Delta 9-tetrahydrocannabinol decreases cytotoxic T lymphocyte activity to herpes simplex virus type 1-infected cells. The purpose of this study was to examine the effect of delta 9-tetrahydrocannabinol (delta 9-THC), the major psychoactive component of marijuana, on T lymphocyte functional competence against herpes simplex virus Type 1 (HSV1) infection. Spleen cells from C3H/HeJ (H-2k) mice primed with HSV1 and exposed to delta 9-THC were examined for anti-HSV1 cytolytic T lymphocyte (CTL) activity. Flow cytometry was used to determine whether delta 9-THC altered T cytotoxic (Lyt-2+) and T helper (L3T4+) lymphocyte numbers or cell ratios. Nomarski optics microscopy was used to determine whether effector lymphocytes from drug-treated mice were able to bind to virally infected L929 (H-2k) target cells. Cytotoxicity assays demonstrated that CTL from mice exposed to delta 9-THC were deficient in anti-HSV1 cytolytic activity. delta 9-THC in vivo treatment had little effect on the number of T lymphocytes expressing the Lyt-2 or L3T4 antigens. Nomarski optics microscopy revealed that the CTL from the drug-treated mice were able to bind specifically to the HSV1-infected targets. However, delta 9-THC in vivo exposure affected CTL cytoplasmic polarization toward the virus-infected target cell. CTL granule reorientation toward the effector cell-target cell interface following cell conjugation occurred at a lower frequency in co-cultures containing CTL from drug-treated mice. These results suggest that delta 9-THC elicits dysfunction in CTL by altering effector cell-target cell postconjugation events.


Reduction of learned helplessness by central administration of quaternary naltrexone. Prior research has established that escape impairment resulting from prior inescapable shock (IS) could be reversed by the peripheral administration of the opiate antagonist naltrexone (NTX), but not the quaternary form of naltrexone (QNTX), which when systemically administered, does not readily pass the blood-brain barrier. As it was unclear whether the failure of systemically administered QNTX to reduce shuttle escape deficits following exposure to IS could be attributed to reasons other than the restricted access of QNTX to receptor sites in the brain, rats were affixed with chronic indwelling ventricular cannulae to allow direct brain administration of QNTX. The present experiment found a significant attenuation of the escape deficit produced by prior inescapable shock following the intracerebroventricular (ICV) administration of QNTX (10 micrograms/rat). These data provide further evidence of a mediational role for central opiate receptors in the expression of escape interference following inescapable shock.


Hormonal responses to fighting in hamsters: separation of physical and psychological causes. Male Syrian hamsters were paired and allowed to interact with a conspecific for 15 min a day for 4 days. On the fifth day, the animals were again paired, but they were kept physically separated by a mesh partition that allowed visual, olfactory, and auditory contact between the animals. Controls were placed with conspecifics on each of the 5 testing days, but the partition between them was never removed. Hamsters that were submissive on days 1-4 exhibited elevated plasma adrenocorticotropin-like immunoreactivity (ACTH-LI), beta-endorphin-like immunoreactivity (B-EP-LI), and cortisol on day 5 even though no fighting occurred on that day. Dominant hamsters did not differ from controls. These data support the hypothesis that there is an important psychological component to the pituitary-adrenocortical response in defeated hamsters.


Comparison of mu opioid receptors in brains of rats bred for high or low rate of self-stimulation. Opiates and endogenous opioid peptides play an important role in reward-mediated behaviors, including self-stimulation. Two strains of rats, LC2-Hi and LC2-Lo, selectively bred for high vs. low rate of lateral hypothalamic self-stimulation, were employed in the present study. Quantitative autoradiography was performed on brains of adult male rats of each strain, using the mu opioid receptor agonist 3H-DAGO. Strain differences in receptor density were observed in the nucleus accumbens and in ventral areas of the hippocampus.


