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Presequence does not prevent folding of a purified mitochondrial precursor protein and is essential for association with a reticulocyte cytosolic factor(s). Ornithine carbamoyltransferase (OTC; subunit, 36,000 Da) [EC 2.1.3.3] is initially synthesized as a precursor (pOTC) with a transient NH2-terminal presequence of 32 amino acid residues, then is imported posttranslationally nto the mitochondrial matrix. We expressed rat pOTC in Escherichia coli, purified it in a denatured form, and showed that could be transported into isolated mitochondria in the presence of rabbit reticulocyte lysate [Murakami et al. (1988) J. Biol. Chem. 263, 18437-18442]. In order to compare the properties of the precursor and mature form of OTC, the rat mature OTC was synthesized in E. coli and purified. The recombinant OTC represented about 5% of the total bacterial protein and was present in both the supernatant and precipitate of the disrupted bacteria. The OTC, extracted from the precipitate with 8 M urea or 6 M guanidine.HCl, was essentially homogeneous, as judged by SDS-PAGE. When guanidine.HCl-denatured mature OTC was diluted and incubated at 0 degrees C for 40-60 h, it was reactivated to a specific activity of 170 mumol/min/mg protein at 37 degrees C (18% of that of the purified mature enzyme). Guanidine.HCl-denatured pOTC was activated to a specific activity of 125 mumol/min/mg protein under similar conditions. The native and reactivated OTC sedimented with an s20.w value of 6.2S, whereas the activated pOTC sedimented with an s20.w of 5.2S. The activated pOTC was more unstable than the reactivated OTC at 50 degrees C. These observations indicate that the presequence does not prevent pOTC from folding into an enzymatically active trimeric form, although the pOTC trimer appears to be less compact than the mature trimer.(ABSTRACT TRUNCATED AT 250 WORDS)

[When the leg is the victim of the foot]. Man (homo-erectus, plantigrade) is in constant contact with the ground via his feet which are platforms on which the legs and, above all, the entire body rest. When the body moves, the only segment which remains stable and fixed is the foot, which forms the point of departure of all the muscular actions of this moving body. The slightest deformity of this platform, this foot, will lead to skeletal, musculotendinous and neurovascular problems in the legs, and to pain. Pain due to skeletal problems may be related to fatigue fractures (tibia, fibula) and to posterior tibial periostitis. Pain may also be due to musculotendinous problems which are characterised by a muscle bed syndrome (anterolateral, posterior) or tensosynovitis. Neurovascular problems are typified by a tarsal sinus syndrome, a musculocutaneous nerve syndrome and dysfunction of Lejears' sole during filling in flat feet and during emptying in hollow feet.

Photoreactions of Cytochrome b-559 and cyclic electron flow in photosystem II of intact chloroplasts. The high potential cytochrome b-559 of intact spinach chloroplasts was photooxidized by red light with a high quantum efficiency and by far-red light with a very low quantum efficiency, when electron flow from water to Photosystem II was inhibited by a carbonyl cyanide phenylhydrazone (FCCP or CCP). Dithiothreitol, which reacts with FCCP or CCCP, reversed the photooxidation of cytochrome b-559 and restored the capability of the chloroplasts to photoreduce CO2 showing that the FCCP/CCCP effects were reversible. The quantum efficiency of cytochrome b-559 photooxidation by red or far-red light in the presence of FCCP was increased by 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone which blocks oxidation of reduced plastoquinone by Photosystem I. When the inhibition of water oxidation by FCCP or CCP was decreased by increased light intensities, previously photooxidized cytochrome b-559 was reduced. Red light was much more effective in photoreducing oxidized high potential cytochrome b-559 than far-red light. The red/far-red antagonism in the redox state of cytochrome b-559 is a consequence of the different sensitivity of the cytochrome to red and far-red light and does not indicate that the cytochrome is in the main path of electrons from water to NADP. Rather, cytochrome b-559 acts as a carrier of electrons in a cyclic path around Photosystem II. The redox state of the cytochrome was shifted to the oxidized side when electron transport from water became rate-limiting, while oxidation of water and reduction of plastoquinone resulted in its shifting to the reduced side.

Correlation between the plasma concentration of free nicotinic acid and some of its pharmacological effects in the fasted rat after an oral dose of sorbinicate and of nicotinic acid. D-Glucitol hexanicotinate (sorbinicate), when given orally to fasted rats, depresses the plasma free fatty acids (FFA) and triglycerides. The depression is about equal in intensity and duration to that induced by corresponding doses of nicotinic acid as such, but occurs in the presence of nicotinic acid plasma levels far lower than those obtained with nicotinic acid. In fact, sorbinicate is absorbed more slowly and more smoothly than is the case with nicotinic acid and the bioavailable nicotinic acid after oral sorbinicate administration is thought to be not more than 3--4% of the dose given. At the dose closest to that in clinical use sorbinicate exerts a more lasting effect than nicotinic acid both on FFA and on triglycerides, and at all the doses tested, contrary to nicotinic acid, sorbinicate did not induce plasma FFA rebound. This particular type of bioavailability, which differentiates sorbinicate from nicotinic acid, might explain the better effect on the plasma lipids as well as the absence of the side-effects that occur with nicotinic acid administration.

Development of callosal connections in the sensorimotor cortex of the hamster. To investigate the development of corpus callosal connectivity in the hamster sensorimotor cortex, we have used the sensitive axonal tracer 1,1 dioctadecyl-3,3,3',3', tetramethylindocarbocyanine perchlorate (DiI), which was injected either in vivo or in fixed brains of animals 3-6 days postnatal. First, to study changes in the overall distribution of developing callosal afferents we made large injections of DiI into the corpus callosal tract. We found that the anterogradely labeled callosal axons formed a patchy distribution in the contralateral sensorimotor cortex, which was similar to the pattern of adult connectivity described in earlier studies of the rodent corpus callosum. This result stands in contrast to previous retrograde studies of developing callosal connectivity which showed that the distribution of callosal neurons early in development is homogeneous and that the mature, patchy distribution arises later, primarily as a result of the retraction of exuberant axons. The initial patchy distribution of callosal axon growth into the sensorimotor cortex described in the present study suggests that exuberant axons destined to be eliminated do not enter the cortex. In addition, small injections of DiI into developing cortex resulted in homotopic patterns of callosal topography in which reciprocal regions of sensorimotor cortex are connected, as has been shown in the adult. Second, to study the radial growth of callosal afferents we followed the extension of individual callosal axons into the developing cortex. We found that callosal axons began to invade the contralateral cortex on about postnatal day 3, with little or no waiting period in the callosal tract. Callosal afferents then advanced steadily through the cortex, never actually invading the cortical plate but extending into layers on the first day that they could be distinguished from the cortical plate. The majority of callosal axons grew radially through the cortex and did not exhibit substantial branching until postnatal day 8, the age when the cortical plate disappears and callosal afferents reach the outer layer of cortex. This mode of radial growth through cortex prior to axon branching could serve to align callosal afferents with their radial or columnar targets before arborizing laterally.

Effect of temperature on the infectivity of Sarcocystis miescheriana cysts in pork. Sarcocysts of Sarcocystis miescheriana in the thigh muscles of pigs became non-infective to pups after heating infected pork in minute pieces at 60 degrees C for 20 min, 70 degrees C for 15 min and 100 degrees C for 5 min. Similar pieces of infected muscle tissues, when exposed to -4 degrees C for 2 days or -20 degrees C for 1 day, became non-infective to pups. The experiment suggests that pork containing sarcocysts of S. miescheriana, and possibly of S. suihominis, requires cooking at a minimum of 70 degrees C for 15 min or freezing at -4 degrees C for 2 days or -20 degrees C for 1 day for making it safe for consumption.

Computer-assisted stereotactic brain operations by means including computerized axial tomography. With a computerized program system for stereotactic brain operations it becomes possible for the first time to react even before running a possible risk, e.g., in case of punctures in the midbrain, the brain stem, or in the hypothalamus, by simulating the operative procedure even before starting the operation itself. This is effected by the ability to change the penetration angle of the electrode or by choosing a different point of trepanation. The inclusion of computerized axial tomography, especially through the presentation of the CT scan, made to measure with the help of the linear transformation, and of the input of the cranial and ventricular coordinates through a digitizer, together with the coordinates resulting from the X-ray picture, brings the definition of the target point to a still greater optimum. Thus the safety and the precision of the stereotactic operation have been improved even further.

The insulin-like growth factor 1 (IGF-1) receptor is responsible for mediating the effects of insulin, IGF-1, and IGF-2 in Xenopus laevis oocytes. Competitive hormone binding studies with membrane and partially purified receptors from Xenopus laevis oocytes revealed that the oocyte possesses high affinity (KD = 1-3 nM) binding sites for both insulin growth factors 1 and 2 (IGF-1 and IGF-2), but not for insulin. Consistent with these findings, IGF-1 activates hexose uptake by Xenopus oocytes with a KA (3 nM) identical with its KD, while IGF-2 and insulin activate hexose uptake with KA values of 50 nM and 200-250 nM, respectively, suggesting activation mediated through an IGF-1 receptor. Both IGF-1 and insulin activate receptor beta-subunit autophosphorylation and, thereby, protein substrate (reduced and carboxyamidomethylated lysozyme, i.e. RCAM-lysozyme) phosphorylation with KA values comparable to their respective KD values for ligand binding and KA values for activation of hexose uptake. The autophosphorylated beta-subunit(s) of the receptor were resolved into two discrete components, beta 1 and beta 2 (108 kDa and 94 kDa, respectively), which were phosphorylated exclusively on tyrosine and which exhibited similar extents of IGF-1-activated autophosphorylation. When added prior to autophosphorylation, RCAM-lysozyme blocks IGF-1-activated autophosphorylation and, thereby, IGF-1-activated protein substrate (RCAM-lysozyme) phosphorylation. Based on these findings, we conclude that IGF-1-stimulated autophosphorylation of its receptor is a prerequisite for catalysis of protein substrate phosphorylation by the receptor's tyrosine-specific protein kinase. The IGF-1 receptor kinase is implicated in signal transmission from the receptor, since anti-tyrosine kinase domain antibody blocks IGF-1-stimulated kinase activity in vitro and, when microinjected into intact oocytes, prevents IGF-1-stimulated hexose uptake.

Multiple sclerosis: fat-oil relationship. Between 1949 and 1984, 150 patients with multiple sclerosis consumed low-fat diets. Fat, oil, and protein intakes; disability; and deaths were determined. With a daily fat consumption less than 20.1 g/day (av 17 g/day), 31% died, and average deterioration was slight. A daily intake greater than 20 g/day (av 25 or 41 g/day) was attended by serious disability and the deaths of 79 and 81%, respectively. Oil intake bore an indirect relationship to fat consumption. Minimally disabled patients who followed diet recommendations deteriorated little if at all, and only 5% failed to survive the 34 yr of the study, whereas 80% who failed to follow diet recommendations did not survive the study period. The moderately disabled and severely disabled patients who followed diet recommendations carefully did far better than those who failed to follow the diet. In general, women tended to do better than men. Those patients treated early did better than those in whom treatment was delayed. High sensitivity to fats suggests that saturated animal fats are directly involved in the genesis of multiple sclerosis.

Food intake and nutrient sources in the diet of middle-aged men in southern Germany: results from the WHO MONICA Augsburg Dietary Survey 1984/85. Diet records of the WHO MONICA Augsburg dietary survey 1984/85 sample of 899 men aged 45-64 were used to derive quantitative data about food intake and the contribution of food groups to energy intake and the intake of those nutrients relevant to the discussion about nutrition and cardiovascular disease: protein, fat, saturated, mono- and polyunsaturated fatty acids, cholesterol, carbohydrate, polysaccharides and total fiber. The present lists of nutrient sources should be helpful for the development of acceptable dietary advises, which make allowance for actual eating patterns as well as for developing improved instruments of dietary assessment.

A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. In primary biliary cirrhosis the hepatic lesions may result, at least in part, from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid), a hydrophilic bile acid without hepatotoxicity, leads to improvement in the condition of patients with primary biliary cirrhosis. We conducted a two-year, multicenter, double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 mumol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction. Treatment failed in 6 patients in the ursodiol group, as compared with 13 in the placebo group (P less than 0.01 by Cox regression model). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (P less than 0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, cholesterol, and IgM (all P less than 0.001); the antimitochondrial-antibody titer (P less than 0.01); and the Mayo risk score (P less than 0.001). Follow-up analysis of 95 liver-biopsy specimens showed a significant improvement in the mean histologic score (P less than 0.002) and in all the characteristic histologic features except fibrosis only in the group given ursodiol. Ursodiol is a safe and effective treatment for primary biliary cirrhosis.

[Sarcoidosis and heredity. 3 familial cases]. It is very uncommon to find several cases of sarcoidosis in the same family. In the majority of published reports, only 2 persons are involved in each family. Genetic predisposition is probably, but its true importance as compared with environmental conditions is uncertain owing to the lack of epidemiology studies. We report 3 cases of sarcoidosis in the same family. In 2 of these cases (2 black sisters) the clinical set up was similar, consisting of multivisceral sarcoidosis involving the lung and mediastinum, the skin and the peripheral lymph nodes and muscles, with poor general condition and dependence on, or resistance to corticosteroids. Although the two sisters lived in different countries for several years and despite the 4-year age difference between them, the disease began in both cases at the age of 40 years. The history of this family is exemplarily in favour of a genetic predisposition and suggests than the penetrance of genetic transmission is underevaluated. Systematic pulmonary clinical and radiological examinations performed in the relatives of patients with sarcoidosis might provide information on the true incidence of familial cases. Studies of the genetic equipment of these familial cases would perhaps constitute a line of research aimed at determining the pathogenesis of the disease.

