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[High-dose Tegafur (FT) for primary lung cancer: a phase I trial]. A phase I clinical study of intravenous Tegafur was conducted in nineteen previously treated patients with primary lung cancer. The dose of Tegafur was elevated from 1.0 to 3.0 g/m2/day for five consecutive days to determine the maximum tolerated dose. The dose-limiting factors were gastrointestinal and neurological toxicity and fatigability observed with the dose level of 2.5 g/m2/day for 5 days. Hematologic, hepatic and renal toxicities were not observed. Gastrointestinal toxicity including nausea, vomiting, anorexia and diarrhea of over grade 2 were seen to result from the dose of 2.5 g/m2/day. Neurological toxicity consisted of headache, dizziness, anxiety and depression. At the dose level of 2.0 g/m2/day, one patient, who had epileptic seizures in the past, experienced a psychomotor seizure. Depression (Grade 2 CNS toxicity) was observed at the dose level of 3.0 g/m2/day. Dose limiting factors were neurological toxicities. The pharmacokinetics of tegafur and 5-FU (the active form of Tegafur) has been studied in all patients. Serum level of tegafur was measured by HPLC method, and serum level of 5-FU was analyzed by GC-MS method. At the dose level greater than 2.0 g/m2/day for 5 days, the mean serum 5-FU values appear over the therapeutic range (0.1 micrograms/ml). In conclusion, 2.5 g/m2/day for 5 days was considered to be MTD, and 2.0 g/m2/day for 5 days intravenous administration was recommended for the phase II trial of single agent chemotherapy.

Efficacy of chest physiotherapy and intermittent positive-pressure breathing in the resolution of pneumonia. We undertook a randomized clinical trial to evaluate the efficacy of chest physiotherapy and intermittent positive-pressure breathing in the treatment of pneumonia. The diagnosis of pneumonia required a compatible clinical history and x-ray confirmation. A total of 54 patients were assigned to treatment and control groups and were similar in age, smoking history, underlying lung disease and prior antibiotic treatment. Antibiotic therapy, guided by Gram stain and sputum and blood cultures, was similar in both groups. Chest physiotherapy, consisting of postural drainage, percussion and vibration, was given concurrently with intermittent positive-pressure breathing with use of racemic epinephrine every four hours. There was no statistically significant difference in duration of fever, extent of radiographic clearing, duration of hospital stay and mortality between the control and treated groups. Chest physiotherapy and intermittent positive-pressure breathing do not hasten the resolution of pneumonia.

On so-called atypical psychosis in early and mid-adolescence. Twenty-three cases of adolescent atypical psychosis were reported, of which 12 were followed for more than three years (at the longest about 18 years). Our cases indicated apparent atypicalness in regard to the symptomatology and to the course, quite different from cyclothymic psychosis and schizophrenia. In an etiological point of view, hereditary predispositions were more frequently recognized in our cases than in schizophrenic cases, but because schizophrenics were found in the families of these patients, it was difficult for us to determine whether our cases belonged to an etiologically independent endogenous psychosis. However, we received the impression that atypical psychosis could be differentiated from others even in adolescents. But this psychosis was seldom found in childhood. While, through the comparison of these patients with adult cases and by considering previous research, we were led to the assumption that adolescent atypical psychosis might be understood as a minor pattern of the fully-developed psychosis in adults but was provided with many properties specific to adolescense.

Cardiovascular complications during exercise training of cardiac patients. The occurrence of major cardiovascular complications during exercise training of cardiac patients in 30 cardiac rehabilitation programs in North America was determined by questionnaire. These programs conducted medically supervised cardiac exercise classes in 103 locations and reported information on 13,570 participants who accumulated a total of 1,629,634 patient hours of supervised exercise. Cardiovascular complications were reported as nonfatal or fatal and included cardiac arrest, myocardial infarction and other. A total of 50 cardiac arrests were observed during exercise, 42 of which were successfully resuscitated while eight were fatal. Seven myocardial infarctions were reported; five were nonfatal and two were fatal. Four other fatalities were reported due to acute cardiopulmonary disorders. The average complication rate for all programs was one nonfatal and one fatal event every 34,673 and 116,402 patient hours of participation, respectively. Complication rates are lower in programs which continuously monitor the electrocardiogram during exercise and are lower when only the experience since 1970 is evaluated. These data support the recommendation that medically prescribed and supervised exercise can be performed reasonably safely by medically selected cardiac patients.

Cerebral blood flow changes during localized hyperthermia. Hyperthermia is becoming a potent therapeutic method for malignant brain tumors, either alone or in combination with radiation therapy. The heat response of organized tissues includes other factors besides the inherent cellular thermosensitivity, that is, tissue pH, PaO2, and nutrient supply, all of which are largely influenced by the tissue blood flow. In this study, the regional cerebral blood flow (rCBF) changes in 15 Japanese normal monkey brains during interstitial microwave hyperthermia were investigated by the hydrogen clearance method. Under general anesthesia and controlled respiration, a parieto-occipital craniectomy, 4 x 4 cm, was performed. A microwave antenna was inserted into the brain to a depth of 2.0 cm, and the brain tissue was heated with 2450 MHz microwave irradiation. The intracerebral temperatures and rCBF were measured in the white matter 1 cm from the brain surface. During hyperthermia, the rCBF linearly increased at a rate of 10% per 1 degrees C temperature rise. Heating at 42 degrees C for 180 minutes resulted in a constant increase in rCBF. The perfusion rate returned to the control levels after the termination of heating. Above 45 degrees C, the rCBF transiently increased and then started to decline during heating. No consistent results were obtained with heating at 43 degrees C. These results show that normal monkey brain tissues respond to hyperthermia by an rCBF increase as long as the threshold values of tissue temperature (43 degrees C) and exposure time (40-60 minutes) are not exceeded. Excessive heating may lead to irreversible damages to normal tissue and vasculature.

Studies on the molecular recognition of synthetic methyl beta-lactoside analogs by ricin, a cytotoxic plant lectin. The binding of methyl beta-lactoside and of all possible monodeoxy derivatives of methyl beta-lactoside to the galactose-specific highly cytotoxin lectin ricin, has been investigated. The distribution of low-energy conformers of the disaccharide structures has been first determined using molecular-mechanics calculations and high-resolution NMR spectroscopy. The nuclear Overhauser enhancements and specific deshieldings observed are in agreement with a similar distribution of low-energy conformers for all studied compounds which may be described by a major conformer defined by phi (H1'-C1'-O1'-C4) and psi (C1'-O1'-C4-H4) torsion angles of 49 degrees and 5 degrees, respectively, with contribution of conformers with angles phi/psi 24 degrees/-59 degrees, 22 degrees/-32 degrees and 6 degrees/-44 degrees. Assuming that the disaccharides bind to the lectin in these preferred conformations, the apparent dissociation constants for the ricin-disaccharide complexes have been interpreted in terms of specific polar and nonpolar interactions. In agreement with X-ray data, the hydroxyl groups at positions 3, 4 and 6 of the beta-D-galactopyranose moiety appear as key polar groups in the interaction with ricin. These results are in contrast to previous results which have established that position 6 is not involved in lectin binding. An important nonpolar interaction involving position 3 of the beta-D-glucopyranose moiety, seems to be operative. The distribution of low-energy conformers of these disaccharide structures permits this interaction to take place with the hydroxyl group at this position intramolecularly bonded, thus rendering this region of the molecule more lipophylic in character for acceptance into nonpolar regions of the combining site.

1H and 15N resonance assignments and secondary structure of the human thioredoxin C62A, C69A, C73A mutant. The complete assignment of 1H and 15N backbone resonances and near-complete 1H side-chain resonance assignments have been obtained for the reduced form of a mutant of human thioredoxin (105 residues) in which the three non-active site cysteines have been substituted by alanines: C62A, C69A, C73A. The assignments were made primarily on the basis of three-dimensional 15N-separated nuclear Overhauser and Hartmann-Hahn spectroscopy, in conjunction with two-dimensional homonuclear and heteronuclear correlation experiments. Based on comparisons of short-range and interstrand nuclear Overhauser effects, patterns of amide exchange, and chemical-shift differences, the structure appears essentially unchanged from that of the previously determined solution structure of the native protein [Forman-Kay, J.D. et al. (1991) Biochemistry, 30, 2685-2698]. An assay for thioredoxin shows that the C62A, C69A, C73A mutant retains activity. The assignment of the spectrum for this mutant of human thioredoxin constitutes the basis for future studies aimed at comparing the details of the active-site conformation in the reduced and oxidized forms of the protein.

Gel electrophoretic analysis of chitosan hydrolysis products. Enzymatic hydrolysis of commercial crustacean chitosan by barley chitosanases was analyzed by subjecting chitosan to electrophoresis in a 10% w/v polyacrylamide slab gel in the presence of 7 M urea and 5.5% v/v acetic acid. Chitosan migrated as a polycation. Chitosan was stained with Coomassie Brilliant Blue R-250 or visualized by ultraviolet transillumination after staining with Calcofluor White M2R. Some chitosan molecules were retarded by gel electrophoresis while small chitosan molecules migrated at the bottom of a 10% w/v polyacrylamide gel. Such analysis revealed that 96 h were necessary to convert all chitosan to oligosaccharides under our assay conditions. Chitosan oligosaccharides generated by enzymatic or chemical hydrolysis were further analyzed by electrophoresis in a 33% w/v polyacrylamide gel containing urea and acetic acid. Coomassie Brilliant Blue R-250 was found to be better than Calcofluor White M2R for staining chitosan oligosaccharides. Chitosan oligomers of four residues (tetramers) or more were easily resolved in such a polyacrylamide gel system. To our knowledge, this is the first report of a gel electrophoretic separation of chitosan and its oligosaccharides.

Leg movements in the supine position of infants with spastic diplegia. Leg movements in the supine position of 49 infants with spastic diplegia (three to 11 months corrected age) were examined. Only simultaneous flexion and extension of the hips and knees were seen, with exceptional isolated hip movements; the simultaneous movements had synergic features. When the knees were flexed, the hips were flexed, abducted and externally rotated, and the ankles were dorsiflexed. When the knees were extended, the hips were extended, adducted and internally rotated and the ankles were plantar-flexed. Hip flexion combined with knee extension (leg elevation) and isolated knee movements were not seen in diplegic infants, but were seen in all control preterm infants with a good prognosis, after five and six months corrected age, respectively. The absence of these movements is a useful diagnostic item for spastic diplegia.

Inferior caval venography in the assessment of renal carcinoma. Inferior caval venography by a non-catheter technique was carried out in 30 cases of renal cell carcinoma. Occlusion of the renal vein was shown in 15 of these and occlusion of the inferior vena cava in a further three. Deformity of the vena cava by adjacent growth was found in nine instances. Renal arteriography was performed in 27 of these patients and the demonstration of the renal vein by this method has been compared with that of caval venography. The incidence of collateral veins on the arteriogram and the finding of impaired renal function as an index of renal vein occlusion has been discussed.

Clinical effects of calcium antagonists in hypertensive diabetics. The incidence of hypertension and coronary artery disease among diabetic patients is approximately two to three times greater than in nondiabetics. Recent evidence suggests that even moderately elevated blood pressure levels may result in diabetic complications involving the eyes or kidneys. However, treatment of diabetic patients with antihypertensive drugs may have a deleterious metabolic effect. Previous studies have suggested that calcium antagonists may reduce insulin secretion and therefore impair glucose tolerance. This has not been substantiated clinically; in general, it would appear that calcium antagonists have a minimal hyperglycemic effect. To establish whether interruption of excitation-contraction coupling in arterial smooth muscle and altered stimulus-secretion coupling occur at pharmacologically equivalent doses of calcium antagonist, the effect of nicardipine on insulin output and vascular resistance was studied in the isolated perfused rat pancreas and in eight hypertensive patients with impaired glucose tolerance during oral glucose tolerance testing (OGTT). Baseline insulin output in vitro was 86 +/- 22 ng/min at 8.0 mM glucose and 2.5 mM calcium. Application of 10 nM nicardipine reduced insulin output to 86% of baseline, whereas output was reduced to 16% by 1 microM nicardipine and to 6% by 10 mM nicardipine. Changes in duodenopancreatic outflow indicated maximal vasodilation of the pancreas at all three concentrations of nicardipine (10 nM-10 mM). In vivo nicardipine 30 mg t.i.d. for 2 weeks reduced systolic blood pressure from 168 +/- 2 mm Hg to 136 +/- 4 mm Hg (p < 0.001) and diastolic blood pressure from 96 +/- 3 mm Hg to 78 +/- 2 mm Hg (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Binding sites for 3H-Leu-enkephalin in rat straitum]. The binding of 3H-Leu-Enkephalin to a particulate fraction from Rat striatum has been investigated in the presence of 20 mum bacitracin which prevents its hydrolysis. After deduction of a low-affinity, "non-saturable" component, the saturation kinetics at equilibrium provide evidence for two distinct saturable sites. The first exhibits Michaelis kinetics with a Kd value of 2.7 +/- 0.1 nM; both morphine and naloxone compete with the binding of 3H-Leu-Enkephalin on this site but not on the second one. The marked decrease in binding of 3H-Leu-Enkephalin observed in the presence of high concentration of sodium ions indicates that these two pentapeptides have the same properties as morphinomimetic analgesics. Taken together, these data indicate that the first site is identical to the "opiate receptor", while the nature of the second saturable site remains to be established.

[Quantitative evaluation of tongue atrophy on midsagittal magnetic resonance images (MRIs)]. This study was undertaken mainly to establish the quantitative parameter to evaluate the tongue atrophy on midsagittal MRIs and to show the clinical usefulness of such quantitative evaluation. Midsagittal MRIs of the tongue of consecutive 103 patients were analyzed. They were classified into 67 patients showing normal size (group without atrophy), 11 patients showing atrophy (group with atrophy) and 25 patients showing unsatisfactory MRIs with artefacts based on the routine evaluation. The patients in the group without atrophy did not show any pathologic processes to produce tongue atrophy on clinical findings. The area and perimeter of tongue and oral cavity, and the ratio of tongue area to oral cavity area and the ratio of tongue perimeter to oral cavity perimeter on midsagittal MRIs were obtained in each patient of groups with and without atrophy by using quantitative image analysis system. In the group without atrophy, regression analysis of the data on age was made and the 95% confidence interval of the data for age was obtained. No evidence that the tongue becomes atrophic with aging was obtained in the group without atrophy. Patients in the group with atrophy were best separated from those in the group without atrophy statistically when the ratio of tongue area to oral cavity area was regressed on age. Among 11 patients in the group with atrophy, 6 patients were not regarded as having tongue atrophy on clinical neurological examinations. Therefore, the evaluation of midsagittal MRIs is clinically useful.