Bombesin-induced hypothermia and hypophagia are associated with plasma metabolic fuel alterations in the rat. Microinfusion of bombesin into the preoptic area (POA) has previously been shown to reduce core body temperature and feeding in rats that are food-deprived or made hypoglycemic with insulin. The present study determined the metabolic fuel state of rats under these experimental conditions. In addition, changes in plasma metabolic fuels following the microinfusion of bombesin (50 ng/0.25 microliters) into the POA were evaluated. Rats (n = 8) were tested under conditions of food satiation, food deprivation (20 h), and insulin pretreatment (10 U/kg). Prior to peptide infusion, food-deprived rats exhibited the expected elevation in free fatty acids coupled with a small decline in plasma glucose. Insulin treatment resulted in hypoglycemia which persisted for at least 120 min. Following bombesin infusion, free fatty acids and corticosterone levels were elevated in food-sated rats. Food-deprived rats exhibited elevation in plasma glucose, free fatty acids, and corticosterone following peptide infusion. In insulin-treated rats, bombesin attenuated the hypoglycemia observed in controls and increased corticosterone levels. These findings suggest that bombesin-like peptides localized within the POA may participate in the regulation of metabolic fuels.


Hormonal reactions to fighting in rat colonies: prolactin rises during defence, not during offence. Male Wistar rats living in colonies of 4 males plus 4 females were compared to noncolony males, cohabitating with a female. Irreversible dominance relationships developed between one dominant male (D) and three subordinates (S). Dominants developed high basal testosterone levels and large preputial glands. Subordinates had reduced preputial glands despite normal testicle weights and normal basal testosterone levels. Basal corticosterone was elevated in both ranks, in S more so than in D, while in acute encounters both ranks showed a similar increase in the corticosterone-to-ACTH ratio. They also underwent a similar reduction in thymus weight, while an increase in adrenal weight was more pronounced in D. In D-S-I encounters, during which D simultaneously attacked S and an intruder (I) for 20 minutes, both defenders showed a 3-4 fold increase in plasma prolactin, while in the offensive dominant the level remained low. Similar, but weaker hormonal contrasts between offence and defence were found for beta-endorphin, ACTH, and corticosterone, while alpha-MSH and testosterone did not discriminate. In our view, the marked hyporesponsiveness of prolactin to acute offence may be associated with a specific offensive setting of dopaminergic inhibitory and beta-adrenergic stimulatory influences.


Defensive burying following injections of cholecystokinin, bombesin, and LiCl in rats. Past research indicates that feeding is reduced for animals injected with cholecystokinin and bombesin. One explanation for this effect suggests that these peptides act as natural satiety signals; an opposing view asserts that bombesin and cholecystokinin reduce feeding through malaise. The present experiment tested the basic assumptions associated with these positions using the defensive burying procedure. Groups of rats were given sweetened condensed milk followed by IP injections of bombesin (6, 16, and 32 micrograms/kg), cholecystokinin (0.7, 1.4, and 2.9 micrograms/kg), LiCl (6.4 mg/ml), or saline. The results showed that animals injected with cholecystokinin, bombesin, and LiCl developed learned aversions to the milk and actively buried the milk spout with their bedding. The findings provide further support for the view that bombesin and cholecystokinin induce malaise rather than satiety.


Characterization of a Tra 2 function of RP1 that affects growth of Pseudomonas aeruginosa PAO and surface exclusion in Escherichia coli K12. pVS438, a clone of part of the Tra 2 region of RP1 in RSF1010, confers two unusual phenotypes: poor growth (Slo+) in Pseudomonas aeruginosa PAO and surface exclusion (Sfx+) in Escherichia coli K12. Both of these phenotypes were found to be encoded by a 1.8-kb fragment of RP1 (from 25.9-27.7 kb) that spans the traB gene. However, whether both phenotypes, neither, or only Slo+ is expressed by this fragment depends on its location and orientation in RSF1010. In pVS438, where this fragment occurs in the SmR locus of RSF1010, expression of the Sfx+ phenotype is due to augmented transcription from the two promoters that cotranscribe the SuRSmR genes. When augmentation is abolished by insertion of Tn5 between these promoters and the cloned fragment, or by insertion of the fragment elsewhere in RSF1010, a Slo+Sfx- phenotype results. DNA that confers only the Slo+ phenotype was mapped to the 26.2-26.8 kb region of RP1 between traE and traB and the designation, traS, given to the gene responsible. Despite the recognition of a traS+ (Slo+) component of DNA within that encoding the Slo+ and Sfx+ phenotypes, this gene seems nevertheless to be responsible for the Sfx+ phenotype since hydroxylamine-induced Slo- mutants of pVS438 are usually also Sfx-. These apparently conflicting observations and the precise interplay between the Slo+, Sfx+, and TraB+ phenotypes were not resolved. Finally, traS is not essential for plasmid transfer since pVS438 and a Slo-Sfx- derivative of it can both equally complement an RP1tra-deletion mutant of part of the Tra 2 region.