[Neuroretinal rim area (NRA) in early glaucoma]. The authors photographically measured the optic disks in 6 groups, namely, normal subjects with small cups and those with large cups, suspected glaucoma with small cups and those with large cups, primary open angle glaucoma (POAG) and low tension glaucoma (LTG). The effect of ocular optical magnification was corrected. The mean NRAs of POAG, LTG and suspected glaucoma with large cups were found less than those of the other 3 groups. In the normal subjects, an evident positive correlation existed between the cup area and the disk area, and the NRA was weakly correlated with the disk area. The diffuse and localized retinal nerve fiber layer defects were negatively correlated with the NRA significantly.

Neuropeptide Y. Differential binding to rat intestinal laterobasal membranes. Neuropeptide Y (NPY), a neurotransmitter contained within intrinsic nerves of the small intestine, inhibits secretion when added to the serosal side of intestinal mucosa mounted in Ussing chambers. Using NPY radiolabeled with IODO-GEN, lactoperoxidase, or the Bolton-Hunter reagent, we have localized high affinity NPY receptors to the serosal laterobasal membranes of the rat intestinal epithelial cell, isolated according to a recently described protocol that minimizes contamination with endoplasmic reticulum, Golgi, and brush-border membranes. In addition, certain species of radiolabeled NPY, including those labeled with IODO-GEN at the tyrosine residue 36, also demonstrated an ability to bind to brush-border membranes. These receptors were specific for NPY since the homologous peptides, pancreatic polypeptide and peptide YY, were less efficient than NPY in inhibiting the membrane binding of radiolabeled NPY. By cross-linking NPY to its receptor with either disuccinimidyl suberate or dithiobis(succinimidyl propionate) and analyzing the resulting complexes on sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by radioautography, we identified two NPY receptor species with molecular sizes of 52-59 kDa and 37-39 kDa. The 37-39-kDa species further possesses a disulfide bond which may attach it to a separate approximately 5-kDa subunit, as evidenced by retarded migration in the absence of the reducing agent dithiothreitol. The intestinal NPY receptor is slightly smaller than the rat brain receptor previously characterized using similar techniques. The localization of NPY receptors on laterobasal membranes is consistent with previous anatomic and physiologic findings, and their identification by cross-linking techniques will constitute the basis for detailed characterization.

Patterns of degeneration in the external cuneate nucleus after multiple dorsal rhizotomies. Unilateral, intradural dorsal rhizotomies (C3-Cs) were performed on adult rats to study the patterns of synaptic organization of ascending dorsal root fibers in the external cuneate nucleus (ECN). Animals were permitted to survive for periods of time ranging from 3 hours to 12 days. Sham-operated animals presented a morphology indistinguishable from that of normal, unoperated animals. In rhizotomized animals, degeneration was observed ipsilaterally at all survival periods. After postoperative survivals of 3 to 14 hours some terminal boutons displayed clumping and diminution in numbers of synaptic vesicles and, in addition, degeneration myelinated axons were observed at this time. There was considerable degeneration in the neuropil between 24 and 48 hours postoperative. Two forms of degeneration occurred in axons and terminal boutons with comparable frequency: electron lucent degeneration and electron opaque degeneration. Reactive phagocytic glial cells contained degenerated masses, lipoid droplets, lysosome-like structures and myelin fragments. After postoperative survivals of four to six days, lucent and opaque degenerating terminals were less numerous. Neurofilamentous degeneration was observed only occasionally. Unaltered synaptic membrane specializations were present and were usually abutted by glia. At 12 days postoperative, synaptic glomeruli and serial synapses were not seen. Invaginating dendritic spines were rarely seen. Bouton populations that remained unualtered were: small (0.3-3.0 micron) boutons that contact dendritic shafts and somata, nodal synaptic boutons and boutons containing granular vesicles (80-100 nm).

[The research process in grounded theory: some examples of nursing education and nursing practice research]. The purpose of this paper is to describe the grounded theory method; especially of the research process in studies using the method. The article is based on the examples of authors' studies of nursing education and nursing practice. The grounded theory method is qualitative and inductive, analyzing data from the empirical world, from which categories and concepts are emerged. Analysis is made by coding and memorizing. The emerging categories will be structured, restructured and developed continually during the research process. In the final theory the concepts, the relationships between them and their internal and external differences are defined in the social process. The meaning of a good description of the research process is emphasized, because the evaluation of the research studies using grounded theory method are based on well documented research process.

[Role of chlamydia in chronic renal and urogenital diseases in man]. Serological examinations by the CFT with the group-specific ornithosis antigen were carried out with 1910 sera from patients with chronic diseases of the kidneys, urinary tracts and male sexual organs, as well as with 556 control sera from patients with cardio-vascular and other diseases for elucidation of the role of chlamydia (OLT group) in the infectious pathology of the kidneys and urinary tracts of man. No complement-fixing antibody was detected with the group-specific ornithosis antigen in control sera. The antibody was found in 5.2% of sera from patients with chronic diseases of the kidneys and upper urinary tracts and in 6.2% of cases with the involvement of the proximal part of the urinary tracts and male sexual organs. The intradermal test (IDT) with ornithosis allergen was performed for those patients whose sera contained complement-fixing antibody. The results of CFT and IDT coincided in 82.8% of the patients, thus confirming the etiological role of chlamydia in human urogenital pathology. Studies on the positive sera with the species-specific ornithosis antigen gave negative results, indicating that a distinct species of chlamydia is the agent of urogenital diseases.

Neural development. FESN Study Group. The FESN-sponsored follow-up meeting on neural development highlighted progress toward understanding several central issues in developmental neurobiology with particular emphasis on investigation into the mechanisms of cell fate determination. In systems as diverse as the HSN neurons of C. elegans, the photoreceptor cells of the Drosophila eye, the wide range of cell types within the vertebrate retina and the neurons of the cerebral cortex, hindbrain and spinal cord, the importance of environment in the determination and maintenance of cell fate was clearly established. Advances in cell marking techniques, including fluorescent dye and retroviral tagging, have enabled the fates of cells in normal and heterotypic environments to be followed and have demonstrated the initial plasticity of the progenitor cell population in many systems. The recent establishment of in vitro systems for studying neural development should further define the precise nature and identity of the environmental signals that act to establish and maintain cell fate. Of course, establishment of cell identity is only the initial phase in the formation of the mature nervous system. Once the fate of individual cells is determined, migration of cells to appropriate locations, extension of axons to appropriate targets and refinement of neuronal circuitry must occur. Both the definition of genes that influence these processes in nematodes and recent advances in imaging techniques that provide a means of observing these later, dynamic processes in 'living' brain slices promise to significantly advance understanding of the complexities of development of functional nervous systems.

Impact of integration of mental health service and comprehensive medical care. Effect of the introduction of mental health services into a comprehensive prepaid medical care facility was studied. The subjects were two independent subsamples of all individuals seen in the mental health service for the first time in 1967, and two comparison groups not seen in the mental health service. Data consisted of medical visits from 1962 through 1969 and mental health visits from 1967 through 1969. Insufficient support was found for the assertion that mental health services produce savings of medical care. Some of the complex interactions between care for somatic and mental health treatment variables, and points for future study are noted.

Inhibition of human T lymphocyte proliferation and cytokine production by 1,25-dihydroxyvitamin D3. Differential effects on CD45RA+ and CD45R0+ cells. 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), the biologically active form of vitamin D3, has been shown to modulate lymphocyte functions in vitro. These effects are exerted through binding to specific receptors that are expressed in activated, but not in resting lymphocytes. 1,25-(OH)2 D3 inhibits lymphocyte proliferation, immunoglobulin production and the release of cytokines including interleukin-2 (IL-2) and interferon gamma (IFN gamma) by mitogen driven blood mononuclear cells (MNC). A distinction between CD45RA+ and CD45R0+ subsets of T cells has, however, proven extremely relevant in terms of immunoactivation and immunopathology. The present study was undertaken to evaluate effects of 1,25-(OH)2 D3 on proliferation and cytokine production by purified CD45RA+ and CD45R0+ T cells. 1,25-(OH)2 D3 caused a dose- and time-dependent reduction in phytohemagglutinin-(PHA) and poke-weed mitogen (PWM)-driven proliferation of purified CD45R0+ T cells. In contrast, proliferation of the CD45RA+ subset was unaffected by this treatment. Comparable levels of lymphotoxin (LT), IFN gamma and IL-2 were obtained in cultures of both subsets. 1,25-(OH)2 D3 reduced these levels, but the suppressive effect of the hormone was delayed in cultures of CD45RA+ T cells. The results suggest that the CD45R0+ subset is relatively more sensitive than CD45RA+ subset to the inhibitory effects of 1,25-(OH)2 D3. This finding may be of pharmacological interest, because the CD45R0+ subset plays a key role in immune activation and because these cells have been associated with the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

SSPE-like inclusion body disorder in treated childhood leukemia. Clinico-pathological report on a boy with cytostatically treated leukemia, dying with cerebral symptoms after passing clinical measles 10 weeks before death. At autopsy, numerous nuclear inclusion bodies in glial and nerve cells were found. By electron microscopy, nuclear inclusions appeared as loosely arranged smooth tubules, corresponding to paramyxovirus nucleocapsids. Frequently, cytoplasmic changes appeared too, consisting of incomplete tubular structures and an abundant dense "fuzzy" material. No regular tubuli of the coated granular type were present, as in common measles virus infection, nor any mature viral structures or differentiation of the surface membrane. The lack of maturation in cytoplasm together with a predominance of nuclear changes suggested a slow type of measles virus infection, while the particular cytoplasmic changes suggested a defect in synthesis of granular nucleocapsids, possibly a basic factor for the slow type of the viral infection. Possible pathogenetic factors are discussed.

Postoperative hearing recovery in a case of delayed hearing loss after acoustic neurinoma removal. Delayed postoperative hearing loss after acoustic neurinoma removal is seldom observed. The presented case illustrates the phenomenon of delayed postoperative hearing loss which was observed 4 days after removal of a large acoustic neurinoma. Intraoperative brainstem auditory evoked potentials (BAEP) revealed a gradual loss of wave V with preservation of wave I. In animal experiments a dissociated loss of BAEP has been associated with impairment of microcirculation due to secondary edema. Vasoactive treatment was initiated and after 11 days a partial hearing recovery could be documented. Transient disturbance in microcirculation of vasa nervorum of the cochlear nerve is assumed to be responsible for postoperative hearing fluctuation.

Bluetongue epidemiology in the Caribbean region: serological and entomological evidence from a pilot study in Barbados. Variation in the percentage of lambs seroconverting to bluetongue viruses was seen between sites and years in Barbados. Transmission at some sites was nearly absent whereas all lambs at one site became seropositive. The agar gel immunodiffusion test for bluetongue gave consistent results in series of serum samples from 112 of 121 sentinel lambs. Collections of biting midges in association with sheep yielded six species: Culicoides insignis Lutz, C. pusillus Lutz, C. phlebotomus (Williston), C. furens (Poey), C. jamaicensis Edwards and C. trilineatus Fox. The first two species comprised 92% of those caught during a sentinel lamb study and were the predominant species trapped for virus isolation. No viruses were recovered from 5517 C. insignis, 614 C. pusillus, three C. trilineatus and two C. furens placed into pools during two brief intensive trapping operations.

Preferential inhibition of lysosomal beta-mannosidase by sucrose. The lysosomal storage disease beta-mannosidosis, described in both goats and humans, can be detected by measuring a deficiency in hydrolysis of the fluorogenic substrate 4-methylumbelliferyl-beta-D-mannoside. An inhibitor of guinea pig beta-mannosidase (beta-man) activity was detected when tissue was homogenized in phosphate-buffered-saline (pH 7.4) containing 0.25 mol/l sucrose. The existence of such an inhibitor was apparent when the enzyme was immunoprecipitated from tissue using a specific beta-man polyclonal antibody. There was up to a threefold increase in activity in the immunoprecipitated enzyme (antibody-enzyme complex) compared to the activity of the nonimmunoprecipitated enzyme. An extensive study was therefore undertaken to determine the nature and specificity of this inhibitor by analyzing the effect of a range of metal ions and sugars on beta-man activity compared to other lysosomal hydrolase activities. Although ferrous, ferric, cobalt, and manganese ions were highly inhibitory to beta-man, they also inhibited other lysosomal hydrolases to a similar extent. Likewise, mannose inhibited both alpha- and beta-man activities equally. The only compound to specifically inhibit beta-man in a manner similar to that observed in the tissue homogenate was glucosyl(beta, 2)fructofuranoside (sucrose). This is an important finding in that tissue samples are commonly prepared in buffers containing sucrose and this could lead to a wrong diagnosis of beta-man deficiency. In order to determine if the absence of an activator factor or alternatively the presence of a specific inhibitor was a contributing factor in the lack of beta-man activity in cultured fibroblasts from affected humans and goats, mixing studies with normal and affected cell extracts were performed but no restoration or inhibition of beta-man activity was found.