Fludarabine therapy in hairy cell leukemia. This study evaluated the efficacy of fludarabine, a new adenine nucleoside analogue, in typical and variant forms of hairy cell leukemia (HCL). Two patients with HCL and one patient with a variant form of HCL (HCL-variant) with resistant or progressive disease with prior treatments were studied. Fludarabine (30 mg/m2) was administered intravenously over 30 minutes daily for 5 days every month. Two patients (one with HCL and one with HCL-variant) achieved partial responses; the third patient had a minor response. This is the first report of encouraging activity of fludarabine in typical and variant forms of HCL. Further experience with fludarabine in these disorders is indicated.

Primary total knee arthroplasty in patients with severe varus deformity. A comparative study. Varus deformity is a common finding in candidates for total knee arthroplasty (TKA), but very little has been written concerning the problems encountered in correcting these deformities at the time of arthroplasty. Compared to patients without deformities, this group of patients require more attention to the technical aspects of the arthroplasty, especially bony alignment and ligament balancing. Specific operative techniques used to correct severe varus deformities at primary TKA were evaluated, and the clinical and roentgenographic results were compared with those of a control group of patients without preoperative angular deformity. Operative findings and clinical results in 27 knees (20 patients) with a minimum preoperative varus deformity of 20 degrees (average follow-up period, 58.7 months; range, 24-102 months) were compared with those of 40 knees (31 patients) with a preoperative angulatory deformity of less than 5 degrees varus or valgus (average follow-up period, 50.0 months; range, 24-90 months), in whom a minimally constrained, posterior-cruciate-ligament-sparing prosthesis was implanted. Operative time was an average of 30 minutes longer in the varus deformity group. The average knee evaluation score in the varus group was 89 points, and for the nondeformity group it was 92 points (p less than 0.02). There were no fair or poor results in the varus deformity group; there was one poor result in the nondeformity group. Postoperative knee are of motion was 98 degrees in the varus deformity group and 107 degrees in the nondeformity group. After arthroplasty, the average angle between the mechanical axis of the femur and the tibia was 3 degrees varus in the varus deformity group and 0 degree varus in the nondeformity group (p less than 0.006). Postoperative functional scores of patients in the varus deformity group approached, but were not equal to, the nondeformity group. Greater variability in results and longer operative times were needed in the varus deformity group. Postoperative alignment of the varus deformity group tended to be in residual varus.

[Significance of apolipoproteins A and B and the remaining lipid fractions as indicators of protein-calorie malnutrition in the elderly]. Effects of calorie/protein malnourishment have been studied on plasma concentrations of cholesterol, triglycerides, HDL-C, LDL-C and apolipoproteins A and B, in institutionalized elderly people, 53 males and 62 females, of whom 19 females and 12 males were malnourished. In malnourished patients, total cholesterol and LDL-C were significantly lower both in males and in females, but HDL-C was lower only in females. No significant differences in plasma triglycerides were found between the control and the malnourished groups. Apolipoprotein A showed no significant changes on malnourished males, but did show a significant lowering in malnourished females. On the opposite, apolipoprotein B was lower in males than in females. The lowering in cholesterol in malnourished patients leads us to think that this could be a early predictor of nutritional risk in the elderly.

Orthodontic force production by closed coil springs. The effects of wire size, lumen size, and wire type on the production of force by closed coil springs were determined. Force production was affected as follows: (1) Keeping the lumen size constant, an increase in wire size produced an increase in force. (2) Keeping the wire size constant, an increase in lumen size produced a decrease in force. (3) For a given wire size, force varied with different wire types. This study has shown that the current recommendations for the use of closed coil springs produce forces of greater magnitude than is necessary for orthodontic tooth movement. The clinician should take care to select the proper closed coil spring for specific clinical situations.

How to optimize drug penetration through the skin. The main problem of the therapy with drugs applied to the skin is the high diffusional resistance of the intact stratum corneum. To increase the flux of a given drug the selection of the vehicle is of utmost importance. Incorporation of the drug at its maximal thermodynamic activity leads to the maximal possible flux, as in vivo studies show with different drugs. The formation of supersaturated solutions and dissociation equilibria as well as drug-vehicle interactions and drug depletion also result from the vehicle selection and influence the flux. The resistance of the stratum corneum is not a constant parameter. It may be reduced by specific vehicle effects, penetration enhancers and hydration. Examples for the increase of drug fluxes are given.

Microcomplement fixation studies on the evolution of alpha-glycerophosphate dehydrogenase within the genus Drosophila. Antisera were prepared against purified alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) (alphaGPDH) from Drosophila melanogaster, D. virilis, and D. busckii. The immunological distances between the enzymes from the 3 species and those from 31 additional drosophilid species agree in general with the accepted phylogeny of the genus. These data permit an estimate that the subgenus Sophophora diverged 52 million years ago from the line leading to the subgenus Drosophila. The antiserum against melanogaster alphaGPDH was capable of distinguishing allelic variants of alphaGPDH. On the basis of presumed single amino acid substitutions, no drosophilid alphaGPDH tested differed from the melanogaster enzyme by more than eight or nine substitutions. The study was extended to include representatives of six other dipteran families. The immunological distances between alphaGPDH from Drosophila and alphaGPDH from these dipterans were reasonably consistent with a phylogeny of the order Diptera established by more conventional means. The unit evolutionary period of this enzyme was estimated to be 18 million years.

A traditional Chinese herbal medicine, ren-shen-yang-rong-tang (Japanese name: ninjin-yoei-to) augments the production of granulocyte-macrophage colony-stimulating factor from human peripheral blood mononuclear cells in vitro. Ren-shen-yang-rong-tang (Japanese name: Ninjin-yoei-to, NYT) is a traditional Chinese herbal medicine. Leukocytosis and elevated levels of colony-stimulating factor (CSF) in peripheral blood were found previously after the administration of this compound to mice. In this study, human peripheral blood mononuclear cells (PBMC) were cultured in the presence of NYT in vitro, and the levels of granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF) in the supernatant of cultured PBMC were measured using a sensitive enzyme-linked immunosorbent assays. NYT significantly (P less than 0.01) augmented GM-CSF production but not G-CSF production by PBMC in vitro.

Novel translocation (2;4) with consistent involvement of 2p23 in acute nonlymphocytic leukemia (M2). A translocation involving the short arm of chromosome 2 and the long arm of chromosome 4 is described in three patients, all of whom had acute nonlymphocytic leukemia (M2). One patient had M2 de novo, one progressed from refractory anemia with excess blasts in transformation to M2 over a 4-month period, and one had had sideroblastic anemia 30 years prior to development of M2. In all three patients, the translocation involved the breakpoint p23 on chromosome 2, but the breakpoints on chromosome 4 varied between q25, q31, and q35. Translocations specifically involving 2p23 have not previously been described in leukemia, but more cases are required to identify a specific association with either the FAB type or prognosis.

Circular dichroic studies of protein kinase C and its interactions with calcium and lipid vesicles. Circular dichroism was used to study the secondary structure of protein kinase C (PKC) in aqueous solution and the conformational changes resulting due to the presence of its regulatory cofactors (e.g. Ca2+, phosphatidylserine (PS) and phorbol 12-myristate 13-acetate (PMA)). Computer analysis of the CD data for the estimates of secondary structure showed that PKC maintains a highly ordered structure containing 36% alpha-helix, 57% beta-sheet and 7% beta-turn. PKC displays a minor conformational change upon addition of Ca2+. However, a larger change is observed on adding phosphatidylserine vesicles in the presence of Ca2+. In this case, the alpha-helix content is decreased by approx. 35% and beta-sheet increased by approx. 16%. The protein does not experience further significant changes in conformation on adding PMA.

Permeation of neutral molecules through calcium channel in sarcoplasmic reticulum vesicles. Permeation of neutral molecules as well as Ca2+ through the Ca2+ channel in sarcoplasmic reticulum vesicles has been studied by the tracer and/or by the light scattering methods. In the absence of KCl, the Ca2+ channel was found not to be able to pass neutral molecules such as glucose, xylose, and glycine under the condition that the channel was open, although the channel could pass Ca2+. On the other hand, submolar concentrations of KCl made the channel become permeable to neutral molecules as well as Ca2+. Since the effect of KCl could be replaced by NaCl and KNO3, but not by sucrose and glucose, this effect of KCl is considered to be due to ionic strength and not to osmotic pressure. These results suggest that low ionic strength transforms the Ca2+ channel protein in such a manner as to block the permeation of neutral molecules without modifying the gating mechanism of the channel.

A population-based study of microinvasive disease of the cervix--a colposcopic and cytologic analysis. A study of 61 cases of microinvasion of the cervix occurring in our population between 1980 and 1989 is reported. The mean age of the women was 39 years, compared with 30 years for cervical intraepithelial grade 3 (CIN III) and 47 years for frank invasion, respectively. Colposcopic suspicion of microinvasion was present in 31 cases, giving a sensitivity of colposcopic diagnosis of 50% and a specificity of 91%. In 21 cases (34%) there was no suspicion either cytologically or colposcopically of microinvasion. Colposcopy predicted microinvasion more accurately with increasing depth of invasion. In 28 women there had been previous smears within 10 years available for review. The time interval between the first abnormal smear and the histological diagnosis ranged from 1 month to 9.8 years (mean, 4 years).

The mineral dust diseases. The mineral dust diseases, also called the pneumoconioses, comprise a wide spectrum of conditions ranging from diseases characterized by diffuse collagenous pulmonary reactions to relatively small lung burdens of bioactive dusts (e.g. silicosis, asbestosis) to diseases characterized by largely non-collagenous reactions in the face of heavy lung dust burdens (e.g. coal workers pneumoconiosis). According to information submitted to the International Labour Office, which is however incomplete, substantial numbers of individuals are still at risk for the mineral dust diseases in the workplaces of the world. An overview of their epidemiology in industrialized and industrializing countries reveals more commonalities than contrasts. Commonalities include the major determinants of disease (including exposure level, intensity and particle size distribution), their clinical manifestations and, probably, secular trends towards less clinically severe disease, at least in the larger, better controlled workplaces. Still a risk however, in both industrializing as well as industrialized countries, are the small, uncontrolled workplaces, often the source of mini-epidemics. Contrasts relate to the incidence and/or prevalence rates of tuberculosis amongst workforces at risk for the mineral dust diseases. Rates, which are invariably higher in industrializing than in industrialized economies, usually reflect the background tuberculosis rates in the populations which furnish the industrial workforces and they should be the target for control measures. Research in the industrialized countries should focus on disease mechanisms and on the bioactivity of workplace contaminants, old and new, and in the industrializing countries on the distribution and determinants of mineral dust diseases in their workplaces.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotoxicity of human eosinophils. Eosinophils contain a substance that is neurotoxic when injected intracerebrally or intrathecally into laboratory animals-an effect known as the "Gordon phenomenon." We found neurotoxic activity in eosinophils from three patients with eosinophilic syndromes by injecting cell preparations into rabbits and guinea pigs. These animals developed a syndrome of muscular rigidity and ataxia, progressing to severe paralysis. No neurotoxic activity was found in preparations of polymorphonuclear or mononuclear leukocytes from normal donors. Examination of the brains of affected animals confirmed widespread loss of Purkinje cells, as described by earlier investigators. A new finding was severe spongy change occurring in the white matter of the cerebellum, brainstem, and spinal cord. Electron microscopic examination showed that vacuoles formed within the myelin sheaths of axons by separation of lamellae. Associated axonal degeneration was common and was also seen occasionally in peripheral nerves. Gray matter in the cerebral hemispheres and spinal cord was normal. This eosinophil-derived neurotoxin was partially purified by ultracentrifugation of sonicated eosinophils and fractionation of the supernate by gel filtration. Fractions with neurotoxic activity eluted at a position consistent with a molecular weight of approximately 15,000. The neurotoxic activity of this material withstood lyophilization and dialysis but was destroyed by heating to 90 degrees C. Injection of eosinophil-derived neurotoxin into laboratory animals may provide a useful short-term experimental model for study of mechanisms of damage to myelinated nerve fibers. The clinical significance of the Gordon phenomenon has yet to be established.

Varieties and distribution of non-pyramidal cells in the somatic sensory cortex of the squirrel monkey. The morphology and distribution of cells which do not conform to the conventional pyramidal pattern have been investigated in rapid Golgi, Golgi-Kopsch and Golgi-Cox preparations from cortical areas 3, 1 and 2 of juvenile and mature squirrel monkeys. The material has been analyzed qualitatively and quantitatively by means of a computer program which permits cells to be rotated so as to display their three-dimensional architecture. Nine non-pyramidal types are identified of which one is a rare giant cell and another, forming a major proportion of the cells in layer VI, is considered to be a modified form of pyramidal cell. Of the other seven types, two have horizontally distributed axons, one essentially confined to layer II, the other sending long (up to 1 mm) branches anter-posteriorly through all layers. Two types have vertical axons. One, corresponding to the "double bouquet dendritique" cell of Cajal, is mainly situated in layer II or the upper part of layer III and has a cluster of large axon branches which descend to layers IV and V and which enclose and terminate on the apical dendrites of pyramidal cells. The other type is the only non-pyramidal cell which has a relatively high concentration of dendritic spines in the adult animal. Its soma lies in layer IV and it has several strongly recurrent, thick axonal branches ascending to layer II, also enclosing the apical dendrites of pyramidal cells. The dendritic field is not truly stellate but is drawn out into a pronounced ascending tuft which ascends into layer IIIb. The cell thus resembles a "star-pyramid" of Lorente de Nó. Nevertheless such cells have many features, notably the distribution of their axons and the distribution of dendritic spines which are identical to those of the well-known "spiny stellate" cell of the visual cortex. Conversely the same features both in these cells and in the spiny stellate cells of the visual cortex (which were also eamined) differ markedly from those of small pyramidal cells with somata of similar dimensions. The three remaining non-pyramida cell types have locally ramifying axons which appear to terminate predominantly on pyramidal cells. In one, the axon forms smoothly curving arcades in layer III, in another it is intensely tangled in layer IV and in the third it is bush-like in layers II-IV. continued.