A truncated Tn916-like element in a clinical isolate of Enterococcus faecium. A 58.7-kb nonconjugative plasmid (pKQ1) previously reported in a clinical isolate of Enterococcus faecium was found to contain both a tetM and an erythromycin resistance (erm) determinant. The plasmid contained a region homologous to the A, F, H, and G HincII fragments of Tn916. However, the 4.8-kb B fragment of Tn916 which contained the tetM determinant was replaced by a 7.3-kb fragment, and the 3.6-kb HincII C fragment of Tn916 was missing. An element homologous to Tn917 was juxtaposed to the truncated Tn916-like element. The Tn917-like element was similar in size to the erm transposon Tn917 as determined by a ClaI restriction digest which spanned approximately 99% of the transposon. When Bacillus subtilis or Streptococcus sanguis were transformed with pKQ1, no zygotically induced transposition of the tetM element was detected. Similarly no transposition of the Tn917-like element was detected.


Highly preferred site of insertion of Tn7 into the chromosome of Vibrio anguillarum. The possible usefulness of Tn7 as a tool for genetic studies in Vibrio anguillarum was examined. Using the plasmid pRK2073 as the transposon donor, Tn7 transposes at high frequency into the chromosome of V. anguillarum. However, hybridization analysis of the mutants DNA digested with different enzymes revealed that all isolates have the insertions in the same site. This indicates that like in many other gram-negative bacteria, Tn7 shows a specificity of transposition in the chromosome of V. anguillarum. Plasmid pRK2013 proved to be a very useful delivery vector for transposon mutagenesis in V. anguillarum.


RecP, a new minor pathway of general recombination in Escherichia coli encoded by plasmid R1drd-19. Plasmid R1drd-19 markedly improves the recombination deficiency of recB and recBrecC mutants of Escherichia coli K12 as measured by Hfr crosses and increases their resistance to uv inactivation. The effect correlates with the production of an ATP-dependent ds DNA exonuclease in recB/R1drd-19 cells. This paper further investigates the suppressive effect of plasmid R1drd-19 on the recB mutation of E. coli. The gene(s) responsible for the effect was localized to the 13.1-kb EcoRI-C fragment of the resistance transfer factor (RTF) portion of R1drd-19. The plasmid-encoded activity does not merely replace the RecBCD enzyme failure but differs in several significant ways. It promotes a hyper-recombinogenic phenotype, as judged by the phenomenon of super oligomerization of the tester pACYC184 plasmid in recB/R1drd-19 cells and two inter- and intramolecular plasmid recombination test systems. It is probably not inhibited by lambda Gam protein and does not restrict plating of T4gp2 mutant. No significant homology between the E. coli chromosomal fragment carrying recBrecCrecD genes and the EcoRI-C fragment of R1drd-19 was observed. It is suggested that the plasmid-encoded recombination activity is involved in a new minor recombination pathway (designated RecP, for Plasmid). RecP resembles in some traits the RecBCD-independent pathways RecE and RecF but differs in activity and perhaps substrate specificity from the main RecBCD pathway.


Noradrenaline uptake inhibition increases melatonin secretion, a measure of noradrenergic neurotransmission, in depressed patients. Eight patients with endogenous depression who had received no antidepressant treatment for the previous year were treated with the noradrenaline (NA) uptake inhibitor, desipramine (DMI). Pre-treatment plasma melatonin concentrations were normal. After one day of DMI treatment plasma melatonin concentrations were increased but the response was impaired compared to normal subjects. The acute effect of DMI on plasma melatonin persisted after six weeks of treatment. These findings question the hypothesis that beta adrenoceptors are supersensitive in depression and that antidepressant drugs act by down-regulating these receptors.


