention. At baseline, symptoms of daytime hypersomnolence, insomnia, restless legs syndrome as well as objectively assessed OSA (apnea hypopnea index (AHI, determined by polygraphic recording)=17[5-46]n/h) were highly present in 26, 24, 10 and 22%, respectively. A history of work related traffic accident was more prevalent in patients with OSA (59%) compared to those without (37%, p<0.08). In the intervention group (n=12) OSA treatment reduced AHI by -23 [-81 to -5]n/h (p=0.002), determined by polysomnography. Reduction of OSA was associated with a significant reduction of subjective sleepiness and blood pressure. Measures of daytime sleep propensity (microsleep episodes from 9 [0-20.5] to 0 [0-12.5], p<0.01) and missed responses during performance tests were greatly reduced, indices of sustained attention improved.

PTOs had a high prevalence of sleep disorders, particularly OSA, which demonstrated a higher prevalence of work related accidents. Elimination of OSA led to significant subjective and objective improvements in daytime function. Our findings argue for greater awareness of sleep disorders and associated impacts on daytime function in public transport drivers.

Are hLA class II associations with rheumatic heart disease more evident and consistent among clinically homogeneous patients?

Discrepancies in reported HLA class II associations with rheumatic heart disease (RHD) may have been due to inaccuracies of serological typing reagents and/or lack of defined clinical classification of patients analyzed. The molecular association between HLA and RHD was investigated in patients with defined clinical outcome. Class II allele/haplotype distribution was determined in 2 groups of RHD patients (n=88) and a control group (n=59). Patients were divided into the mitral valve disease (MVD) category (ie, those with mitral regurgitation with or without mitral stenosis) and the multivalvular lesions (MVL) category, with impairment of aortic and/or tricuspid valves in addition to mitral valve damage. The MVD category (n=65) accounted for 74% of patients and included significantly fewer recurrent RF episodes compared with MVL patients (P=0.002).

Significant increases in DRB1*0701 and DQA1*0201 alleles and DRB1*0701-DQA1*0201 haplotypes were found in patients. Removal of the MVL patients from analysis increased the strength of HLA associations among the MVD sample. The frequency of DQA1*0103 allele was decreased and the DQB1*0603 allele was absent from the patient group, suggesting that these alleles may confer protective effects against RHD. DQ alleles in linkage disequilibrium with DR alleles appear to influence risk/protection effect: whereas the DRB1*13-DQA1*0501-3-DQB1*0301 haplotype showed a trend toward risk, the DRB1*13-DQA1*0103-DQB1*0603 haplotype was absent in the RHD sample. Our data indicate that certain class II alleles/haplotypes are associated with risk or protection from RHD and that these associations appear to be stronger and more consistent when analyzed in patients with relatively more homogeneous clinical manifestations.

Does lymphocyte glucocorticoid receptor mRNA correlate negatively to serum leptin in normal weight subjects?

The aim of the present study was to test the hypothesis that glucocorticoid receptor mRNA concentrations decreased with increasing fatness in normal subjects. Serum leptin concentrations, fat distribution parameters, lymphocyte glucocorticoid (GCR) mRNA, beta2-adrenoceptor mRNA and c-fos mRNA concentrations measured by RT-PCR-HPLC. Fifteen healthy non-obese young subjects with a mean body mass index (BMI) of 23. 5+/-0.3 (+/-s.e.m.) kg/m2. Lymphocyte GCR and beta2-adrenoceptor mRNA concentrations averaged 4.2+/-0.2 (+/-s.e.m. ) amol/microg total RNA and 1.4+/-0.1 amol/microg total RNA, respectively. There was a significant negative correlation between serum leptin and lymphocyte GCR mRNA (P<0.01). Serum leptin correlated positively with the waist-hip ratio (P<0.03), whereas lymphocyte GCR mRNA correlated negatively to the waist-hip ratio (P<0.04). Serum cortisol correlated with the weight of the subjects but not the waist-hip ratio or GCR mRNA.

It is suggested that the decrease in lymphocyte GCR mRNA concentration with increasing serum leptin concentrations is a counterregulatory response to an increased body fat content. Further studies are warranted, especially to elucidate the relationship between GCR mRNA in lymphocytes and in fat cells and to clarify the mechanism of the decrease in GCR mRNA.

Are cervical laminectomy width and spinal cord drift risk factors for postoperative C5 palsy?

Cervical laminectomy and fusion (CLF) is a treatment option for multilevel cervical spondylotic myelopathy. Postoperative C5 nerve palsy is a possible complication of CLF. It has been suggested that C5 nerve palsy may be due to posterior drift of the spinal cord related to a wide laminectomy trough. To test the hypothesis that excessive spinal cord drift into a wide laminectomy trough is associated with C5 palsy. Retrospective case-control study. Seventeen patients with C5 palsy, 8 patients as control group. Spinal cord positional measurements on magnetic resonance imaging (MRI). All patients who underwent elective CLF for cervical spondylotic myelopathy or ossified posterior longitudinal ligament using posterior instrumentation between 2004 and 2008 were included. Patients who underwent CLF for trauma, infection, or tumors were excluded. Clinical and radiographic outcomes were assessed by chart review (minimum of 1 y follow-up). Patients who developed a new postoperative C5 nerve palsy underwent repeat MRI. The control group also underwent CLF, did not develop a neurological deficit, and received a postoperative MRI for evaluation of possible infection. MRI measurements included the width of the laminectomy trough, the distance from the posterior vertebral body or disk to the anterior spinal cord, the width of the spinal cord herniated into the laminectomy defect, and C2-7 sagittal alignment. Preoperative radiographic measurements included preoperative vertebral body diameter, spinal canal diameter, and sagittal vertical offset. There were seventeen patients with C5 nerve root palsy and 8 patients without C5 nerve root palsy. There were no baseline differences in fusion levels, instrumentation used, patient age, or sex. MRI measurements revealed an increase in mean postoperative cord drift in patients with C5 palsy at C3 (4.2 vs. 2.2 mm, P=0.002), C4 (4.6 vs. 2.8 mm, P=0.056), C5 (5.1 vs. 2.4 mm, P=0.011), and C6 (5.2 vs. 2.4 mm, P=0.003). There was a significant increase in C5 laminectomy trough width among patients with postoperative C5 palsy (17.9 vs. 15.2 mm, P=0.032), but there was no difference in sagittal alignment.

A wider laminectomy at C5 was associated with an increased risk of postoperative C5 palsy. Increased preoperative spinal canal diameter is also associated with increased risk of C5 palsy. In addition, patients who experienced C5 nerve palsy had a significantly greater posterior spinal cord drift. Strategies to reduce postoperative laminectomy trough width and spinal cord drift may reduce the risk of postoperative C5 palsy.

Is transition from in situ to invasive testicular germ cell neoplasia associated with the loss of p21 and gain of mdm-2 expression?

The tumor suppressor gene p53 has been shown to transcriptionally regulate expression of the cell cycle dependent kinase inhibitor p21. p53 is in turn regulated by the ubiquitin ligase mouse double minute-2 (mdm-2). We have set out to examine p21 expression in testicular germ cell tumors and its relationship with p53 and mdm-2 expression. Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue for p53, p21, and mdm-2 in 31 testicular germ cell tumors, which included 17 pure seminomas and 14 mixed germ cell tumors composed predominantly of embryonal carcinoma. Twenty-seven cases contained adjacent areas of intratubular germ cell neoplasia (ITGCN). 17 out of 17 seminomas and 14 out of 14 embryonal carcinomas expressed p53 in both ITGCN and the invasive tumor. In contrast, none of the 17 seminomas and only 2 of 14 embryonal carcinomas revealed positive staining for p21 protein. p21 expression was noted in 18 of 27 cases (67%) of ITGCN, and in 16 of these cases (89%) the corresponding invasive tumor had lost p21 expression. In nine additional cases p21 expression was absent in both the invasive and intratubular tumor. mdm-2 expression was present in 8 out of 17 (47%) seminomas and 13 out of 14 (93%) embryonal carcinomas but was present in only 2 out of 27 (7%) cases of ITGCN. Statistically significant associations for loss of p21 and gain of mdm-2 expression in invasive tumors were present (P < .0001).

The co-expression of p53 and p21 in ITGCN is consistent with preservation of p53-directed induction of p21. The loss of p21 expression in invasive tumors suggests a disruption of the p53 regulatory pathway. The inverse correlation of p21 and mdm-2 expression in both ITGCN and invasive tumors could indicate that loss of the functional p53 regulatory pathway may be correlated with the onset of mdm-2 expression. These results raise the possibility that the loss of p21 expression may be associated with the development of invasive germ cell tumors from ITGCN. Persistent p53 expression in the presence of mdm-2 suggests that in testicular germ cell tumors, while mdm-2 can block the transactivation potential of p53, it can no longer target p53 for degradation.

Is high grade prostatic intraepithelial neoplasia still a risk factor for adenocarcinoma in the era of extended biopsy sampling?

There is controversy regarding the role of high grade prostatic intraepithelial neoplasia (HGPIN) on prostatic needle biopsy (PNB) as a risk factor for prostatic adenocarcinoma. We utilise a large Canadian database to determine whether HGPIN detected on extended PNB is a significant risk factor for prostatic adenocarcinoma. Pathological findings from PNBs from 12 304 men who underwent initial PNB during an 8 year period were analysed. Patients were included in the study if their initial diagnosis was HGPIN alone or a benign diagnosis, if at least one follow-up PNB was performed, and if both the initial and follow-up PNB contained at least 10 prostate cores. In the benign group of 105 patients and the HGPIN group of 120 patients, 14.1% and 20.8% were diagnosed with prostatic adenocarcinoma, respectively. When the HGPIN group was further subdivided into unifocal (1 core) and multifocal (>or=2 cores) groups, 9.4% and 29.9% developed prostatic adenocarcinoma, respectively (p<0.0001). Cox regression analysis adjusting for age and prostate specific antigen (PSA) confirms the significance of HGPIN as a risk factor for prostatic adenocarcinoma (p = 0.0045).

Patients with an initial diagnosis of multifocal HGPIN on extended PNB are at a greater risk for subsequent prostatic adenocarcinoma than those with unifocal HGPIN or benign diagnoses.

Does daily Injection But Not Continuous Infusion of Apomorphine inhibit Form-Deprivation Myopia in Mice?

To compare the effects of daily injection versus continuous infusion of a nonspecific dopamine agonist, apomorphine (APO), on refraction and ocular growth in normal postnatal mice and mice with form-deprivation myopia (FDM). The C57BL/6 mice were subjected (or not) to monocular FD by covering the left eye with a frosted goggle and leaving the right (fellow) eye uncovered. During postnatal days 28 to 56, both groups received APO (5 mg/kg/d) or vehicle either as daily intraperitoneal injection or by continuous subcutaneous infusion with mini-pumps. After these treatments, binocular refractions were measured by photoretinoscopy and binocular ocular dimensions were measured by optical coherence tomography. Monocular photopic flash electroretinograms were recorded from non-FD mice. In normal mice, daily injection or continuous infusion of APO did not affect normal postnatal development of refraction. However, in the FD group, daily APO-injection attenuated ocular growth and also myopia development, as reflected in the interocular differences for APO-injected mice compared with vehicle-injected mice: (1) refraction, -1.04 ± 0.37 diopter (D) (APO-injection) compared with -4.14 ± 0.77 D (vehicle-injection) (P < 0.05); (2) vitreous chamber depth: -0.002 ± 0.005 mm compared with 0.032 ± 0.009 mm (P < 0.05); and (3) axial length: 0.000 ± 0.005 mm compared with 0.057 ± 0.007 mm (P < 0.05). By contrast, continuous APO-infusion failed to affect these biometric parameters. Furthermore, daily APO-injection decreased the ERG a- and b-wave amplitudes, whereas continuous APO-infusion increased these responses.

In monocularly FD mice, daily APO-injection, but not continuous infusion, attenuated myopia development. Therefore, evaluating different dopamine agonist administration paradigms is important for identifying effective dopamine-based treatment for myopia.

Does spry2 expression correlate with BRAF mutation in thyroid cancer?

BRAF mutations activate the mitogen-activated protein kinase pathway and often confer an aggressive thyroid cancer (TC) phenotype. Spry2 is an inducible negative feedback regulator of the mitogen-activated protein kinase (MAPK) pathway. The aim of this study was to investigate the role of Spry2 in TC. TC cell lines were analyzed for Spry2 expression and MAPK pathway activation. Cells were treated with MEK inhibitor and Spry2 small hairpin RNA. Cells were analyzed for Spry2 expression and MEK/ERK phosphorylation (pMEK, pERK). Thirty human papillary TCs were analyzed for mitogen-activated protein kinase pathway activating mutations and Spry2 expression. Increased baseline pMEK levels and Spry2 expression was found in BRAF V600E mutant (BRAF+) cells. MEK inhibition in BRAF+ cells showed decreased Spry2 expression and decreased pMEK/pERK levels. From our tissue samples, 10 papillary TCs had BRAF mutation, and increased Spry2 expression was found only in BRAF+ tumors.

Spry2 expression correlates with BRAF status in vitro and in human tissue. Spry2 may serve as a negative feedback regulator of the mitogen-activated protein kinase pathway in BRAF+ TC. Increased Spry2 expression may serve as a surrogate marker of mitogen-activated protein kinase pathway activation with prognostic and therapeutic implications.

Does early partial monolateral zygomatic arch defect lead to unilateral craniofacial malformation?

This study used reconstructed three-dimensional imaging to examine the influence of early partial monolateral zygomatic arch defect on the craniofacial development in a minipig model. Five 7-week-old Chinese minipigs were used in this study. Each of them underwent skull radiography, three-dimensional computed tomography (CT), and surgery at 8 weeks of age. Bilateral zygomatic arches were randomized and divided into the experimental side and the control side. A standard 2-cm-long zygomatic arch defect was made by an electric drill on the experimental side. The contralateral side was left intact. One of them underwent skull radiography and three-dimensional CT 2, 4, 8, and 12 weeks after surgery. The other 3 minipigs underwent scanning 4, 8, and 12 weeks after surgery. The bone defect was observed by radiography and three-dimensional CT. All three-dimensional CT data were examined by Mimics 10.01 software, and three-dimensional images were reconstructed. The length of both zygomatic arches, the length and width of the skull, and the hemicranial angles of both sides were measured and compared. The zygomatic arch developed to a summit at approximately 20 weeks of age. The zygomatic arch length of the experimental side is longer than that of the control side at each time point after surgery. The hemicranial angle of the experimental side is less than that of the control side at each time point after surgery.