Cardiac pathology of transvenous pacemakers in dogs. Transvenous right ventricular pacemaker catheters were implanted in 18 mongrel dogs for periods of 2 to 18 months (average 4.9 months). Heart block was produced in 15 of these dogs by injection of 37 per cent formaldehyde into the interatrial septum. In the other three dogs which served as controls, no heart block was produced and no electrical stimulation was applied to the implanted catheters. After the animals had been put to death, gross and microscopic examination of the hearts revealed four categories of morphological changes: (1) connective tissue sheath formation around the catheters, (2) endocardial papillary thickening, (3) interatrial septal changes, and (4) myocardial damage. Changes 1, 2, and 4 occurred in one or more intracardiac locations in all 18 dogs. Change 3 occurred only in the 15 dogs in which heart block was produced. The most striking histologic findings were areas of cartilagenous metaplasia in endocardium an underlying myocardium and areas of marked cellular proliferation of the endocardial cells both in the endothelium and underlying stroma. Chronic implantation of transvenous intracardiac pacemaker catheters in dogs consistently produces morphologic changes which may interfere with cardiac and pacemaker function and may hinder attempts to remove nonfunctional or unneeded catheter electrodes. The changes observed appear to be related to the presence of foreign material per se and not external electrical stimulation of the heart.

Kinetic and pharmacological properties of low voltage-activated Ca2+ current in rat clonal (GH3) pituitary cells. 1. Low voltage-activated (LVA) Ca2+ current in clonal (GH3) pituitary cells was studied with the use of the whole-cell recording technique. The use of internal fluoride to facilitate the rundown of high voltage-activated (HVA) Ca2+ current allowed the study of LVA current in virtual isolation. 2. In 10 mM [Ca2+]o, detectable LVA current begins to appear at about -50 mV, with half-maximal activation occurring at -33 mV. The time course of activation was best described by a Hodgkin-Huxley expression with n = 3, suggesting that at least three closed states must be traversed before channel opening. 3. Deactivation was found to vary exponentially with membrane potential between -60 and -160 mV, indicating that channel closing is rate-limited by a single, voltage-dependent transition. 4. Onset and removal of inactivation between -40 and -130 mV were best described by the sum of two exponentials. Between -80 and -130 mV, both components of removal of inactivation showed little voltage dependence, with time constants of approximately 200-300 ms and 1-2 s. At membrane potentials above -40 mV, a single component of inactivation onset was detected. This component was voltage independent between -20 and +20 mV (tau = 22 ms). Thus inactivation of LVA current is best described by multiple, voltage-in-dependent processes. 5. Significant inactivation of LVA current occurred at -65 mV without detectable macroscopic current. This suggests that inactivation is not strictly coupled to channel opening. 6. Peak LVA current increased with increasing [Ca2+]o, with saturation approximately 50 mM. The Ca(2+)-dependence of peak LVA current was reasonably well described by a single-site binding isotherm with half-maximal LVA current at approximately 7 mM. 7. LVA current in GH3 cells was largely resistant to blockade by Ni2+. The relative potency of inorganic cations in blocking GH3 LVA current was (concentrations which produced 50% block): La3+ (2.4 microM) greater than Cd2+ (188 microM) greater than Ni2+ (777 microM). 8. Several organic agents, including putative LVA blockers, HVA current blockers and various anesthetic agents, were tested for their ability to block LVA current. The concentrations that produced 50% block are as follows: nifedipine (approximately 50 microM), D600 (51 microM), diltiazem (131 microM), octanol (244 microM), pentobarbital (985 microM), methoxyflurane (1.41 mM), and amiloride (1.55 mM). Phenytoin and ethosuximide produced 36 and 10% block at 100 microM and 2.5 mM, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

[Hepatinecrosis caused by furosemide. Special lesions of various species?]. Furosemide is a wellknown hepatotoxic agent in rodents. Toxicity is result of the production of a catabolite by action of microsomal enzymes. The goal of this study was to demonstrate differences in toxicity between two rodents species: rat and hamster. Animals received 400 mg/k/i.p. of furosemide, with or without pretreatment with phenobarbital as enzymatic inducer. Adequates controls were used. Microscopic findings were different in both groups. Rats treated with furosemide plus phenobarbital, exhibited extensive mediozonal necrosis; when those without pretreatment, showed less extensive necrosis of liver cells, erratic in distribution. In contrast, it was a lack of necrosis in hamsters' livers, showing only unremarkable changes.

The effects of erythropoietin in vitro on spleen colony-forming cells. Erythropoietin (epo) added to liquid cultures of mouse bone marrow cells effected both the numbers of spleen colony-forming cells (CFU) in the cultures and the types of spleen colonies formed from these cells in irradiated hosts. Epo caused an increase in the number of CFU detected in cultures on the second day; this effect persisted through day 10, with the maximal increase occurring on the seventh day. The magnitude of the rise on day 7 was proportional to the amount of epo added. The increase in spleen colonies found with cells cultured in the presence of epo was due solely to erythroid colonies. After seven days in culture without epo, there was a peak of cells that formed non-erythroid colonies. This peak did not appear when the cells were cultured in the presence of epo.

Antigen expression in canine tissues, recognized by a monoclonal antibody generated against canine melanoma cells. A murine hybridoma monoclonal antibody (MAB), IBF9, was generated by fusing myeloma cells (P3X63Ag8.653) with spleen cells from a BALB/c mouse immunized with the canine melanoma cell line CML-10c7. Initial screening of hybridoma antibodies was performed by use of an indirect immunoperoxidase assay on formalin-fixed CML-10c7 cells. The isotype of MAB IBF9 was IgG1 as determined by radial gel immunodiffusion. The antibody was tested for reactivity against a panel of formalin-fixed, paraffin-embedded normal and neoplastic canine tissues, using immunoperoxidase staining. Immunostaining was observed in melanomas (24 of 38), a few carcinomas, basal cell tumors, and cutaneous lymphosarcomas. Immunostaining was not observed in fibrosarcomas, hemangiosarcomas, hemangiopericytomas, or histiocytomas. Staining of normal adult canine tissues was limited to a few epithelial tissues and a small percentage of lymphocytes. Fetal tissues were not reactive with MAB IBF9. There were statistically significant differences in frequency of reactivity among melanomas with regard to oral vs non-oral, malignant vs benign, and mitotic indices greater than or equal to 1 vs mitotic indices less than 1. Differences were not significant when tumors were compared for degree of pigmentation or histologic type. On the basis of these findings, we suggest that MAB IBF9 may be of assistance in diagnosis of nonpigmented melanomas and in assessing the malignant potential of melanomas.

In vitro study of anticancer acridines as potential antitrypanosomal and antimalarial agents. The requirement for rational drug design in the search for new agents that are active against parasitic protozoa prompted our in vitro studies with a group of 9-anilinoacridines. In vitro growth assays with Trypanosoma lewisi identified a series of C-1' alkylaminoacridines which possess previously unreported potent growth-inhibitory activities against T. lewisi at a concentration range of 0.1 to 1 microM. In contrast, several 9-anilinoacridines that possess acridine ring NH2 substituents at C-3 and C-6 were inactive against T. lewisi, but they possessed strong activity against Plasmodium falciparum at a concentration range of 0.1 to 2.8 microM. In mammalian cells, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide] inhibits DNA topoisomerase II; however, amsacrine was only weakly active against T. lewisi. Such differences in the patterns of susceptibility of mammalian cells, T. lewisi, and P. falciparum to these 9-anilinoacridines may reflect enzyme differences between different parasites and mammalian cells that can be exploited by further improvements in drug design.

Hormone signalling via G-protein: regulation of phosphatidylinositol 4,5-bisphosphate hydrolysis by Gq. Heterotrimeric GTP-dependent regulatory proteins (G-proteins) mediate modulation by many cell surface receptors. Activation of the G-proteins promotes dissociation of their alpha and beta gamma subunits. The similarity of behaviour of beta gamma subunits derived from a variety of G-proteins has led to their use as affinity reagents for the analysis of the more unique alpha subunits. The evolution of these uses is presented. One of the more insightful results was the isolation of a new class of G-protein alpha subunits (the alpha q subfamily) which have been shown to regulate the activity of a phospholipase C (PLC) specific for phosphatidylinositols. The experimental evidence leading to this conclusion is discussed. The activation by alpha q increases the apparent Vmax of the beta isoform of phosphatidylinositol-specific phospholipase C (PLC beta) and can be modulated by beta gamma subunits.

Aspergillus fumigatus complement inhibitor: production, characterization, and purification by hydrophobic interaction and thin-layer chromatography. Aspergillus fumigatus has previously been shown to produce a soluble extracellular inhibitor of the alternative complement pathway, called Aspergillus complement inhibitor, or CI. We now report an efficient method for production of CI which relies on the fact that poorly conidiating cultures yielded CI activity with approximately sevenfold-higher potency than CI produced by conidiating cultures. CI from poorly conidiating cultures provided 50% inhibition of alternative pathway-mediated binding of 125I-labeled complement component C3 to cryptococcal blastoconidia at a mean concentration of 60 micrograms/ml. The ability of crude CI to inhibit the alternative complement pathway seemed to be independent of intact protein or polysaccharide structure, as evidenced by resistance of inhibitory activity to digestion by proteases, including subtilisin, alpha-chymotrypsin, papain, and pepsin as well as endoglycosidases F and H. Separation of the active inhibitory component of CI from contaminating materials contained in crude CI preparations was achieved by using Phenylsuperose hydrophobic interaction chromatography in a fast protein liquid chromatography system. The active material proved to be extremely hydrophobic, desorbing from the column only during elution with ethanol; it contained only 15% protein and 5% polysaccharide. Furthermore, results from preparative thin-layer chromatography indicated that lipids which comigrated with phosphatidylserine/phosphatidylinositol and phosphatidylethanolamine possessed significant complement-inhibitory activity. Taken together, these data suggested that phospholipids from A. fumigatus contributed to the functional activity of CI.

Association of labial salivary gland histopathology with clinical and serologic features of connective tissue diseases. Focal sialadenitis is now widely accepted as an objective criterion for the oral component of Sjögren's syndrome (xerostomia). We investigated the association between labial salivary gland histopathologic changes and the clinical and serologic features of 192 patients with suspected connective tissue disorders. A retrospective review of the medical records of all patients was performed, and historical, physical, laboratory, histologic, and roentgenographic data were abstracted. Each patient had undergone labial salivary gland biopsy as part of a rheumatologic evaluation. There were significant associations between positive findings on lip biopsy and the presence of keratoconjunctivitis sicca (P = 0.013), positive antinuclear antibodies (titer greater than or equal to 1:80) (P = 2 x 10(-8)), and positive Ro antibodies (P = 1 x 10(-8)). However, sicca symptoms and glandular enlargement were not statistically associated with positive findings on lip biopsy. Features predictive of a positive lip biopsy included Ro antibodies (P = 0.914), keratoconjunctivitis sicca (P = 0.700), and positive antinuclear antibodies (P = 0.590).

[Legislation regarding safety in the work environment and the handling of toxic substances in the 19th century and the beginning of the 20th century]. The paper deals with selected occupational safety and health regulations in Croatia in the last century and at the beginning of this century, which aimed at protecting the worker in crafts, industry, on farms and in various other occupations against the effects of toxic and other noxious substances and against injury at the workplace. Regulations relating to health protection of the general population from the adverse effects of particular substances are also discussed. Toxic metals (e.g. lead, copper, tin, arsenic) were to be found in various types of pottery or in the colouring matter for use in foodstuffs and drinks as well as in dyes used in the manufacturing of toys, paints and wall-paper. Apart from sporadic decisions and legal actions organized occupational health care was non-existent at that time. Laws and regulations concerning protection from occupational and non-occupational hazards came into force progressively, with developing knowledge about beneficial and adverse features of various substances in human use.

Terbium as a solid-state probe for RNA. This paper continues previous work on the analysis of nucleic acid-terbium complexes in the solid state. The fluorescence excitation and emission spectra of the RNA-terbium(III) complex is reported. The fluorescence excitation and emission spectra of both the RNA-terbium(III) and DNA-terbium(III) complexes as trapped on millipore filters is reported. One hundred percent of the DNA combined with terbium was trapped on millipore filters. Deoxyribonucleic acid was recovered from DNA-terbium(III) complexes trapped on millipore filters using SDS-extraction. Energy transfer was shown to occur from the bases in nucleic acids to the terbium ion, whereas the actual binding of terbium to nucleic acids was due to phosphate groups. The relative fluorescence of homopolyribonucleotide-terbium complexes showed that the guanine moiety was responsible for most of the observed fluorescence. Binding studies showed an equal affinity of radioactive terbium for all the homopolyribonucleotides. The fluorescence of solid-state DNA and RNA terbium complexes was used to measure picomole quantities of DNA or RNA.

Temporal appearance, geographic distribution, and species of origin of bluetongue virus serotypes in the United States. Beginning in 1973, all available laboratory and field strains of bluetongue virus (BTV) from the United States were serotyped. Of the viral strains serotyped, 27 were collected from 1953 through 1972; 173 were collected from 1973 through 1977. Although 20 BTV serotypes have been found worldwide, only BTV serotypes 10, 11, 13, and 17 have been found in the United States. Since 1973, serotypes 11 and 17 have been the prevalent serotypes. Samples were collected over a 24-year period in the United States and represent a wide geographic area and diverse host sources (sheep, cattle, wild ruminants, and insect vectors). The collection was not a statistical sampling.