Adrenocorticotropin hormone, beta-endorphin and cortisol responses to oCRF in melancholic patients. Several authors have reported attenuated adrenocorticotropin hormone (ACTH) responses to corticotropin releasing factor (CRF) administration in melancholic patients as compared with healthy controls. In order to explore the integrity of the hypothalamic-pituitary-adrenal (HPA)-axis in melancholics, we examined the following parameters in 98 subjects: the ACTH; beta-endorphin; and cortisol responses to ovine CRF (oCRF) (100 micrograms/i.v.); and the postdexamethasone cortisol values. We found significant lower CRF-induced ACTH responses in melancholic patients as opposed to healthy controls and minor depressives, while major depressives occupied an intermediate position. The psychopathological correlates of the blunted CRF-induced ACTH responses were feelings of worthlessness, self-reproach, or excessive guilt. The CRF-stimulated beta-endorphin and cortisol response did not differ between the study samples. Higher baseline plasma cortisol was associated with attenuated CRF-induced ACTH responses, but these effects were not pertinent to melancholia. There were no relationships between the disordered oCRF test results, and postdexamethasone cortisol values, age, body size, sex and severity of illness. The diagnostic power of the oCRF and the dexamethasone suppression test for melancholia is enhanced when both test results are combined.


The common cold, pattern sensitivity and contrast sensitivity. Results from two studies involving challenge with respiratory syncytial viruses showed that volunteers who developed colds were more sensitive to a visually distracting pattern presented prior to virus challenge than were volunteers who did not get a cold. Volunteers with sub-clinical infections reported more illusions after virus challenge than they had done before, whereas uninfected volunteers and those with colds tended to report fewer illusions on the second test. These effects did not occur when volunteers were challenged with either a coronavirus or rhinovirus. Overall, the results confirm that behavioural measures may be related to susceptibility to subsequent illness, and that viral infections may influence visual perception. They also show that the effects vary according to the nature of the infecting agent, which agrees with results from studies looking at other aspects of behaviour.


PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil. Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.


Reinforcing and subjective effects of oral delta 9-THC and smoked marijuana in humans. The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N = 10) was tested with smoked marijuana and the other (N = 11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.


Benzodiazepine receptor mediation of behavioral effects of nitrous oxide in mice. Nitrous oxide produces behavioral effects, the underlying mechanism of which is not known. In the mouse staircase test, exposure to nitrous oxide caused a reduction in rearing activity, an effect similar to that produced by benzodiazepines in this paradigm, when its opioid action on locomotion is blocked by naloxone. In this study, we tested whether effects of nitrous oxide might be mediated by benzodiazepine receptors, using chlordiazepoxide as a control. The abilities of nitrous oxide and chlordiazepoxide to reduce rearing were significantly attenuated in mice pretreated with the benzodiazepine receptor blocker flumazenil or rendered tolerant to benzodiazepines. These findings suggest an involvement of benzodiazepine receptors in mediation of certain behavioral effects of nitrous oxide.


Purification, subunit characterization and ultrastructure of three soluble bovine lectins: conglutinin, mannose-binding protein and the pentraxin serum amyloid P-component. Conglutinin and mannose-binding protein (MBP) are members of the C-type lectins which are widely present in mammalian plasma. Serum amyloid P-component (SAP) is a member of the pentraxin family with lectin properties. A scheme for the partial purification of all three lectins by carbohydrate affinity chromatography and selective elution was developed. The purification was monitored by SDS-PAGE, Western blotting and electron microscopy. Binding of the lectins to Sephadex-iC3b, their collagenase sensitivity, and the size and antibody reactivity of their subunits was investigated. The demonstration, by SDS-PAGE, of 25-kDa subunits, which were unaffected by collagenase treatment but bound to Sephadex-iC3b and antibodies to human SAP, indicated the existence of bovine SAP. Bovine conglutinin (BK) also showed calcium-dependent binding to Sephadex-iC3b, whereas bovine MBP did not. The binding of BK was inhibitable with GlcNAc. A 3000-fold increase in BK activity (ELISA) was obtained in eluates from Sephadex-iC3b. SDS-PAGE analyses of BK and MBP revealed subunits with an Mr of 43 kDa and 30 kDa, respectively. These subunits were sensitive to collagenase treatment which reduced the Mr to 20 kDa. Electron micrographs revealed a prominent flexible tetramer molecule (diameter 96 nm) in the BK preparations, a predominantly hexameric structure (diameter 30 nm) in the MBP preparations, and single annular pentameric disc-like molecules (diameter 11 nm) in the SAP preparations.


Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Between 650 and 2000 different peptides are associated with the major histocompatibility complex class II molecule I-Ad. Sequences for nine of these were obtained by a combination of automated Edman degradation and tandem mass spectrometry. All of the peptides are derived from secretory or integral membrane proteins that are synthesized by the antigen-presenting cell itself. Peptides were 16 to 18 residues long, had ragged NH2-and COOH-termini, and contained a six-residue binding motif that was variably placed within the peptide chain. Binding data on truncated peptides suggest that the peptide binding groove on class II molecules can be open at both ends.


Staging of pediatric cancers: problems in the development of a national system. The majority of the common pediatric cancers are managed on clinical protocols and are treated in pediatric oncology centers. For this reason these neoplasms are being staged by a variety of protocols depending on the protocol study. Examples of the evaluation and currently used staging systems for Wilms' tumor, neuroblastoma, and rhabdomyosarcoma are presented. The goal is to develop a nationally accepted staging system for these common pediatric tumors that is broadly accepted for treatment planning, determining prognosis, and comparing institutional end results. It is obvious that, if a nationally accepted staging system is to evolve, the leadership of the existing national clinic research trials must be part of the process.


Prophylaxis of cytomegalovirus infection after bone marrow transplantation. Viral infections occur frequently during the reconvalescence phase of allogeneic bone marrow transplantation due to the persistence of severe immunodeficiency. Recent advances in the treatment of cytomegalovirus-associated interstitial pneumonia have resulted in the development of an effective strategy for the prevention of this disease. Cytomegalovirus infection as determined by rapid culture from prospective bronchoalveolar lavage specimens on day +35 has been identified as a formidable risk factor for the development of pneumonia. Preemptive therapy with ganciclovir alone prevents the evolution from infection to pneumonia in this subgroup while protecting most other patients from unnecessary drug exposure.


Effect of calcium channel blockers on platelet GPIIb-IIIa as a calcium channel in liposomes: comparison with effects on the intact platelet. The platelet membrane glycoprotein IIb-IIIa complex is essential for platelet aggregation and functions as a fibrinogen receptor on the activated platelet. When incorporated into phospholipid vesicles, this glycoprotein complex can function as an apparent calcium channel which facilitates the transit of calcium across a phospholipid barrier. In order to further evaluate this calcium channel, the effect of calcium channel blockers of the dihydropyridine (nifedipine and nicardipine), arylalkylamine (verapamil) and benzothiazepine (diltiazem) classes were evaluated on GPIIb-IIIa liposomes with encapsulated fura-2 (a fluorescent calcium indicator). Nicardipine, verapamil, and nifedipine significantly inhibited calcium influx into GPIIb-IIIa liposomes; however, this required 190 microM, 400 microM, and 140 microM drug, respectively. These concentrations are 10-1,000 fold greater than those clinically obtainable. In contrast, diltiazem at concentrations greater than 220 microM and amiloride at concentrations greater than 800 microM showed no inhibitory effects. When aspirinized platelets were activated with 30 micrograms/ml bovine fibrillar collagen, both nicardipine and diltiazem produced a decrease in both the initial rise and maximum cytoplasmic calcium concentration. Parallel experiments were performed to assess the effects of verapamil, nicardipine, and diltiazem on platelet aggregation in platelet rich plasma. Nicardipine, 190-380 microM, induced a prolongation of the lag phase, but no effect on the final degree of platelet aggregation to collagen. Similar inhibition of platelet aggregation was seen with diltiazem and verapamil although the effect of diltiazem was less pronounced particularly at higher concentrations of collagen. No effect was seen on aggregation with 32 microM ADP which is release independent, or on the primary wave of low dose ADP induced platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)