Effect of ceftazidime and gentamicin on the oropharyngeal and faecal flora of patients with haematological malignancies. Thirty-four patients with haematological malignancies were studied to investigate the effect of empirical broad-spectrum antibiotic therapy (ceftazidime and gentamicin) on the gastro-intestinal flora. Twenty-five patients with acute myeloid leukaemia or post-autologous bone-marrow transplantation were given framycetin, nystatin and colistin (Fracon), and two patients with non-Hodgkin's Lymphoma were on co-trimoxazole, as long-term gut prophylaxis. Semi-quantitative microbiology was carried out on oropharyngeal swabs and quantitative microbiology on faecal specimens. The oropharyngeal flora consisted mainly of streptococci, coagulase-negative staphylococci and coryneforms, and was little affected by ceftazidime/gentamicin. A strain of Enterobacter cloacae resistant to ceftazidime and gentamicin colonized one patient, who later developed septicaemia. The faecal flora of patients on Fracon was dominated by enterococci; the few enterobacteria present were eliminated by ceftazidime/gentamicin. The anaerobic flora was absent in 15% of patients; in the remainder, it consisted mainly of Bacteroides spp., and was little affected by ceftazidime/gentamicin. The faecal flora of patients not on Fracon always contained anaerobes, and some strains of enterobacteria persisted throughout antibiotic treatment. None of the patients was colonized by Clostridium difficile or Pseudomonas aeruginosa. Broad-spectrum therapy with ceftazidime and gentamicin appeared to have little effect on the gastro-intestinal flora, except to encourage the overgrowth of enterococci and reduce the numbers of enterobacteria.

Enhancement by asbestos of oncogenesis by Moloney murine sarcoma virus in CBA mice. Five micrograms of finely ground crocidolite asbestos (UICC standard sample) were injected intraperitoneally into 3-week-old CBA mice, together with 10(5) FFU of Moloney murine sarcoma virus. Altogether 44 out of 61 mice (72.1%) so treated developed palpable intraperitoneal tumours, and half of these died of such tumours within 100 days. The same amount of quartz and carbon similarly administered gave lower tumour incidences, namely, 19.4% (3.2% fatal) and 11.9% (1.5% fatal) respectively. Only 1 out of 59 mice inoculated with the virus alone developed a palpable intraperitoneal tumour, and this regressed spontaneously within 10 days of its first appearance. No tumours were encountered in mice treated with either asbestos, quartz or carbon alone. All the neoplasms had the appearance, under the light microscope, of anaplastic sarcomas. Most of them were confined to the serosal surface of the abdominal cavity, although invasion of underlying tissues was observed in some of the animals that died. Electron microscopical examination of tumours revealed the presence of C-type particles budding off from cellular surface. Some neoplastic cells showed characteristic features of mesothelial lining cells. The role of milky spots (taches laiteuses) in oncogenesis by asbestos and virus, especially in the induction of mesothelioma, is discussed.

Hormonal control of gluconeogenesis in tubule fragments from renal cortex of fed rats. Effects of alpha-adrenergic stimuli, glucagon, theophylline and papaverine. 1. In incubated tubule fragments from renal cortex of fed rats gluconeogenesis from pyruvate was stimulated by adrenaline (1mum optimum) and by the selective alpha-adrenergic agonists oxymetazoline and amidephrine. The selective beta-agonists isoproterenol and salbutamol were ineffective at concentrations up to 10mum. 2. Stimulation of gluconeogenesis by 1mum-adrenaline was almost completely blocked by 10mum-phentolamine (alpha-antagonist), partially blocked by 10mum-phenoxybenzamine (alpha-antagonist) and unaffected by 10mum-propranolol (beta-antagonist). 3. Adrenaline stimulation of gluconeogenesis was rapid and was sustained for at least 1h. 4. Oxymetazoline (alpha-agonist) was extremely potent in stimulation of gluconeogenesis. This compound stimulated glucose production from pyruvate, lactate and glutamate, but not from succinate or glycerol. 5. In the absence of Ca(2+) oxymetazoline was ineffective, whereas some stimulatory effect of adrenaline on gluconeogenesis was still observed. 6. Glucagon had no effect on gluconeogenesis from pyruvate in the presence of 1.27mm-Ca(2+) and inhibited the process in the presence of 0.25mm-Ca(2+). Parathyrin (parathyroid hormone) stimulated gluconeogenesis at 1.27mm-Ca(2+). 7. In short incubations of tubule fragments glucagon, papaverine and adrenaline significantly increased 3':5'-cyclic AMP. Adrenaline also slightly decreased 3':5'-cyclic GMP. Oxymetazoline had no effect on the amount of either cyclic nucleotide. 8. At all concentrations tested, theophylline and papaverine decreased gluconeogenesis from pyruvate. 9. It is concluded that renal gluconeogenesis may be increased by alpha- but not beta-adrenergic stimuli and that this is probably independent of changes in 3':5'-cyclic AMP or 3':5'-cyclic GMP. An involvement of Ca(2+) in the action of oxymetazoline appears likely, but this is less certain with adrenaline.

Post-polio syndrome. An emerging threat to polio survivors. The manifestations of post-polio syndrome typically occur 20 to 40 years after an acute episode of poliomyelitis and are confined to previously affected muscles. Because of motor unit remodeling and direct mechanical damage, weakness increases in individual muscles until it exceeds their narrow margin of reserve and becomes clinically apparent. Although the exact cause is not clear, generalized weakness often occurs when several muscles are affected and various postural limb strategies used by the patient are no longer able to compensate for the loss of muscle strength. The mainstays of treatment are life-style changes to avoid overexertion and use of light-weight orthoses and assistive aids to unload the extremities. Exercise and surgery have a limited role in management.

Risks and benefits of therapy with flumazenil (Anexate) in mixed drug intoxications. Flumazenil, the first specific benzodiazepine (BZD) antagonist, is one of the most innovative drugs to become available within the last few years. Flumazenil is indicated for the reversal of the centrally depressant effects of BZDs, in BZD-induced anaesthesia, in BZD sedation in intensive care and in patients comatose after drug overdoses including BZDs. A conference of experts experienced in the treatment of mixed drug overdoses by various means, including flumazenil, was held in order to try to reach a consensus regarding the safe use of flumazenil in this indication. From the knowledge and experience gained to date, it was concluded that flumazenil may be useful and safe in the treatment of suspected BZD and mixed drug overdoses, provided that the appropriate precautions are observed.

Nerve growth factor prevents vinblastine destructive effects on sympathetic ganglia in newborn mice. Vinblastine injections in newborn mice produce severe atrophy of sympathetic ganglia; after a 7-day treatment the ganglia are 80% reduced in volume. Histological examinations show that this effect is due to a marked decrease in the neuronal cell population. The most precocious ultra-structural alterations are localized in the nuclear compartment, followed by axonal swelling and microtubule disappearance. Simultaneous injections of nerve growth factor entirely prevent the noxious effects of the vinca alkaloid, and result in partial appearance of the growth effects of nerve growth factor. Such protective action is not due to inhibition of vinblastine uptake which is the same in control mice and in mice pretreated with nerve growth factor. It is suggested that nerve growth factor prevents the vinca alkaloid action by favoring the assembly or organization, or both, of microtubules, which, from in vitro studies, have been proved to be inaccessible to vinblastine.

Pathology of hearts after aortocoronary saphenous vein bypass grafting for coronary artery disease, studied by post-mortem coronary angiography. A detailed pathological study was made in 10 patients dying up to 13 months after aortocoronary saphenous vein bypass grafting for coronary atherosclerosis. The coronary arteries and vein grafts were investigated by injection with a radio-opaque mass, radiography, dissection, and histology. The report is to some extent historical since the patients died during a period when the operation was first being introduced into two cardiothoracic hospitals. About 80 operations were performed during the time the 10 deaths occurred, a mortality of 12-5 per cent (including cases followed up to 13 months after operation). Seven of the patients were operated on for intractable angina and 3 with a view to aneurysmectomy. All the patients selected for operation were severely disabled despite medical treatment. The main cause of death was extremely severe coronary artery disease and its effects on the left ventricle; in one case, over two-thirds of the left ventricle had been destroyed by infarction before operation. Other causes or contributing causes of death were pulmonary embolism, myocardial infarction complicating angiography (ostial stenosis), and cerebral damage. Ten of the 14 vein grafts (71%) were patent at necropsy. A free flow of injection medium usually occurred between patent grafts and coronary arteries. Thrombosis of a graft was thought to have contributed to death in 3 patients, but not in a fourth who died of pulmonary embolism. Since thrombosis of grafts was usually secondary to poor run-off blood into severely atheromatous coronary arteries, this was also an indirect effect of the advanced coronary arterial disease. In one case, thrombosis followed severe chronic intimal thickening of a graft in place for 13 months. The study of these deaths emphasizes that in some patients the pathological changes in the coronary arteries and left ventricle are too severe for them to benefit from surgery. Vein grafts cannot be expected to distribute blood effectively through grossly narrowed coronary arteries. In addition, when a large part of the left ventricle is infarcted or scarred, it is almost certain that improving the blood supply by grafting will not result in significant regeneration of cardiac muscle. Since the time when this study was made, there have been few deaths among the many vein graft operations subsequently carried out in the hospitals involved. The two most important factors thought responsible for the improvement are the selection of cases more suitable for surgery by continued improvement of diagnostic techniques, and also the employment of more radical surgical procedures in the form of coronary endarterectomy and the insertion of more grafts per patient.

[Differentiation of the sex of Trichinella larvae collected in Changchun]. The length of the rectum in male Trichinella spiralis larvae is about twice that in female larvae, being 54.39 (50.4-63.0) microns in males and 28.05 (18.9-31.35) microns in females. The gonad rudiment of the female larvae has already differentiated obviously into seminal receptacle rudiment and uterus rudiment, while that of the male larvae remains undifferentiated. The seminal receptacle rudiment is a granular, small mass and dark brown in color, while the uterus rudiment is composed of a column of several cells, and the total length of these two rudiments is 62.18 (50.4-75.6) microns. Verifications through experimental infections proved that the length of rectum and the degree of differentiation of gonad rudiment might be used as indices to identify the sex of larvae. It was found that the sexual ratio of T. spiralis collected in Changchun was 1.82:1 (1.17-2.59:1).

Long-term survival of mouse corpus callosum grafts in neonatal rat recipients, and the effect of host sensitization. Previous studies have suggested that the incidence of spontaneous rejection among immunogenetically mismatched neural transplants in neonatal recipients varies significantly depending on the cellular composition of the graft material. For example, neuron-rich grafts of embryonic mouse retina generally survive for extended periods without showing signs of rejection after implantation into neonatal rats, whereas cortical xenografts, which contain abundant glial and endothelial cells as well as neurons, typically undergo rejection 4-6 weeks after implantation. To determine whether the presence of donor glia is responsible for this high incidence of spontaneous rejection, we examined the fate of a non-neuronal graft material composed predominantly of xenogeneic glial cells (post-natal day 3, PD3, CD-1 mouse corpus callosum) implanted into the mesencephalon of PD1 Sprague-Dawley rats. The distribution and survival of donor astrocytes were assessed using a monoclonal antibody specific for a mouse astrocyte surface antigen, M2. Thirteen of 16 animals sacrificed within 2 months of implantation had detectable transplants. In these animals, M2-positive cells frequently migrated well away from body of the graft, clustering in large numbers in several characteristic regions of the host brain. Unlike cortical grafts of similar age, the vast majority (93%) of callosal transplants showed no histological signs of rejection or major histocompatibility complex antigen expression in and around the transplant-derived cells. As previously noted in the neonatal retinal transplant paradigm, however, well-integrated 1-month-old corpus callosum grafts could be induced to reject by appropriate sensitization of the host immune system, implying that the host was not immunologically tolerant to the foreign neural graft. With longer survival times in unsensitized hosts, a progressively smaller percentage of animals had detectable donor astrocytes (5 of 10 animals at 3 months postimplantation and 4 of 16 animals at 4 months); in those 9 animals with surviving grafts, only small numbers of M2-positive cells were seen within the graft bed and surrounding host brain. However, only 2 of the 26 "long-term" animals showed evidence of graft rejection. These results indicate that mouse astrocytes show characteristic patterns of migration into the host brain when implanted into neonatal rats; however, these xenogeneic cells have a limited duration of survival. The infrequency with which even subtle signs of spontaneous rejection were detected in animals that had received corpus callosum xenografts suggests that an immune-mediated process is unlikely to be responsible for the time-dependent elimination of the donor astrocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of biomaterials as occupational hazards in dentistry. Many of the biomaterials and auxilliary products used in dentistry are chemically and biologically reactive and may be of concern in occupational safety programmes. Observations from 1936 to 1975 indicated that most occupational problems were related to skin contact with procaine, soaps, eugenol, iodine, formalin, phenol, and other disinfectants. Methyl methacrylate monomer was identified as an irritant and allergen in the later part of this period. Investigations from 1975 to 1985 indicated that disinfectants and detergents were still important causes of dermatoses, whereas reactions to procaine had been replaced by reactions to pantocaine. Furthermore, adverse reactions to methyl methacrylate monomer and to elastomeric impression materials had replaced the former iodine, tricresol and eugenol reactions. In recent studies the frequency of occupation-related dermatoses varied from 21 per cent to 43 per cent, depending on the prevailing material usage in the various specialties. Reactions to local anaesthetics seemed to have disappeared. Transient, irritative reactions of the eyes and airways have been observed, mostly associated with exposure to volatiles from resin-based materials, X-ray chemicals and cleansers. The occupational problems related to biomaterials in dentistry seem to have been fairly constant over the years, reflecting the type of materials in common use, and with dermatological disorders being a tenacious companion. Neuropathological conditions in dental technicians have been associated with prolonged exposure to vapours of methyl methacrylate monomer. The more recent extensive use of volatile resin-based materials, and the use of protective gloves seems to have created new problems that need to be investigated.