Early partial monolateral zygomatic arch defect accelerates its growth in the sagittal plane and impedes the hemicranial growth in the coronal plane. Early reconstruction of zygomatic arch defect may be essential to minimize the developmental craniofacial malformation in children.

Do melodic pitch perception and lexical tone perception in Mandarin-speaking cochlear implant users?

To examine the relationship between lexical tone perception and melodic pitch perception in Mandarin-speaking cochlear implant (CI) users and to investigate the influence of previous acoustic hearing on CI users' speech and music perception. Lexical tone perception and melodic contour identification (MCI) were measured in 21 prelingual and 11 postlingual young (aged 6-26 years) Mandarin-speaking CI users. Lexical tone recognition was measured for four tonal patterns: tone 1 (flat F0), tone 2 (rising F0), tone 3 (falling-rising F0), and tone 4 (falling F0). MCI was measured using nine five-note melodic patterns that contained changes in pitch contour, as well as different semitone spacing between notes. Lexical tone recognition was generally good (overall mean = 81% correct), and there was no significant difference between subject groups. MCI performance was generally poor (mean = 23% correct). MCI performance was significantly better for postlingual (mean = 32% correct) than for prelingual CI participants (mean = 18% correct). After correcting for outliers, there was no significant correlation between lexical tone recognition and MCI performance for prelingual or postlingual CI participants. Age at deafness was significantly correlated with MCI performance only for postlingual participants. CI experience was significantly correlated with MCI performance for both prelingual and postlingual participants. Duration of deafness was significantly correlated with tone recognition only for prelingual participants.

Despite the prevalence of pitch cues in Mandarin, the present CI participants had great difficulty perceiving melodic pitch. The availability of amplitude and duration cues in lexical tones most likely compensated for the poor pitch perception observed with these CI listeners. Previous acoustic hearing experience seemed to benefit postlingual CI users' melodic pitch perception. Longer CI experience was associated with better MCI performance for both subject groups, suggesting that CI users' music perception may improve as they gain experience with their device.

Does high-resolution array CGH clarify events occurring on 8p in carcinogenesis?

Rearrangement of the short arm of chromosome 8 (8p) is very common in epithelial cancers such as breast cancer. Usually there is an unbalanced translocation breakpoint in 8p12 (29.7 Mb - 38.5 Mb) with loss of distal 8p, sometimes with proximal amplification of 8p11-12. Rearrangements in 8p11-12 have been investigated using high-resolution array CGH, but the first 30 Mb of 8p are less well characterised, although this region contains several proposed tumour suppressor genes. We analysed the whole of 8p by array CGH at tiling-path BAC resolution in 32 breast and six pancreatic cancer cell lines. Regions of recurrent rearrangement distal to 8p12 were further characterised, using regional fosmid arrays. FISH, and quantitative RT-PCR on over 60 breast tumours validated the existence of similar events in primary material. We confirmed that 8p is usually lost up to at least 30 Mb, but a few lines showed focal loss or copy number steps within this region. Three regions showed rearrangements common to at least two cases: two regions of recurrent loss and one region of amplification. Loss within 8p23.3 (0 Mb - 2.2 Mb) was found in six cell lines. Of the genes always affected, ARHGEF10 showed a point mutation of the remaining normal copies in the DU4475 cell line. Deletions within 12.7 Mb - 19.1 Mb in 8p22, in two cases, affected TUSC3. A novel amplicon was found within 8p21.3 (19.1 Mb - 23.4 Mb) in two lines and one of 98 tumours.

The pattern of rearrangements seen on 8p may be a consequence of the high density of potential targets on this chromosome arm, and ARHGEF10 may be a new candidate tumour suppressor gene.

Is there any difference in the use of complementary and alternative therapies in patients asthma and COPD?

Data on the use and efficacy of complementary and alternative medicine (CAM) in patients with asthma are limited, and there is a lack of studies documenting the use of CAM in patients with chronic obstructive pulmonary disease (COPD) in Turkey.AIM: To determine the prevalence of CAM usage in patients with asthma and COPD and to assess the clinical and demographic factors associated with the use of CAM. A total of 521 patients (313 with asthma and 208 with COPD) were randomly enrolled into this cross-sectional survey. A face-to-face interview was conducted using a structured questionnaire. One hundred sixty-three patients (52%) with asthma and 70 patients (33%) with COPD were reported to be using some form of CAM (p<0.001). The most popular modalities were herbal remedies (46% and 28% in the two groups, respectively) and animal products (28% and 5% in the two groups, respectively). CAM-practicing asthma patients were typically younger with longer duration of disease and higher income than the CAM-practicing COPD patients. For the patients, the main source of information on CAM practices was their relatives and friends. Only a small number of the patients consulted with their physicians about CAM. The main reasons to use CAM for patients with asthma and COPD were harmlessness and symptomatic relief, respectively. CAM-related adverse effects and difficulties to obtain CAM were significantly higher in patients with asthma than in patients with COPD.

There is a high prevalence of CAM usage in patients with asthma and COPD in Turkey. Hence, becoming familiar with CAM therapy and inquiring about patient practice of CAM as part of the routine medical history will allow the physicians to provide reliable information to their patients on these medical practices.

Does serum metabolomics reveal γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease?

We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases. Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls. We found that γ-glutamyl dipeptides, which were biosynthesized through a reaction with γ-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several γ-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis.

γ-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease.

Do Children and Adolescents with Anorexia Nervosa Display an Inefficient Cognitive Processing Style?

This study aimed to examine neuropsychological processing in children and adolescents with Anorexia Nervosa (AN). The relationship of clinical and demographic variables to neuropsychological functioning within the AN group was also explored. The performance of 41 children and adolescents with a diagnosis of AN were compared to 43 healthy control (HC) participants on a number of neuropsychological measures. There were no differences in IQ between AN and HC groups. However, children and adolescents with AN displayed significantly more perseverative errors on the Wisconsin Card Sorting Test, and lower Style and Central Coherence scores on the Rey Osterrieth Complex Figure Test relative to HCs.

Inefficient cognitive processing in the AN group was independent of clinical and demographic variables, suggesting it might represent an underlying trait for AN. The implications of these findings are discussed.

Six months of desipramine for dysthymia: can dysthymic patients achieve normal social functioning?

There is evidence that antidepressant medication improves social dysfunction during acute treatment in dysthymic patients but it is unknown if the gain in social functioning persists or progresses with longer-term antidepressant treatment. We examine the effect of 6 months of desipramine treatment on social functioning in dysthymic patients. Forty-six subjects with DSM-III-R dysthymia (70% with superimposed major depression) who had responded to 10 weeks of open-label desipramine (DMI) treatment received 16 additional weeks of continuation DMI. Social functioning was measured at weeks 0, 10 and 26 with the Social Adjustment Scale-Self Report. Euthymia was maintained and a marginally significant trend for further improvement in overall social functioning appeared during continuation treatment. Only 24% of subjects achieved normative level of social adjustment after 6 months of DMI treatment. The main limitation was the lack of a placebo control group.

Acute improvement in social functioning persists during continuation treatment. However, most dysthymic patients did not achieve a community level of social adjustment. Significant social dysfunction persists in dysthymic patients with low levels of depressive symptomatology after 6 months of intense DMI treatment.

'Make it another for me and my mates': Does social capital encourage risky drinking among the Danish general population?

The aim of this study was to examine the relationship between several indicators of social capital and risky single occasion drinking (RSOD) in a representative survey sample of the Danish general population. Data from the 2011 Danish national survey (n=2569) with respondents aged 15-79 years were used. Ordered logit modelling was applied to investigate the influence of social networks, social support, social participation and trust on RSOD. A strong positive relationship was found between frequency of contact with male friends and RSOD between both sexes. Furthermore, social trust among men and membership in voluntary organisations among women was significantly associated with RSOD. Additionally, contact with male family members for women and active participation in religious services for both sexes were strongly and negatively correlated with RSOD.

Some aspects of social capital can be positively related to at-risk health behaviours, as was found for RSOD in the Danish general population.

Is hyperinsulinemia associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans?

Whereas postprandial hyperlipidemia is a well-described feature of insulin-resistant states and type 2 diabetes, no previous studies have examined intestinal lipoprotein production rates (PRs) in relation to hyperinsulinemia or insulin resistance in humans. Apolipoprotein B-48 (apoB-48)-containing lipoprotein metabolism was examined in the steady-state fed condition with a 15-hour primed constant infusion of [D3]-l-leucine in 14 nondiabetic men with a broad range of body mass index (BMI) and insulin sensitivity. To examine the relationship between indices of insulin resistance and intestinal lipoprotein PR data were analyzed in 2 ways: by correlation and by comparing apoB-48 PRs in those whose fasting plasma insulin concentrations were above or below the median for the 14 subjects studied (60 pmol/L). ApoB-48 PR was significantly higher in hyperinsulinemic, insulin-resistant subjects (1.73+/-0.39 versus 0.88+/-0.13 mg/kg per day; P<0.05) and correlated with fasting plasma insulin concentrations (r=0.558; P=0.038), despite great heterogeneity in apoB-48 kinetic parameters, particularly among the obese subjects. There was no significant difference in clearance of apoB-48 between the 2 groups, nor was there a significant correlation between apoB-48 fractional clearance rate and fasting insulin or homeostasis model assessment-insulin resistance.

These are the first human data to conclusively demonstrate that intestinal apoB-48-containing triglyceride-rich lipoprotein PR is increased in hyperinsulinemic, insulin-resistant humans. Intestinal lipoprotein particle overproduction is a newly described feature of insulin resistance in humans.

Is tunneled tunica vaginalis flap an effective technique for recurrent urethrocutaneous fistulas following tubularized incised plate urethroplasty?

In the last several years the use of the tubularized incised plate hypospadias repair has greatly increased. The most significant complication after this mode of urethroplasty is urethrocutaneous fistula development. Tunneled tunica vaginalis flap is a well described technique for repair of urethrocutaneous fistula. However, to our knowledge its use after tubularized incised plate repair has not yet been described. We present our results with this technique. We retrospectively reviewed all patients undergoing repair of urethrocutaneous fistula after initial tubularized incised plate repair between January 2001 and December 2005. We analyzed the initial number and location of fistulas, number of previous urethrocutaneous fistula repairs, duration of surgery, and intraoperative and postoperative complications. A total of 16 boys (median age 2.2 years) underwent tunica vaginalis flap repair at our institution for urethrocutaneous fistula following initial failed tubularized incised plate repair. Of these patients 4 had not previously undergone urethrocutaneous fistula repair and 12 had undergone 1 to 4 failed repair attempts. All boys had a subcoronal fistula and 8 had additional fistulas along the penile shaft, 4 each with 3 and 4 fistulas, including 1 penoscrotal fistula. Mean surgical time was 45 minutes, and no intraoperative or postoperative complications occurred. After a mean followup of 18 months (range 4 to 36) no patient had recurrence of urethrocutaneous fistula.

Tunneled tunica vaginalis flap repair is a highly successful technique for the treatment of urethrocutaneous fistula after initial failed tubularized incised plate repair. The technique is technically simple to perform, and we encountered no complications. Tunneled tunica vaginalis flap repair should be considered for treating urethrocutaneous fistula following initial failed tubularized incised plate hypospadias surgery, particularly in a repeat surgical setting.

Do tenidap and flurbiprofen enhance uptake of matrix metalloproteinase inhibitor 4-dedimethylaminotetracycline in inflamed joints of adjuvant arthritic rats?

To identify a mechanism by which a matrix metalloproteinase (MMP) inhibitor might act synergistically with other agents to decrease MMP activity and thereby lessen the radiologic severity of adjuvant arthritis. Rats with adjuvant arthritis were treated with either flurbiprofen (FBP) or tenidap (TDP), along with 4-dedimethylaminotetracycline (CMT-1), a potent MMP inhibitor. Indices of inflammatory severity and of radiologic destruction were assessed and compared to serum and bone levels of the MMP inhibitor. Combination therapy with the MMP inhibitor plus either of the other drugs led to synergistic improvement in radiologic severity. For example, CMT-1 combined with TDP reduced radiologic severity 45% while decreasing collagenase and gelatinase activities by 61 and 72%, respectively, more than doubling bone CMT-1 levels (7.6 micrograms/g to 16.4 micrograms/g). FBP had similar effects.

MMP inhibitors need access to the arthritic joint to interact with their target enzymes. Concomitant antiinflammatory therapy is required to assure drug entry into the inflamed tissues.

Do childhood growth indicators in developing countries cluster?

The effectiveness of geographic targeting in nutrition programmes depends largely on the degree to which malnutrition clusters within particular areas. This study investigates the extent to which the childhood nutrition indicators, stunting (height-for-age Z-score<-2) and wasting (weight-for-height Z-score<-2), are spatially clustered; this information is used to determine the implications of spatial clustering for the effectiveness of geographic targeting. Analysis of data from Demographic and Health Survey (DHS) results. Clustering is assessed by calculating intra-cluster correlation coefficients (ICCs). Estimating the proportion of malnourished children covered by a programme successfully targeting 10% of clusters with the highest malnutrition prevalences allows an assessment of the effectiveness of geographic targeting. Fifty-eight DHS III (1992-1997) and DHS IV (1998-2001) reports from 46 developing countries. Pre-school children of mothers interviewed by DHS. The extent of clustering of nutritional status was surprisingly low (median ICC for national samples: stunting=0.054, wasting=0.032) and most countries were characterised by having an ICC<0.1--i.e. low clustering--for childhood undernutrition (91% of countries for wasting and 78% for stunting). Our assessment of the effectiveness of geographic targeting showed that coverage was better for wasting than for stunting; for wasting, 23% of countries would achieve less than 20% coverage, compared with 76% of countries achieving less than 20% coverage for stunting. Coverage is dependent on the overall prevalence of malnutrition and the ICC.

Childhood nutritional status is determined at the household, or even individual, level; nutrition programmes that are geographically targeted may result in high levels of under-coverage and leakage, thereby compromising their cost-effectiveness; the lack of clustering questions the appropriateness of current nutrition interventions.

Are locking screws advantageous with plate fixation of humeral shaft fractures?