The mode of action of CY216 and CY222 in plasma. Three fractions of the low molecular weight heparin CY216 (fraxiparin, mean molecular weight [MMW] 5,090), with MMWs of respectively, 3,090, 4,400 and 7,910 were prepared by gel permeation chromatography. From CY222 (MMW 3,770) as well as from CY216 and its three fractions the material with high affinity to antithrombin III (AT III) was obtained by chromatography on immobilised AT III. The molecular weight distribution of each of the ten preparations thus obtained was determined by high performance liquid chromatography, while the content of AT III binding material was determined by stoichiometric titration of AT III, monitored by intrinsic fluorescence enhancement. We measured the effect of all heparins on the decay of endogenous thrombin in plasma and on the overall generation of thrombin in plasma, triggered via the extrinsic or via the intrinsic pathway. From these data we calculated the time course of prothrombin conversion, i.e. the course of factor Xa activity as expressed by prothrombinase activity. It was found that in platelet-poor plasma the anticoagulant properties of the heparins are largely dependent on their antithrombin action, which is determined by their content of high affinity material with a MW of 5,400 or higher. The specific antithrombin activity of all heparins, when expressed in terms of material with high affinity to antithrombin III (HAM) with a MW greater than 5,400 is 13.0 min-1/(microgram/ml) (range 10.5-15.9).(ABSTRACT TRUNCATED AT 250 WORDS)


Modulation of protein C inhibitor activity by histidine-rich glycoprotein and platelet factor 4: role of zinc and calcium ions in the heparin-neutralizing ability of histidine-rich glycoprotein. Effects of zinc and calcium ions on the heparin-neutralizing abilities of histidine-rich glycoprotein (HRG) and platelet factor 4 (PF4) were examined. Both HRG and PF4 effectively neutralized the ability of heparin to accelerate the activated protein C (APC) and the thrombin inhibitions by protein C inhibitor (PCI). the heparin-neutralizing ability of HRG in the APC inhibition by PCI, however, was decreased in a Ca(2+)-dependent manner and apparently lost at 1 mM Ca2+, while it was enhanced by Zn2+ regardless of the presence or absence of Ca2+. The heparin-neutralizing ability of HRG in the thrombin inhibition by PCI was not affected by Ca2+. In contrast to HRG, there was no significant difference in the heparin-neutralizing ability of PF4 in the presence or absence of 1 mM Ca2+. These results strongly suggest additional physiological functions of HRG and PF4 as modulators of PCI.


[Virus and cancer].

[Virus and cancer]. There are at least four viruses tightly associated with human cancer: HTLY-I and HTLY-II with certain leukemias, EBV with lymphomas, BHV with hepatocarcinomas and HPV with genital cancer. In this work we discuss some evidences indicating these associations; in particular we emphasize the characteristics of human papillomavirus (HPV), due to its growing importance in the development of uterine-cervix carcinoma and the mortality of Mexican women. The low percentage of infected individuals that develop these neoplasias and the long latency periods observed indicate that both cellular and environmental factors are involved in tumor induction. Among cellular factors, oncogenes (such as myc) and antioncogenes could play important roles in the induction and development of the malignant phenotype. The understanding of these factors could lead to the development of methods for early diagnosis and therapy of cancer.