Adsorption of apolipoprotein A-IV to phospholipid monolayers spread at the air/water interface. A model for its labile binding to high density lipoproteins. The mechanisms that mediate the labile binding of apolipoprotein A-IV (apoA-IV) to high density lipoproteins (HDL) are not known. We therefore used a surface balance and surface radioactivity detector to investigate the adsorption of apoA-IV to egg phosphatidylcholine monolayers spread at the air/water interface. ApoA-IV bound rapidly and reversibly to phospholipid monolayers and generated a maximum increase in surface pressure of 19 millinewtons (mN)/m at a subphase concentration of 2 x 10(-5) g/dl. Binding decreased linearly with increasing initial surface pressure; at pressures greater than 28-29 mN/m, apoA-IV could no longer penetrate the lipid monolayer. The area occupied by the amino acid residues in apoA-IV reached an unusually low limiting molecular area of 10-12 A2/residue at surface saturation. The surface pressure of native HDL3 was calculated to be 33 mN/m, and it rapidly decreased with the action of lecithin:cholesterol acyltransferase on the particle surface. We conclude that the surface activity of apoA-IV is lower than that of any other human apolipoprotein; its binding and surface conformation are particularly sensitive to pressure; and at saturation, a significant portion of the molecule is excluded from the interface. The exclusion pressure of apoA-IV may be only slightly lower than the surface pressure of HDL; in vivo, the action of lecithin:cholesterol acyltransferase and lipid transfer proteins may cause the HDL3 surface pressure to oscillate about a narrow range that spans the exclusion pressure of apoA-IV. The resultant labile association of apoA-IV and HDL may be of central importance to its role in lipoprotein metabolism.

Carbonic anhydrase activity and erythrocyte count in the blood of zinc-deficient rats. Eighteen male Sprague Dawley rats were divided into three groups. They were offered a semisynthetic casein diet containing either 1.2 mg Zn/kg dry matter (depletion group) or 100 mg Zn/kg dry matter (ad libitum and pair-fed control groups). At the beginning and on the 5th and 24th day of the experiment, blood was removed from a tail vein by incision to determine erythrocyte count and carbonic anhydrase activity. The zinc-depleted animals displayed a great increase in erythrocytes during the course of the experiment as compared to the ad libitum control animals. The erythrocyte counts of the pair-fed animals were also increased after 24 days on experiment, but remained significantly lower than those of the depleted animals. The activity of the carbonic anhydrase per ml blood was the same in all groups at the end of the experiment. When, however, the carbonic anhydrase activity was expressed per unit of erythrocytes, the zinc-deficient animals had a significantly lower enzyme activity than both the ad libitum and the pair-fed control rats.

[Tuberculous hilar lymphadenopathy: a survey of recent cases. Study of the variations in clinical manifestations and the mode of onset]. Forty-eight cases of tuberculous hilar lymphadenopathy were studied comparatively between the groups experienced before and after 1975. We found the following characteristics in the clinical manifestations and in the mode of onset among the recent cases as against the classical ones. (1) Age distribution of cases shifted from younger to elderly groups. (2) Roentgenologically, typical primary complex has been decreasing, while the atypical patterns such as solitary mediastinal lymphadenopathy or those associated with healed pulmonary lesions have increased. (3) Since the introduction of RFP to the treatment of tuberculosis, cases of hilar lymphadenopathy incidentally diagnosed with the early exacerbation due to RFP has been increasing. (4) Of the total of 48 cases, 10 were presumed not being originated from the primary infection, but from reactivation. (5) Relative increase of such cases may partly explain the shift of hilar lymphadenopathy to elderly group.

Involvement of the cholinergic system in the effects of nefiracetam (DM-9384) on carbon monoxide (CO)-induced acute and delayed amnesia. The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)-acetamide (DM-9384, nefiracetam), a cyclic derivative of GABA, were investigated in the carbon monoxide (CO)-induced amnesia model in mice using the passive avoidance task. Memory deficiency occurred when mice were exposed to CO before memory was completely consolidated after training (acute amnesia), at 7 days before training and 7 days after training (delayed amnesia). DM-9384 prolonged the step-down latency in mice with CO-induced amnesia. Scopolamine blocked the anti-amnesic effect of DM-9384 on delayed amnesia that had been induced by pre- or post-training exposure to CO. Bicuculline had a tendency to antagonize the anti-amnesic effect of DM-9384, but this tendency was not significant. Under these conditions, no significant change in the activity of choline acetyltransferase and glutamic acid decarboxylase was observed in the frontal cortex, striatum and hippocampus. These results suggest that DM-9384 potentiates cholinergic neuronal function and that it may modify acquisition and/or consolidation of memory.

Testing therapeutic measures for controlling chronic gingivitis in man: the results of two studies. A previous paper described a suggested protocol which could be used for testing therapeutic measures. In this paper the protocol has been used as a basis for testing experimental toothpastes over short and medium periods of time. The effects on plaque and gingivitis of a chlorhexidine paste used for 4 weeks, and of two other experimental products used over 8 weeks, have been investigated. Statistically significant improvements in gingivitis were observed during the use of chlorhexidine and one of the experimental pastes compared with their respective placebo pastes. The benefit observed for the experimental paste became evident when the data were analyzed considering only participants with 'frank' gingivitis. The findings have also been presented in various ways in attempts to express the benefits of the therapeutic measures in clinical terms by using arbitrarily determined success criteria.

Allophenic mice in cleft-palate investigations. T1Wh (Rb (5;19)1Wh), an albino strain of mice not previously used in the investigation of cleft palate (CP), is homozygous for a (5;19) Robertsonian translocation which provides conspicuous chromosomal markers. Preliminary studies in this laboratory revealed that CP is induced in all the offspring of T1Wh females treated with 2.5 mg of cortisone acetate on days 11-14 of pregnancy and that palatal closure is accomplished at a later morphological and chronological age than in C57BL/6J strain mice. The latter strain had a CP frequency of 42% under similar experimental conditions. Eight- to 16-cell embryos were aggregated in the following combinations: T1Wh in equilibrium T1Wh, C57BL/6J in equilibrium C57BL/6J and T1Wh in equilibrium C57BL/6J. The resulting allophenic blastocysts were transferred to pseudopregnant C57BL/6J recipients which were given the above cortisone treatment and killed on the 18th day of pregnancy. CP was found in all of the 48 T1Wh in equilibrium T1Wh fetuses, 4 (20%) of of 20 C57BL/6J in equilibrium C57BL/6J fetuses and in 17 (26.2%) of 65 T1Wh in equilibrium C57BL/6J fetuses. Analysis of chromosome preparations from the palates of the T1Wh in equilibrium C57BL/6J fetuses demonstrated that there is a positive correlation between the presence of CP and the percentage of susceptible cells in the palate (P less than 0.02). Other data suggest a possible growth advantage in favor of C57BL/6J cells in the palates of T1Wh in equilibrium C57BL/6J allophenic mice.

Type III restriction enzymes need two inversely oriented recognition sites for DNA cleavage. Type III restriction/modification enzyme recognize short, non-palindromic sequences that can be methylated on only one strand, with the paradoxical consequence that during replication of what is in effect hemimethylated DNA totally unmodified sites arise. Why the unmodified sites are not subject to suicidal restriction was not clear. Here we show that restriction requires two unmodified recognition sites that can be separated by different distances but which must be in inverse orientation. All of the unmodified sites in newly replicated DNA are of course in the same orientation, which explains why they are not restricted. This result may be of relevance to other manifestations of anisotropy in double-stranded DNA, such as genetic imprinting.

[Antibiotics and anti-inflammatory agents: drug interactions]. Antibiotics (AB) are sometimes used in patients taking anti-inflammatory drugs (AID) (steroidal and non steroidal anti-inflammatory drugs). At the present time, the usefulness of AID in bacterial infections has been established in a limited number of clinical situations. AID are able to modify the kinetics of AB through different mechanisms which are illustrated by results obtained with cephalosporins and phenylbutazone or diclofenac. In some conditions, these modifications might have consequences on in vivo effect of AB. Conversely, some AB are able to alter metabolism and/or kinetics of some steroids. Interactions of AI on AB toxicity have also been investigated on kidney and central nervous system. AB/AI kinetic interactions have to be investigated for a better understanding of the mechanisms through which AI improve the evolution of an infectious process.

Antioxidant vitamins and prevention of lung disease. Although the evidence for oxidative stress for air pollution in the human lung is fragmentary, the hypothesis that oxidative stress is an important, if not the sole, mechanism of toxicity of oxidizing air pollutants and tobacco smoke is compelling and growing. First, biochemical mechanisms have been worked out for oxidation of lung lipids by the gas phase of cigarette smoke, NO2 and O3. The oxidation of lung lipids can be prevented by both vitamins C and E. Vitamin C is more effective in preventing oxidation by NO2, and vitamin E is more effective against O3. Second, multiple species of experimental animals develop lung disease similar to human bronchitis and emphysema from exposure to NO2 and O3, respectively. The development of these diseases occurs over a near lifetime exposure when the levels of NO2 or O3 are at near ambient air pollution values. Third, isolated human cells are protected against oxidative damage from NO2 and O3 by both vitamins C and E. Fourth, the vitamin C level in the lung either declines on exposure to NO2 for short-term exposures or increases on chronic cigarette smoke exposure. The effects of cigarette smoking on serum vitamin C is apparently complex and may be related to the daily intake of vitamin C as well as smoking. Serum vitamin C levels may be poor indicators of lung demands when daily vitamin C intakes are above 100 mg/day. Fifth, vitamin C supplementation protects against the effects of ambient levels of air pollution in adults as measured by histamine challenge. An augmented response to histamine challenge may represent increased lung permeability brought about by air pollution. In experimental animal and human experiments, the amount of vitamin C or E that afforded protection was in excess of the current recommended dietary allowance. Although animal studies do not provide evidence for complete protection against NO2 or O3, they do illustrate that current recommended daily allowances are inadequate for maximum protection against air pollution levels to which over 100 million Americans are exposed. The problem of air pollution and its effects on humans is truly of global concern. Air pollution is not restricted to North America or Japan where it was first recognized, but is a major public health problem in Europe as well. When data are available, air pollution probably will be shown to be a major public health problem in all urban areas of the world.(ABSTRACT TRUNCATED AT 400 WORDS)

[Psychosomatic aspects of cardiac and circulatory disorders (author's transl)]. Psychic stresses may cause cardiac reactions equal to those caused by physical strain. The intensity necessary for the psychic component to cause manifest clinical symptoms depends on the distinctness of the basic somatic cardiac disorder. Representing the group of functional cardiac and circulatory disorders the so-called phobic cardiac neurosis is discussed more in detail as well as the myocardial infarct as representatives of the group of coronary diseases. On the basis of tests (MMPI plus questionnaire) two groups may be differentiated. One group is characterized by pronounced dependance, sparing attitude, avoidance of situations and narrowing of environmental relations, the other by compensatory activity and physical engagement. The distinction is of relevance for therapeutic reasons and for reasons of somatic diagnosis. Among infarct patients we are presently trying to determine single psychic variables with respect to their importance as risk factors. Compulsiveness and rigidity or sociability and extraversion respectively appear to play a role.

Localization of epidermal growth factor immunoreactivity in sheep skin during wool follicle development. Interactions among the cells and matrices of the epidermis and mesenchyme of skin are essential for hair follicle initiation and development. The identification of receptors for epidermal growth factor (EGF) on epithelial components of the follicle during growth has suggested that the ligand participates in some of these events. We have used affinity-purified antibodies together with an alkaline phosphatase detection procedure to investigate the distribution of EGF in the skin of the sheep during wool follicle formation. Immunoreactivity was restricted to the periderm and intermediate layers of fetal epidermis at 55 d of gestation, when the first wave of wool follicles are initiated. This particular distribution persisted during subsequent development but never became associated with the basal cells of the epidermis. The activity was lost around 118 d, coinciding with sloughing of the periderm. No immunoreactivity was found in the plugs or the dermal condensations of the developing follicles. At approximately 105 d of gestation, however, reactions were detected in the outer root sheath as the follicles matured and in the differentiating cells of the sebaceous glands. A similar distribution pattern was also noted at 140 d, just prior to birth, and in adult animals, indicating that EGF was sequestered and perhaps synthesized within the follicle. The presence of immunoreactive material was also associated with the pilary canals and the skin surface, suggesting that this may have had its origin in the sebaceous glands. We examined this using a radioreceptor assay for EGF. Material washed from the skin surface and sebaceous gland extracts were found to displace 125I-EGF from rat liver membranes, in parallel with mouse EGF.

Genetic analysis of resistance to total bromodeoxyuridine substitution in mammalian cell hybrids. Somatic cell hybrids derived from the fusion of Chinese hamster ovary cells (CHO) and mutant Syrian hamster melanoma cells (2E) were tested for their ability to grow with all of the thymidine (dThd) in their DNA replaced with 5-bromo-2'-deoxyuridine (BrdU), a phenotypic capability of the 2E cells but not of the CHO cells. Under these conditions, the 2E cells survived and grew, all of the hybrid clones survived and grew to varying degrees, and the CHO cells did not survive at all. When 2E cells were tested, they were also found to be resistant to the toxic effects of BrdU substitution and white light irradiation, relative to CHO cells. Thus, when the DNAs of 2E and CHO cells were equally (50%) substituted with BrdU, and the two cell lines irradiated with identical doses of white light, the survival of CHO cells was reduced to less than 1% of that of unirradiated cells, while 40% of the 2E cells survived. The 2E x CHO hybrid clones were found to survive at values from 10% to 40% under these identical conditions. Thus, the phenotypic characteristics of 2E cells involving total substitution and resistance to the toxic effects of BrdU substitution and white light irradiation appear to be expressed in a codominant fashion in somatic cell hybrids.