To investigate whether locking screws offer any advantage over nonlocking screws for plate fixation of humeral shaft fractures for weight-bearing applications. : Mechanical evaluation of stiffness in torsion, bending, and axial loading and failure in axial loading in synthetic and cadaveric bone. Biomechanical laboratory in an academic medical center. : We modeled a comminuted midshaft humeral fracture in both synthetic and cadaveric bone. Humeri were plated posteriorly. Two study groups each used identical 10-hole, 3.5-mm locking compression plates that can accept either locking or nonlocking screws. The first group used only nonlocking screws and the second only locking screws. Stiffness testing and failure testing were performed for both the synthetic bones (n = 6) and the cadaveric matched pairs (n = 12). Fatigue testing was set at 90,000 cycles of 440 N of axial loading. Torsion, bending, and axial stiffness and axial failure force after cyclic loading. With synthetic bones, no significant difference was observed in any of the 4 tested stiffness modes between the plates with locking screws and those with nonlocking screws (anteroposterior, P = 0.51; mediolateral, P = 0.50; axial, P = 0.15; torsional, P = 0.08). With initial failure testing of the constructs in axial loading, both plates failed above anticipated physiologic loads of 440 N (mean failure load for both constructs>4200 N), but no advantage to locking screws was shown. The cadaveric portion of the study also showed no biomechanical advantage of locking screws over nonlocking screws for stiffness of the construct in the 4 tested modes (P>0.40). Fatigue and failure testing showed that both constructs were able to withstand strenuous fatigue and to fail above anticipated loads (mean failure>3400 N). No difference in failure force was shown between the 2 groups (P = 0.67).

Synthetic and cadaveric bone testing showed that locking screws offer no obvious biomechanical benefit in this application.

Does low Pelvic Incidence be Associated With Proximal Junctional Kyphosis in Patients Treated With Growing Rods?

Retrospective review of a prospectively collected pediatric orthopedic spine database. To investigate whether pelvic incidence (PI) changes during growing rod treatment and to report the effects of PI, if any, on complications during treatment. Growing rods have been demonstrated to correct spinal deformity in early onset scoliosis while allowing for spinal growth. There has been little investigation into the potential effects, if any, of abnormal PI on complications, especially proximal junctional kyphosis (PJK). We retrospectively reviewed clinical and surgical data from our prospectively collected pediatric orthopedic spine database. Our final cohort of 48 patients had at least one lateral radiograph throughout the course of treatment containing the femoral heads and sacral endplate, and a minimum follow-up of 2 years. Defined failures were identified prospectively. Radiographs were measured for PI and development of PJK. Mean age at initial treatment was 6.9 years (range 2.8-10.8 yr), with 35 females and 13 males. The mean length of follow-up was 8.1 years (range 2.0-22.1 yr). No statistical change in PI was observed throughout this study (P = 0.655). Development of any failure as well as total number of failures was associated with younger age at initial treatment (P < 0.0005 for both). Development of PJK was associated with younger age at initial treatment (P = 0.030), female sex (P = 0.002), and lower mean PI (P = 0.042).

PI remains constant throughout growth and the course of treatment with growing rods. Low PI was associated with increased PJK. When using growing rods in early onset scoliosis patients with decreased PI, increased attention should be paid to sagittal plane balance in an attempt to avoid PJK.

Does acute aquatic treadmill exercise improve gait and pain in people with knee osteoarthritis?

To examine the acute effects of aquatic and land treadmill exercise on gait kinematics as well as the level of disease-specific and movement-related pain for individuals with osteoarthritis. Quasi-experimental crossover design. Biomechanics laboratory. Participants (N=14; age, 43-64y) diagnosed with osteoarthritis at the knee (n=12), osteoarthritis at the knee and ankle (n=1), or osteoarthritis at the knee and hip (n=1). Participants performed 3 exercise sessions separated by at least 24 hours in 1 week for each mode of exercise (aquatic treadmill and land treadmill). Gait kinematics and pain were measured before and after each intervention. The angular velocity gain score during stance for left knee extension was improved by 38% after aquatic treadmill exercise (P=.004). Similarly, during swing, the gain scores for angular velocity were also greater for left knee internal rotation and extension by 65% and 20%, respectively (P=.004, P=.008, respectively). During stance, the joint angle gain score for left hip flexion was 7.23% greater after land exercise (P=.007). During swing, the angular velocity gain score for right hip extension was significantly greater for aquatic exercise by 28% (P=.01). Only the joint angle gain score for left ankle abduction during stance was significantly higher after land exercise (4.72%, P=.003). No other joint angle gain scores for either stance or swing were significantly different for either condition (P=.06-.96). Perceived pain was 100% greater after land than aquatic treadmill exercise (P=.02). Step rate and step length were not different between conditions (P=.31-.92).

An acute training period on an aquatic treadmill positively influenced joint angular velocity and arthritis-related joint pain. Acute aquatic treadmill exercise may be useful as a conservative treatment to improve angular speed of the lower-extremity joints and pain related to osteoarthritis.

Can a community evidence-based asthma care program improve clinical outcomes?

Asthma is associated with significant morbidity. Previous studies highlight significant variations in asthma management approaches within primary care settings where the adoption of published asthma guidelines is typically suboptimal. To determine whether the implementation of an evidence-based asthma care program in community primary care settings leads to improved clinical outcomes in asthma patients. A community-based participatory research project was implemented at 8 primary care practices across Ontario, Canada, consisting of elements based on the Canadian Asthma Consensus Guidelines (asthma care map, program standards, management flow chart and action plan). A total of 1408 patients aged 2-55 years participated. Conditional logistic regression analyses were used to calculate the odds ratios (OR) comparing baseline to follow-up while adjusting for age, gender, socioeconomic status and other covariates. At 12-month follow-up, there were statistically significant reductions in self-reported asthma exacerbations from 77.8% to 54.5% [OR = 0.35; 95% confidence interval (CI): 0.28-0.43]; emergency room visits due to asthma from 9.9% to 5.5% (OR = 0.47; 95% CI: 0.32-0.62); school absenteeism in children from 19.9% to 10.2% (OR = 0.37; 95% CI: 0.25-0.54); productivity loss in adults from 12.0% to 10.3% (OR = 0.49; 95% CI: 0.34-0.71); uncontrolled daytime asthma symptoms from 62.4% to 41.4% (OR = 0.34; 95% CI: 0.27-0.42); and uncontrolled nighttime asthma symptoms from 46.4% to 25.4% (OR = 0.29; 95% CI: 0.23-0.37).

Development and implementation of a community-based primary care asthma care program led to risk reductions in exacerbations, symptoms, urgent health service use and productivity loss related to asthma.

Does dBZ block LPS-induced monocyte activation and foam cell formation via inhibiting nuclear factor-ĸB?

It has been widely accepted that chronic inflammation plays important roles in the atherogenesis. Danshensu Bingpian Zhi (DBZ) is a novel synthetic compound derived from the traditional Chinese medicine (TCM) formula Fu Fang Dan Shen (FFDS), which is effective on atherosclerosis clinically. We hypothesized that DBZ possessed the anti-atherosclerosis potentials. Here, we examined the inhibitory effects of DBZ on LPS-induced monocyte activation and foam cell formation. The effects of DBZ were assessed on LPS-induced inflammatory factors expression in monocyte/macrophage. Activation of NF-κB and AP-1 was analyzed by luciferase reporter assay and signaling pathway of NF-κB was investigated to elucidate mechanisms underlying DBZ mediated anti-inflammatory activity. Effects of DBZ on macrophage lipid accumulation were evaluated in native LDL and LPS co-incubated macrophages. DBZ inhibited LPS-induced inflammatory factors expression dose dependently in monocytes. DBZ inhibited NF-κB activation strongly and AP-1 slightly. DBZ suppressed the LPS-induced degradation of IκBα, thereby decreasing the translocation of p65 to nucleus. Furthermore, DBZ suppressed LPS-activated macrophages lipid accumulation, partly due to inhibiting the expression of LPS-induced aP2 and ADRP in macrophges.

These results demonstrate that DBZ has potentials on anti-atherosclerosis by suppressing monocyte activation and foam cell formation.

Do preadmission Resuscitate advanced directive is associated with adverse outcomes following acute traumatic injury?

Do Not Resuscitate (DNR) orders have been associated with poor outcomes in surgical patients. There is limited literature on admitted trauma patients with advanced directives indicating DNR status before admission (preadmission DNR [PADNR]). A retrospective review of the trauma registry of a suburban county was carried out for admitted trauma patients with age ≥41 years, who were admitted between 2008 and 2013. Of 7,937 admitted patients, 327 had a preadmission advanced directive indicating DNR. PADNR patients were significantly older (87 vs 69 years), with more frequent comorbidities, and were more often admitted after a fall (94.2% vs 65.8%). PADNR patients had a higher Injury Severity Score (14 vs 11). They also had significantly increased rates of pneumonia, sepsis, myocardial infarction, and death (33.6% vs 5.9%). On multivariate logistic regression, the presence of a preadmission advanced directive indicating DNR status was independently associated with a 5.2-fold increased odds of mortality.

An advanced directive indicating DNR is associated with adverse outcomes following trauma.

Does gene therapy with extracellular superoxide dismutase attenuate myocardial stunning in conscious rabbits?

Administration of Cu/Zn superoxide dismutase (SOD) without catalase fails to alleviate myocardial stunning, but extracellular SOD (Ec-SOD) may be more effective because it binds to heparan sulfate proteoglycans on the cellular glycocalyx. We therefore used in vivo gene transfer to increase systemic levels of Ec-SOD and determined whether this gene therapy protects against myocardial stunning. The cDNA for human Ec-SOD was cloned behind the cytomegalovirus (CMV) promoter and incorporated into a replication-deficient adenovirus (Ad5/CMV/Ec-SOD). Injection of this virus (2x10(8) pfu/kg IV) produced high levels of Ec-SOD in the liver, which could be redistributed to the heart and other organs by injection of heparin. Conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days starting 3 days after intravenous injection of Ad5/CMV/Ec-SOD or Ad5/CMV/nls/LacZ (negative control). Both groups were given heparin (2000 U/kg IV) 2 hours before the first sequence of occlusions. The severity of myocardial stunning was measured as the total deficit of LV wall thickening after the last reperfusion. On day 1, the total deficit of wall thickening was markedly decreased in Ad5/CMV/Ec-SOD rabbits versus controls and similar to that seen on days 2 and 3 in controls.

The results demonstrate that in vivo gene transfer of the cDNA encoding Ec-SOD provides the heart with substantial protection against myocardial stunning without the need for concomitant administration of catalase. The present observations provide the basis for controlling gene therapy at the posttranslational level and for simultaneously protecting multiple organs from oxidant stress.

Does hypothermic low-flow cardiopulmonary bypass impair pulmonary and right ventricular function more than circulatory arrest?

Hypothermic circulatory arrest (HCA) is used during surgical treatment of certain congenital heart defects. The possibility of ischemic neurologic injury associated with HCA has led some surgeons to use low-flow cardiopulmonary bypass (CPB) during the hypothermic interval (hypothermic low flow [HLF]). This study investigates the inflammatory response to HCA and HLF, and reports the consequences of this response on pulmonary and right ventricular function. Piglets (3.1 to 6.6 kg) were cooled to 16 degrees to 18 degrees C using CPB, and randomized: HCA for 60 minutes (n = 7), or HLF (50 cc.kg(-1).min(-1)) for 60 minutes (n = 6). The piglets were rewarmed to 36 degrees C and weaned from CPB. Serum tumor necrosis factor-alpha (TNF-alpha) concentration, percent lung water, and pulmonary and cardiac function were measured before and after CPB. Tumor necrosis factor-alpha was higher after HLF (2,990.5 +/- 884.5 pg/mL), compared with HCA (347.6 +/- 89.2 pg/mL; p = 0.03). The percent lung water was higher after HLF (84.8% +/- 0.3%) than HCA (82.0% +/- 0.4%; p < 0.001). The alveolar to arterial oxygen gradient was worse after HLF (457 +/- 42 mm Hg) than HCA (285.8 +/- 45 mm Hg; p = 0.02). Pulmonary vascular resistance was greater after HLF (36.08 +/- 8.28 mm Hg.mL(-1).m(-2).min(-1)) than HCA (14.55 +/- 3.46 mm Hg. mL(-1).m(-2).min(-1); p = 0.049). The right ventricular pressure waveform peak derivative, corrected for systolic pulmonary artery pressure, was lower after HLF (14.1 +/- 1.4 sec(-1)), than HCA (23.8 +/- 2.7 sec(-1); p = 0.01).

Hypothermic low flow extends exposure to CPB, and is associated with an increased inflammatory response compared with HCA. The greater inflammatory response after HLF may result in substantial nonneurologic morbidity in the postoperative period, demonstrated by pulmonary and right ventricular dysfunction. Interventions that attenuate the inflammatory response to CPB may prevent pulmonary and right ventricular dysfunction after HLF.

Does expectancy priming of smoking cessation messages enhance the placebo effect of tailored interventions?

Previous research (Webb, Simmons, & Brandon, 2005) suggested that smokers' reactions to self-help materials were more positive if they believed that the materials had been personally tailored to their individual characteristics and if they held expectancies that tailored interventions are superior to standard, or generic, interventions. The authors' objective in the current study was to replicate and extend this research by testing the efficacy expectancy priming before intervention delivery. In a 2 x 2 factorial experiment, 210 smokers (M = 23 cigarettes/day) recruited from the community (62% female; 92% Caucasian; mean age = 49) were randomly assigned to 1 of 4 conditions: placebo-tailored intervention/no priming, placebo-tailored intervention/priming, standard intervention/no priming, or standard intervention/priming. The tailoring-related expectancies of participants' in the priming conditions were primed before they were presented with the respective intervention booklets. Content evaluations, readiness to quit smoking, cessation self-efficacy, smoking-related knowledge, and progress toward quitting (behavior changes). Assessments occurred by mail at baseline and at 1-month postintervention. Similar to the earlier study, the placebo-tailored booklets produced superior evaluations and smoking-related cognitive and behavioral changes. Moreover, the pretreatment expectancy priming successfully altered participants' tailoring-related expectancies and also produced superior evaluations and outcomes.

Findings support a causal role of tailoring-related expectancies on the efficacy of tailored interventions and suggest that interventions can be enhanced via expectancy priming.

Does coadministration of ritonavir strongly enhance the apparent oral bioavailability of docetaxel in patients with solid tumors?

To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer. A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 +/- 1.5 and 2.8 +/- 1.4 mg/h/L, respectively, compared with 1.9 +/- 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% +/- 90% and 161% +/- 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated.

Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.

Do depressed patients lose their sense of humor?