Changes in plasma thrombomodulin antigen in rabbit developing endotoxin-induced disseminated intravascular coagulation and the effect of heparin. Soluble thrombomodulin (TM) antigen level was 1.64 +/- 0.64 microgram/ml (n = 18, mean +/- S.D.) in plasma of normal male rabbits as measured by enzyme immunoassay, and the antigen consisted of subspecies of 94, 83 and 51 kd. When disseminated intravascular coagulation (DIC) was induced by intravenous infusion of endotoxin into rabbits, the TM antigen level in plasma was elevated to about 1.5 times of the control value, and an increase in the 83 kd subspecies as well as the appearance of new subspecies of 76 and 48 kd was observed concomitantly with disappearance of the 94 kd subspecies in plasma. Elevation of the antigen level and disappearance of the 94 kd subspecies caused by infusion of endotoxin were reduced by simultaneous infusion of heparin. Addition of leukocytes stimulated with endotoxin plus FMLP to cultured endothelial cells induced release of TM antigen to the medium accompanying cell injury as measured by 51Cr release, which was prevented by treatment with heparin. It was suggested that the increase in plasma TM antigen level in parallel with the generation of DIC reflected endothelial injury of rabbits, and that the elevation of TM antigen and the endothelial cell injury were prevented by heparin treatment.


Correlation between anti-Xa and occurrence of thrombosis and haemorrhage in post-surgical patients treated with either Logiparin (LMWH) or unfractionated heparin. Post-surgery Logiparin Study Group. A total of 1290 patients (Pts) undergoing general surgery were enrolled in a randomized, multicentre double-blind study in order to investigate the efficacy and safety of two different doses of a low molecular weight heparin (LMWH) (Logiparin) for the prevention of deep vein thrombosis. Patients were randomized to either 5,000 IU unfractionated heparin twice daily, 2,500 anti-Xa or 3,500 anti-Xa units of Logiparin once daily. Each treatment was given subcutaneously two hours before surgery and continued for seven to ten days. All coagulation tests were performed blindly in a core laboratory. Blood samples were collected before surgery and then 3 hours after injection on Day 3 and 5 after surgery. Anti-Xa amidolytic activities were significantly higher in the two LMW Heparin groups than in the unfractionated heparin group (mean peak levels +/- s.e.m. on Day 3: 0.097 +/- 0.004; 0.152 +/- 0.004 and 0.034 +/- 0.003 IU respectively). As expected a significant correlation was observed between anti-Xa activity and the dose of LMW Heparin injected. The correlation coefficient was higher when the doses were expressed in anti-Xa units/kg body weight. However, the body weight accounts for only 16% of the interindividual variability of anti-Xa activity. Therefore, there is no clear evidence to suggest that weight-adjusted doses should be recommended when this LMW Heparin is used as prophylactic treatment in general surgery. A weak negative correlation was found between anti-Xa activity and thrombosis as demonstrated by a positive radiolabelled fibrinogen uptake test and confirmed by positive phlebography. No significant correlation was demonstrated between anti-Xa activity and the occurrence of postoperative bleeding.


[Bone defect filling material in jaw bones using tricalcium phosphate]. Our experience shows that resorbable Beta-Tricalcium-phosphate is a useful alternative as filling material for cystic defects of the maxilla and mandible. It proves to be biocompatible and causes no immunologic reactions. Granulate has been used in 51 patients, in most cases it was Tricalciumphosphate. In three patients it had to be removed. Radiologically as well as histologically it was shown that resorption of Tricalciumphosphate takes place and that is replaced by osseous integration.


Oat cell carcinoma of urinary bladder.

Oat cell carcinoma of urinary bladder. Oat cell carcinoma of the urinary bladder is extremely uncommon. There have been 52 reported cases in world literature to date. On light microscopic, histochemical, and ultrastructural grounds, these tumors are similar to oat cell carcinoma of the bronchus and other extrapulmonary oat cell carcinomas. Furthermore, they may be grouped together as a clinical entity characterized by an aggressive clinical course with early and extensive metastases, and partial remission with certain chemotherapeutic agents. We report a case of primary small cell carcinoma of the urinary bladder in a forty-two-year-old man and review previous reports with similar histology. The importance of establishing this diagnosis and the optimum forms of therapy are discussed.