Levels of glucose and insulin during twenty-four hours in hyperprolactinemic women with pituitary microadenoma. Excursions of plasma glucose and insulin throughout the 24-hour metabolic clock were evaluated in hyperprolactinemic women with pituitary microadenoma. The glucose response to food intake and 24-hour excursion of plasma glucose were not altered in hyperprolactinemic women compared to normal women. Premeal and 24-hour insulin levels were significantly increased in hyperprolactinemic women, though fasting insulin levels were not. Postprandial insulin increments appeared to be more sustained in these patients compared to normal women, though the difference was not statistically significant. And therefore the increased 24-hour concentration of insulin in hyperprolactinemic women appears to be due to the sustained insulin response to meals and increased premeal insulin levels. A slight resistance to insulin was observed in hyperprolactinemic women. That the 24-hour excursion of plasma glucose is not altered in hyperprolactinemic women in the face of decreased sensitivity to insulin may be accounted for by the increased insulin secretion.

Antibodies to core lipid fractions of endotoxin in children with rheumatic disease. The titer of IgG and IgM antibodies to two fragments of endotoxin derived from Salmonella minnesota R 595, lipid A width a 2-keto-3-deoxyoctanate oliosaccharide (KDO lipid A), and monophosphoryl lipid A (mono-P lipid), were measured in normal children, children with cystic fibrosis, and children with SLE and all forms of chronic juvenile arthritis. Elevated titers of IgM anti mono-P lipid A were found in all of the rheumatic diseases, but not in cystic fibrosis. The elevated IgM titers were not correlated with concentration of activation fragments of C3 or C4, but IgG anti mono-P lipid A titers, even though not usually elevated, did correlate with C3a and C3d concentrations. The elevated IgM titers to mono-P lipid A may represent a genetically determined hyper-reactivity to normal gastrointestinal antigens, an increased antigenic stimulus from the intestinal tract, or polyspecificity of an antibody of undetermined primary reactivity.

The role of radiology in urinary tract infection in children. Of 758 children examined by uroradiography at the Transvaal Memorial Hospital for Children, 232 (30%) had been referred for the diagnosis of urinary tract infection. The incidence of radiological anomaly or abnormality in these children was an overall 30%; in the first 3 years of life this figure rose to 40%. Radiological investigation of these children should be undertaken routinely. Excretory urography alone is a satisfactory screening procedure in children over the age of 3 years; under this age, formal voiding cysto-urethrography is of immense importance. The incidence of 70% of underlying radiologically detectable abnormalities associated with Pseudomonas infection was statistically significantly higher than the 30% found in association with all other infecting organisms.

Growth hormone-releasing hormone is produced by rat Leydig cell in culture and acts as a positive regulator of Leydig cell function. Rat GH-releasing hormone (GHRH), mainly contained in hypothalamic neurons, has also been identified in several extraneural tissues, including the gastrointestinal tract, placenta, ovary, and testis. In the testis, GHRH mRNA is ontogenically regulated, and GHRH immunoreactivity can be observed in interstitial cells and tubules, suggesting an intratesticular role for the peptide. Leydig cells in culture are able to produce hypothalamic releasing hormones, i.e. CRH, which acts as an autocrine negative regulator of Leydig cell function. In this study we investigated whether GHRH is present in Leydig cells and evaluated the role of the peptide in Leydig cell function. Adult Leydig cells in culture produced considerable amounts of immunoreactive GHRH [23.9 +/- 2.1 (+/- SE) pg/10(6) cells.30 min], and the release of the peptide was acutely stimulated by hCG. HPLC analysis of GHRH in media from basal and hCG-treated cultures showed the presence of a single peak eluting at the same retention time as that of hypothalamic rat GHRH. Radioligand binding and activation studies revealed a common receptor for vasoactive intestinal peptide (VIP) and rat GHRH in Leydig cell membrane. Specific binding of [125I]VIP to Leydig cell membranes showed the presence of a single site, with high affinity and low binding capacity. The relative potencies of VIP-related peptides for inhibition of radioligand binding were: VIP > rat GHRH > secretin > human GHRH. In cultured Leydig cells, GHRH and VIP stimulated cAMP production, consistent with coupling of the receptor to the adenylate cyclase system. VIP displayed a lower ED50 than GHRH in stimulating cAMP production (P < 0.01), comparable with the higher binding potency of this peptide. No additive effects of VIP- and GHRH-stimulated cAMP generation were observed, suggesting that both peptides compete for the same receptor protein. GHRH and VIP had no effect on basal steroidogenesis, indicating a lack of tonic actions and compartmentalization of the peptides' effect. On the other hand, GHRH acted as a potentiator of the acute gonadotropin stimulation of testosterone production and cAMP generation. [125I]hCG binding to the Leydig cells in culture showed that GHRH was unable to affect the number or affinity of binding sites for hCG, indicating that the GHRH-sensitizing effect on LH action is beyond the level of gonadotropin binding and possibly is through the facilitation of LH receptor coupling functions.(ABSTRACT TRUNCATED AT 400 WORDS)

[The structural changes in chromatin at different levels of its organization during aging]. The data about changes in the molecular organization of the cell nucleus during aging are reviewed. Changes in DNA primary and secondary structure include deletions of some sequences, changes in base methylation pattern and the increasing number of DNA breaks. Conditions underlying poor reproducibility of the results obtained in corresponding experiments are discussed. Changes observed in the nucleosomal and supranucleosomal chromatin structure reflect either its increasing compactization or the loss the nucleosomal structure during aging. The data about the increased DNA superhelicity and topoisomerase activity in aging organisms contradict the accepted views about age-related decrease in chromatin activity. It is suggested that the gene activity in aging organisms is specifically altered rather than generally decreased. The data are presented about the ways of preventing or reverting the age-related changes in chromatin structure.

Maximal rate of the left ventricular pressure fall (peak negative dP/dt) in early stage of myocardial ischemia following experimental coronary occlusion. Short-term, repeated myocardial ischemia was produced in 20 opened-chest anesthetized dogs by left anterior descending (LAD) branch occlusion. Left ventricular pressure (LVP) and its dP/dt were recorded by Satham SF-1 transducer, and isometric local force (F) was measured by a Walton-Brodie strain gauge arch sewn onto LV free wall. In all experiments, within a few beats after LAD occlusion, peak negative dP/dt started to diminish its amplitude, reaching a nadir after 20-30 sec (63 +/- 5% of control, 9 dogs). It recovered to 83 +/- 3% of control level in 45 sec and remained essentially unchanged thereafter. This change preceded those of LVP and max dP/dt, which showed only minor falls. In 6 dogs, changes by occluding root of LAD were compared with those by its branch occlusion. The greater the extent of ischemia, the more marked and prolonged were the changes. While F in the ischemic center (Fc) rapidly lost its contractile activity following LAD occlusion, F in marginal zone between infarcted and non-infarcted region (Fm) showed variable extent and different time-course of its diminution. Thus, it was concluded that the change in peak negative dP/dt following LAD occlusion was one of the sensitive signs of early ischemic changes, and was attributed at least in part to characteristic changes in contractile activity of myocardium surrounding the ischemic injury.

Doppler evaluation of umbilical and uterine-arcuate arteries in the postdates pregnancy. To assess the correlation between Doppler velocimetry and perinatal outcome in the postdates pregnancy, 75 women who were at least 41 weeks' gestation were evaluated twice weekly until delivery. Evaluation included Doppler velocimetry of the umbilical and uterine-arcuate arteries, as well as nonstress testing and amniotic fluid volume estimation. The mean umbilical artery systolic-diastolic ratio (S/D) was significantly higher in the pregnancies with subsequent abnormal perinatal outcomes than in those with normal outcomes (2.42 versus 2.19; P = .03). Using a receiver operating characteristic curve, an abnormal umbilical artery S/D was defined as 2.40 or greater. Using this value, sensitivity was 57.1% and specificity was 77.8%. Our study suggests that an umbilical artery S/D of 2.40, rather than the more traditionally accepted cutoff of 3.0, may be a useful threshold to identify those postdates pregnancies at high risk for abnormal perinatal outcome.

Interferon-alpha and 3'-azido-3'-deoxythymidine are highly synergistic in mice and prevent viremia after acute retrovirus exposure. This study was undertaken to calculate the in vivo drug interactions between recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) and 3'-azido-3'-deoxythymidine (AZT) in a quantitative model for retroviral viremia. When given as single agents, both AZT and rHuIFN-alpha A/D suppressed virus-induced splenomegaly in a dose-dependent fashion in mice inoculated with Rauscher murine leukemia virus (RLV). However, suppressive doses of single-agent AZT caused anemia after 20 days of therapy. Combining rHuIFN-alpha A/D with AZT allowed drastic dose reductions for each agent while maintaining greater than or equal to 93% inhibition of splenomegaly. No clinically significant toxicity was seen. Computer analysis with the isobologram technique and combination index method showed that these combination regimens were highly synergistic. A 20-day course of AZT + rHuIFN-alpha A/D started 4 h after virus exposure was protective against RLV viremia and disease. After cessation of therapy, the animals were resistant to rechallenge with fully infectious RLV. We conclude that prompt initiation of effective combination therapy after retroviral exposure prevented viremia and disease and led to protective immunity.

[The use of a dry cow preparation for the prevention of summer mastitis in maiden heifers (author's transl)]. An investigation was made of the preventive value of topical application to juvenile udders of a dry cow preparation containing 300,000 IU of procaine penicillin G (Penzal N 300). Penicillin concentrations in udder secretions of 30 young cows were examined. In calves up to 10 weeks and in maiden heifers up to 7 weeks after application an average concentration of 0.05 ml IU per ml of secretion was found. In the same groups, 12 and 9 weeks respectively after application, the concentration was 0.01 IU per ml of secretion. Experiences in practice in an area with a high infection rate have shown an obvious protection in 700 maiden heifers. Some cases of infection did occur both shortly (1.0%) and from 5 weeks after application (1.9%). The clinical character of the latter was much milder than is usual for summer mastitis. When administered in time and in the correct manner the dry cow preparation examined showed reasonable protection against summer mastitis.

A comparative study of [Leu1]Tuftsin and tuftsin, a natural phagocytosis-stimulating peptide. 1. [Leu1]tuftsin was reported to have greater phagocytosis-stimulating activity than tuftsin (Thr-Lys-Pro-Arg). 2. However, a study on inactivation of tuftsin by polymorphonuclear leukocytes (PMNs) demonstrated that leucine aminopeptidase, an ecto-enzyme, located on PMN surface was responsible for this mechanism. 3. Since leucine aminopeptidase is known to cleave Leu more easily than Thr at the N-terminal position of peptides, this suggested to us that [Leu1]tuftsin might then be inactivated by PMNs more easily than tuftsin, and thus this analog might be less active than tuftsin. 4. In addition, many tuftsin preparations used in earlier studies were not fully active, as high-performance liquid chromatography was not available to separate out many contaminating diastereomers. 5. In view of this, we have synthesized and purified [Leu1]tuftsin and compared its phagocytosis-stimulating activity with tuftsin. 6. Our results indicate that [Leu1]tuftsin is not as active as tuftsin in stimulating phagocytosis.

Metabolism of antiepileptic medication: newborn to elderly. Epilepsy affects individuals of all ages. Regimens of antiepileptic drugs (AEDs) and side-effect profiles differ for infants, children, adults, and the elderly. Thus, the epileptologist must be familiar with the specific changes of AED metabolism with age. In general, metabolic rates are fastest in children; therefore, AED half-lives are shortest in this group. Rates of AED elimination are slowest in neonates, infants, and children. Thus, children need larger dosages, on a mg/kg basis, than adults. The usual phenytoin (PHT) dosage in adults is 4-6 mg/kg per day, but children may need a dosage three to five times higher. On the other hand, the PHT dosages in the elderly may need to be 3-4 mg/kg per day to achieve therapeutic levels. Likewise, the half-life of carbamazepine (CBZ) is shortest in children and the elderly. Profiles of metabolites may also be age-specific, a difference of particular importance for valproate (VPA). The relative amount of VPA metabolized to 4-ene is more than twofold less in adults than in children, which may explain the different profile of hepatotoxicity seen by age. The elderly may be more vulnerable to adverse effects of AEDs. Many elderly have neurologic deficits that may render them more vulnerable to neurotoxic effects such as ataxia and cognitive disturbances. Also, low serum albumin concentrations, which result in decreased binding, may mask high serum AED concentrations. The hyponatremia associated with CBZ may be a particular concern in the elderly. Gingival hyperplasia, a concern in children, may not be a problem in the elderly.

A tool for the design and evaluation of alternative quality-control procedures. I have developed an interactive microcomputer simulation program for the design, comparison, and evaluation of alternative quality-control (QC) procedures. The program estimates the probabilities for rejection under different conditions of random and systematic error when these procedures are used and plots their power function graphs. It also estimates the probabilities for detection of critical errors, the defect rate, and the test yield. To allow a flexible definition of the QC procedures, it includes an interpreter. Various characteristics of the analytical process and the QC procedure can be user-defined. The program extends the concepts of the probability for error detection and of the power function to describe the results of the introduction of error between runs and within a run. The usefulness of this approach is illustrated with some examples.