The role of angiotensin, AT1 and AT2 receptors in the pressor, drinking and vasopressin responses to central angiotensin. Angiotensin II (Ang II) given centrally produces an increase in blood pressure and motivation to drink. The physiological mechanisms that mediate the pressor response include release of vasopressin (AVP) and activation of the sympathetic nervous system. Using 2 new Ang II receptor antagonists, we were able to investigate the role of AT1 or AT2 receptors in mediating these effects. Adult male Sprague-Dawley rats were cannulated in the lateral ventricle and 5 days later catheterized in the carotid artery for blood pressure measurements. All experiments were carried out in conscious rats. Three treatments were given intraventricularly (i.v.t.), in 2 microliters artificial cerebrospinal fluid (ACSF) at 30 min intervals: (1) 50 ng Ang II, (2) 0.7 micrograms AT1 antagonist Losartan or 7.0 micrograms AT2 antagonist PD123177, followed by 50 ng Ang II, and (3) 50 ng Ang II, to test for recovery. Blood pressure and drinking measurements were recorded. Also, blood samples for assay of AVP were drawn at 1 or 3 min post-injection in 2 separate groups of rats. We found that both Losartan and PD123177 significantly reduced release of AVP to Ang II 1 min post-injection. Losartan significantly blocked the pressor response (P less than 0.001), while PD123177 had no significant effect. Drinking was also antagonized by Losartan (P less than 0.05) and reduced (n.s.) by PD123177. The results suggest that the pressor response to Ang II (i.v.t.) is predominantly AT1 mediated, while the drinking and AVP responses may be mediated by both receptor subtypes.

The impact of cancer treatment guidelines on actual practice in Italian general hospitals: the case of ovarian cancer. Over the past ten years the Italian National Research Council (C.N.R.) has carried out an educational program based on the preparation and dissemination of guidelines to facilitate delivery in community hospitals of the most up-to-date care to patients with ovarian cancer. In 1988 an assessment was begun to determine (a) whether the guidelines reached the target physician population; (b) whether they were accepted by those they reached, and (c) whether treatment patterns thereafter conformed to the guidelines. Overall results of this evaluation provide no evidence of clinically relevant effects of the program. The guidelines were not widely disseminated: only 44% of responders were aware of them. Moreover, analysis of practice patterns showed serious deficiencies in diagnostic procedure and surgical staging (information on grading and residual tumour was available only in 30% and 45% of cases, respectively, and only 10% of the patients had random biopsies as part of their surgical staging). The only observation supporting some effect of this educational intervention in terms of knowledge modification was of certain therapeutic preferences among those aware of the guidelines. This finding, however, is highly susceptible to confounding by other factors (e.g. physicians' greater expertise, spillover effect of the program) not entirely avoidable in an observational study. We conclude that any assessment of procedures based on dissemination of information must include a careful analysis of the method of dissemination. The availability of clinically applicable information must also be realistically appraised before the guidelines approach can be accepted as the most effective.

Disseminated echinococcosis with repeated anaphylactic shock. Treated with mebendazole. A 46-year-old man, who was twice operated on for echinococcosis and who suffered from recurrent angioneurotic edema, was hospitalized with anaphylactic shock. Chest x-ray examination showed round lesions in the lungs; Casoni, immunofluorescence and hemagglutination tests for echinococcosis were strongly positive. With a diagnosis of disseminated echinococcosis, drug treatment with mebenzadole was given for 29 weeks (the last 22 weeks a dose of 1,200 mg daily). No side effects were observed, allergic manifestations disappeared, and the round lesions were noticeably reduced. The titer of hemagglutination fell gradually, and IgE concentration initially increased and later fell. Mebendazole is proposed as a drug of choice in the cure of disseminated hydatidosis; it may both alter the indication for operation and considerably improve the prognosis.

[Malignant neuroleptic syndrome--a possibility for early diagnosis]. A 17-year-old man developed the malignant neuroleptic syndrome and recovered after the neuroleptic drug was discontinued. When the treatment with the neuroleptic was resumed four weeks later, an elevated serum creatine kinase level was found without any other symptoms of the malignant neuroleptic syndrome. The neuroleptic was discontinued and the serum creatine kinase level was normalized. In both episodes, serum creatine kinase level was followed daily. The elimination of creatine kinase followed a first order kinetic, indicating that release of the enzyme to the blood stopped as soon the neuroleptic was discontinued. In the second episode, the increase in serum creatine kinase level was found before the symptoms of malignant neuroleptic syndrome appeared. This opens a possible way to early diagnosis and in that way prevention of severe symptoms.

Friedreich's ataxia: a descriptive epidemiological study in an Italian population. All the cases of Friedreich's ataxia (FA) diagnosed between 1945 through 1984 among residents of a defined area of northwestern Italy were ascertained (N = 59). Cases were diagnosed according to the criteria of the "Quebec Cooperative Study on Friedreich's Ataxia (QCSFA)" with minor modifications. We identified 39 families with 47 probands and 12 secondary cases. Therefore ascertainment probability was 80%. Male to female ratio was 1:1. Pedigrees were compatible with autosomal recessive inheritance. Segregation ratio was 0.28 with both Weinberg's method and the "singles" method (under incomplete ascertainment). Point prevalence ratio was 1.2/100,000 population. Birth incidence rate was 1/36,000 live births. Gene frequency was estimated to be 1/191. The ratio of first-cousin marriages observed among parents of FA patients (3%) was lower than expected from Dahlberg's formula (8%). This finding is not compatible with the hypothesis of genetic heterogeneity for FA.

Cell proliferation kinetics in two human tumors grown in athymic nude mice. The technique of labelled mitoses was used to investigate the cell proliferation kinetics in two human neoplasms, one a malignant melanoma and one a fibrosarcoma, transplanted to and grown serially in the athymic nude mutant (ANM) mouse. The experimental data obtained codrealted well with a theoretical percentage labelled mitoses curve based on the assumption that the time spent by a cell in each of the phases M, G1, S and G2 is described by four independent log-normal distributions. However, no unique second wave was defined by the experimental results. This means that only the deductions made about the duration of the G2 and S phases are reliable. The median duration of tma and the fibrosarcoma, respectively. By comparing these results with results published on cell cycle studies of transplantable animal tumors and human tumors in situ, it is concluded that the cell cycle parameters of a human tumor grown in the ANM mouse are close to those of the same tumor in the donor patient.

Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. beta-Amyloid (A beta) deposition in fibril form is the central event in a number of diseases, including Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D). A beta is produced by degradation of a larger amyloid precursor protein (APP). Recently a mutation in the APP gene has been found in HCHWA-D causing a glutamine for glutamic acid substitution at residue 22 of A beta. The influence of this mutation on fibrillogenesis is not known, although it is clear that affected patients have accelerated cerebrovascular amyloid deposition, with disease symptoms early in life. We report the in vitro demonstration of accelerated fibril formation in a 28 residue synthetic peptide homologous to the Dutch variant A beta. Furthermore, in eight residue peptides homologous to A beta the presence of the mutation is necessary for fibril formation. These findings provide a mechanism for accelerated amyloid formation in the Dutch variant of APP.

Discrepant increase in factor VIII: C and von Willebrand factor after DDAVP infusion in a patient with variant von Willebrand's disease. We have studied a patient with von Willebrand's disease (vWd) whose von Willebrand factor (vWf) multimer patterns showed significant decreases of all but the major fast moving vWf multimer (promoter). Bleeding time (BT) was very prolonged, there was almost no ristocetin-induced platelet aggregation (RIPA) and vWf levels were very low. The factor VIII: C/vWf: Ag ratio appeared to be higher than normal because of the relatively increased concentration of factor VIII: C. The infusion of DDAVP normalized BT, improved RIPA and restored normal factor VIII: C levels, these effects lasted for 5 h even though only a slight increase of vWf: Ag and vWf: RCoF was observed. RIPA was completely inhibited by an anti-glycoprotein (GP) Ib monoclonal antibody that recognizes the ristocetin-induced vWf binding site. Plasma vWf multimer analysis revealed only slight increases of all components and an additional, more pronounced representation of vWf protomer. These data suggest that the patient has an abnormal vWf molecule characterized by a greater ability to carry factor VIII than would be expected from the vWf levels. Furthermore, since the vWf protomer was the only significant vWf component present both before and after DDAVP infusion we hypothesize that some of the haemostatic functions of the patient's vWf may depend on it.

[Therapy groups with patients and nursing staff in a geriatric hospital (author's transl)]. Within a very short time the non-demented, chronically hospitalized old person turns into a hospital-activity-oriented patient. He thereby gives up a considerablle part of his personality. In order to understand this process, special attention has to be paid to the intertwining of the dynamics of the chronic geriatric patient with the dynamics of the nursing staff. As a therapy experiment we have been conducting parallel talk-groups with patients and with their nursing staff for one year. As a result, the patients showed increased activity, increased dynamism, improved contact ability, increased interest in the outside world, and improved affect. The nursing staff also reported improvement of the group-patients' condition on the floor. With the nursing staff we found a reduction of the defensive mechanisms, a separation from old nursing-role definitions, acceptance and encouragement of the patients in their new role, and improved satisfaction with patient contact. On the other hand, the nursing staff expects more personal contact to come from the patients. The groups have shown to be useful and have to a large extent reached the therapy goals.

Coronary microvascular resistance in hypertensive cats. Chronic systemic hypertension has been shown to alter the distribution of vascular resistance in many microvascular beds. The purposes of this study were to assess the effects of chronic systemic hypertension on the pressure distribution in the coronary microcirculation and to determine the microvascular site where coronary vascular resistance is increased. Cats were made hypertensive using a one-kidney, one-wrap model (Page model). A servonulling system was used to directly measure pressures in the epimyocardial microvessels of the beating left ventricle in normotensive and hypertensive cats. In chronically hypertensive cats, mean arterial pressure was 153 +/- 5 mm Hg compared with 98 +/- 3 mm Hg in normotensive cats (p less than 0.05). Left ventricular mass was increased approximately 34% in hypertensive cats (9.4 +/- 0.3 versus 7.0 +/- 0.3 g, p less than 0.05). Myocardial perfusion measured using radiolabeled microspheres was not different between hypertensive and normal cats. Coronary vascular resistance of the left ventricle was increased in hypertensive cats (0.90 +/- 0.08 versus 0.66 +/- 0.05 mm Hg x min x 100 g/ml, p less than 0.05). Microvascular pressures were measured in three groups of microvessels: small, less than 200 microns; medium, 200-300 microns; and large, greater than or equal to 300 microns. Mean microvascular pressures of large, medium, and small arterial microvessels in hypertensive cats were 144 +/- 8, 127 +/- 6, and 115 +/- 7 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Fusimotor reflexes influencing secondary muscle spindle afferents from flexor and extensor muscles in the hind limb of the cat. The purpose of this study was to investigate secondary muscle spindle afferents from the triceps-plantaris (GS) and posterior biceps and semitendinosus (PBSt) muscles with respect to their fusimotor reflex control from different types of peripheral nerves and receptors. The activity of single secondary muscle spindle afferents was recorded from dissected and cut dorsal root filaments in alpha-chloralose anaesthetized cats. Both single spindle afferents and sets of simultaneously recorded units (2-3) were investigated. The modulation and mean rate of firing of the afferent response to sinusoidal stretching of the GS and PBSts muscle were determined. Control measurements were performed in the absence of any reflex stimulation, while test measurements were made during reflex stimulation. The reflex stimuli consisted of manually performed movements of the contralateral hind limb, muscle stretches, ligament tractions and electrical stimulations of cutaneous afferents. Altogether 21 secondary spindle afferents were investigated and 20 different reflex stimuli were employed. The general responsiveness (i.e. number of significant reflex effects/number of control-test series) was 52.4%, but a considerable variation between different stimuli was found, with the highest (89.9%) for contralateral whole limb extension and the lowest (25.0%) for stretch of the contralateral GS muscle. The size of the response to a given stimulus varied considerably between different afferents, and, in the same afferent, different reflex stimuli produced effects of varying size. Most responses were characterized by an increase in mean rate of discharge combined with a decrease in modulation, indicative of static fusimotor drive (Cussons et al., 1977). Since the secondary muscle spindle afferents are part of a positive feedback loop, projecting back to both static and dynamic fusimotor neurones (Appelberg Et al., 1892 a, 1983 b; Appelberg et al., 1986), it is suggested that the activity in the loop may work like an amplified which, during some circumstances, enhance the effect of other reflex inputs to the system (Johansson et al., 1991 b).

Observer variation in recording clinical data from women presenting with breast lesions. Report from the Yorkshire Breast Cancer Group. The degree of observer variation in recording 11 186 items of clinical data from 242 woman who presented complaining of a lump in the breast to a group of 10 surgeons was studied. Each women was interviewed and examined twice and the findings (of the two clinicians) compared. There was a wide range of variation among the observers. Variation in recording the presence or absence of axillary nodes was considerable (45%), as was that in sizing the primary lesion (55%). In 20% of cases the two assessments of primary lesion size differed by over 2 cm. In other respects the results were more encouraging; much variation could be eliminated by wording the proforma more clearly. Moreover, variation was not person-specific, so that these findings are probably reasonably representative. Any future trial of breast lesions should (a) design specific proformata, (b) define terminology, (c) make these definitions universally available, and (d) conduct observer variation studies before the start of the full trial.

Carbohydrate metabolism of heat-acclimated hamsters. V. Control of gluconeogenesis. The rate of gluconeogenesis was similar in liver of both fed heat-acclimated and control hamsters. Twenty-four hours of fasting calsed 6 times elevation in hepatic gluconeogenesis of the control animals whereas only 4 times enhancement of this pathway was found in heat-acclimated animals. Thus, significant difference existed between the two experimental groups in fasting. Triiodothyronine stimulated the rate of gluconeogenesis only in fed heat-acclimated hamsters whereas dibutyryl cyclic AMP caused elevation of this pathway in liver slices of fed control hamsters only. The results suggest that a decrease in hepatic gluconeogenesis in heat acclimation occurs only in fasted animals and it is controlled by thyroid hormones.