Humor is an important coping mechanism and can improve mood. However, it is unclear whether depressed patients are able to enjoy funny material, e.g. jokes, and make use of their sense of humor for coping with adverse situations. This study aims at investigating the influence of depression on various aspects of humor abilities such as sense of humor, appraisal of funny material and exhilaration. Nineteen patients with major depression and 18 healthy controls were examined with standardized self-assessment questionnaires to study potential group differences in humor type preferences, state and trait cheerfulness, seriousness and bad mood as well as humor coping. Patients and controls did not differ in their humor type preferences and the degree to which humorous stimuli were rated as being funny. The readiness to react to funny stimuli with exhilaration was significantly less pronounced in the patient group. The patients' tendency to use humor as a coping strategy was significantly lower than in the control group.

The susceptibility to humorous material seems to be unaffected by the disorder. Introducing means to promote humor behavior might therefore be beneficial to depressed patients. Study limitations were that only self-rating instruments were used and that the medication was inhomogeneous.

Difference in the use of preventive services between fee-for-service plans and HMOs: is more better?

Based on the US Preventive Services Task Force recommendations, we studied how health insurance type, ie, fee-for-service (FFS) or health maintenance organization (HMO), affects the utilization of preventive services of differing effectiveness. Household survey data from the 1993 and 1994 National Health Interview Surveys. We compared the use of mammograms, Pap smears, blood pressure measurements, counseling about hormone replacement therapy (HRT), and general physical examinations in FFS plans and HMOs. We used the bivariate probit model to control for selection bias caused by the unobservable factors in the choice of health insurance type. Enrollees in HMOs obtained more Pap smears, blood pressure measurements, mammograms (women 40 to 49 years old), and general physical examinations than enrollees in FFS plans. No significant difference was found between FFS plans and HMOs for the use of mammograms (women aged 30 to 39 years and 50 to 64 years) or HRT counseling. The correlation ratios from bivariate probit estimations indicated no selection bias favoring HMOs; for some preventive services, selection bias favored FFS plans.

Compared with enrollees in FFS plans, persons in HMOs used more preventive services, including less effective ones. Not controlling for selection bias underestimated the HMO effect.

Do insulin resistant rats display enhanced rewarding effects of nicotine?

Tobacco use among persons with Type II diabetes exponentially increases negative health consequences and mortality rates. It is especially troubling that diabetic persons who smoke have a greater difficulty with tobacco cessation as compared to non-diabetic smokers. Diabetes is a metabolic syndrome that consists of insulin resistance due to disruptions in insulin signaling. We have previously shown that insulin depletion enhances the motivational effects of nicotine. The present study expands our previous work by examining whether insulin resistance, produced by a high-fat diet (HFD) regimen, enhances the rewarding effects of nicotine, as measured by the conditioned place preference (CPP) paradigm. Rats were placed on either a regular diet (RD) or a HFD for 5 weeks, after which they were assessed for insulin resistance via blood glucose measurements after an insulin challenge. Rats then underwent a nicotine CPP study. The findings revealed that HFD produced insulin resistant and non-insulin resistant animals. Interestingly, the magnitude of nicotine CPP was larger in insulin resistant rats versus RD rats. Nicotine CPP was absent in non-insulin resistant animals. A similar increase in body weight was observed in insulin resistant and non-insulin resistant rats as compared to RD rats. These findings suggest that neither the increased body weight nor the HFD per se in the insulin resistant rats contributed to the enhanced nicotine reward.

These present study suggests that insulin resistant rats undergo unique neurobiological changes related to a disruption in insulin signaling that promotes the rewarding effects of nicotine.

Does rates and correlate of seeking mental health services among Cambodian refugees?

We assessed the rates and correlates of seeking mental health services among a probability sample of Cambodian refugees who needed such services. Interviewers conducted face-to-face interviews with a representative sample drawn from the largest US community of Cambodian refugees. The analytic sample included 339 persons who met past 12-month criteria for posttraumatic stress disorder, major depression disorder, or alcohol use disorder. Respondents described contact with service providers for psychological problems during the preceding 12 months. We examined bivariate and multivariate predictors of seeking services. Respondents reported high rates of contact with both medical care providers (70%) and mental health care providers (46%). Seeking services from both types of providers was associated with lack of English-speaking proficiency, unemployment, 3 or fewer years of preimmigration education, and being retired or disabled. Women, individuals with health insurance, and persons receiving government assistance also were more likely to seek services.

Cambodian refugees with mental health problems had high rates of seeking service for psychological problems during the preceding 12 months. Research is needed to examine the effectiveness of services received by Cambodian refugees.

Do interferon-α/β and anti-fibroblast growth factor receptor 1 monoclonal antibody suppress hepatic cancer cells in vitro and in vivo?

Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC. We used Western blot and flow cytometric and immunocytochemical analyses to investigate the regulation of FGFR1 expression by interferon-α/β in several human hepatic cancer cell lines. In addition, we tested the efficacy of combined treatment with anti-FGFR1 monoclonal antibody and interferon-α/β in a murine xenograft model of human HCC. We found that interferon-α/β induces expression of FGFR1 in human HCC cell lines, and that an anti-FGFR1 monoclonal antibody (mAb) targeting of the induced FGFR1 can effectively inhibit growth and survival of HCC cells in vitro and in vivo. Moreover, the combination of interferon-α, anti-FGFR1 mAb and peripheral blood mononuclear cells (PBMCs) exerted a significant antitumor effect in vitro.

Our results suggest that the combined use of an anti-FGFR1 antibody and interferon-α/β is a promising approach to the treatment of HCC.

Do self-referent metacognition and residential context predict depressive symptoms across late-life span?

There is controversial evidence concerning the variables favoring depression in community-dwelling elderly individuals. This study mainly investigates the impact of lifestyle, residential environment, cognitive efficiency and social desirability in predicting self-assessed depressive signs in late adult span. One hundred forty-nine elders were recruited in Northern Italy and Sardinia - an Italian island characterized by the longevity of people living in the inner areas. Participants were presented a battery of questionnaires assessing cognitive efficiency and self-referent measures of depression, metacognition and social desirability. A hierarchical regression analysis showed that residential environment was the most effective predictor of depressive symptoms, along with gardening and spending time for hobbies. In contrast, social desirability and metacognitive scores played a minor role in predicting mental health. An analysis of variance showed that Sardinian elders showed fewer signs of depression than age-matched elders residing in Northern Italy.

The Sardinian residential environment is a strong predictor of preserved mental health in late adulthood. In contrast, self-rated metacognitive efficiency and social desirability play a very marginal role in predicting depression among the elderly.

Is work volume in strength training affected by rest interval strategy?

Between-set rest intervals (RI) may be determined using exercise-recovery-ratio (ERR) or fixed periods. The study investigated the influence of different ERR and fixed RI on the training volume in sessions aiming for hypertrophy with upper-body exercises recruiting different muscle mass (bench press-BP and triceps extension-TE). Sixteen men (25±2 years, 78±6 kg, 178±5 cm) with previous experience in resistance training performed 5 sets of maximum repetitions in each exercise with five RI protocols (RR1:3 [I3]; ERR1:5 [I5]; ERR1:7 [I7]; increasing ERR [IP] (1:3-1:5-1:7-1:9); 2-min fixed [2F]) in a counterbalanced design. The number of repetitions and work volume (load x repetitions) in each set and along the sessions (load x repetitions x sets) were compared across the RI protocols. The maximum repetitions decreased along with the sets in both exercises, but TE had lower percent decrease compared to BP, due to a longer time to perform the sets and therefore longer absolute rest time (P<0.05). The I3 exhibited the lowest repetitions sustainability (P<0.05). The training volume in I7, IP and 2F was always higher than I3 and I5 (P>0.05). However the absolute RI in 2F (~2 min) was shorter than in I7 and IP (~3 min), which reduced the total duration of the training session.

Determining between-set RI based on ERR instead of using fixed intervals does not enable more work to be done in multiple-set/high intensity resistance training sessions.

Do estimation of age specific incidence rates of childhood burns from a prevalence survey of burn scars?

This paper describes two methods of estimating the age specific incidence rates of childhood burns from a prevalence survey of burn scars. A prevalence survey of burn scars was carried out in 1992 on 15,742 Ghanaian children aged 5 years or less. Nine hundred and fifty five (6.1%) of these children had scars from burn, and for 630 (66%) of these children, additional information about the burn incident, including the child's age at the time of the burn, was obtained from the mother two to three months later. Thirty four per cent of mothers of children with burn scars were not interviewed due to absence, relocation, or inaccessibility. Age specific incidence rates of burns were estimated for eight age groups using two methods. In method I, the number of incident cases of burns for each age group were estimated from the burn scars by subtracting the estimated contribution of scars from burns that had occurred at earlier ages. In method II, the estimate was based on the mother's recall of the age of the child at the time of the burn. Slightly different results were obtained with the two methods, and problems were noted with both methods.

We recommend the use of these methods for estimating age specific incidence rates from retrospective population surveys for health conditions which result in long term residual markers.

Are copeptin concentrations elevated in gestational diabetes mellitus?

To investigate copeptin levels in women with GDM and women with uncomplicated pregnancies. This case-control study was conducted on 45 women with GDM and 40 women with uncomplicated pregnancies. The maternal serum levels of copeptin were measured with enzyme-linked immunosorbent assay. Copeptin levels were not different among groups (0.93 ± 0.75 vs. 1.15 ± 0.93 ng/ml, p: 0.24). HOMA-IR and insulin levels were significantly higher in woman with GDM when compared with control group (2.90 ± 1.88 vs. 1.91 ± 0.50, p: 0.002; 11.74 ± 6.43 vs. 8.52 ± 2.28, p: 0.004, respectively). The copeptin concentrations were significantly correlated with insulin levels and HOMA-IR values (r = 0.329 p = 0.002, r = 0.289 p = 0.007, respectively).

The present study shows that serum copeptin concentrations did not differ in woman with GDM and non-GDM patients. However, we found a significant correlation between copeptin and HOMA-IR. Future studies are needed with larger populations in gestational diabetic patients on copeptin secretion, metabolism and action.

Is universal bone densitometry screening combined with alendronate therapy for those diagnosed with osteoporosis highly cost-effective for elderly women?

To investigate the cost-effectiveness of universal bone densitometry in women aged 65 and older combined with alendronate treatment for those diagnosed with osteoporosis (femoral neck T-score < or = -2.5). A Markov model with a lifetime time horizon and eight health states (no fracture, distal forearm fracture, radiographic (but clinically inapparent) vertebral fracture, clinical vertebral fracture, hip fracture, hip and vertebral fracture, and other fractures), using the societal perspective. Women living independently and those in nursing homes. Caucasian women aged 65, 75, 85, or 95. Bone densitometry of the hip, with 5 years of alendronate therapy for those found to have osteoporosis versus no intervention (densitometry or drug therapy). Lifetime accumulated quality adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios. The cost per QALY gained for the screen-and-treat strategy was 43,000 dollars per QALY gained for 65-year-old women and 5,600 dollars per QALY gained for 75-year-old women. For 85- and 95-year-old women, the screen-and-treat strategy was cost saving. Sensitivity analyses showed that the screen-and-treat strategy was cost-effective even under assumptions of reduced adherence to drug therapy, reduced fracture reduction benefit from alendronate therapy, or reduced QALYs saved by preventing fracture.

Universal bone densitometry combined with alendronate therapy for those found to have osteoporosis is highly cost-effective for women aged 65 and older and may be cost saving for ambulatory women aged 85 and older (whether independently living or residing in nursing homes).

Do metabolic signatures differentiate ovarian from colon cancer cell lines?

In this era of precision medicine, the deep and comprehensive characterization of tumor phenotypes will lead to therapeutic strategies beyond classical factors such as primary sites or anatomical staging. Recently, "-omics" approached have enlightened our knowledge of tumor biology. Such approaches have been extensively implemented in order to provide biomarkers for monitoring of the disease as well as to improve readouts of therapeutic impact. The application of metabolomics to the study of cancer is especially beneficial, since it reflects the biochemical consequences of many cancer type-specific pathophysiological processes. Here, we characterize metabolic profiles of colon and ovarian cancer cell lines to provide broader insight into differentiating metabolic processes for prospective drug development and clinical screening. We applied non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography and gas chromatography for the metabolic phenotyping of four cancer cell lines: two from colon cancer (HCT15, HCT116) and two from ovarian cancer (OVCAR3, SKOV3). We used the MetaP server for statistical data analysis. A total of 225 metabolites were detected in all four cell lines; 67 of these molecules significantly discriminated colon cancer from ovarian cancer cells. Metabolic signatures revealed in our study suggest elevated tricarboxylic acid cycle and lipid metabolism in ovarian cancer cell lines, as well as increased β-oxidation and urea cycle metabolism in colon cancer cell lines.

Our study provides a panel of distinct metabolic fingerprints between colon and ovarian cancer cell lines. These may serve as potential drug targets, and now can be evaluated further in primary cells, biofluids, and tissue samples for biomarker purposes.

Does improvement in executive subfunctions following cerebrospinal fluid tap test identify idiopathic normal pressure hydrocephalus from its mimics?

Patients with idiopathic normal pressure hydrocephalus (iNPH) present cognitive deficits that overlap with other neurological conditions such as Parkinson's disease or vascular dementia, therefore mimicking iNPH. This prospective study aimed to compare cognitive performances between iNPH and iNPH mimics before and after cerebrospinal fluid (CSF) tapping. A total of 57 patients with suspicion of iNPH (75.84 ± 6.42 years; 39% female) were included in this study (37 iNPH and 20 iNPH mimics). Neuropsychological assessments were performed before and 24 h after CSF tapping of 40 ml. Multivariate logistic regressions were used to examine the association between iNPH and cognitive functions, adjusted for age, education, baseline cognitive assessment and disease duration. Both groups presented the same baseline cognitive performances. After CSF tapping, iNPH patients improved their semantic (P = 0.001) and phonemic verbal fluencies (P = 0.001), whereas iNPH mimics presented similar performances to before CSF tapping. The phonemic verbal fluency (odds ratio 1.43, 95% confidence interval 1.05; 1.96) and the Color Trails Test (odds ratio 0.10, 95% confidence interval 0.01; 0.76) improvements were the two discriminative cognitive tests that identified iNPH from iNPH mimics.

Improvement in executive subfunctions after CSF tapping identified iNPH patients from other neurological conditions that mimic iNPH. These findings respond to clinical issues encountered on a daily basis and would improve the diagnostic process of iNPH.

Does milrinone attenuate thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes?