Protamine and polyarginine bacteriolysis. Similarities in its mechanism with chromatin DNA picnosis. Protamine and polyarginine had bacteriolytic effects indicating their primary sites of action as being wall components and showing bacterial diversity genetically determined. Shake-incubation was required in producing cell-lysis. Studies on Bacillus subtilis revealed a high polycation multiplicity per cell in lytic event displaying multihit lysing kinetics; bacteriolysis was inhibited by trypsin, pronase, purified polyanionic wall polysaccharide, and by dissociative actions of salt hypermolarities used in isolation of nucleic acids. The inactivation of polycation lytic abilities during bacteriolysis was accompanied by modifications in electrophoretic running of protamine and polyarginine. It is suggested as mechanism of cell-lysis, the multiple zonal surface condensations of polyanionic wall components by basic polypeptides, likely similar with chromatin DNA picnosis. This analogy is discussed.

Inhibition of palmitoyl co-enzyme A hydrolase in mitochondria and microsomes by pharmaceutical organic anions. Rat microsomes and mitochondria were isolated and incubated with selected pharmaceutical organic anions at concentrations of 0, 0.2, 0.5, 1.0, and 2 mM. Activity of palmitoyl CoA hydrolase (PCAH) was shown to be reduced in a dose-dependent manner in microsomes by ibuprofen, valproate, acetyl salicylate, 2,4-dichlorophenoxyacetate (2,4-D), and 4-pentenoate, but not salicylate. Mitochondrial PCAH activity was inhibited by clofibrate, ibuprofen, valproate, and 2,4-D. Mitochondrial oxidative phosphorylation was impaired or uncoupled by each of the mitochondrial PCAH inhibitors. The inhibition of PCAH by some of these agents may lead to fatty acyl CoA accumulation. Very low concentrations of fatty acyl CoA are known to cause mitochondrial uncoupling and increase permeability. This action may play a role in the mitochondrial injury caused by some of these agents or related disease processes.

Thrombolysis in patients with unstable angina improves the angiographic but not the clinical outcome. Results of UNASEM, a multicenter, randomized, placebo-controlled, clinical trial with anistreplase. The value of thrombolytic therapy in unstable angina is unclear. To study this problem, 159 patients were studied in a double-blind, placebo-controlled multicenter trial. Patients without a previous myocardial infarction, with a typical history of unstable angina, and ECG abnormalities indicative of ischemia were included. After baseline angiography, study medication (anistreplase or placebo) was given. Angiography was repeated after 12-28 hours. A significant decrease occurred in diameter stenosis between the first and second angiogram in the anistreplase group compared with the placebo group (11% versus 3%, p = 0.008). This difference was caused by reopening of occluded vessels in the thrombolytic group. However, no beneficial clinical effects of thrombolytic treatment were found. Bleeding complications were significantly higher in patients who received thrombolytic therapy (21 versus seven patients, p = 0.001). Thus, angiographic but no clinical improvement after thrombolytic treatment with anistreplase was found in patients with unstable angina with an excess of bleeding complications. Therefore, thrombolytic treatment cannot be recommended in patients diagnosed as having unstable angina until proven otherwise.

Do different hemodynamic effects of antihypertensive drugs translate into different safety profiles? Various antihypertensive drugs reduce blood pressure by different mechanisms. In some instances, adverse reactions occur because of specific hemodynamic effects. Examples include syncope with alpha-blockade or vasodilator therapy; fatigue or exercise intolerance with the reduction in cardiac output following the use of beta-adrenergic inhibitors; edema, headaches, or dizziness with the use of vasodilators such as calcium entry blockers; renal failure in patients with renal artery stenosis or renal insufficiency following the use of ACE inhibitors; and marked hyponatremia with volume depletion following the use of diuretics, especially in elderly patients. In the majority of patients, however, blood pressure lowering can be achieved without significant adverse effects. Combining small doses of different agents with different hemodynamic actions often results in good blood pressure control and minimal reactions. Examples of these include diuretics and beta-adrenergic inhibitors, diuretics and ACE inhibitors, and beta-blockers and vasodilators.

[Water regulation in slaughter-houses and meat works. Showering pigs intended for slaughter (author's transl)]. On a number of relatively cold and hot days, the effect of showering pigs in the pens of a pig slaughter-house was studied. During the resting period of approximately two hours, 50 per cent of a group of 459 pigs were showered and the other 50 per cent were not. The situation in the pens, the variations in body temperature and the quality of the pork were determined. It can be concluded that showering pigs intended for slaughter in pens using water of approximately 13 degrees C: -- reduces pollution in the slaughter line; -- results in a significant decrease in body temperature; -- reduces the number of animals showing an abnormal quality of the pork on hot days. Showering has a less beneficial and occasionally even adverse effect on the quality of the pork on cold days.

A modified bronchoalveolar lavage procedure that allows measurement of lung epithelial lining fluid volume. We replaced the standard serial bronchoalveolar lavage technique with a new "rewash" lavage procedure to allow estimation of the volume and protein concentration of the epithelial lining fluid (ELF) in anesthetized sheep. A bronchoscope 6.0 mm in diameter wedged in an airway was used to lavage a segment of lung with four cycles of instillation and aspiration of the lavage solution containing a radioactive tracer (technetium pertechnetate, 99mTcO4-). Errors caused by the fall in concentration of the tracer during the lavage were minimized by extrapolating the tracer concentration back to time zero when the lavage solution had mixed with the ELF, but had not had time to be affected by loss of the tracer or influx of fluid from the interstitium. In control sheep, the ELF of these lavaged segments had a mean volume of 1.6 +/- 1.0 ml and a mean protein concentration that was 26 +/- 19% of the protein concentration measured in the plasma. Increasing the left atrial pressure 19 +/- 5 cm H2O to cause "cardiac lung edema" had no significant effect on the ELF volume, but it increased the mean protein concentration to 57 +/- 30% of the plasma value (p less than 0.01). Lung injury caused by intravenous oleic acid caused lung edema, increased the mean ELF volume to 6.8 +/- 2.2 ml, and increased the mean ELF protein concentration to 86 +/- 26% of the plasma value (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Roles of immobilized glycosylated proteins and lipoprotein(a) in adhesivity of endothelial cells: possible implications for atherogenesis. The adherence of peripheral blood monocytes to adult bovine endothelial cells grown to confluence in the microplates was studied. The microplates were coated with different proteins or used without special treatment. It was shown that endothelial cells seeded on immobilized glycosylated proteins (serum albumin or skin gelatin) adhered more monocytes than the cells grown on non-modified proteins. Endothelial cells grown in lipoprotein(a) coated wells bound more monocytes than the cells grown in non-treated microplates or in wells coated with low density lipoproteins (LDL). The effect of lipoprotein(a) coating could not be reproduced by treating the plates with plasminogen (as a homolog of apo(a)) or with a mixture of LDL and plasminogen. These results indicate that the composition of extracellular substrata has a profound effect on adhesive properties of cultured endothelial cells. The implications of these findings for atherogenesis and for the general aspects of regulation of cell adhesion are discussed.

Regulation of the anterior-like cell state by ammonia in Dictyostelium discoideum. Ammonia appears to be an important regulatory signal for several aspects of the Dictyostelium life cycle. The postulated role of ammonia in the determination of the prespore pathway in cells of the slug stage has led us to examine the effect of ammonia on the prestalk/prespore ratio of migrating slugs. In the presence of 10(-3) M ammonium chloride, the volume of the prestalk region decreases by 40.8%. The kinetics of the process make it unlikely that this is due to a shift in the differentiation pathway. A test of the hypothesis that the decrease in volume of the prestalk region is due to the conversion of prestalk cells to anterior-like cells shows that the percent of anterior-like cells in the posterior region increases by the amount predicted by the hypothesis. This suggests that ammonia may be the molecular signal, produced by the tip, that prevents anterior-like cells from chemotactically migrating to the tip and thereby becoming anterior cells. The effect of enzymatic removal of ammonia from vitally stained migrating slugs is the appearance of a series of dark stripes beginning at the posterior end and progressing forward. We interpret this as a result of progressive removal of anterior-like cells from tip dominance and essentially as the formation of new potential tips. Indeed, in a few cases one or even two of the stripes separate from the posterior of the cell mass and form small fruiting bodies. We consider the phenomenon of stripe formation further evidence that the tip acts on anterior-like cells through ammonia.

Gentamicin in 1978. For a decade gentamicin has been used extensively because of its antimicrobial efficacy and the relatively low prevalence of clinical toxicity. Recently the more frequent appearance of resistant organisms, reports of increased nephrotoxicity and ototoxicity, and the development of newer aminoglycoside antibiotics have raised doubts about the continued use of this agent. This paper reassesses the role of gentamicin. It is clear that an appreciation of the pharmacokinetics and the clinical use of gentamicin as well as an understanding of the patterns of toxicity in animals and humans can lead to more efficient treatment with this antimicrobial agent. Despite ample competition from a number of newer aminoglycoside antibiotics, gentamicin will probably continue to be used widely in the near future.

A mathematical model for the rate of oxygenation of blood in pulmonary capillaries using nth-order one-step kinetics of oxygen uptake by haemoglobin. A mathematical model is described for the process of gas exchange in pulmonary capillaries by taking into account the transport mechanisms of molecular diffusion, convection, and the facilitated diffusion due to haemoglobin. The nth-order one-step kinetics of oxygen uptake by haemoglobin has been incorporated. The rate k at which blood becomes oxygenated is determined by setting up an appropriate eigenvalue problem. This method eventually leads to a transcendental equation in k. A multiprecision technique due to Verma and Sharan (1980) is employed to obtain a physically acceptable solution. It is shown that, at equilibrium, the saturation of haemoglobin with oxygen computed from the analysis is fairly close to the data of Severinghaus (1966). It was found that 97.15% of the total haemoglobin combined with oxygen. The blood is oxygenated well before it leaves the pulmonary capillary. The dissolved oxygen takes longer to achieve equilibration whereas the carbon dioxide traverses a comparatively smaller distance in the capillary.

[The effect of the prophylactic use of benzonal on the cytochrome P-450 content of the liver in irradiated rats]. The rats (100 mg/kg, once a day, per os, during 3 days) were administered suspension of benzonal in starch gel before irradiation of 12 Gy. Induced and uninduced rats were irradiated on the following day after stopping benzonal administration and were decapitated at 10, 12, 15 and 21 o'clock during the first and second day after irradiation and also on the fourth day (day of mass death of irradiated rats). It has been established that irradiation changes the dynamics of cytochrome P-450 concentration in microsomal fraction of rat liver. The essential decrease of the content of cytochrome on the second day after irradiation was accompanied by intensification of the process of its inactivation, but stoichiometry between the decrease of P-450 and the increase of cytochrome P-420 was not observed. The high inducing and stabilizing effects of benzonal on cytochrome P-450 and on the liver persisted. In comparison with irradiation the unfavourable effect of benzonal on immunocompetent organs (thymus, spleen) was not found.

Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Helicobacter pylori infection, histological features of the gastric mucosa, and gastric motor and secretory functions were evaluated in 45 consecutive patients with chronic idiopathic dyspepsia. H. pylori infection was found in 60% of dyspeptic patients, compared with 33% of 15 healthy controls (P = 0.1). No difference was detected in basal or stimulated gastric acid secretion between dyspeptic patients and healthy controls. Gastric emptying was significantly (P less than 0.01) delayed in dyspeptic patients compared with healthy controls when standardized for age and sex. Delayed gastric emptying was associated with a low frequency of H. pylori infection, female gender, and young age. Epigastric pain or burning and postprandial fullness were, respectively, more severe in patients with H. pylori infection (P less than 0.02) and in those with delayed gastric emptying (P less than 0.01). These findings support the existence of separate subsets of patients with chronic idiopathic dyspepsia. Despite the presence of overlaps, there appear to be partially different functional derangements and clinical features in different subgroups of dyspeptic patients.

Secretion of pre-beta-migrating apoA-I by cynomolgus monkey hepatocytes in culture. Cynomolgus monkey hepatocytes that had been stored frozen were thawed, established in culture, and used to study apoA-I secretion. Protein synthetic activity was low at first, but increased with time, approaching what appeared to be the constitutive levels of the intact liver by day 7. During the first week, cellular RNA levels increased from 5.3 +/- 0.3 to 18.6 +/- 1.0 micrograms/10(6) cells; albumin secretion rates increased from undetectable to 55.4 micrograms/10(6) cells per day; apoA-I mRNA levels increased from 174 +/- 12 to 564 +/- 145 ng/10(6) cells; and apoA-I secretion rates increased from undetectable to 2.11 +/- 0.27 micrograms/10(6) cells per day. Analysis of day 7-conditioned media by agarose electrophoresis, gradient gel electrophoresis-immunoblotting, and column chromatography, showed that the apoA-I produced by the cells was present in three distinct forms. One had an apparent molecular mass greater than 1 million Da, migrated pre-beta, and accounted for 11 +/- 3 (mean +/- SD)% of the total; one had an apparent molecular mass of 104 kDa, had alpha migration, and accounted for 27 +/- 2% of the total; and one had an apparent molecular mass of 50 kDa, migrated pre-beta, and accounted for 46 +/- 9% of the total. These data support the proposition that the pre-beta-migrating, 50 kDa, apoA-I-containing particles identified in the plasma of cynomolgus monkeys are nascent hepatic HDL.