Benign obstructing papilloma of the ampulla of Vater in infancy. Obstructive jaundice due to benign neoplasms of the extrahepatic bile ducts is rare in all age groups. A case is reported which represents the first obstructing papilloma of the ampulla of Vater found in the pediatric age group and the literature pertaining to benign obstructing neoplasms is reviewed briefly. Differential diagnosis of persistent jaundice past the immediate neonatal period is discussed and the need for operative cholangiogram and open liver biopsy in difficult cases is stressed. Obstructing papillomas and other neoplasms of the extrahepatic bile ducts should be added to the differential diagnosis of jaundice in the pediatric age group.

Intramedullary syndrome due to an extradural neurinoma near the foramen magnum. A case of right sided extradural neurinoma at the level of the foramen magnum is reported which presented as an intramedullary spinal cord syndrome. Ischemia of the anterior spinal artery or of the vertebral artery was considered to be an important pathogenic factor in the production of the neurological syndrome. The outer part of the spinothalamic tract, where sensory fibers carrying pain and thermal sensibility from the sacral segments are situated, escaped ischemia as that part is supplied by penetrating branches of the pial arterial plexus. The discrepancy between the level of neurological deficit (C5) and site of the tumor (C1-2) was due to distant ischemia. The lack of a history of root pain and the rapid recovery following removal of the tumor also favor a vascular origin for the neurological deficit.

Effect of warfarin on the kinetics of the vitamin K-dependent clotting factors in rats. The objectives of this study were to compare the time course of activities and rates of synthesis of activities for the separate clotting factors II, VII, IX, and X and to relate the rate of synthesis of activity of each factor to the plasma concentration of warfarin in individual rats after acute and chronic dosing with warfarin. Sequences of blood samples were obtained from each rat for 50 to 70 hours after an acute dose of warfarin or for 120 hours after a chronic loading dose plus 12-hour maintenance doses of warfarin and assayed for factor activities and warfarin concentration. The half-lives for degradation of factor activities ranged from 2.6 to 9.0 hours for the four factors. During periods of changing warfarin concentration (acute dosing) factor VII and X activities and rates of synthesis of activity showed large rapid changes, while factors II and IX responded more slowly. As the warfarin concentration diminished, the factor X rate of synthesis of activity appeared to exceed predrug values in all rats. During chronic dosing with warfarin the factor II activity and rate of synthesis of activity was depressed the most. The percent depression of the rate of synthesis of activity for each factor was related linearly to the logarithm of the plasma concentration of warfarin for the range 0 to 80% depression with acute dosing. However, this relationship was not suitable to explain the apparent overshoot in factor X rate of synthesis of activity.

[Present views on classification of cerebrovascular diseases]. In conjunction with the declaration of the "brain decade" which was called for by the unfavourable position as regards early diagnosis and by inadequate treatment of cerebral diseases, the author reflects on the importance of classification of cerebrovascular diseases. He submits a historical review of different classifications of cerebrovascular diseases starting with the international classification of diseases introduced into practice as early in 1893, the clinical and research classification elaborated by Millikan in 1975--both are still used by WHO--to the most recent suggestions of Hachinski of 1990 and the Classification of spontaneous intracerebral haematoma by Mizukami elaborated in 1985. The paper contains also the author's own modification of the clinical and research classification.

Second messengers mediating activation of chloride current by intracellular GTP gamma S in bovine chromaffin cells. 1. Intracellular mechanisms and second messengers involved in chloride current activation by intracellular GTP gamma S (guanosine 5'-O-(3-thiotriphosphate] in bovine chromaffin cells were studied using the whole-cell patch-clamp technique combined with measurements of intracellular calcium [Ca2+]i. 2. No correlation between the time of current activation and the appearance of [Ca2+]i transients was observed; intracellular introduction of sufficient EGTA (10 mM) to suppress the [Ca2+]i transients did not affect the current activation by GTP gamma S. 3. The cyclic nucleotides, cyclic AMP or cyclic GMP, did not activate the current when introduced intracellularly (50-250 microM). The ability of GTP gamma S to activate the current decreased when cyclic GMP (250 microM), together with MgATP (2 mM), was added to the perfusate. 4. Neomycin (0.5-1 mM), a presumed inhibitor of phospholipase C effectively prevented the current activation by GTP gamma S but it did not prevent [Ca2+]i transients. 5. Modulation of protein kinase C activity using specific inhibitors (H-7, 300 microM; polymyxin B, 400 U/ml) or activators (phorbol ester PMA, 100 nM, 20-90 min at 37 degrees C) did not affect the current activation by GTP gamma S nor did it cause current activation in the absence of GTP gamma S. 6. Activation of the current by GTP gamma S could be prevented by incubating the cells for 10-15 min with 2.5 microM p-bromophenacyl bromide (p-BPB), an inhibitor of phospholipase A2 activity. Exogenous arachidonic acid (5-10 microM), applied extracellularly or intracellularly, neither activated the current itself nor did it interfere with its activation by GTP gamma S. 7. Activation of the current by GTP gamma S could also be prevented by incubating the cells with 1 microM-nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, but not with indomethacin (2 microM), an inhibitor of cyclo-oxygenase pathway of arachidonic acid metabolism. 8. It is suggested that chloride current activation by GTP gamma S in bovine chromaffin cells involves G protein-mediated stimulation of phospholipase A2 activity and subsequent formation of lipoxygenase product(s) of arachidonic acid metabolism.

Association of Vibrio cholerae with fresh water amoebae. An investigation was undertaken to determine whether Acanthamoeba polyphaga SHI and Naegleria gruberi 1518/1e could affect the survival of various strains of Vibrio cholerae in laboratory microcosms. In microcosms pre-inoculated with trophozoites of amoebae, all six strains of V. cholerae tested survived and multiplied during 24 h. In control microcosms without trophozoites of amoebae, survival of the V. cholerae strains was much decreased. Two strains of V. cholerae were used to determine whether V. cholerae might survive ingestion within amoebae and subsequent encystment. Strain 152 was re-isolated from encysting N. gruberi 1518/1e but not from A. polyphaga SHI. Strain 9112 could not be isolated from cysts of either species of amoebae.

Influence of lung volume on collateral resistance in normal man. We measured the influence of changing the end-expiratory lung volume (EELV) on collateral resistance (Rcoll) in 6 normal volunteers (5 male, 1 female, aged 23-45 years). With subjects lying supine in an iron lung, a 5.3 mm fibroscope was introduced under local anesthesia and wedged into a sub-segmental bronchus of the right lower lobe. A truncated 5f Swan-Ganz catheter was tightly fitted into the suction port of the fibroscope. One lumen of the catheter served to deliver a constant flow (200 ml/min) of 5% CO2 in air. The pressure in the wedged segment (Ps) was measured by the other channel. Airway pressure (used as alveolar pressure (Palv)) was determined with a low bias flow catheter taped to the side of the bronchoscope, its tip positioned 20 cm from the end of the bronchoscope. Rcoll was obtained by the formula: Rcoll = (Ps-Palv)/flow. EELV was passively changed by applying a constant extrathoracic pressure in the iron lung at 5 cm H2O steps from 0 to +15 and from 0 to -20 cm H2O. The changes obtained in Rcoll (% baseline, mean +/- SEM) at each extrathoracic pressure (ETP) were: -5 cm H2O, 73 +/- 4%; -10, 56 +/- 7%; -15, 56 +/- 9%; -20, 35 +/- 10%; +5, 118 +/- 6%; +10, 129 +/- 7%; +15, 118 +/- 11%. Rcoll progressively decreased with increasing EELV (negative ETP) and increased slightly as EELV was reduced (positive ETP). The relationship between the log Rcoll and delta EELV was linear; the slope of this line was 9.8%.

The comprehensive child health care centres in the Sudan. In 1963, Morley initiated the concept of clinics for children under five years old. This paper describes our experience in applying that concept in Omdurman town (Sudan) where existing maternity and child health centres and hospitals in the area were involved in the scheme. It was found necessary to establish a main centre to develop methodology and to provide a specialized training of staff. The medical problems were similar to those described by Morley. The approach to their solution was essentially the same except that we used more professional staff and placed more emphasis on nutrition education than hitherto advocated. It is concluded that, in theory, Morley's concept provides a system of comprehensive child health care which suits the needs of developing countries. But our adaptation of Morley's ideas to existing health structures, even on the small scale we achieved in Omdurman, was difficult because of the high initial and running costs and in view of the long established dichotomy between curative and preventive medicine.

Renal haemodynamic effects of short term cyclosporin A administration in patients with insulin-dependent diabetes mellitus. To investigate the time relationships involved in cyclosporin-induced nephrotoxicity we studied changes in blood pressure, renal haemodynamics and sodium excretion in 22 adult patients with insulin-dependent diabetes mellitus treated with cyclosporin (CsA) for 4 +/- 2 days, compared to 22 insulin-dependent diabetic patients receiving conventional insulin therapy, who were matched for age and duration of diabetes. To further clarify the pathogenic role of the renin-angiotensin system, insulin-dependent diabetic patients receiving CsA were studied before and after sublingual administration of 75 mg captopril. An average of 4 days CsA treatment markedly increased blood pressure and renal vascular resistance, but did not alter glomerular filtration rate, renal plasma flow, sodium urinary excretion, or body-weight. The marked renal vasoconstriction without early changes in GFR suggests that the late decrease in GFR may involve other factors in addition to renal hypoperfusion. Acute inhibition of angiotension II formation was still able to decrease blood pressure and renal vascular resistance, although not to normal control values. These results indicate that a physiological concentration of angiotensin II may potentialise but may not be the sole factor involved in the vasopressor effect of CsA.

DNA measurements on cell nuclei of normal, proliferating and neoplastic thyroid tissues in rats. Nuclear DNA content was measured in 3 normal, 9 hyperplastic and 16 neoplastic rat thyroid glands. Thyroid hyperplasia and tumor growth were induced after treatment of the animals with X-rays and methylthiouracil. In the control animals only diploid thyroid epithelial cells were observed. At the stages of diffuse and nodular thyroid hyperplasia, the total DNA content per nucleus indicated for a diploid chromosome number and only a few cells were hyperdiploid. In the thyroid adenomas and carcinomas a scattering of the diploid region and an increase in the number of hyperdiploid cells was found. Among the various types of thyroid tumors neither difference in the number of hyperdiploid cells, nor typical pattern of distribution of these cells in the histogram was found. The increased number of hyperdiploid cells in the hyperplastic and neoplastic thyroids suggest an increase in the proportion of the cells entering the cell cycle and does not indicate for appearance of a neoplastic stemline.

Assessment and treatment of torture victims: a critical review. This paper presents the main issues in the diagnosis and treatment of psychiatric sequelae in torture victims. The concept of post traumatic stress disorder is used to organize literature on psychiatric casualties resulting from massive psychic trauma, e.g., the Nazi Holocaust, the Vietnam and Israeli wars, and the current world epidemic of torture. Torture is a unique human made stressor resulting in category-specific diagnostic symptoms. Medical assessment can be complemented with photographs, x-rays, electroencephalograms, and sleep studies. Individual psychotherapy and group techniques focus on the issues of denial and trust, loss, survivor guilt, and reparation. Programs of psychological and social rehabilitation and treatment with benzodiazepines, tricyclic antidepressants, and other compounds are reviewed. Future research needs include the conceptualization of the trauma of torture and its sequelae in broader terms, the application of standardized measurements to facilitate international comparisons, and the testing of various approaches to intervention in an experimental design. An ethical physician must resist the pressures of totalitarian governments to assume neutrality in the presence of human rights violations affecting his/her patients.

[Influence of chlorpromazine and temperature on glucose transport in human erythrocyte ghosts]. Glucose transport was determined by oxygen adsorption in solution when glucose was oxidized with glucoseoxidase, injected into erythrocyte ghosts. Temperature dependence of glucose transport velocity shows a break at 20 degrees C, which was described in literature. Small concentrations of chlorpromazine (about 2-10(-5) M) somewhat activates the transport but does not changes its temperature dependence. Higher concentrations of anaesthetics (beginning with 1-10(-4) M) inhibit the transport, decrease the temperature of break and increase the activation energyies of the process both lower and higher of the transition temperature. The change of working velocity of glucose carrier under the action of anaesthetic and temperature is accounted for by structural reconstructions in lipids, which are heterogeneously distributed along the erythrocyte membrane plane.

Growth hormone secretion in patients with Turner's syndrome as determined by time series analysis. Twenty-four-hour growth hormone (GH) profiles in 26 girls with Turner's syndrome were compared with those of 26 normally growing short children and 24 slowly growing short children. All children were prepubertal and below 12 years of age. A subgroup of 13 girls was treated with ethinyl estradiol and a 24-h GH profile was reassessed. In an additional group of 45 girls with Turner's syndrome (aged 6.7-18.9 years) the effect of age, spontaneous breast development and ethinyl estradiol treatment was studied. The profiles were assessed by Fourier analysis. The oscillatory activity and the mean 24-h GH concentration were similar in children with Turner's syndrome and the normally growing short children, in contrast to lower levels in the slowly growing short children. The periodicity of GH secretion was similar in all groups. In the longitudinal study, ethinyl estradiol treatment resulted in a significant increase in pulse amplitude, but not in periodicity. In the cross-sectional study there was no significant difference between the subgroups of girls with either presence or absence of breast development or ethinyl estradiol treatment. GH secretion was not significantly related to age, height in standard deviation score or height velocity. These data imply that there is no abnormality in GH secretion in girls with Turner's syndrome.