Neonatal pulmonary hypertension (PPHN) is characterized by pulmonary vasoconstriction, due in part to dysregulation of the thromboxane prostanoid (TP) receptor. Hypoxia induces TP receptor-mediated hyperresponsiveness, whereas serine phosphorylation mediates desensitization of TP receptors. We hypothesized that prostacyclin (IP) receptor activity induces TP receptor phosphorylation and decreases ligand affinity; that TP receptor sensitization in hypoxic myocytes is due to IP receptor inactivation; and that this would be reversible by the cAMP-specific phosphodiesterase inhibitor milrinone. We examined functional regulation of TP receptors by serine phosphorylation and effects of IP receptor stimulation and protein kinase A (PKA) activity on TP receptor sensitivity in myocytes from neonatal porcine resistance pulmonary arteries after 72 h hypoxia in vitro. Ca(2+) response curves to U46619 (TP receptor agonist) were determined in hypoxic and normoxic myocytes incubated with or without iloprost (IP receptor agonist), forskolin (adenylyl cyclase activator), H8 (PKA inhibitor) or milrinone. TP and IP receptor saturation binding kinetics were measured in presence of iloprost or 8-bromo-cAMP. Ligand affinity for TP receptors was normalized in vitro by IP receptor signalling intermediates. However, IP receptor affinity was compromised in hypoxic myocytes, decreasing cAMP production. Milrinone normalized TP receptor sensitivity in hypoxic myocytes by restoring PKA-mediated regulatory TP receptor phosphorylation.

TP receptor sensitivity and EC(50) for TP receptor agonists was regulated by PKA, as TP receptor serine phosphorylation by PKA down-regulated Ca(2+) mobilization. Hypoxia decreased IP receptor activity and cAMP generation, inducing TP receptor hyperresponsiveness, which was reversed by milrinone.

Is the starburst giant cell useful for distinguishing lentigo maligna from photodamaged skin?

Because lentigo maligna (LM) occurs in areas of the body that are subjected to long-term UV radiation (UVR), it may be difficult to distinguish atypical melanocytes in LM from the pleomorphic, atypical melanocytes in actinically damaged skin. The purpose of this study was to determine whether the presence of multinucleated melanocytes would help to make this distinction. A total of 89 cases of LM were reviewed for the presence or absence of multinucleated melanocytes and, if present, the maximum number of nuclei was recorded. As controls, 107 elliptical excisions of basal cell carcinoma or squamous cell carcinoma were randomly selected. The tips of the ellipses were reviewed for the presence or absence of multinucleated melanocytes. Multinucleated melanocytes with a "starburst" appearance, because of their prominent dendritic processes, were present in 85% of LM cases but in only 21% of sun-damaged control specimens (p < 0.00001; odds ratio [OR] = 22.6; 95% confidence interval [CI] = 10.6-47.9). The sensitivity and specificity of starburst giant cells (SGCs) in the diagnosis of LM was 85% and 78%, respectively. The maximum number of nuclei per SGC ranged from 2 to 30 in the LM cases (mean, 6.8 +/- 6.1) and from 2 to 6 in the controls (mean, 2.7 +/- 1.1) (p < 0.001). If only those SGCs with more than two nuclei are considered, 76% of cases but only 8% of controls contained SGCs (p < 0.00001; OR = 35.3; CI = 15.2-81.7). Similarly, 64% of cases and 3% of controls had SGCs with more than three nuclei (p < 0.00001; OR = 61.8; CI = 18.1-210.6).

The SGC is a useful indicator for the diagnosis of LM. The diagnosis of LM is also more likely as the number of nuclei in SGC increases.

Does cisplatin induce apoptosis in SH-SY5Y human neuroblastoma cell line?

Cisplatin (CDDP) is cytotoxic, inducing apoptosis in some tumoral cell lines in vitro. Since CDDP is an effective drug in vivo treatment of neuroblastoma, we tested this drug on the human neuroblastoma SH-SY5Y cell line. Materials and methods. The effect of CDDP on cultured SH-SY5Y cells was determined with trypan blue dye exclusion test, LDH activity and DNA electrophoresis. Cultures were observed by light and electron microscope. Flow cytometric analysis was also carried out. CDDP inhibits the growth of neuroblastoma cells and reduces cell viability. Cell death occurs by apoptosis, as evidenced by morphological criteria and typical DNA laddering. Flow cytometry demonstrates that CDDP-treated cells are arrested in the G2/M phase before entering programmed cell death.

CDDP is thus effective on the human neuroblastoma SH-SY5Y cell line, inducing apoptosis.

Do low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy?

Sensory peripheral neuropathy caused by paclitaxel is a common and dose limiting toxicity, for which there are currently no validated predictive biomarkers. We investigated the relationship between the Charcot-Marie-Tooth protein NDRG1 and paclitaxel-induced neuropathy. Archived mammary tissue specimen blocks of breast cancer patients who received weekly paclitaxel in a single centre were retrieved and NDRG1 immunohistochemistry was performed on normal nerve tissue found within the sample. The mean nerve NDRG1 score was defined by an algorithm based on intensity of staining and percentage of stained nerve bundles. NDRG1 scores were correlated with paclitaxel induced neuropathy. 111 patients were studied. 17 of 111 (15%) developed severe paclitaxel-induced neuropathy. The mean nerve NDRG1 expression score was 5.4 in patients with severe neuropathy versus 7.7 in those without severe neuropathy (p = 0.0019). A Receiver operating characteristic (ROC) curve analysis of the mean nerve NDRG1 score revealed an area under the curve of 0.74 (p = 0.0013) for the identification of severe neuropathy, with a score of 7 being most discriminative. 13/54 (24%) subjects with an NDRG1 score < = 7 developed severe neuropathy, compared to only 4/57 (7%) in those with a score >7 (p = 0.017).

Low NDRG1 expression in nerve tissue present within samples of surgical resection may identify subjects at risk for severe paclitaxel-induced neuropathy. Since nerve biopsies are not routinely feasible for patients undergoing chemotherapy for early breast cancer, this promising biomarker strategy is compatible with current clinical workflow.

Does vitreous treatment of retinal pigment epithelial cells result in decreased expression of FGF-2?

Changes in gene expression were investigated after treatment of cultured human retinal pigment epithelial (RPE) cells with vitreous. This may have implications for proliferative diseases such as proliferative vitreoretinopathy. Cells were cultured in the presence or absence of human vitreous, and gene expression was examined using the differential display polymerase chain reaction technique. Differentially expressed RNAs were cloned, screened for differential expression, and sequenced. The expression of one of these RNAs (that for fibroblast growth factor [FGF]-2/basic FGF) was examined by in situ hybridization and ribonuclease protection assays. The level of FGF-2 protein was examined by immunoblot analysis. The effects of adding FGF-2 to cells cultured in the presence of vitreous were examined. Treatment of low passage human RPE cells with 25% vitreous resulted in the epithelial-to-fibroblast-like morphologic changes reported by others and in the decreased expression of FGF-2 mRNA and FGF-2 protein. Addition of FGF-2 to cultures at the same time as addition of vitreous prevented some of the effects of vitreous on these cells.

Vitreous treatment of RPE cells in culture results in decreased expression of FGF-2 mRNA and protein. Because supplementation of FGF-2 prevents some of the vitreous-mediated effects, this may indicate that modulation of FGF-2 levels by the vitreous may play an important role in the phenotypic changes seen in RPE cells exposed to vitreous.

Does levodopa accelerate the pathologic process in Parkinson disease brain?

Several in vitro studies have suggested levodopa (L-dopa) to be toxic to dopaminergic neurons and that it can modulate the aggregation process of α-synuclein. We investigated the relationship between cumulative lifetime dose of l-dopa and nigral neuronal count and Lewy body (LB) pathology in Parkinson disease (PD). Density of pigmented neurons was measured unilaterally in a single section of substantia nigra (SN) with delineation of the dorsal and ventral tiers in 96 cases of PD with well-documented clinical records relating to antiparkinsonian drug treatment. Cortical and nigral LB densities were determined using a morphometric approach. Mean lifetime dose of L-dopa correlated significantly (p<0.001) with duration of PD in the entire study population (n = 96) and it was not possible to disentangle their individual effect. This was not the case in a subgroup analysis of younger onset patients with a longer duration of PD (n = 40) who showed no significant correlation between L-dopa and total SN neuronal density (p = 0.07), after adjustment for duration of illness. There was, however, a lower neuronal density in the ventral (p = 0.02) but not in the dorsal (p = 0.27) tier detected with the cumulative dose of L-dopa. We found no difference in L-dopa dose between Braak PD stages (p = 0.58). Furthermore, the subgroup analysis showed no relationship of L-dopa dose to either cortical (p = 0.47) or nigral (p = 0.48) LB density.

Chronic use of L-dopa in PD does not enhance progression of PD pathology as far as can be determined by our observations with SN neuronal counts and LB densities.

Are glypican-3 and KRT19 markers associating with metastasis and poor prognosis of pancreatic ductal adenocarcinoma?

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with metastasis in most patients at diagnosis. The molecular mechanisms associated with its high malignancy have not been fully elucidated. This study investigated the clinicopathological significances of GPC3 and KRT19 expression in PDAC. GPC3, KRT19, and CA19-9 protein expression were measured by immunohistochemistry. GPC3 and KRT19 protein levels were overexpressed in PDAC tumors compared to normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P< 0.01). The percentage of positive GPC3 and KRT19 expression were significantly higher in PDAC patients with larger tumor size, poorly differentiated tumor, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with small tumor size, well-differentiated tumor, no lymph node metastasis and invasion, as well as TNM stage I/II stage disease (P< 0.05 or P< 0.01). Benign pancreatic lesions with positive GPC3 and KRT19 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive GPC3 and KRT19 expression survived significantly shorter than patients with negative GPC3 and KRT19 expression (P < 0.05 or P< 0.001). Cox multivariate analysis revealed that positive GPC3 and KRT19 expression were independent poor prognosis factors in PDAC patients.

GPC3 and KRT19 overexpression are associated with carcinogenesis, progression, and poor prognosis in patients with PDAC and a valuable biomarker for diagnosis of PDAC.

Are cytotoxic effects of sodium dodecyl benzene sulfonate on human keratinocytes associated with proinflammatory cytokines expression?

Keratinocytes play a crucial role in the biological function of skin barrier. The relationship between sodium lauryl sulfate (SLS) and keratinocytes has been studied. However, the cytotoxicity and effects of sodium dodecyl benzene sulfonate (SDBS), a common detergent similar to SLS, on keratinocytes are still not known. This study aimed to investigate the effects of SDBS on cytotoxicity and expression of proinflammatory cytokines in cultured human keratinocytes. This study was carried out using the keratinocytes cell line, HaCaT cells. The cytotoxicity of SDBS on HaCaT cells was evaluated with cell counting kit-8 (CCK-8) and phase-contrast microscopy. After exposure to different concentrations of SDBS, the total RNA of the HaCaT cells was extracted for evaluating the relative mRNA expression of IL-1α, IL-6, IL-8, and TNF-α by qPCR. The supernatants of cells were collected for measuring the levels of IL-6 and IL-8 by enzyme-linked immunosorbent assay (ELISA). SDBS at concentrations of 20 µg/ml and over showed direct cytotoxicity and induced morphological changes of the HaCaT cells. The mRNA expressions of IL-1α, IL-6, IL-8, and TNF-a in different concentrations of SDBS at different time were comparable with that of controls. SDBS at concentrations of 5, 10, and 15 µg/ml had no significant effects on IL-6 and IL-8 excretion from HaCaT cells after 24-hour exposure. Moreover, no significant effects on the IL-6 and IL-8 excretion were found after 10 and 15 µg/ml SDBS stimulations for 6, 12, and 24 hours, respectively.

SDBS at higher concentrations had cytotoxicity on HaCaT cells but had no effects on the mRNA expression of IL-1α, IL-6, IL-8, and TNF-a, that was different from SLS.

Is alteration of intestinal microflora associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome?

The influence of the gastrointestinal (GI) microflora in patients with irritable bowel syndrome (IBS) has not been clearly elucidated. This study was undertaken to see if patients with IBS have an imbalance in their normal colonic flora, as some bacterial taxa are more prone to gas production than others. We also wanted to study whether the flora could be altered by exogenous supplementation. In a previous study we have characterized the mucosa-associated lactobacilli in healthy individuals and found some strains with good colonizing ability. Upon colonization, they seemed to reduce gas formation. The study comprised 60 patients with IBS and a normal colonoscopy or barium enema. Patients fulfilling the Rome criteria, without a history of malabsorption, and with normal blood tests underwent a sigmoidoscopy with biopsy. They were randomized into two groups, one receiving 400 ml per day of a rose-hip drink containing 5 x 10(7) cfu/ml of Lactobacillus plantarum (DSM 9843) and 0.009 g/ml oat flour, and the other group receiving a plain rose-hip drink, comparable in color, texture, and taste. The administration lasted for 4 wk. The patients recorded their own GI function, starting 2 wk before the study and continuing throughout the study period. Twelve months after the end of the study all patients were asked to complete the same questionnaire regarding their symptomatology as at the start of the study. All patients tolerated the products well. The patients receiving Lb. plantarum had these bacteria on rectal biopsies. There were no major changes of Enterobacteriaceae in either group, before or after the study, but the Enterococci increased in the placebo group and remained unchanged in the test group. Flatulence was rapidly and significantly reduced in the test group compared with the placebo group (number of days with abundant gas production, test group 6.5 before, 3.1 after vs 7.4 before and 5.6 after for the placebo group). Abdominal pain was reduced in both groups. At the 12-month follow-up, patients in the test group maintained a better overall GI function than control patients. There was no difference between the groups regarding bloating. Fifty-nine percent of the test group patients had a continuous intake of fermented products, whereas the corresponding figure for the control patients was 73%.

The results of the study indicate that the administration of Lb. plantarum with known probiotic properties decreased pain and flatulence in patients with IBS. The fiber content of the test solution was minimal and it is unlikely that the fiber content could have had any effect. This type of probiotic therapy warrants further studies in IBS patients.

Does hydroxymethylation of DNA influence nucleosomal conformation and stability in vitro?

Hydroxymethylation of DNA at the C5 position of cytosine (5hmC) is recognized as an important epigenetic mark. The molecular role of 5hmC in gene regulation, however, is not well understood. We studied the effects of 5-hydroxymethylation (5hmC) on nucleosome properties in vitro using a combination of biochemical and fluorescence assays. Competitive reconstitution was used to evaluate the effect of 5hmC on nucleosome formation. The effects of 5hmC on nucleosome compactness and stability were characterized using FRET assays. These findings have also been compared with another important epigenetic mark, the cytosine methylation (5mC) of DNA. We observed that hydroxymethylation increases the binding affinity of DNA for the histone octamer. The formed nucleosome exhibits slightly different conformations based on the sequence and epigenetic context of DNA. DNA hydroxymethylation decreases the stability of formed nucleosomes in salt-induced dissociation processes.