[Characterization of erythrocyte deformability by filtration technics. 5. The effect of leukocytes on the filterability of erythrocytes]. Filterability measurements have been used widely in medical research and clinical practice to characterize erythrocyte deformability. In the present paper the influence of white blood cells (WBC) on the of filterability indices is investigated and discussed. We found for two gravity filtration systems using cellulose filters and concentrated erythrocyte suspensions sensitivities of their filterability indices of 1% per 100 WBC/microliters (initial) filtration rate measurement) and 3% per 100 WBC/microliters (hemofiltrometer). The necessity, advantages and disadvantages of additional methods for WBC removal are discussed in comparison to nuclepore filtration systems with sensitivities of 5-12% per 100 WBC/microliters. The standardization of residual WBC-count in limits of 500 +/- 300 WBC/microliters at a hematocrit of 60% is proposed.

Relationships between pressure and flow in the umbilical and uterine circulations of the sheep. We studied the relationship of fetal and maternal vascular pressures to umbilical and uterine blood flow in the unanesthetized ewe and in the sheep fetus in utero by placing electromagnetic flow transducers around both the common umbilical and uterine arteries. Reductions in umbilical arterial pressure or elevations in umbilical venous pressure decreased umbilical blood flow without affecting either the uterine arterial blood flow or other maternal cardiovascular variables which were studied. Elevations in uterine venous pressure or reductions in uterine arterial pressure decreased uterine arterial flow but these interventions had no effect on umbilical blood flow until fetal hypoxemia and bradycardia occurred. When the bradycardia of the fetal hypoxic response was inhibited by atropine, alterations in maternal vascular pressure had no effect on umbilical arterial flow. These data do not support the presence of a "sluice" or "waterfall" effect in the umbilical-placental circulation of the sheep fetus in utero.

Factor analysis of the items of the State-Trait Anxiety Inventory. The present investigation was designed to determine by factor analysis the nature of the items that comprise the A-State and A-Trait scales of the State-Trait Anxiety Inventory. Three factors were identified. Factor I was defined exclusively by items from the A-State scale. The underlying dimension tapped by the scale was interpreted as state anxiety (how one feels at a particular moment in time); support thus was provided for Spielberger's A-State concept. Items from the A-Trait scale, however, identified two separate factors, neither of which was clearly consonant with Spielberger's concept of A-Trait. Factor II appeared to tap state anxiety according to how the individual generally feels or a typical level of state anxiety as remembered over an indefinite period of time. Factor III was interpreted as a measure of neuroticism.

Evaluation of ultrasound for prediction of carcass fat thickness and longissimus muscle area in feedlot steers. Four hundred fifty-two yearling steers from two experiments were measured for subcutaneous fat thickness and longissimus muscle area between the 12th and 13th ribs using real-time linear array ultrasound equipment. Ultrasonic predictions were compared to corresponding carcass measurements to determine accuracy of ultrasound measurements. In Exp. 1, 74% of the ultrasonic estimates of fat thickness were within 2.54 mm of carcass values (r = .81) and muscle area was predicted within 6.45 cm2 for 47% of all carcasses (r = .43). Although similar correlation coefficients between ultrasonic and carcass fat thickness were obtained in Exp. 2 (r = .82), estimates were more biased; only 62% of ultrasound estimates were within 2.54 mm of carcass measurements. Improvement in longissimus muscle area estimates was noted in Exp. 2, in which 54% of ultrasonic estimates were within 6.45 cm2 of carcass values (r = .63). The extremes for each trait proved most difficult to predict; fat thickness was underestimated on fatter cattle and muscle area was underpredicted on more heavily muscled steers. Ultrasonic measurements of fat thickness are precise and accurate in determining carcass fat thickness, but muscle area estimates are inconsistent and warrant further investigation.

Membrane conductance changes in single nodes of Ranvier, measured by laser-induced temperature-jump experiments. Temperature-jump experiments on isolated myelinated nerve fibers were done using a pulsed laser system in the Q switched mode. Voltage-clamp and temperature perturbations were used to measure the relaxing ionic conductances of both the Na+ and K+ systems. It is shown that the T jump can be used to probe the K+ and Na+ conductances during non-steady state conditions and thereby elicit relaxation times for a variety of initial states. Temperature-induced K+ conductance relaxation times were consistent with voltage-clamp measurements. The temperature-perturbation experiments were done as a combination of a temperature step and impulse change due to an adsorption of carbon black particles on the nerve. The experiments support the hypothesis that the relaxation times of the K+ system are independent of the previous history of the axon. It is concluded that the K+ conductance is at least a second-order system whose relaxation spectrum is composed of two exponential terms the magnitudes of which are markedly dependent on the initial conditions.

Current assessment practices for noncancer end points. The need for assessing noncancer risks for agents to which humans are routinely exposed indoors arises from the large amount of time spent indoors (i.e., employed persons spend about 60% of their time at home indoors, 30% at work indoors, and 5% in transit). Sources of air pollutants include heating and cooling systems, combustion appliances, personal use products, furnishings, tobacco products, pesticides, bioeffluents from humans and animals, and other microbial contamination such as toxins from molds. The purpose of this paper is to describe current dose-response assessment methods applicable to assessing risk following exposure to indoor air pollutants. The role of structure-activity relationships in hazard identification is also described. Risk assessments from exposure to indoor air pollutants require exposure assessments and dose-response assessments. Dose-response assessment methodologies include the inhalation reference concentration (RfC), structure-activity relationships, dose-response models, and the decision analytic approach. The RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The current RfC method provides guidelines for making the necessary dosimetric adjustments for gases and aerosols. Human equivalent concentrations for no-observed-adverse-effect levels in animals are determined by using mathematical relationships that adjust for regional deposition, solubility, ventilation rate, and blood:air partition coefficients. The RfC methodology exists as an interim methodology. Future scientific advancements are expected to further refine the approach.

Functional anatomy of human hand sensorimotor cortex from spatiotemporal analysis of electrocorticography. We measured chronic electrocorticography (ECoG) of sensorimotor cortex during contralateral median nerve stimulation in 6 patients with partial seizures evaluated for surgery. We analyzed the spatiotemporal structure of the somatosensory evoked response (SER) using multiple source modeling to investigate functional anatomy of its neuronal sources. Two dipole sources in postcentral gyrus explained the large majority of the first 60 msec of the SER, indicating a subregion of hand somatosensory cortex generating this activity. The source locations agreed with normal functional anatomy from cortical stimulations, intraoperative photographs, and postoperative neurological examinations after focal excisions. The time patterns of both sources were biphasic like the previously described N20-P30 and P25-N35 peaks. The spatiotemporal patterns of both sources overlapped. Spatiotemporal analysis with multiple dipole sources appears useful to determine the number, locations, and spatiotemporal field patterns of cortical regions active during peripheral somatosensory stimulation and reveals simplicity in the macroscopic functional anatomy of dynamic human sensorimotor cortex.

Transferrin uptake by rabbit alveolar macrophages in vitro. Rabbit alveolar macrophages were shown to bind 125I-human transferrin in vitro. The binding reaction was characterized by three stages: (1) adsorption of transferrin to the cells, followed by (2) rapid uptake of the protein to reach (3) a constant level of cell-bound transferrin. The latter two stages were dependent upon temperature and metabolic energy. Macrophages released 125I-transferrin rapidly when incubated with unlabelled transferrin. Small quantities of 125I-rabbit and 125I-bovine serum albumin, by comparison, were bound to and released by the cells; the attachment of these proteins may be solely the result of adsorption. Transferrin, 80% saturated with iron, was bound to a greater extent than 10 or 50% saturated transferrin; 10% saturated transferrin was bound more readily than the 50% saturated preparation. The findings are consistent with the presence of a transferrin receptor on the cell membrane of the alveolar macrophage and imply that transferrin may interact directly with this cell type in order to remove or donate iron.

Pattern flash visual evoked potentials in patients with homonymous hemianopia. Visual evoked potentials from seven horizontally spaced electrodes were recorded from normal subjects and subjects with homonymous hemianopia in response to hemifield pattern flash stimulation. Stimulation produced a large early peak that was positive on the scalp contralateral to the hemifield and negative on the ipsilateral scalp. From computer fitting of the amplitudes versus electrode position, the position of the equivalent source was found to be in the contralateral hemisphere. The horizontal orientation of the dipole source was approximately tangential (parallel) to the occipital scalp surface with negative polarity toward the medial fissure. In normal subjects, visual evoked potential amplitudes at the first peak were positive on the left and negative on the right for right hemifield stimulation. Left hemifield stimulation showed the opposite results. Three patients with homonymous hemianopia showed normal visual evoked potential results from their functional hemifields and nearly flat results from their hemianopic hemifields. The normal visual evoked potentials originated in their intact cortical hemispheres.

Isobutyl 2-cyanoacrylate (bucrylate) in obliteration of gastric coronary vein and esophageal varices. Percutaneous transhepatic portography was performed in 22 patients with liver cirrhosis and portal hypertension. All patients had bled or were bleeding from presumed esophageal varices. One or more veins feeding esophageal varices were occluded with bucrylate. Follow-up examination in eight patients 1-12 months later showed recanalization of previously obliterated veins in six; however, these veins were markedly smaller than before the procedure. In patients where veins were still occluded, new veins had opened up and carried blood to the esophageal varices, which were filled to a lesser degree than before. In our experience, bucrylate is superior to Gelfoam, thrombin, and Etolein in producing venous occlusion.

Facilitating generalization of on-task behavior through self-monitoring of academic tasks. This study (1) examined whether a self-monitoring procedure taught in a laboratory setting would increase independent on-task behavior there and would generalize without further teaching to a classroom setting, and (2) analyzed the durability of the training effects over the course of 5 months for one subject and 10 months for two other subjects. Two multiple-baseline designs, one across three normal and the other across three deviant children, showed that self-monitoring of academic task-completions facilitated on-task responding for all subjects in the generalization (classroom) setting. A subsequent reversal design showed that these effects were durable, in two of the three subjects still available, at least as much as 1 year after commencement of training. This latter design also suggested that one subject who was not maintained by self-monitoring could be supported in on-task behavior by a peer who was maintained by self-monitoring.

The significance of lymphocytosis in congenital hypoplastic anemia. Two infants with congenital hypoplastic anemia had an unusual number of lymphocytes in their peripheral blood and in the bone marrow. This caused an erroneous diagnosis of acute lymphocytic leukemia to be made in the first case and inappropriate therapy to be administered for three months. The second of these cases provided an unusual opportunity to study human erythrocyte precursor dynamics. Serial bone marrow aspirates, obtained after institution of treatment with a corticosteroid, revealed an initial increase in labeled lymphocytes, a concomitant decrease in their number, and the subsequent appearance of erythroid elements. These findings suggest that cells classified morphologically as lymphocytes may serve as erythroid precursors in human beings.

Studies of the effect on tumor and normal cells in vitro with bioactive materials isolated from algae by a microcalorimetric method. Recently much attention has been focused on the human physiological actions with bioactive materials from algae to enhance immunocompetence and to strengthen antineoplastic activity. In the study reported in this paper an MS 80 standard Calvet microcalorimeter was used for measuring the thermogram of HeLa, human breast carcinoma (Bcap-37) and diploid fibroblasts from human feral lung (2BS) under conditions with or without the presence of bioactive materials (Sp) from algae. At the same time, the cell number was counted, the inhibition rate of growth and the death rate were obtained. It has been shown that the Sp (100 micrograms/ml) was the growth inhibitor and lethal to tumor cells (Bcap-37 and HeLa), but had no influence on the normal (2BS) cells under the same conditions in vitro.

[Immunoglobulins and their specific activity in cholera]. The authors studied the quantitative content of nonspecific immunoglobulins and antibodies of the IgG-, IgA-, and IgM-classes to the O-antigen of the cholera vibrio. There proved to be no marked dynamics of the quantitative immunoglobulins indices of various classes established at periods from the 3rd and the 18th day from the beginning of the disease in persons who sustained cholera. In persons who sustained cholera in the nonendemic focus of the disease serum antibodies were represented chiefly by the IgM-antibodies. The formation of IgA-antibodies in the persons examined differed from the regularities detected for the IgG- and IgM-classes and were characterized by rapidity and short duration. No correlation was found between the immunoglobulin levels of various classes and the serum antibody levels in case of cholera affection.

Temperature dependence of transepithelial potential in isolated perfused rabbit proximal tubules. The response of the transepithelial potential to rapid cooling in isolated perfused proximal convoluted (PCT) and proximal straight (PST) tubules has been studied. Tubules were perfused with solutions which simulated glomerular filtrate (A), filtrate minus glucose and alanine (B), and late proximal tubular fluid (C). The values of the potentials at 37 and 10 degrees C as well as the temperature-sensitive component were found to vary with perfusate composition. Temperature sensifound to vary with perfusate composition. Temperature sensitivity in PCT was seen only when glucose and alanine were present in the perfusate. In contrast, a portion of the potential difference in PST was temperature dependent under each of the perfusion conditions. Temperature sensitivity in PST was inhibited by 10(-5) M ouabain in the bath. It is concluded that the lumen-negative, temperature-sensitive component of PCT potential may reflect the coupled luminal entry of Na+ along with glucose and alanine. In PST, the temperature-sensitive component can be associated with Na+ transport but is not dependent on luminal concentrations of glucose, alanine, HCO3- or Cl- over the ranges examined. Potentials in both segments at 10 degrees C are interpreted as resulting from processes that are passive in nature.