[In vitro chemosensitivity test with several antitumor agents against eight malignant brain tumor cell-lines]. We performed an in vitro chemosensitivity test with 8 malignant brain tumor cell lines, which were established in our Department. It was shown that ACNU was moderately tumoricidal against only one cell (ONS-86) line. IFN-beta (interferon-beta) was more active against 4 cell (ONS-6, -20, -76, and -81) lines. VCR (vincristine), MTX (methotrexate), and Ara-C (cytosine arabinoside) and FK 973 were most effective against all 8 cell lines. There were some difference in the drug sensitivities among the tumors with the same pathological diagnosis. Since IFN-beta was tumoricidal against to the cells, co-culture of IFN-beta and one of other antitumor agents seemed to induce more antitumor effects. With regard to the side effects of IFN-beta, the combined therapy with IFN-beta and other drugs induced more antitumor effects against malignant brain tumor cells and seemed to reduce the side effects.

Regulation of surface antigens expression in Paramecium primaurelia: genetic and physiological factors involved in allelic exclusion. In paramecium aurelia, allelic exclusion can be considered as a basic feature of the surface antigens system in the same way as intergenic exclusion. Our studies on allelic exclusion in G156/G168 heterozygotes show that (1) allelic exclusion does not depend on discrete regulatory genes dispersed throughout the genome; (2) it does not seem to be influenced by cytoplasmic factors; (3) it occurs regardless of the surface antigen expressed by the parental strains at the time of the cross. These results are discussed in relation to both intergenic and interallelic exclusion for which a common basis is proposed.

Metabolic activity of articular cartilage in osteoarthritis. An in vitro study. Biochemical changes and in vitro rates of glycosaminoglycan synthesis were studied in thirty-seven samples of human articular cartilage from nineteen osteoarthritic and four normal control patients who were fifty to seventy-five years old. The samples were compared on the basis of histological grade of the arthritis, and subgroups based on the duration of disease, synovial pathological changes, joint studied, and sex were also compared. The osteoarthritic samples showed a progressive loss of glycosaminoglycans in the cartilage as the histological grade increased. In the early stages of the disease there was an increase in the chondroitin sulphate content as well as in the rate of glycosaminoglycan synthesis in several cases when the values for the osteoarthritic articular-cartilage samples were compared with those for the age-matched controls. In the late stages there was a progressive decrease in the rate of glycosaminoglycan synthesis and a relative decrease in chrondroitin sulphate synthesis compared with keratan sulphate synthesis, and these decreases were highly correlated with the histological grade.

Percutaneous cholecystostomy: does transhepatic puncture preclude a transperitoneal catheter route? Percutaneous cholecystostomy is now commonly performed for the diagnosis and treatment of gallbladder and biliary disorders. The optimal method and route of percutaneous cholecystostomy catheter placement, however, remain controversial and may depend on the indication for the procedure. The ability to predict traversal of the extraperitoneal plane of fixation ("bare area") between the liver and gallbladder with a transhepatic approach was investigated. With sonographic guidance, 21 transhepatic catheterizations were attempted: 19 in cadavers and two in patients who subsequently underwent cholecystectomy. In all cases, 8-F or 5-F self-retaining catheters were used. At autopsy or surgery, the catheter course and gallbladder puncture site were evaluated. Of 21 punctures, 19 (90%) were transhepatic and two (10%) were transperitoneal. Among the 19 transhepatic punctures, eight catheters (42%) traversed the bare area, while 11 (58%) entered the free gallbladder wall adjacent to the serosal attachment. There were four instances of guide-wire dislodgment during catheter placement; all occurred following puncture of the free wall of the gallbladder. No guide-wire dislodgment occurred when the bare area was transversed. Transhepatic gallbladder puncture does not prevent puncture of the free gallbladder surface. However, the liver and bare area do seem to provide guide-wire stability during catheter placement.

Molecular changes in cell surface membranes resulting from trypsinization of sarcoma 180 tumor cells. Sarcoma-180 tumor cells in culture or grown as an ascites form in the CD-1 mouse have been subjected to mild trypsinization procedures in order to study morphological and molecular changes resulting from proteolysis. The cells attached to a substratum become rounded within 20 min. and most undergo cell division, but they do not detach from the substratum. Removal of trypsin permits the cells to go back to their original spindle shape over an 8-20 h period. Surface membranes were isolated from trypsinized ascites and cultured cells and subjected to dodecyl sulfate-acrylamide gel electrophoresis. Both cell types showed the same two kinds of changes in electrophoretic patterns. First, there was a loss of glycoproteins from both cell types even though they show different complements of cell surface glycoproteins. Second, there is a loss of high molecular weight polypeptides, which have previously been suggested to play a role in membrane stabilization and cell shape. These results further implicate these polypeptides in the control of cell morphology and offer circumstanital evidence for transmembrane interactions of surface glycoproteins with the high molecular weight polypeptides as a factor in controlling cell morphology.

Serum levels of carboxyterminal propeptide of type I procollagen in healthy children from 1st year of life to adulthood and in metabolic bone diseases. Type I collagen is the major component of bone matrix; circulating carboxyterminal propeptide of type I procollagen (P-I-CP) levels reflect type I collagen synthesis in tissues and may be an useful index to investigate bone metabolism. We measured P-I-CP by a new radioimmunoassay in 300 healthy children and adolescents and in 40 healthy adults to provide reference data for P-I-CP values. In addition, 79 patients with diagnosed disorders of phospho-calcium metabolism (rickets, vitamin D deficient and vitamin D resistant, hyperparathyroidism, hypo- and pseudo-hypoparathyroidism, osteopenia) were evaluated. In the healthy subjects, serum P-I-CP values were higher in children than in adults; variations of P-I-CP levels were observed according to age and sexual maturation: higher values were found in the first years of life and during pubertal development; pubertal increase reflects the different timing of pubertal development in the two sexes. P-I-CP levels were increased in primary hyperparathyroidism and reduced in diseases related to impaired secretion or action of parathyroid hormone. Higher P-I-CP levels were found in vitamin D deficient and vitamin D resistant rickets. P-I-CP was reduced in anorexia nervosa and during chronic glucocorticoid treatment while it was increased in thyrotoxic osteoporosis. In idiopathic juvenile osteoporosis, P-I-CP values ranged from reduced to increased values. We conclude that P-I-CP may represent an additional biochemical marker of bone metabolism. Since age-related variations are present, reference data for the various ages are need for clinical application of this assay.

Protein rotational diffusion and lipid/protein interactions in recombinants of bovine rhodopsin with saturated diacylphosphatidylcholines of different chain lengths studied by conventional and saturation-transfer electron spin resonance. Bovine rhodopsin has been reconstituted in seven different saturated diacylphosphatidylcholine species of odd and even chain lengths from C-12 to C-18 at a lipid/protein ratio (60:1 mol/mol) comparable to that in the native rod outer segment disk membrane. All recombinants were found to be photochemically active, in that optical bleaching produced a temperature- and lipid chain-length-dependent mixture of species absorbing at 480 and 380 nm. Both the rotational diffusion of rhodopsin and lipid-protein interactions in the various recombinants were studied by saturation transfer and conventional electron spin resonance spectroscopy of spin-labeled rhodopsin and of spin-labeled phosphatidylcholine, respectively. In the fluid lipid phase, the rotational diffusion rate of rhodopsin was found to be dependent on the lipid chain length of the different recombinants in a nonmonotonic manner. The diffusion rate in dilauroylphosphatidylcholine was found to be very slow, indicating extensive protein aggregation, whereas that in dipentadecanoylphosphatidylcholine was rapid (effective correlation time ca. 7 microseconds), consistent with the presence of monomeric protein. For recombinants with longer lipid chain lengths, the rotational diffusion rate again decreased, indicating the presence of di- or oligomeric protein. The fraction of lipid motionally restricted at temperatures in the fluid phase was also dependent on the chain length of the phosphatidylcholine used in the reconstitution.(ABSTRACT TRUNCATED AT 250 WORDS)

Stroke rehabilitation: a family-team education program. A stroke causes considerable anxiety and practical difficulties to the family of the patient. Additional confusion results because the difference between the acute care and the prolonged rehabilitation is poorly understood. For these reasons, a family-team conference was established at the Massachusetts Rehabilitation Hospital. Its purpose was to relieve anxiety and explain the scientific and professional aspects of the team approach to rehabilitation. The family-team program consisted of role descriptions presented by the representatives from the various disciplines involved in the rehabilitation process and a discussion of individual family-patient problems. Results of a three-year study were used to evaluate the sucess of the conference. Records of family attendance were compared with the number of persons contacted. Questionnaires completed by family members at the conference showed that the anxiety level of individual families had decreased. A better understanding of the team approach was indicated in more than 75% of those participating. More than 70% of the families felt more comfortable in visits to their relatives and in approaching team members with future questions. The family-team program is a practical instrument for expanding stroke rehabilitation and for including the needs and participation of the family.

[Blood serum protein study in oncological patients]. The authors report the data on the protein spectrum of blood serum, examined by DEP method in PAAG in 21 patients with ovarian and endometrial cancer and in 20 female-donors. Totally 27 fractions were obtained. The following differences in proteinographs of the groups under examination were revealed: protein in the patients was reliably decreased by 30-90% in the 4th, 9th, 26th fractions, and it was increased by 25-100% in the 15th, 16th, 18th and 22d fractions; 62 patients showed the fraction with Rt 2.10 in the prealbumin zone, which was usually absent in donor blood serum. Moreover, proteinographs from patients with malignant neoplasms of different locatization were studied comparatively. It is believed that the differnces revealed may be used for diagnostic purposes.

Stimulation of hepatic lipogenesis by eicosa-5,8,11,14-tetraynoic acid in mice fed a high linoleate diet. Liver slices, from mice fasted for one day and then refed for three days either a 15% corn oil diet or a 15% corn oil diet containing eicosa-5,8,11,14-tetraynoic acid (TYA), were incubated with [1-14C] acetate or [3H] H2O to determine lipogenic capacity. Dietary TYA produced a twofold stimulation in fatty acid and cholesterol synthesis. TYA also caused an increase in the relative proportion of linoleate (C18:2) and a decrease in that of arachidonate (C20:4) in liver. Thus, (a) despite high levels of C18:2, hepatic lipogenesis can be increased, and (b) even short term feeding of TYA can alter the hepatic fatty acid composition presumably by inhibition of arachidonate synthesis from linoleate.

Immunocytochemical localization and enzymatic distribution of rat ovarian aromatase. A rabbit antiserum directed against purified human placental aromatase was used for immunohistochemical localization of the enzyme in rat ovaries. Immunostaining was conducted on tissue from animals at various ages and in different reproductive states: immature; immature, eCG-treated; immature pseudopregnant; adult cycling; and adult pregnant. Various labeling protocols were employed (e.g. horseradish peroxidase-conjugated secondary antibody, peroxidase-antiperoxidase, and avidin-biotin-peroxidase on fresh frozen and Bouin's fixed paraffin-embedded sections), but the avidin-biotin-peroxidase method on paraffin sections proved to be superior to the others. In immature rats, most of the immunostaining, which was quite weak, was limited to the stroma. After stimulation with eCG, some of the granulosa cells of antral follicles exhibited immunostaining; in pseudopregnant rats, most staining occurred in the luteal cells. In mature animals, the corpora lutea of pregnant and cycling rats demonstrated the greatest degree of immunostaining. No significant immunoreactivity was detected in pre-antral follicles, but in early antral follicles and preovulatory follicles, both theca and granulosa cells exhibited immunostaining. Aromatase enzymatic activity was also determined on ovarian microsomal fractions of eCG-treated immature animals, pregnant animals at term, and cycling animals. Furthermore, enzyme activity and estradiol concentrations were examined after ovaries from proestrous rats were dissected into follicular, luteal, and residual components. Activity was found in all regions and correlated with immunostaining and estrogen production. These results argue against a model in which all the immunoreactive/enzymatically active protein is localized in granulosa cells of Graafian follicles and suggest that corpora lutea may be involved in estrogen synthesis during the rat estrous cycle as well as during pregnancy.

Involvement of the CDw50 molecule in allorecognition. The CDw50 differentiation antigen is defined by 101-1D2 and 140-11 monoclonal antibodies (mAb), both produced and characterized in our laboratory. This molecule is broadly expressed on hematopoetic cells but not on other cells. In this report we show that these 2 mAb recognize different epitopes of the same molecule, which are resistant to neuraminidase and proteases. We also demonstrate that the CDw50 antigen is expressed on thymocytes and T lymphocytes as an N-glycosylated glycoprotein monomer with a relative molecular weight (Mr) of 130,000 daltons with intrachain disulfide bonds, and that this molecule is resistant to treatment with phosphatidylinositol (PI) phospholipase C and therefore probably not PI-anchored to the membrane. CDw50 is a poorly or non-constitutively phosphorylated molecule that becomes phosphorylated by treatment with phorbol 12-myristate 13-acetate (PMA) of peripheral blood mononuclear cells (PBMC). The addition of affinity-purified CDw50 mAb inhibits primary mixed lymphocyte culture (MLC) but not secondary MLC, cytotoxicity or proliferation induced by mitogens. The inhibition of alloreactivity is mediated at the level of both responding and stimulator cells.

Rapid establishment of therapeutic serum concentrations of salicylates. A minimum serum salicylate concentration of 150 microgram/ml is required to control certain inflammatory disease processes. A loading regimen designed to rapidly achieve this minimal level was evaluated in six normal volunteers (age 22 to 27 years, weight 70.5 to 84.1 kg) using a randomized crossover design. The control group received 650 mg aspirin (ASA) every 4 hours for 48 hours. The loading regimen was 2600 mg ASA divided into two equal doses 4 hours apart. Maintenance dosing of 650 mg ASA every 4 hours was then started 4 hours after the completion of the loading regimen and continued for 40 hours. Serum samples were drawn at 0, 2, 4, 6, 8, 12, 24, 36, and 48 hours after initiation of the study and were assayed for salicylate concentration by UV spectrophotometry. Loading with aspirin produced serum concentrations which were significantly higher (P less than 0.01) for the first 24 hours and reduced the time to reach 150 microgram/ml (15.3 +/- 5.9 hours versus 30.4 +/- 8.65 hours, P less than 0.001) for five of six subjects when compared to a conventional regimen. One subject did not achieve 150 microgram/ml at 48 hours with either regimen. Considerable intersubject variation in serum concentration was noted at 48 hours for both regimens. We suggest that a loading regimen for aspirin may have utility for patients in whom rapid attainment of a therapeutic antiinflammatory serum concentration is desirable.