DNA containing 5hmC is more likely to be incorporated into nucleosomes. Once formed, the 5hmC nucleosomes might be in an open and transcriptionally active state due to the weakened interaction of hydroxymethylated DNA with the H2A-H2B dimers.

Does dissociation predict symptom-related treatment outcome in short-term inpatient psychotherapy?

Previous research has indicated that dissociation might be a negative predictor of treatment outcome in cognitive behavioural therapy for patients with obsessive-compulsive and anxiety disorders. Using a naturalistic design it was hypothesized that higher levels of dissociation predict poorer outcome in inpatients with affective, anxiety and somatoform disorders participating in a brief psychodynamic psychotherapy. A total of 133 patients completed the Symptom Check List (SCL-90), the German short version of the Dissociative Experiences Scale and the Inventory of Interpersonal Problems at the beginning and the end of treatment. The Global Severity Index (GSI) of the SCL-90 was chosen as outcome criterion. A total of 62.4% of study participants were classified as treatment responders, that is, they showed a statistically significant change of their GSI scores. Controlling for general psychopathology, the non-responders had significantly higher baseline dissociation scores than the responders. In a logistic regression analysis with non-response as a dependent variable, a comorbid personality disorder, low baseline psychopathology and high dissociation levels emerged as relevant predictors, but interpersonal problems and other comorbid disorders did not.

Dissociation has a negative impact on treatment outcome. It is suggested that dissociative subjects dissociate as a response to negative emotions arising in psychotherapy leading to a less favourable outcome. Additionally, dissociative patients may have an insecure attachment pattern negatively affecting the therapeutic relationship. Thus, dissociation may directly and indirectly influence the treatment process and outcome.

Is distractor P3 associated with attentional capture by stimulus deviance?

A simple distractor elicits a large P3 when the standard and target are difficult to discriminate in the three-stimulus oddball paradigm. This study investigated whether the distractor P3 reflects attentional capture by stimulus deviance or cognitive interference with maintaining the standard representation. Event-related brain potentials were recorded from 12 participants who performed a visual three-stimulus oddball paradigm. Four task conditions were defined by a combination of two presentation types of distractor stimuli (central or bilateral) and two levels of standard/target discrimination difficulty (easy or difficult). Bilateral distractors had stimulus deviance but did not interfere with maintenance of the standard representation. Central distractors elicited a P3, the amplitude of which was larger in the difficult task than in the easy task. In contrast, bilateral distractors elicited a large P3 in both the easy and difficult tasks.

Distractor P3 reflects attentional capture by stimulus deviance, rather than cognitive interference with maintaining the standard representation.

Does cathepsin K Inhibitor regulate Inflammation and Bone Destruction in Experimentally Induced Rat Periapical Lesions?

Cathepsin K is highly expressed in osteoclasts and plays an essential role in bone resorption. NC-2300 is an artificially designed cathepsin K inhibitor, and its application to experimentally induced arthritis induces down-regulation of bone destruction. In this study, we evaluated the effects of NC-2300 on inflammation and bone destruction in experimentally induced rat periapical lesions. The dental pulps of lower first molars in rats were extirpated, and the pulp chambers were left open to the oral environment. NC-2300 and phosphate-buffered saline were administered orally twice a day in the experimental and control groups, respectively. Animals were sacrificed on day 21, and the mandibles were extracted. The left hemimandibles were used for micro-computed tomographic and histologic examination. For the right hemimandibles, RNA was extracted from the periapical tissues surrounding the root apices, and inflammatory mediator expression was examined by real-time polymerase chain reaction using complementary DNA converted from extracted RNA. The size of the periapical lesion, number of tartrate-resistant acid phosphatase-positive osteoclasts and major histocompatibility complex class II molecule-expressing macrophages in the experimental group decreased significantly when compared with the control group. The expression of proinflammatory cytokines in the experimental group was significantly suppressed when compared with the control group.

These results suggest that the cathepsin K inhibitor may inhibit not only cathepsin K activity in osteoclasts but also inflammatory mediator synthesis relating to osteoclastogenesis, and these synergistic effects may be involved in the suppression of periapical lesion expansion.

Orbital fractures and ocular injury: is a postoperative ophthalmology examination necessary?

To determine whether formal ophthalmology evaluation is necessary after operative repair of orbital fractures and the association of an ocular injury to the severity of facial injury. This was a retrospective cohort study of patients with orbital fractures undergoing operative repair from 2005 to 2013. Subjects were included if they had undergone reconstruction of orbital floor fractures and had data from pre- and postoperative examinations by the oral and maxillofacial surgery and ophthalmology services available. The predictor variables included the service performing the ocular examination (oral and maxillofacial surgery or ophthalmology) and the number of fractures present. The outcome variables were the presence of pre- and postoperative ocular injuries. Logistic regression models were used to determine the relationship of the fracture number to ocular injury. A total of 28 subjects had undergone repair of orbital fractures with preoperative and postoperative examinations performed by both services. Preoperative ocular injuries were found in 17 of the 28 subjects. Those detected by oral and maxillofacial surgeons were limited to changes in visual acuity, pupillary response, and extraocular muscle dysfunction in 11 subjects. Two subjects had new postoperative ocular findings that were considered minor and did not alter management. An increasing number of facial fractures was associated with an increased risk of ocular trauma. Those with 3 or more fractures had an odds ratio of 14.625 (95% confidence interval, 2.191 to 97.612, P = .006) for the presence of ocular injury.

Operative repair of orbital fractures did not lead to new ocular injuries that would change the management. Thus, those without preoperative ocular injuries will not require a formal postoperative ophthalmology examination. However, the subjects with more fractures had an increased likelihood of ocular injuries.

Does the subjective evaluation of medical student surgical knowledge correlate with written and oral exam performance?

Medical student performance evaluations have historically contained a significant subjective component. Multiple tools are used to assess fund of knowledge including subjective evaluation by faculty and residents as well as objective evaluations through standardized written and oral exams. We hypothesized that subjective evaluation of medical student knowledge would correlate with objective evaluation through written and oral exams. Records of consecutive medical students assigned to the surgery clerkship from January 1999 and March 2001 were reviewed. The core surgical rotation consisted of two 4-week blocks on a private, county, or VA hospital service. Surgical knowledge was assessed subjectively by both faculty (FES) and senior residents (RES) using a 10-point scale with verbal anchors. Objective measures of student surgical knowledge included the National Board shelf exam (WE) and a semistructured oral exam (OE). Data are reported as mean +/- SEM. Spearman rank correlation coefficient (r) was used to assess relationships between groups (r>or = 0.5 -->positive correlation). A total of 354 students were evaluated. The mean FES was 7.8 +/- 0.05 (median = 7.75, range 4.75 to 9.75). The mean RES was 7.7 +/- 0.06 (median = 8.0, range 3.5 to 10.0). There was poor correlation between the subjective perception and objective measures of surgical knowledge (Table 1). Comparison of the FES and RES also showed poor correlation (r = 0.38).

Subjective evaluation of surgical knowledge by faculty and residents correlates poorly with performance measured objectively. These results question whether subjective evaluation of surgical knowledge should be included as part of the evaluation process.

Is increased expression of intranuclear matrix metalloproteinase 9 in atrophic renal tubules associated with renal fibrosis?

Reduced turnover of extracellular matrix has a role in renal fibrosis. Matrix metalloproteinases (MMPs) is associated with many glomerular diseases, but the histological association of MMPs and human renal fibrosis is unclear. This is a retrospective study. Institutional Review Board approval was obtained for the review of patients' medical records, data analysis and pathological specimens staining with waiver of informed consents. Specimens of forty-six patients were examined by immunohistochemical stain of MMP-9 in nephrectomized kidneys, and the association of renal expression of MMP-9 and renal fibrosis was determined. MMP-9 expression in individual renal components and fibrosis was graded as high or low based on MMP-9 staining and fibrotic scores. Patients with high interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), and were more likely to have chronic kidney disease (CKD) and urothelial cell carcinoma. Univariate analysis showed that IFS and GFS were negatively associated with normal and atrophic tubular cytoplasmic MMP-9 expression and IFS was positively correlated with atrophic tubular nuclear MMP-9 expression. Multivariate stepwise regression indicated that MMP-9 expression in atrophic tubular nuclei (r = 0.4, p = 0.002) was an independent predictor of IFS, and that MMP-9 expression in normal tubular cytoplasm (r = -0.465, p<0.001) was an independent predictor of GFS.

Interstitial fibrosis correlated with MMP-9 expression in the atrophic tubular nuclei. Our results indicate that renal fibrosis is associated with a decline of MMP-9 expression in the cytoplasm of normal tubular cells and increased expression of MMP-9 in the nuclei of tubular atrophic renal tubules.

Are group M-based HIV-1 Gag peptides frequently targeted by T cells in chronically infected US and Zambian patients?

The enormous sequence diversity of HIV-1 has been a major obstacle in the development of a globally useful vaccine for AIDS. The consensus and ancestral sequence-based immunogens minimize the genetic distance between contemporary isolates and vaccine strains. Hence these sequences may be promising candidates for HIV vaccines or serve as a universal reagent set for evaluating Gag-specific responses. In this study, we measured the T-cell reactivity to consensus (subtype A, B, C and group M), ancestral (group M and subtype B) and HXB2 Gag peptides (15-mers overlapping by 11) in HIV-1-infected subjects from two reference populations. We evaluated the Gag-specific T-cell responses in 43 chronically infected US (subtype B) and 13 Zambian (subtype C) subjects using an interferon-gamma enzyme-linked immunosorbent spot assay. Our findings demonstrate a broad cross-reactivity of nearly 70% among all the seven Gag immunogens evaluated. Consensus M sequences elicited similar levels of responses as did the consensus B, ancestral subtype B and HXB2 peptides in subtype B-infected US patients. In subtype C-infected Zambian subjects, responses of similar breadth and magnitude were elicited by consensus C, consensus M and ancestral M peptides.

Our data demonstrate that peptide pools based on consensus or ancestral M-based sequences can be used to evaluate Gag-specific responses elicited by subtype B or subtype C-based immunogens.

Is the ErbB4 growth factor receptor required for colon epithelial cell survival in the presence of TNF?

The ErbB4 receptor tyrosine kinase regulates cell growth, survival, and differentiation in several tissues, but its role in the gastrointestinal tract has not been reported. We tested the hypothesis that ErbB4 promotes intestinal cell survival and restitution following injury or inflammation. ErbB4 expression in human inflammatory bowel disease was determined by immunohistochemistry. Mice were subjected to dextran sulfate sodium (DSS, 3%) colitis or injected with tumor necrosis factor (TNF), and ErbB4 expression was quantified by immunohistochemistry and Western blot. Cultured young adult mouse colon (YAMC) cells were exposed to TNF, and ErbB4 messenger RNA, protein, and phosphorylation levels were measured. Cells transfected with ErbB4 small interfering RNA (siRNA), or over expressing ErbB4, were subjected to wound healing and apoptosis assays. ErbB4 levels increased in Crohn's colitis and the colon epithelium of mice with DSS colitis or injected with TNF. In YAMC cells, TNF induced ErbB4 messenger RNA, protein, and phosphorylation; nuclear factor kappaB activation also stimulated ErbB4 accumulation. ErbB4 siRNA sensitized cells to TNF-stimulated apoptosis, while over expression blocked apoptosis induced by TNF plus cycloheximide. Additionally, ErbB4 siRNA decreased YAMC cell wound healing. ErbB4 knockdown attenuated, while over expression elevated, phosphorylation of Akt in response to TNF. Inhibition of the phosphatidylinositol 3-kinase/Akt signaling cascade reversed the ability of ErbB4 over expression to protect from cytokine-induced apoptosis.

ErbB4 expression and signaling are key elements for TNF responses in vivo and in cell culture, protecting intestinal epithelial cells from apoptosis in the inflammatory environment, possibly through Akt activation.

Is urinary matrix metalloproteinase-7 level associated with the presence of metastasis in bladder cancer?

• To assess the presence of matrix metalloproteinase (MMP)-7 in urine samples of patients with bladder cancer and to investigate the correlation between MMP-7 urine concentration and clinicopathological variables. • The presence of MMP-7 in the urine of patients with bladder cancer was tested in 32 representative cases using immunoprecipitation followed by western blot analysis. • Urinary MMP-7 concentration levels were analyzed in 132 patients with bladder cancer and 96 controls using an enzyme-linked immunosorbent assay. • MMP-7 levels did not differ significantly between patients with localized bladder cancer and controls (P= 0.174). On the other hand, we detected a fourfold, significantly elevated MMP-7 concentration in urine samples of patients with bladder cancer with regional or distant metastasis (P= 0.003). • Using a threshold value of 6.88 ng/ml, determined by receiver-operating characteristic curve analysis, a specificity of 82% and a sensitivity of 78% were observed. • Western blot analysis revealed that the 55-kDa tissue inhibitor of metalloproteinase 1 complexed MMP-7 is the dominant form of urinary matrilysin.

• MMP-7 is present in detectable amounts in the urine of patients with bladder cancer. Its concentrations are significantly elevated in patients with metastatic disease. • Determination of urinary matrilysin level could help to detect bladder cancer metastasis, and may therefore provide a more reliable prognosis and influence therapy decisions.

Does recombinant human BMP-2 enhance the effects of materials used for reconstruction of large cranial defects?

Cranial defect reconstruction presents 2 challenges: induction of new bone formation, and providing structural support during the healing process. This study compares quantity and quality of new bone formation based on various materials and support frameworks. Eighteen dogs underwent surgical removal of a significant portion of their cranial vault. Demineralized bone matrix was used to fill the defect in all animals. In 9 dogs, recombinant human bone morphogenetic protein-2 (rhBMP-2) was added, while the other 9 served as the non-rhBMP-2 group. In each group, 3 animals were fixed with cobalt chrome plates, 3 with adding platelet-rich plasma, and 3 fixed with a Lactosorb (Walter Lorenz Surgical, Inc, Jacksonville, FL) resorbable mesh. Necropsy was done at 12 weeks postoperative. Histomorphometry, density, and mechanical properties of the regenerate were analyzed. The non-rhBMP-2 groups showed minimal substitution of demineralized bone matrix with new bone, while only sporadic remnants of demineralized bone matrix were present in the rhBMP-2 groups. The defect showed more new bone formation (P < .001) and density (P < .001) in the rhBMP-2 groups by Kruskal-Wallis test. The area of new bone was not significantly different among the rhBMP-2 subgroups. The resorbable mesh struts showed no sign of bone invasion or substitution. In the non-rhBMP-2 resorbable mesh group, demineralized bone matrix almost totally disintegrated without replacement by new bone.