Effect of blood vitamin A levels on the dark adaptation of mineworkers. The average dark adaptation time for newly recruited Black mineworkers is longer than that reported for Whites. While this longer dark adaptation time may result from a number of pathological conditions, its most likely cause is a deficiency of vitamin A in the diet. A study was conducted in which the vitamin A level of the blood and the dark adaptation times were correlated in a group of Black mineworkers upon arrival and again after 4 - 6 months continuous work underground in a gold mine. The study indicated that a very marked decrease occurred in the miners' serum vitamin A level between the time of arrival at the mine and the second examination. This difference was found to be highly significant. This decrease was accompanied by an increase in mean dark adaptation time, which was significant at the 5% level. These observations accord with the findings of a previous study and are indicative of an inadequate dietary intake of vitamin A during the period when the miners were on the mine diet.

Laminin on Toxoplasma gondii mediates parasite binding to the beta 1 integrin receptor alpha 6 beta 1 on human foreskin fibroblasts and Chinese hamster ovary cells. We investigated the role of parasite-bound laminin and the host cell beta 1 integrin receptors for this extracellular matrix protein in Toxoplasma gondii binding to fibroblasts. Laminin but not fibronectin was detected on extracellular tachyzoites by immunofluorescence and immunoblotting. Binding of parasites to CHO cells was inhibited by polyclonal antibodies to laminin and by a monoclonal antibody directed against the globular carboxyl-terminal portion of the long arm of laminin (at or near the suggested ligand-binding sites for alpha 3 beta 1 and alpha 6 beta 1), but not by a monoclonal antibody directed against the lateral short arms of laminin near the cross region of the molecule. Antibodies to the alpha 6 but not the alpha 2, alpha 3, or alpha 5 chains of the beta 1 family of integrins blocked parasite attachment to human foreskin fibroblasts and CHO cells. Attachment of T. gondii to cells via laminin on the parasite surface and laminin receptors on the mammalian cell is consistent with the capacity of the parasite to invade almost all nucleated cells.

Some roots of preference: roles, activities and familial values. This paper examines some of the connecting links between modernization in a developing society, particularly urbanization and increased education for women, and preferences for number of children. Using 1973 Taiwan data, preferences for smaller families are found to be consistently related to modern attitudes and behavior in the three domains examined: intrafamilial husband-wife role relationships, extrafamilial activities of the wife, and familial and religious values relating the family to the larger institutional setting. Modernization of these attitudes, behaviors, and values has an impact on reproductive goals independent of their association with structural variables. The wife's outside activities and exposure to modern influences through the mass media are especially important linkages, having a particularly strong mediating effect in the education effect on preferences. Intrafamilial relations appear to be of less importance. Modernization of familial and religious values mediates between urbanization and family size preferences. The measure of preference used is a scale value which has been found in other research to be more predictive of reproductive behavior than the conventional single-valued statement of number of children wanted. As the level of contraceptive use rises in developing societies, family size preferences increasingly become a factor in birth rates, and understanding the sources of change in these preferences takes on added importance. The policy implications of these findings are discussed.

[Large granular lymphocytic leukemia]. We investigated the surface markers, cell-function, clonality, and the association of IL-2 receptors and a second messenger of src family of tyrosine kinase p56lck in IL-2 signal transduction of the leukemic cells of 12 patients with large granular lymphocytic leukemia (LGL leukemia). The leukemic cells of 5 patients were CD3+ and 5 of them were CD3-. In three patients with CD3- leukemia examined, one showed karyotype abnormality of 46, XY, -10, +mar and the delta gene of TCR was rearranged in one patient. The TCR of the leukemic cells of a patient MH with CD3+, CD4 and CD8 (double positive marker: DP) recognised rabbit IgG presented by macrophages. The recognition was class II restricted. We examined the expression pattern of CD8 subunits and found that DP leukemic cells commonly expressed CD8 alpha+ beta-. These results suggested that DP leukemic cells were CD4+ T cells and expressed CD8 alpha secondarily. The p75 IL-2 receptors were detected, however, the modulation of p56lck in the process of IL-2 signal transduction were not found out. There was no association between p75 and p56lck when leukemic LGL cells proliferated on stimulation with IL-2.

Lassa fever, Marburg and Ebola virus diseases and other exotic diseases: is there a risk to Canada? There are seven exotic diseases of concern; three of these, the most unpredictable and least understood, are Lassa fever, Marburg virus disease and Ebola virus disease. In this article the epidemiologic aspects of these diseases are discussed, with particular emphasis on exportation from their indigenous areas in Africa and on the occurrence of secondary cases. Any of these conditions could be brought into Canada either by aeromedical evacuation or inadvertently. Between 1972 and 1978 there were seven occasions when Canada could have been involved with handling cases of Lassa fever. The Government of Canada has purchased several containment bed and transit isolators. These units, with filtered air under negative pressure, accommodate infectious patients being transported and cared for without contaminating medical attendants or the environment.

[The Dutch Reading Test for Adults: a measure of premorbid intelligence level]. The construction of the Dutch Adult Reading Test (DART) is described. The DART is the Dutch version of the National Adult Reading Test. Both tests consist of a series of words with an irregular pronunciation. The score on the test is a predictor of premorbid intelligence of brain damaged patients. Furthermore, results of reliability and validation studies with the DART are reported. The main findings, which were obtained with the NART, were replicated by the DART. These findings consist of a high correlation (.85) with verbal intelligence in healthy controls (n = 22) and insensitivity to cerebral deterioration in brain damaged and demented patients (n = 53). The test also appeared to be insensitive to cognitive deterioration in a group of psychotic patients (n = 43).

Hypertension associated with skeletal traction in children. Since traction-associated hypertension seems to be a relatively unknown phenomenon, a survey was done of its incidence in children treated with skeletal traction for fractures and orthopaedic diseases. The correlation with hypercalcaemia, a possible aetiological factor, was also explored. Blood pressure was recorded three times a day with an automatic oscillometric unit during the stay in the hospital. Serum calcium, creatinine and total protein concentrations were measured once a week. Patients with pre-existing diseases or renal trauma were excluded. Arterial hypertension (systolic and/or diastolic) was found in 31/50 children (62%). In almost half of these the rise in systolic blood pressure was 10 mmHg or more above the 95th percentile. Hypertension occurred in most cases within the first 3 weeks of treatment; in 7 children it developed after 3 or more weeks of traction. All children became normotensive within 1 week after discontinuation of traction. Clinical symptoms were rare: two children complained of headache. In no instance had traction to be discontinued before the planned date because of hypertension. In the hypertensive group were more preschool children and more humeral fractures as compared to the normotensive group (n = 19). Hypercalcaemia occurred in 11 children and was equally distributed in hypertensive and in normotensive children. It is concluded that arterial hypertension is a frequent finding in children in traction, but its clinical relevance is uncertain. Hypercalcaemia is not a rare finding in immobilized children, but probably plays no causative role in traction-related hypertension.

Comparison of the effect of various methods of dissociation on the protein composition of rat liver ribosomal subunits. Rat liver ribosomes were dissociated into subunits using EDTA, sodium pyrophosphate, high concentrations of KC1, as well as by incubation with puromycin in presence of 0.5 M KC1. The subunits obtained were analyzed using the density gradient centrifugation technique and their ribosomal proteins were separated by means of two-dimensional polyacrylamide gel electrophoresis. The ribosomal protein patterns of the two subunits isolated using each of the dissociating method were compared to the protein patterns of monosomes prepared by puromycin treatment alone. Our results revealed that the use of chelating agents to dissociate the ribosomes resulted in the loss of some ribosomal proteins from the small subunit. On the other hand, the use of KC1 in high concentrations to dissociate the ribosomes did not appear to cause any major loss of proteins from the ribosomes except for some acidic proteins.

Priming of CD4+ T cells specific for conserved regions of human immunodeficiency virus glycoprotein gp120 in humans immunized with a recombinant envelope protein. A nonglycosylated denatured form of human immunodeficiency virus (HIV) 1 glycoprotein gp120 (Env 2-3), which does not bind to CD4, was used with muramyl tripeptide as adjuvant to immunize HIV-seronegative healthy volunteers. In all the volunteers, three 50-micrograms injections of Env 2-3 induced priming of CD4+ T cells specific for conserved regions of the native glycosylated gp120. Moreover, we found that several major histocompatibility complex class II (DR) alleles can function as restriction molecules for presentation of conserved epitopes of gp120 to T cells, implying that a T-cell response to these epitopes can be obtained in a large fraction of the population. The possibility to prime CD4+ T cells specific for conserved epitopes of a HIV protein is particularly important in view of the lack of such cells in HIV-infected individuals and of a possible role that CD4+ T cells may play in the development of protective immunity against AIDS.

Protein-DNA interactions at the H4-site III upstream transcriptional element of a cell cycle regulated histone H4 gene: differences in normal versus tumor cells. Upstream sequences of the H4 histone gene FO108 located between nt -418 to -213 are stimulatory for in vivo transcription. This domain contains one protein/DNA interaction site (H4-Site III) that binds factor H4UA-1. Based on methylation interference, copper-phenanthroline protection, and competition assays, we show that H4UA-1 interacts with sequences between nt -345 to -332 containing an element displaying sequence-similarity with the thyroid hormone response element (TRE). Using gel retardation assays, we also demonstrate that H4UA-1 binding activity is abolished at low concentrations of Zn2+ (0.75 mM), a characteristic shared with the thyroid hormone (TH) receptor DNA binding protein. Interestingly, phosphatase-treatment of nuclear proteins inhibits formation of the H4UA-1 protein/DNA complex, although a complex with higher mobility (H4UA-1b) can be detected; both complexes share identical protein-DNA contacts and competition behaviors. These findings suggest that phosphorylation may be involved in the regulation of H4-Site III protein/DNA interactions by directly altering protein/protein associations. H4-Site III interactions were examined in several cell culture systems during cell growth and differentiation. We find that H4UA-1 binding activity is present during the cell cycle of both normal diploid and transformed cells. However, during differentiation of normal diploid rat calvarial osteoblasts, we observe a selective loss of the H4UA-1/H4-Site III interaction, concomitant with an increase of the H4UA-1b/H4-Site III complex, indicating modifications in the heteromeric nature of protein/DNA interactions during downregulation of transcription at the cessation of proliferation. Transformed cells have elevated levels of H4UA-1, whereas H4UA-1b is predominantly present in normal diploid cells; this alteration in the ratio of H4UA-1 and H4UA-1b binding activities may reflect deregulation of H4-Site III interactions in transformed cells. We propose that H4-Site III interactions may contribute, together with protein/DNA interactions at proximal regulatory sequences, in determining the level of H4-FO108 histone gene transcription.

Selegiline as a primary treatment of Parkinson's disease. In order to investigate the efficacy of selegiline as a primary treatment in Parkinson's disease (PD), we carried out a placebo controlled, double-blind prospective trial. Fifty-four de novo patients with PD were randomized to receive either selegiline (10 mg/day) or matching placebo. We continued the monotherapy until the initiation of levodopa therapy became necessary. The disability of the patients was evaluated with three different rating scales at baseline, after 3 weeks, 2, 4, 8, and 12 months, and every 4 months thereafter. Fifty-two patients were eligible for the final analysis: 27 in the selegiline group and 25 in the placebo group. The median duration of time without levodopa was 545 +/- 90 days in the selegiline treated patients and 372 +/- 28 days in the placebo treated ones (p = 0.03). The disability of the patients was significantly milder in the selegiline than in the placebo group up to 12 months. More patients showed symptomatic improvement in the selegiline than in the placebo group. However, the symptomatic effect alone did not explain the prolongation of the time without levodopa in the selegiline treated patients. Selegiline was well tolerated and no severe side effects were encountered.

Hepatobiliary and pancreatic ascariasis in India. 500 patients with hepatobiliary and pancreatic disease due to Ascaris lumbricoides infection were studied. 274 patients had duodenal ascariasis, 171 biliary ascariasis, 40 hepatic ascariasis, 8 gall bladder ascariasis, and 7 pancreatic ascariasis. Five clinical presentations were recognised: acute cholecystitis (64 patients), acute cholangitis (121), biliary colic (280), acute pancreatitis (31), and hepatic abscess (4). Ascarides in the duodenum (which were seen to invade only the ampullary orifice) induced either severe biliary colic or episodes of acute pancreatitis. 27 patients had pyogenic cholangitis and were managed by surgical (2) or endoscopic (25) biliary decompression and drainage. Removal of worms from the ampullary orifice and their extraction by mouth led to rapid relief of biliary colic (214 patients) and acute pancreatitis (16). 4 patients died (acute pancreatitis 2, pyogenic cholangitis 1, hepatic abscess 1). In 12 patients worms persisted in the biliary tree at 3 weeks; dead worms were removed from the biliary tree by surgery (5 patients) or with an endoscopic basket (7). Worms moved out of the ductal system in 211 patients. During a mean follow-up of 48 months (SD 14), 76 patients had worm re-invasion of the biliary tree due to ascaris re-infection. Intrahepatic duct and bile duct calculi developed in 7 patients in whom dead worms formed the nidus of stones.