Generation of anaphylatoxin C3a in plasma and bronchoalveolar lavage fluid in trauma patients at risk for the adult respiratory distress syndrome. To determine the generation of anaphylatoxin C3a in plasma and bronchoalveolar lavage fluid in trauma patients at risk for the adult respiratory distress syndrome (ARDS). Prospective study. ICU in a university hospital. Severely traumatized patients at risk for the ARDS (n = 25). EDTA plasma samples and bronchoalveolar lavage fluid were obtained. Complement proteins C3, C4, C5, and the inhibitors C1-inhibitor, Factor H, and Factor I were quantitated in EDTA-plasma samples obtained every 6 hrs during the first 48 hrs after ICU admission and every morning from days 4 to 14 after injury. In bronchoalveolar lavage fluid, the complement activation production of C3a-desArg was quantitated and the volume of epithelial lining fluid was calculated. All patients showed a decrease of the complement proteins C3, C4, C5 and of the inhibitors C1-inhibitor, Factor H, and Factor I during the first 24 hrs, indicating complement consumption. Patients developing ARDS (n = 11) showed significantly higher C3 concentrations and a higher C3a/C3 ratio in the first few hours after multitrauma. Follow-up bronchoalveolar lavages demonstrated highly increased amounts of C3a in epithelial lining fluid during the first 24 hrs, mainly in ARDS patients and, to a lesser degree, in non-ARDS patients. To determine the origin of C3a in bronchoalveolar lavages, the ratio of C3a in epithelial lining fluid and plasma was calculated. The C3a of epithelial lining fluid to plasma ratio was extremely high in patients developing ARDS, but even the non-ARDS group had a ratio greater than 1, indicating that a substantial local complement activation occurs in the lung.

Lipogenesis in Ehrlich ascites tumor cells under anaerobic culture conditions. Anaerobic culture conditions (95% argon/5% CO2) caused a slightly greater increase in total lipids of Ehrlich ascites tumor cells than a gas phase of 20% O2, 75% N2, 5% CO2. Whereas the rate of [U-14C]acetate incorporation into total lipids and lipid-subclasses rose markedly in the absence of oxygen, a drastic decrease of [U-14C]pyruvate and [1-14C]octanoate incorporation as well as a 30% reduction of 3H incorporation into lipids from tritiated water were observed under these conditions. Since profound changes in the metabolic state of cells cause alterations in the specific activity of the acetyl-CoA pool but do not alter the specific activity of intracellular water, this precursor is considered to be an adequate monitor for lipogenesis under aerobic and anaerobic culture conditions. Therefore, it is concluded that Ehrlich ascites tumor cells are not able to reoxidize NADH/NADPH in the absence of oxygen by a stimulation of biosynthesis of fatty acids as is discussed to be the case in normal cells. The slight increase in total lipids of anaerobically cultured cells seems to be the result of an imbalance between normal uptake and impaired utilization of lipids from serum-supplemented culture medium.

In vivo anti-tumour activity of FCE 23762, a methoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells. FCE 23762 is a new doxorubicin derivative obtained by appending a methoxymorpholinyl group at position 3' of the sugar moiety. The compound is greater than 80 times more potent than doxorubicin, it is highly lipophilic, and presents equivalent anti-tumour activity when administered by i.p., i.v. or oral route. The pattern of anti-tumour activity of FCE 23762 differs from that of doxorubicin in maintaining anti-tumour activity against two P388 murine leukaemia sublines resistant to doxorubicin and, although at borderline levels of efficacy, against LoVo human colon adenocarcinoma resistant to doxorubicin. FCE 23762 exhibits remarkable efficacy against MX-1 human mammary carcinoma, with most treated mice being cured both after i.v. and oral treatment. Anti-tumour activity was also observed against L1210 murine leukaemia and two sublines resistant to cis-platinum and melphalan, M5076 murine reticulosarcoma, MTV murine mammary carcinoma and N592 human small cell lung cancer.

Distal embolization during mechanical thrombolysis: rotational thrombectomy vs. balloon angioplasty. To determine the incidence and extent of distal embolization during percutaneous transluminal balloon angioplasty (PTA) and rotational thrombectomy (PRT), we collected, filtered, and weighed the distal effluent of acute thrombotically occluded canine arteries following mechanical thrombolysis. PRT (n = 11) and PTA (n = 10) were equally effective in recanalizing occluded vessels (91% vs. 90%) and reduced percent diameter stenosis to a similar degree (97 +/- 6% to 8 +/- 11% and 100 +/- 0% to 17 +/- 23%, respectively). Distal embolization following mechanical intervention was observed in 10 of 10 and 8 of 9 arteries recanalized with PRT and PTA, respectively. The mean weights of collected emboli were similar between the two groups (18 +/- 24 mg vs. 37 +/- 79 mg, PRT vs. PTA, P = NS), although the range of size and weight of thromboemboli was larger in the PTA group (0-206 mg vs. 2-51 mg, PRT). Angiographically defined residual thrombus was significantly less frequent in arteries recanalized with PRT as compared with PTA (10% vs. 55%, P = 0.03). In summary, PRT and PTA are equally effective in recanalizing acutely occluded canine arteries and result in similar reductions in percent diameter stenosis. Each intervention results in distal embolization of thrombi. PRT is associated with a reduced incidence of angiographically evident residual thrombus at the site of arterial injury and may avoid embolization of large fragments occasionally produced by PTA. Thus PRT may serve as a useful alternative to coronary angioplasty during acute myocardial infarction.

Rabbit aortic histamine synthesis following short-term cholesterol feeding. The histidine decarboxylase (HD) activity of thoracic and abdominal aortic segments obtained from male, Dutch-belted rabbits fed a diet containing 0.5 per cent cholesterol for periods of either 2 or 4 weeks was examined. Mean thoracic aortic HD activities, expressed as histamine-forming capacity (HFC), were 3911 plus or minus 492, 6254 plus or minus 656, and 6215 plus or minus 878 dpm/100 mg benzenesulfonylhistamine (BSH) for the control group and from rabbits fed cholesterol for 2 and 4 weeks, respectively. Both treatment means were significantly higher than the control (P smaller than 0.05). Similar examination of abdominal aortic HD activities yielded mean HFC's of 4029 plus or minus 399, 5694 plus or minus 521, and 4762 plus or minus 902 dpm/100 mg BSH for control animals and those of the 2- and 4-week treatment groups, respectively. The difference between mean HFC's of the control and 2-week treatment group was significant (P smaller than 0.05). All increases occurred in the absence of either aortic structural alterations or any lipid deposition. These results give credence to the concept that the atherogenic process represents, at least in part, a delayed-prolonged inflammatory response phenomenon of the arterial wall.

The comparison of fluoxetine and nisoxetine with tricyclic antidepressants in blocking the neurotoxicity of p-chloroamphetamine and 6-hydroxydopamine in the rat brain. Fluoxetine prevents the loss of 5-hydroxytryptamine (5HT) uptake in synaptosomes of cerebral cortex after intraperitoneally administered p-chloroamphetamine (p-CA) with an ED50 of 3.8 mg/kg i.p. in rats. However, at 50 mg/kg, it does not prevent the loss of norepinephrine (NE) uptake in synaptosomes of hypothalamus after intraventricularly administered 6-hydroxydopamine (6-OHDA). Nisoxetine, on the other hand, centrally protects NE uptake from the neurotoxic effect of 6-OHDA with an ED50 value of 5 mg/kg i.p. At 50 mg/kg, it gives only 35% protection of 5HT uptake from the neurotoxic effect of p-CA. In comparison with the ED50 values of tricyclic antidepressants, both fluoxetine and nisoxetine are more potent and selective blockers of neurotoxicity resulting from the central actions of p-CA and 6-OHDA, respectively, in vivo.

Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. An inducible rabbit endothelial adhesion molecule that is selective for mononuclear leukocytes has been identified. This adhesion protein was expressed on the surface of activated cultured endothelium in two forms, 118 and 98 kilodaltons, the amino-terminal sequence of each being highly homologous to human VCAM-1. In dietary hypercholesterolemic and Watanabe heritable hyperlipidemic rabbit models of atherosclerosis, this adhesion molecule was found to be expressed in a localized fashion by aortic endothelium that overlies early foam cell lesions. This lesion-localized expression suggests a potential endothelium-dependent mechanism for mononuclear leukocyte recruitment during atherogenesis and may provide a molecular marker for early atherosclerosis.

[Disturbances of micturition after general surgical operations (author's transl)]. Impaired micturition after general surgical operations can be due to three causes, which occur individually or in combination. The first comprises side effects of anesthetics upon the autonomic nervous system. Inhibition of the abdominopelvic reflex, initiating micturition, due to the operative trauma represents the scond cause. Both the vegetative and the mechanical traumas, lead to decompensation of the urinary bladder, whose function is impaired by neuropathic factors and outflow obstruction. Pulmonary, cerebral, and abdominal insufficiency prolong the effects of both traumas. The third cause is direct operative injury of the sacroplexus pelvus.--Approximately 25% of all patients undergoing surgery will shown voiding disturbances in the postoperative period. The treatment consists sympatholytic therapy. In cases of neuropathic and obstructed bladders, the treatment of choice is transurethral correction of the bladder outlet.

Extent of columnar epithelium on the ectocervix between the ages of 1 and 13 years. Among 103 girls between the ages of 1 year and the prepubertal period, who came to autopsy, the incidence of columnar epithelium on the ectocervix was 42.7%. The extent of this change was mostly small, exceeding 30% of the length of the ectocervix in only 9 subjects. In some girls, only areas of squamous metaplasia or residual columnar structures (glands, channels, nabothian cysts) were present. The diagnosis of columnar epithelium in photographs at low magnification or by colposcopy is least exact among older girls. Such diagnostic difficulties appear to be related mainly to the small extent of columnar epithelium and to the diminished structural difference between areas of the original squamous epithelium and the columnar epithelium on the ectocervix.

Oral contraceptives and neoplasia of the uterine corpus. Effects of oral contraception on neoplasia of the uterine corpus are reviewed on the basis of epidemiologic studies reported to date. A duration-related protective effect against endometrial cancer occurs from use of combined oral contraceptives, those in which each active pill contains both estrogen and progestogen. The risk before age 60 years is reduced by about 38% with two years of use; use of combined OCs for 4, 8, and 12 years, respectively, confers an estimated 51%, 64%, and 70% reduction in endometrial cancer risk. The protective effect appears not to be diminished by discontinued use, even 15 or more years after stopping. Whether protection continues throughout the entire postmenopausal period, even in the presence of long-term hormone replacement therapy, remains to be seen. Use of combined OCs may protect against uterine leiomyomas ("fibroids"), but the evidence is not conclusive. The few findings about effects of oral contraception on the risk of adenomatous hyperplasia are of uncertain validity. Only one study, with few patients, has considered oral contraception in relation to uterine sarcomas.

Out-of-hospital pleomorphic ventricular tachycardia and resuscitation: association with acute myocardial ischemia and infarction. Pleomorphic ventricular tachycardia is characterized by QRS complexes with repeated variation in polarity, amplitude, and regularity. When associated with prolongation of the QT interval, the term torsades de pointes is used to describe the arrhythmia. It usually is seen clinically in association with class IA antiarrhythmic drugs such as quinidine and procainamide, bradycardia, hypokalemia, and, much less often, other drugs and electrolyte disorders as well as a result of congenital and neurogenic causes. It also may accompany acute myocardial infarction or ischemia. We describe four patients in whom pleomorphic ventricular tachycardia was observed as the presenting rhythm or during the course of resuscitation in out-of-hospital cardiac arrest. In all four patients, acute myocardial ischemia appeared to be the provocative mechanism. Therapeutic implications include an awareness of the unusual behavior of this arrhythmia, especially its propensity to terminate spontaneously. Such awareness may prevent the delivery of unnecessary defibrillatory shocks.

Computer modelling of the NAD binding site of ADP-ribosylating toxins: active-site structure and mechanism of NAD binding. Five ADP-ribosylating bacterial toxins, pertussis toxin, cholera toxin, diphtheria toxin, Escherichia LT toxin and Pseudomonas exotoxin A, show significant homology in selected segments of their sequence. Site-directed mutagenesis and chemical modification of residues within these regions cause loss of catalytic activity and of NAD binding. On the basis of these results and of molecular modelling based on the three-dimensional structure of exotoxin A, the geometry of an NAD binding site common to all the toxins is deduced and described in the paper. For diphtheria toxin, sequence similarity with exotoxin A is such that its preliminary structure can be computed by molecular modelling, whereas for the other toxins similarity appears to be restricted to the NAD binding site. Moreover, an analysis of molecular fitting of the NAD molecule into its binding cavity suggests a new model for the conformation of the bound NAD that better accounts for all available experimental information.

Effects of hyperglycemia on ischemic brain damage, local cerebral blood flow and ischemic cerebral edema. The effects of hyperglycemia on ischemic brain damage, local cerebral blood flow (LCBF), and ischemic cerebral edema were studied in a rat model of transient middle cerebral artery (MCA) occlusion with a microclip. Hyperglycemia was induced by intraperitoneal injection of 50% glucose, and same volume of 50% D-mannitol or physiological saline were injected in the controls. LCBF was measured by the quantitative autoradiogram using 14C-iodoantipyrine at 2 hours after MCA occlusion and 2 hours after reperfusion. Cerebrovascular permeability was measured by same technique using 14C-alpha-aminoisobutyric acid (AIB) at 2 hours after reperfusion following 2 hours ischemia. Specific gravity of the brain, determined by the gradient column, was used to study the topographic changes of brain water content at 2 hours after MCA occlusion and 2 hours after reperfusion. Some rats were prepared for neuropathological observation 72 hours after reperfusion. Histological study 72 hours after restoration of CBF following 2 hours MCA occlusion revealed ischemia neuronal cell damage to be more extensive in hyperglycemic rats than in normoglycemic rats. LCBF in the ischemic focus decreased significantly in hyperglycemic rats compared with the controls at 2 hours after MCA occlusion. Furthermore, the reduction of LCBF was observed also in the contralateral non-ischemic side. At 2 hours after reperfusion, in hyperglycemic rats, hyperemia up to 121-156% of the contralateral LCBF was observed within the previously ischemic area, along with a zone of reduced CBF in the surrounding area. At 2 hours after MCA occlusion, the decrease of specific gravity of the ischemic brain, in hyperglycemic rats, was significant compared with the control, and these decreases became more prominent in the entire territory of the MCA at 2 hours after reperfusion. Furthermore, 14C-AIB autoradiogram disclosed the prominent and wide leakage of the tracer within the previous ischemic focus of MCA occlusion. In contrast, in normoglycemic rats, ischemic brain edema showed a reducing trend after reperfusion, and no demonstrable changes of cerebrovascular permeability were disclosed on autoradiograms. These findings suggest that the enhancing mechanisms of hyperglycemia for ischemic brain damage are severely reduced CBF during ischemia and postischemic vasogenic edema.