The addition of rhBMP-2 to demineralized bone matrix accelerated new bone formation in large cranial defects, regardless of the supporting framework or the addition of platelet-rich plasma. The use of a resorbable mesh in such defects is advisable only if rhBMP-2 is added.

Does prednison provoke serum and vasoactive substances in a mice model of immune thrombocytopenia?

The main objective of this study was to investigate the variations of β-endorphin (β-EP), vasoactive intestinal peptide (VIP), serotonin (5-HT) and norepinephrine (NE) of immune thrombocytopenia (ITP) mice as well as the regulatory mechanism of prednison. Sixty BALB/c mice were randomly divided into control group, model group and prednison intervention group. ITP mice model was duplicated by injecting with glycoprotein-antiplatelet serum (GP-APS) except in control group. After ITP disease model was successful established, prednison was used in prednison intervention group. The β-EP, VIP, 5-HT and NE contents of ITP mice were detected by enzyme linked immunosorbent assay (ELISA). Compared with the values in control group, the detection values of VIP and 5-HT in model group declined, while the detection values of β-EP and NE increased. Compared with prednison intervention group, the detection values of VIP and 5-HT in model group increased, while the detection values of β-EP and NE showed no significant change.

In this study, the β-EP, VIP, 5-HT and NE contents in ITP mice injected with GP-APS were changed by prednison. It shows that prednison as the first-line therapy for ITP with effective hemostasis function is likely to increasing the contents of VIP and 5-HT. These results suggest the therapeutic value of prednison for the treatment of ITP.

Is atrophy of type I and II muscle fibers reversible in the case of grade > 2 fatty degeneration of the supraspinatus muscle : an experimental study in rabbits?

Although clinical investigations indicate that the limit of reversibility of rotator cuff muscles fibers type I and II atrophy is grade 2 of fatty degeneration (FD) according to the Goutallier computed tomography classification, little is known about the morphometric verification of these findings. The supraspinatus tendon was detached from the greater tubercle and the infraspinatus and subscapularis in 12 rabbits, and a 12-week observation period followed. This proved to be sufficient for development of grade >2 FD of the supraspinatus tendon. The tendon was then reinserted. The animals were euthanized 24 weeks after tendon reconstruction. The sections of middle part of supraspinatus were stained for adenosine triphosphatase reaction, and morphometric measurements were taken of type I and II muscle fiber diameters. The contralateral shoulders served as controls. The macroscopic inspection of the supraspinatus tendons revealed complete healing in all cases. No statistically significant differences were found between controls and operated-on shoulders for type I (P = .13) and type II (P = .55) muscle fibers.

Atrophy of type I and II muscle fibers in rabbit supraspinatus muscle, characterized by grade >2 fatty degeneration according to the Goutallier computed tomography classification, is reversible after 24 weeks from reattachment of its tendon. A requirement for type I and II muscle fibers hypertrophy is a change in the biomechanical and functional conditions of the muscle after its tendon is reconstructed.

Is depression with psychotic features influenced by the polymorphism of the serotonin transporter gene?

Current diagnostic classifications regard psychotic symptoms during depressive episodes as indicators of depression severity. However, growing evidence suggests that depression with psychotic symptoms (MDP) may represent a distinct subtype of depression. In the course of the search for discriminating factors we tested the hypothesis that the serotonin transporter gene (5-HTTLPR) may interact with the manifestation of psychotic symptoms in acute depression. 112 inpatients (61 female) with a depressive episode (16 bipolar, 86 unipolar) at admission were genotyped for 5-HTTLPR variants. Psychotic symptoms und general psychopathology were evaluated comprehensively using the Manual of the Association for Methodology and Documentation in Psychiatry (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie, 1981). For statistical analysis a chi-square test and a logistic regression model was used. 16 (14.3%) out of 112 patients were currently presenting with psychotic symptoms. The primary finding of our study was the higher prevalence of the s-allele of the 5-HTTLPR within the group of MDP patients (Pearson χ²=7.87; df=2; p<0.03). Secondly, in a logistic regression model, 5-HTTLPR was found to significantly contribute to the diagnosis of MDP (χ²=6.5; df=1; p=0.01). This effect was even more pronounced upon comparing only severely depressed patients with MDP patients. From a psychopathological perspective, MDP patients showed higher AMDP hostility and apathy scores but equal AMDP depression scores.

This is the first study to show an influence of 5-HTTLPR on psychotic symptoms in acutely depressed patients.

Tap water and the Malone antegrade continence enema: a safe combination?

The Malone antegrade continence enema provides independence and improved quality of life in patients with fecal incontinence or intractable constipation. However, isolated reports of fatal hypernatremia after irrigation with normal saline have raised safety concerns about frequent colonic irrigation in children. Significant electrolyte abnormalities have also been reported with hypertonic phosphate and high colonic tap water enemas. Because our patients routinely use tap water for Malone antegrade continence enema irrigations, we examined the safety profile of this practice In the last 3.5 years 71 patients at our institution have used antegrade tap water enemas for managing fecal incontinence or intractable constipation. Standard serum electrolytes were measured We obtained 101 sets of serum electrolyte measurements in 71 patients at a mean of 8.4 months postoperatively (range 1 to 33). A girl who presented with severe hyponatremia and hypochloremia had not used the Malone antegrade continence enema for several days. The most interesting finding was significantly elevated sodium and chloride in 1 case 6 weeks after surgery that was associated with tap water treated with a home softening system. Electrolytes reverted to normal 1 week after using untreated tap water

We did not detect significant hyponatremia or hypochloremia in any patient using tap water for Malone antegrade continence enema irrigation. Although dangerous electrolyte abnormalities are rare, potential morbidity in those cases warrants periodic evaluation. Due to the elevated sodium content in softened tap water families should be alerted to use untreated tap water for preparing enemas.

Does high-intensity Interval training enhance mobilization/functionality of endothelial progenitor cells and depressed shedding of vascular endothelial cells undergoing hypoxia?

Exercise training improves endothelium-dependent vasodilation, whereas hypoxic stress causes vascular endothelial dysfunction. Monocyte-derived endothelial progenitor cells (Mon-EPCs) contribute to vascular repair process by differentiating into endothelial cells. This study investigates how high-intensity interval (HIT) and moderate-intensity continuous (MCT) exercise training affect circulating Mon-EPC levels and EPC functionality under hypoxic condition. Sixty healthy sedentary males were randomized to engage in either HIT (3-min intervals at 40 and 80 % VO The results demonstrated that after the intervention, the HIT group exhibited larger improvements in VO

HIT is superior to MCT for improving hemodynamic adaptation and Mon-EPC production. Moreover, HIT effectively enhances EPC functionality and suppresses endothelial injury undergoing hypoxia.

Does halothane interfere with the release, action, or stability of endothelium-derived relaxing factor/nitric oxide?

Halothane attenuates endothelium-dependent relaxation. To differentiate halothane's effect on endothelium-derived relaxing factor/nitric oxide (EDRF/NO) production from its effect on nitric oxide action on vascular smooth muscle, halothane's effect on endothelium-dependent relaxation was studied in a bioassay system. Indomethacin-treated, bovine aortic endothelial cells (BAEC) grown on microcarrier beads, continuously perfused by oxygenated and carbonated (95% O2, 5% CO2) Krebs-Ringer solution served as nitric oxide donors while an isolated denuded rabbit aortic ring directly superfused by the effluent of the BAEC and precontracted with phenylephrine was used to detect EDRF/NO release. The effect of basal and bradykinin-stimulated EDRF release on the tension of the vascular ring was measured. In the bioassay, it was possible to treat either the vascular denuded ring alone or the vascular ring plus the BAEC with halothane by adding it to the perfusate either upstream or downstream from the BAEC. Halothane (final concentration 2.2%) was added to the perfusate at these two positions, and its effect on the relaxation induced by EDRF/NO was determined. In some experiments, the preparations were treated with hemoglobin or L-monomethyl-L-arginine to attenuate the relaxation induced by the EDRF/NO pathway. Finally, halothane's effect on vascular relaxation induced by an increasing concentration of sodium nitroprusside was measured. Halothane's concentration in the perfusate was determined by gas chromatography using electron capture for anesthetic measurement. EDRF/NO released by the BAEC was responsible for the relaxation of the vascular ring. Halothane added to the perfusate potentiated the tension induced by phenylephrine (7.1 +/- 1.89%) and attenuated the relaxation induced by the release of EDRF/NO. This effect was reversible after discontinuation of halothane. Halothane's effect was present even when the anesthetic was added to the perfusate downstream to the perfusion of the endothelial cells. Halothane had no effect on the vascular relaxation induced by sodium nitroprusside.

The authors' data demonstrate that halothane does not interfere with endothelial cell release of EDRF/NO and its smooth muscle cell relaxation but seems to modify either EDRF/NO half-life or its activated redox form.

Are plasma chromogranin A levels increased in a small portion of patients with hereditary head and neck paragangliomas?

The majority of patients with head and neck paragangliomas (HNPGL) have biochemically silent tumours. Chromogranin A (CgA) is a tumour marker for neuroendocrine tumours. To assess the role of CgA as a tumour marker in patients with hereditary HNPGL. We included 95 consecutive patients with hereditary HNPGL for screening of plasma CgA levels and catecholamine excess by measurement of 24-h urinary excretion of (nor)metanephrine, (nor)adrenaline, VMA, dopamine and 3-methoxytyramine. In all patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by (123) I-MIBG scintigraphy, MRI and/or CT. Plasma CgA levels were increased in only 15 of 95 patients (16%). Thirty-three of the 95 patients (35%) had increased urinary excretion rates of catecholamines. Six of these 33 patients (18%) had increased plasma CgA levels. Nine of the 62 patients (15%) with a biochemically silent tumour, i.e. no increased urinary excretion of catecholamines or their metabolites, had increased CgA levels. Increased plasma CgA levels were positively correlated with urinary excretion rates of noradrenaline (r = 0·68, P = 0·005) and normetanephrine (r = 0·68, P = 0·005). There was a positive correlation between maximal HNPGL diameter and plasma CgA levels in the 57 patients with a single HNPGL (r = 0·57, P = 0·001).

Plasma CgA levels are increased in only a small portion of patients with hereditary HNPGL and have limited additional value to the combination of radiological and routine biochemical assessment of patients with HNPGL. Increased plasma CgA levels are associated with increased noradrenergic activity and tumour size in patients with a single HNPGL.

Is tLR4 lower in resistance-trained older women and related to inflammatory cytokines?

Regular exercise may offset age-associated increases in inflammatory cytokines and reduce the risk of developing diseases with an inflammatory etiology by exerting "anti-inflammatory" effects. Toll-like receptor 4 (TLR4) signaling stimulates inflammatory cytokine production, and may explain the "anti-inflammatory" effect attributed to regular exercise. Therefore, the purpose of the present study was to compare the effect of acute (3 sets, 9 exercises, 10 repetitions at 80% of the 1-repetition maximum) and chronic resistance exercise on TLR4 and inflammatory cytokines. Venous blood samples were collected from trained (TR, N = 10) and untrained (UT, N = 10) older (65-80 yr) postmenopausal women: before (PRE), immediately post (POST), and 2 h (2H), 6 h (6H), and 24 h (24H) after completion of exercise. Cell-surface expression of TLR4 (two-color immunofluorescent cytometry), LPS (25 microg x mL(-1))-stimulated cytokine production (ELISA), plasma cytokines (ELISA), and mRNA expression of TLR4 and cytokines (RT-PCR) were determined for each sample. TR had 124% less cell-surface TLR4 expression than UT (P < 0.05). A significant time effect was found for LPS-stimulated IL-6, IL-1beta, and TNF-alpha, where 6H was significantly greater than all other samples. No significant effects were found for plasma (IL-6 and TNF-alpha) or mRNA expression (IL-6, TNF-alpha, and IL-1beta) of inflammatory cytokines. When subjects were grouped according to cell-surface TLR4 expression (HI and LO), LPS-stimulated TNF-alpha (302%), IL-1beta (209%), and IL-6 (167%) production was greater for HI than LO (P < 0.05).

Regularly exercising older women expressed less cell-surface TLR4 but did not have lower plasma levels or produce less LPS-stimulated inflammatory cytokines at rest or in response to a single bout of resistance exercise. TLR4 changes may explain the "anti-inflammatory" effect that has recently been attributed to chronic (2x wk for previous 24 months) resistance exercise training.

Does serum biological antioxidant potential predict the prognosis of hemodialysis patients?

It is well known that oxidative stress is enhanced in patients with end-stage renal disease. However, little is known about the relationship between serum antioxidant capacity and clinical outcome in hemodialysis (HD) patients. We examined the relationship between serum biomarkers of oxidative stress and clinical outcomes including all-cause mortality, hospitalization rate and incidence of cardiovascular events in HD patients. As biomarkers of oxidative stress, we measured serum levels of coenzyme Q10 (CoQ10) and biological antioxidant potential (BAP). 108 patients were observed for 30 months as the follow-up periods. The survival group (n = 83) showed significantly higher BAP values compared with those in death groups (n = 25; p < 0.05). When serum BAP levels were divided into two groups by their median value, the group with higher BAP values had a better survival rate than that with lower BAP values on the Kaplan-Meier survival analysis (p = 0.05). Although serum levels of CoQ10 did not show any association with clinical outcomes, lower BAP was selected as an independent risk factor for all-cause mortality as well as the absence of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers therapy by age-adjusted Cox regression analysis.

This study indicated that BAP could predict the prognosis of HD patients.

Does proteomic analysis reveal that apolipoprotein A1 levels are decreased in patients with Budd-Chiari syndrome?

Budd-Chiari syndrome (BCS) is a rare vascular liver disorder caused by thrombosis of the hepatic veins. In some patients, no known thrombophilic factor can be identified. This study aimed to identify novel factors that might play a role in thrombosis in BCS-patients by using a proteomic approach. The abundance of plasma clot-bound proteins was compared between nine BCS-patients and nine controls by using two-dimensional difference gel electrophoresis. The protein with the most significant decrease in patients was identified by mass spectrometry. Plasma levels of this protein were measured and the results were validated in a large cohort of BCS-patients. A total of 26 protein spots significantly differed (p<0.001). The spot that decreased with the highest statistical significance in patients was identified by mass spectrometry as apolipoprotein A1 (apo A1). The mean level of apo A1 in the plasma of these BCS-patients (0.74 g/L) was also significantly lower than in controls (1.45 g/L, p=0.002). This finding was validated in a large cohort of 101 BCS-patients and 101 controls (0.97 g/L vs. 1.32 g/L, p<0.0001). There was no major correlation between plasma levels of apo A1 and various liver function tests.