Epidermal growth in the skin equivalent. The skin equivalent (SE) has been validated as a model for studies on proliferation of keratinocytes. SEs were prepared from normal skin by implanting punch biopsies on dermal equivalents consisting of fibroblasts in a collagen matrix. The outgrowths were measured by planimetry. An immunohistochemical investigation with antibodies against markers associated with proliferation was performed on frozen sections from SEs during outgrowth at 3-6 days (SE6) as well as after completion of outgrowth at 21 days (SE21). Biopsies from normal controls and from uninvolved and involved skin in psoriatic patients were also studied. The antibodies used were Ki-67, cytokeratin 8.12, and antibodies against the receptors for epidermal growth factor (EGFr) and transferrin (TFr). The increase in area was linear during the first 7 days of culture and usually reached the edges of the dermal equivalent at this time. In SE6 TFr was expressed in the basal part of the outgrowth while the other markers were not observed. In SE21 and in psoriasis there was abundant epidermal staining of Ki-67-positive nuclei and cytokeratin 8.12 was detected in the suprabasal part of the epidermis. EGFr and TFr were seen in the basal layer in SE21. In the psoriatic lesions these receptors were found both in the basal and suprabasal layers. The lack of proliferation markers in SE6 indicates that the initial increase in the area of keratinocytes is due to migration from the punch biopsies. Increased cell proliferation is present in SE21, a finding in common with psoriasis and wound healing. The skin equivalents should therefore be an appropriate model for studies on these phenomena.

[Antibacterial effects of gamma-interferon in experimental Klebsiella infection]. The results of the experimental study on the effect of the natural and recombinant gamma-interferons (gamma-IFs) of mice on the process of the infection caused by Klebsiella sp. are presented. The infection was reproduced by intraperitoneal contamination of mice with a virulent culture of Klebsiella pneumoniae 5055, line SHK. The gamma-IFs were administered to the animals in a dose of 250 units per mouse on days 1 and 3 after the contamination. Survival of the animals, clearance of the pathogen from the blood and liver and functional activity of the phagocytes in the contaminated mice were investigated. It was shown that both the natural and recombinant gamma-IF stimulated the phagocytic activity and oxidative metabolism of the phagocytes in the contaminated mice. Activation of these functions after the use of the natural gamma-IF correlated with its marked protective effect and accelerated elimination of the pathogen from the host which was not observed after the use of the recombinant gamma-IF.

A novel function for zinc(II) in a nucleic acid-binding protein. Contribution of zinc(II) toward the cooperativity of bacteriophage T4 gene 32 protein binding. The contribution of Zn(II) toward the binding of bacteriophage T4 gene 32 single-stranded nucleic acid-binding protein (gp32) has been examined by the use of two independent approaches. Studies carried out with successively longer oligonucleotides which have the general structure p(dT)n, where n is equal to 8, 16, 24, or 32 nucleotides, suggest that removal of Zn(II) decreases the cooperativity of binding by as much as 30-fold. Hence, whereas apo-gp32 and native gp32 have similar apparent affinities for the single-site lattice p(dT)8, native gp32 has an approximately 10-fold higher affinity compared to apo-gp32 for a two-site lattice, such as p(dT)16. In contrast to native gp32, where full cooperativity (in terms of the strength of a single gp32-gp32 interaction) is reached with only a two-site lattice, the cooperativity of apo-gp32 binding appears to increase approximately 4-fold upon going from a two- to a four-site lattice such as p(dT)32. The conclusion reached from these oligonucleotide studies agrees well with a series of titrations with polyribo(ethenoadenylic) acid, in 0.275-0.40 M NaCl. These latter studies indicate that the 6-38-fold higher affinity of native gp32 as compared to apo-gp32 for polyribo(ethenoadenylic) acid results primarily from the higher cooperativity of binding of native gp32. By stabilizing a specific subdomain within gp32 that is essential along with the NH2-terminal domain (residues 1-9), Zn(II) contributes from 20 to 50% of the free energy of cooperative gp32-gp32 interactions that occur along a polynucleotide lattice.

Phosphopeptides of enamel matrix. Although the tripeptides Glu-O-Phosphoserine-Tyr and Glu-O-Phosphoserine-Leu have been identified in embryonic bovine enamel proteins, 1, 2 the issue of whether both sequences occur in each of the phosphopeptides, or whether certain sequences occur in specific peptides only, has recently been resolved by isolating homogeneous samples of E33 and E44. All three of the Ser residues of both peptides are phosphorylated. All three in E3 are in the sequence Glu-O-Phosphoserine-Leu, and all three in E4 are in the sequence Glu-O-Phosphoserine-Tyr. It was not possible to sequence either of the polypeptide chains directly by automatic peptide sequencing. However, a partial sequence of E4 was constructed from data derived from peptides isolated after cyanogen bromide, trypsin and chymotrypsin digestions. The presence of Glu, Tyr and Leu adjacent to and near the O-Phosphoserine [Ser(L)] residues and the 2 degrees, 3 degrees and higher ordered structures of the enamel phosphopeptides may be important in calcium binding and mineralization.

Detecting evolutionary trends from molecular data. 1. Some measures of compositional nonrandomness. The measures of compositional nonrandomness to be discussed as to their physical significance and to their power of detecting evolutionary significant variations are (see article)(pi a priori probability for amino acid i, ni its number of occurrences in a protein of length L). As a concrete example, the pi are here supposed to represent equal frequencies of all non-stop codons. For each quantity, four levels are defined: The base level, with optimal (i.e. minimal nonrandomness) composition, admitting non-integer values of ni; the integer level with optimal integer composition; the noise level, represented by a typical random cain; and the real protein level. On all these levels, S, which is the measure with the most direct physical sense, shows the smoothest behavior with the smallest relative fluctuations and thus the highest resolution.

Hemodynamic determinants of subdiaphragmatic venous return during closed-chest CPR in a canine cardiac arrest model. To assess the hemodynamic determinates of peripheral subdiaphragmatic venous-to-right-heart return during closed-chest CPR. Seven anesthetized dogs subjected to electrically induced ventricular fibrillation for five minutes. Conventional closed-chest CPR and closed-chest CPR with continuous abdominal binding at a chest compression rate of 60 per minute, a compression-to-relaxation ratio of 50:50, and a ventilation-to-compression ratio of 1:5. Solid-state catheters were positioned in the ascending aorta, right atrium (RA), and inferior vena cava (IVC). Cannulating electromagnetic flow probes were inserted into the IVC and a carotid artery. Analog-to-digital conversion was performed electronically. Five minutes after ventricular fibrillation was induced, interventions were performed in an alternating sequence. Systolic, diastolic, and mean pressures and flows were measured and compared. Two-tailed, unpaired t test applied to equal sample size, linear regression analysis, and multiple regression analysis. Abdominal binding during CPR significantly increased (P less than .05) all measured systolic and diastolic CPR intravascular pressures compared with CPR without abdominal binding but did not affect IVC-to-right-heart venous return. During conventional CPR without abdominal binding, venous return was dependent on the diastolic IVC pressure (r = .86, P = .014), mean IVC pressure (r = .80, P = .03), and carotid blood flow (r = .99, P = .001) but not on the IVC-to-RA pressure gradient. With abdominal binding, venous return was not correlated with any study hemodynamic variable, including the peripheral venous-to-RA pressure gradient. Venous return from the subdiaphragmatic venous bed during CPR is dependent on venous pressure, not on the peripheral venous-to-right-heart pressure gradient. Abdominal binding during CPR does not affect venous return. Venous return during CPR diastole is highly dependent on central venous capacitance (left heart outflow during CPR systole).

Tumour necrosis factor induction of ELAM-1 and ICAM-1 on human umbilical vein endothelial cells--analysis of tumour necrosis factor-receptor interactions. Induction of the adhesion molecules ELAM-1 and ICAM-1 on endothelial cells is a key pro-inflammatory effect of tumour necrosis factor (TNF). Earlier work in non-human systems has suggested that unlike other cell types, endothelial cells interact with the N-terminus of the TNF molecule, thereby implying novel TNF receptors on endothelial cells. This is also supported by 125I-TNF cross-linking studies on bovine endothelial cells. The present study aimed to see whether TNF induction of ELAM-1 and ICAM-1 on human umbilical vein endothelial cells (HUVECs) involved novel TNF-receptor interactions. Three approaches were employed. First, antibodies directed at different sites on the TNF molecule were tested for inhibition of TNF-induction of ELAM-1 and ICAM-1 on HUVECs. Inhibition was seen only with antibodies reacting with epitopes outside the N-terminal region. Second, an N-terminal TNF peptide (residues 1-26) failed to induce ELAM-1 and ICAM-1 on HUVECs or antagonise TNF induction of these molecules. Third, HUVEC/125I-TNF cross-linking revealed a major complex characteristic of the known 55 kDa TNF receptor: this was confirmed with receptor-specific monoclonal antibodies. It is concluded that (a) the same part of the TNF molecule interacts with TNF-receptors on HUVECs and other cell types and (b) TNF induction of ELAM-1 and ICAM-1 on HUVECs is mediated via the well-characterized 55 kDa TNF receptor.

[Consumption coagulopathies and severe postpartum hemorrhage]. 15 patients were referred to the Intensive Care Unit immediately after delivery for severe post-partum haemorrhage. In 7 cases complications followed retroplacental haemotoma formation and in the other 8 cases they were due to secondary haemorrhages from the placental site and/or from tears of the cervix or vagina. It is a clinical picture that is associated with a state of shock, with continuing massive bleeding associated with failure of the blood to clot and which persists and becomes worse with the transfusion of stored blood and of the coagulation factors. In all these cases severe coagulation pathology due to consumption defects is revealed. We must point out that tears of the cervix and vagina which have been neglected and failure to compensate for the original blood loss are among the aetiological factors. Treatment with Heparin giving a dose of 1 to 3 mg per kg of body weight per 24 hours and controlled by a strict biological check together with symptomatic resuscitation from the state of shock and from the coagulation factors is successful (9 cases) if it is undertaken early on. A fatal outcome, whether it is due to a persistent state of shock (1 case) or to visceral complications of diffuse intravascular coagulation (C.I.V.D.) (5 cases) can be found where treatment is delayed and when insufficient blood is replaced and when antifibrinolytics are prescribed. A preventive therapeutic plan as well as a curative one can be drawn up for these cases of obstetrical drama.

[Spontaneous reversal of portal flow in cirrhosis. Angiographic study of 15 cases (author's transl)]. Spontaneous reversal of intra-hepatic portal flow in cirrhoses appears to be best demonstrated by arteriography, which shows a direct sign, i.e. retrograde opacification of intra-hepatic portal branches during selective hepate arteriography, and an indirect sign, i.e. the appearance of functional amputation of these same portal branches at the time of superior mesenteric venous return. Reversal of portal flow is sometimes complete (5 out of 15 cases), the flow being entirely away from the liver and sometimes incomplete (10 out of 15 cases), limited to the interior of the liver, portal flow then being bidirectional. Reflux of arterial blood in the intra-hepatic portal branches via the development of intra-hepatic arterioportal communications appears to be the determining factor in the reversal of portal flow in cirrhosis. The degree of portal flow away from the liver seems to depend essentially upon the extent of development of porto-caval anastomoses. Certain features suggest that there is a relationship between the development of the hepatic arterial circulation and that of the porto-caval anastomoses. These two elements which determine the degree of portl hypertension may mutually influence each other. This hypothesis is interesting in the context of understanding the haemodynamic abnormalities of advanced cirrhosis.

Localization of histidase to human chromosome region 12q22----q24.1 and mouse chromosome region 10C2----D1. The human gene for histidase (histidine ammonia-lyase; HAL), the enzyme deficient in histidinemia, was assigned to human chromosome 12 by Southern blot analysis of human X mouse somatic cell hybrid DNA. The gene was sublocalized to region 12q22----q24.1 by in situ hybridization, using a human histidase cDNA. The homologous locus in the mouse (Hal) was mapped to region 10C2----D1 by in situ hybridization, using a cell line from a mouse homozygous for a 1.10 Robertsonian translocation. These assignments extend the conserved syntenic region between human chromosome 12 and mouse chromosome 10 that includes the genes for phenylalanine hydroxylase, gamma interferon, peptidase, and citrate synthase. The localization of histidase to mouse chromosome 10 suggests that the histidase regulatory locus (Hsd) and the histidinemia mutation (his), which are both known to be on chromosome 10, may be alleles of the histidase structural gene locus.

[Roles of T cell subsets in the protective immunity of mice against Plasmodium yoelii]. BALB/c mice which had developed protective immunity against Plasmodium yoelii (P. y.) challenge were injected with anti-CD4 or anti-CD8 monoclonal antibody, and were then challenged again with P. yoelli. No impairment of protection was observed. CD8+T cells obtained from spleens of these mice were transferred to BALB/c nude mice and induced partial protection, while transfer of CD4+T cells did not so. In P. yoelli-mouse model, the parasites invaded reticulocytes in the early infection, and the infected reticulocytes could be recognized and attacked by sensitized CD8+T cells. In late infection when P. yoelli also invaded mature erythrocytes, the protective effect of CD8+T cells decreased and the main role of protection was played by antibodies.