BCS-patients show decreased clot-bound protein abundance and plasma levels of apo A1. Decreased levels of apo A1 may play a role in the etiology of thrombosis in BCS-patients and possibly in other patients with venous thrombosis.

Does overexpression of pyruvate dehydrogenase kinase support dichloroacetate as a candidate for cutaneous melanoma therapy?

We aimed to verify if there is evidence to consider dichloroacetate (DCA), which inhibits the pyruvate dehydrogenase kinase (PDK) and reverts the metabolic shift of cancer cells from glycolysis to oxidative phosphorylation, as a promising drug for therapy of cutaneous melanoma (CM) patients. We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumors express the DCA targets, if this expression correlates with the activation of important signaling cascades for melanomagenesis and also with the prognosis of melanoma patients. We also established the sensitivity of melanoma cell lines to DCA treatment, by assessing their metabolic alterations, proliferation and survival. We observed that both PDK 1 and 2 isoforms are overexpressed in CM compared to nevi, this expression being associated with the expression of the mTOR pathway effectors and independent of the BRAF mutational status. Melanoma cell lines treated with DCA showed a shift in metabolism, that is, a decrease in glucose consumption and lactate production, downregulation of proliferation, an increase of apoptosis and a decrease in mTOR pathway activation.

Our results suggest that PDK expression may play a role in melanoma development and that DCA can be useful for CM therapy, alone or in combination with mTOR inhibitors.

Does tabernaemontana divaricata leave extract exacerbate burying behavior in mice?

Tabernaemontana divaricata (TD) from Apocynaceae family offers the traditional folklore medicinal benefits such as an anti-epileptic, anti-mania, brain tonic, and anti-oxidant. The aim of the present study was to evaluate the effect of ethanolic extract of TD leaves on burying behavior in mice. Mice were treated with oral administration (p.o.) of ethanolic extract of TD (100, 200, and 300 mg/kg). Fluoxetine (FLX, a selective serotonin reuptake inhibitor) was used as a reference drug. Obsessive-compulsive behavior was evaluated using marble-burying apparatus. TD at doses of 100, 200, and 300 mg/kg dose-dependently inhibited the obsessive and compulsive behavior. The similar results were obtained from 5, 10, and 20 mg/kg of FLX. TD and FLX did not affect motor activity.

The results indicated that TD and FLX produced similar inhibitory effects on marble-burying behavior.

Can medical schools rely on clerkships to train students in basic clinical skills?

Many medical schools have drawn up lists of basic clinical skills that students are required to have mastered at the end of medical training. To determine whether undergraduate students actually perform these basic clinical skills during clerkships and whether different approaches to skills training led to different results, we surveyed 365 final-year medical students in 1996 and 1997. A questionnaire containing items on 265 skills in eight body systems was administered to students from two conventional medical schools (Ghent and Antwerp, Belgium), and one Dutch medical school, Maastricht, which offers a problem-based curriculum and systematic skills training. Although quite a few skills were not performed by Maastricht students, the results of this school compared favourably to those of the Ghent and Antwerp medical schools. Significant differences between Ghent and Antwerp were found for surgery, paediatrics and gynaecology/obstetrics. In the non-obligatory clerkships in dermatology, otorhinolaryngology and ophthalmology a great percentage of skills were not performed.

The main conclusion is that all three medical schools cannot rely on clerkship experiences alone to provide adequate basic skills training. A problem-based learning environment and training in a skills laboratory appear to result in students performing more skills during clerkships. Assessment of clinical skills, obligatory clerkships in specialties and general practice, and continuous monitoring of the quality of clerkships may also be strong determinants of the present findings.

Does transient posterior localization of a kinesin fusion protein reflect anteroposterior polarity of the Drosophila oocyte?

During oogenesis in Drosophila, determinants that will dictate abdomen and germline formation are localized to the 'polar plasm' in the posterior of the oocyte. Assembly of the polar plasm involves the sequential localization of several messenger RNAs and proteins to the posterior of the oocyte, beginning with the localization of oskar mRNA and Staufen protein during stages 8 and 9 of oogenesis. The mechanism by which these two early components accumulate at the posterior is not known. We have investigated whether directed transport along microtubules could be used to accomplish this localization. We have made a fusion protein composed of the bacterial beta-galactosidase enzyme as a reporter, joined to part of the plus-end-directed microtubule motor, kinesin, and have found that the fusion protein transiently localizes to the posterior of the oocyte during stages 8 and 9 of oogenesis. Treatment with the microtubule-depolymerizing agent colchicine prevents both the localization of the fusion protein and the posterior transport of oskar mRNA and Staufen protein. Furthermore, the fusion protein localizes normally in oocytes mutant for either oskar and staufen, but not in other mutants in which oskar mRNA and Staufen protein are mislocalized.

Association with a plus-end-directed microtubule motor can promote posterior localization of a reporter protein during oogenesis. The genetic requirements for this localization and its sensitivity to colchicine, both of which are shared with the posterior transport of oskar mRNA and Staufen protein, suggest that similar mechanism may function in both processes.

Is survival associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer?

To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-κB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-κB inflammatory pathway play in the development and progression of PC. We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing. Median age was 67 (28.0-91.0) years, and 57% were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P < 0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3) were associated with a 10- and 6-month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the G allele, hazard ratio of 0.57 (95% confidence interval: 0.42-0.77); P = 0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant.

SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci.

Does aRMS2 increase the risk of early and late age-related macular degeneration in the European Eye Study?

To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2. Population-based, cross-sectional European Eye Study in 7 countries in Europe. Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling. Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression. Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status. Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (P<3 × 10(-20)). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1 × 10(-26) (late AMD).

A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed.

Does maternal cigarette-smoking during pregnancy disrupt rhythms in fetal heart rate?

To examine the effects of maternal cigarette smoking during pregnancy on the developing infant's autonomic regulation before the possible effects of parturition and neonatal withdrawal could alter outcome measures. Heart rate variability (HRV) was assessed for 10 min during late gestation for 21 cigarette-exposed (CE) and 22 nonexposed (NE) fetuses. HRV was significantly lower in fetuses whose mothers smoked cigarettes during pregnancy. Spectrum analysis of that variability showed temporally organized rhythms at a frequency similar to rhythms previously found in fetal cyclic motility (approximately .3 cycles per min). Lower powered rhythms--associated with poorer development--at the first, second, and dominant rhythms, as well as lower overall power of the power spectrum, were found for CE fetuses. Pearson correlations showed significant negative correlations between the amount of maternal cigarette smoking during the first trimester of pregnancy and measures of fetal HRV and power of spectral peaks.

Results show that CE fetuses have lower HRV and disrupted temporal organization of autonomic regulation before effects of parturition, postnatal adaptation, and possible nicotine withdrawal contributes to differences in infant neurobehavioral function.

Do serum Cholesterol Levels within the High Normal Range Are Associated with Better Cognitive Performance among Chinese Elderly?

The association between cognitive function and cholesterol levels is poorly understood and inconsistent results exist among the elderly. The purpose of this study is to investigate the association of cholesterol level with cognitive performance among Chinese elderly. A cross-sectional study was implemented in 2012 and data were analyzed using generalized additive models, linear regression models and logistic regression models. Community-based setting in eight longevity areas in China. A total of 2000 elderly aged 65 years and over (mean 85.8±12.0 years) participated in this study. Total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) concentration were determined and cognitive impairment was defined as Mini-Mental State Examination (MMSE) score ≤23. There was a significant positive linear association between TC, TG, LDL-C, HDL-C and MMSE score in linear regression models. Each 1 mmol/L increase in TC, TG, LDL-C and HDL-C corresponded to a decreased risk of cognitive impairment in logistic regression models. Compared with the lowest tertile, the highest tertile of TC, LDL-C and HDL-C had a lower risk of cognitive impairment. The adjusted odds ratios and 95% CI were 0.73(0.62-0.84) for TC, 0.81(0.70-0.94) for LDL-C and 0.81(0.70-0.94) for HDL-C. There was no gender difference in the protective effects of high TC and LDL-C levels on cognitive impairment. However, for high HDL-C levels the effect was only observed in women. High TC, LDL-C and HDL-C levels were associated with lower risk of cognitive impairment in the oldest old (aged 80 and older), but not in the younger elderly (aged 65 to 79 years).

These findings suggest that cholesterol levels within the high normal range are associated with better cognitive performance in Chinese elderly, specifically in the oldest old. With further validation, low cholesterol may serve a clinical indicator of risk for cognitive impairment in the elderly.

Treatment of adolescent varicocele: is percutaneous embolization better?

There are still doubts as to the most suitable criteria when considering surgery as the indication and optimal treatment for adolescent varicocele. We reviewed the hospital and primary health care histories of patients diagnosed by ultrasound for varicocele over the last 7 years. The data was taken from computerised clinical histories and hard copy back-up material stored and processed in computer format. We studied 135 cases (mean age 12.8 years). These patients (125) were referred for scrotal swelling or as a result of chance detection, except for 10 patients who reported pain or scrotal asymmetry. Seventy-three underwent surgery and 62 continued as controls over the study period. The surgical indication was significant progressive asymmetry in testicular volume (28 children), high grade varicocele (41) as well as other reasons (4). We undertook percutaneous embolization in 44 patients (with a 66% relapse rate) and laparoscopic section of the spermatic cord with no arterial preservation in 29 (no relapses but 7 post-surgery hydroceles). No testicles were lost. At the end of the study 10 children continued as controls, 34 were discharged after recovery, 56 were referred to urology due to their age group, and 35 were lost to the study. In the controversy over the treatment of varicocele our experience shows a high degree of relapses after embolization. Section of the spermatic vessels (including the artery) with no lymphatic preservation is highly effective but involves 27% post-op hydroceles, usually self-limiting (only one had later to undergo surgery), with no testicular atrophy or other complications.

We prefer complete laparoscopic section of the spermatic pedicle to embolization but it would be advisable to introduce modifications to avoid post-surgical hydrocele. Embolization must be reserved for patients with one testicle or with bilateral disease. Efforts must be made to communicate more effectively, in order to reduce the high drop-out rate.

Does aspiration of dead space allow normocapnic ventilation at low tidal volumes in man?

Aspiration of dead space (ASPIDS) improves carbon dioxide (CO2) elimination by replacing dead space air rich in CO2 with fresh gas during expiration. The hypothesis was that ASPIDS allows normocapnia to be maintained at low tidal volumes (VT). Prospective study. Adult intensive care unit in a university hospital. Seven patients ventilated for neurological reasons were studied. All patients were clinically and haemodynamically stable and monitored according to clinical needs. ASPIDS implies that, during expiration, gas is aspirated through a catheter inserted in the tracheal tube. Simultaneously, a compensatory flow of fresh gas is injected into the inspiratory line. ASPIDS was achieved with a computer/ventilator system controlling two solenoid valves for aspiration and injection. At the basal respiratory rate of 12.6 breaths min-1, with ASPIDS VT decreased from 602 to 456 ml, as did the airway pressures to a corresponding degree. PaCO2 and PaO2 remained stable. At a frequency of 20 breaths min-1, with ASPIDS VT was further reduced to 305 ml with preserved normocapnia. ASPIDS did not interfere with the positive end-expiratory pressure (PEEP) level. No intrinsic PEEP developed. All patients remained stable. No haemodynamic or other side effects of ASPIDS were noticed.

The results of this study suggest that ASPIDS may be a useful and safe modality of mechanical ventilation that limits alveolar pressure and minute ventilation requirements while keeping PaCO2 constant.

Do losartan and atenolol have differential effects on BNP and central haemodynamic parameters?

It has been suggested that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have a differential effect on brachial and aortic haemodynamics. This is why they seem to have beneficial effects that are beyond brachial blood pressure (BP) lowering. We aimed to investigate if this was the case with losartan when compared to atenolol. We also investigated the differential effect of losartan and atenolol on the prognostic marker, brain type natriuretic peptide (BNP). We studied 17 patients who were similar to those in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Patients were randomised to receive four months of losartan and atenolol in a crossover fashion. Main outcome measures were BNP and Augmentation index (AIx), which gives an indication of central haemodynamics. Brachial pulse wave velocity (PWV) and time to reflected wave (Tr) were measured as an indication of vascular stiffness. BNP was significantly lower on losartan than atenolol (p=0.007). AIx was lower on losartan than atenolol (p=0.03), however, this result was not significant when heart rate was considered as a covariate (p=0.09). Heart rate was significantly lower on atenolol than losartan (p=0.03). There was no difference between treatments for both brachial PWV and Tr (p=0.2 and p=0.99, respectively).

The benefits seen when losartan was compared to atenolol in the LIFE trial may be due to a reduction in BNP. We failed to detect a differential effect in central compared to peripheral haemodynamics when losartan was compared to atenolol.

Does the anxiogenic drug yohimbine reinstate methamphetamine seeking in a rat model of drug relapse?

Brain noradrenaline is involved in footshock stress-induced reinstatement of drug seeking in a rat relapse model. We studied whether yohimbine, an alpha-2 adrenoceptor antagonist that increases noradrenaline release and induces anxiety-like responses in human and nonhuman subjects, would reinstate methamphetamine seeking in rats. In experiment 1, the effect of yohimbine (1.25-2.5 mg/kg) on reinstatement was compared with that of intermittent footshock (5 min;.2-.6 mA) in rats that were trained to lever press for intravenous methamphetamine (9-11 days) and subsequently underwent 7 days of extinction training. In experiment 2, the effect of yohimbine on reinstatement of drug seeking was determined during early (1 day) and late (21 or 51 days) withdrawal periods. On the test days, rats were first given 3-hour extinction sessions and were then tested for reinstatement induced by yohimbine. In experiment 1, both yohimbine and footshock stress reinstated methamphetamine seeking after extinction. In experiment 2, extinction responding was higher after 21 or 51 withdrawal days than after 1 withdrawal day. In contrast, no significant time-dependent changes in yohimbine-induced reinstatement were observed.

Results indicate that yohimbine is a potent stimulus for reinstatement of methamphetamine seeking in a rat relapse model.