Coronavirus infection in mink (Mustela vison). Serological evidence of infection with a coronavirus related to transmissible gastroenteritis virus and porcine epidemic diarrhea virus. Antibodies to a transmissible gastroenteritis virus (TGEV)-related coronavirus have been demonstrated in mink sera by indirect immunofluorescence, peroxidase-linked antibody assays and immunoblotting. This is the first serological evidence of a specific coronavirus infection in mink. The putative mink coronavirus (MCV) seems to be widespread in the Danish mink population with a prevalence approaching 100%. Analysis by immunoblotting has shown that MCV is closely related to TGEV by the spike (S), matrix (M) and nucleoprotein (N) polypeptides. Furthermore, antibodies to MCV also cross-reacted with N and M polypeptides of porcine epidemic diarrhea virus (PEDV). Thus MCV may occupy an intermediate position between the TGEV group of coronavirus and PEDV. The possibility that MCV may be associated with syndromes of acute enteritis in preweaning mink is discussed.


Experimental infection of pigs with the porcine respiratory coronavirus (PRCV): measure of viral excretion. Twelve pigs were experimentally infected with a porcine respiratory coronavirus (PRCV) by the oronasal route. Viral excretion was measured daily by two means-deep nasal swabs and air samples obtained in a cyclone sampler. Clinical signs were very slight on infected pigs. Airborne virus could be recovered from day 1 to day 6 post-infection in the cyclone sampler as well as in petri dishes placed in the same loose-box. Viral titres obtained from nasal swabs were significantly correlated with those obtained from air samples. Different collection media were compared. The most efficient media for the collection of infectious viral particles contained a protective agent such as foetal calf serum.


A new bluetongue virus serotype isolated in Kenya. An apparently new strain of bluetongue virus was first isolated in Kenya in 1965 and since, has been obtained on 7 further occasions from diseased sheep during clinical outbreaks of disease. It proved to be serologically different from the 16 bluetongue virus strains then held at this laboratory. The virus was modified by passage in embryonated hens eggs to produce a live virus strain suitable for inclusion in a polyvalent vaccine. Recent neutralisation tests, carried out with 24 guinea pig immune sera prepared at Pirbright against the currently known World serotypes, have confirmed the earlier results and show that it is different from any of the existing serotypes.


Comparison of blocking dot ELISA and competitive ELISA, using a monoclonal antibody for detection of bluetongue virus antibodies in cattle. A blocking (B) dot enzyme-linked immunosorbent assay (ELISA), using a monoclonal antibody (mAb) against a group specific antigen of bluetongue virus (BTV) is described for the detection of BTV antibodies to BTV in cattle sera. Dots of BTV antigens were adsorbed to nitrocellulose (NC) strips and/or NC mounted in the windows of dipsticks. After blocking the remaining sites of the NC paper with milk powder solution and immersion in the test sample, the NC strips and dipsticks were exposed to mAb. Bound mAb was detected with peroxidase conjugated anti-mouse IgG (H and L). In the absence of anti-BTV antibody in the test sample, BTV antigen sites were reactive with mAb as indicated by a brown colored dot in the presence of the enzyme substrate, hydrogen peroxide and diaminobenzidine. In the presence of sufficient anti-BTV antibodies no color reaction was observed. The performance of these assays in detecting anti-BTV antibody in field blood eluate samples, prepared from whole blood dried on filter paper, from 395 bluetongue-free cattle in Canada and 635 sentinel cattle in Florida, USA, was evaluated and compared with the standard competitive (C) ELISA. The specificity of the dipstick B-dot ELISA was identical to that of the C-ELISA in testing of BT-free Canadian cattle but not in the testing of samples from the sentinel cattle in Florida, resulting in values of 100% diagnostic and 88.9% relative specificity, respectively. Based on the C-ELISA, the specificity of the NC strip B-dot ELISA was low and in the same order as that of the dipstick assay.(ABSTRACT TRUNCATED AT 250 WORDS)


Hepatitis A outbreak in Anchorage, Alaska, traced to ice slush beverages. The Alaska Department of Health and Social Services investigated a community outbreak of hepatitis A in Anchorage. A total of 57 persons who had hepatitis A between June and September 1988 were studied. Patients ranged from 1 to 54 years of age. A market was implicated as the source of the outbreak. An employee who prepared beverage mixtures in a bathroom was a contact of a person who had had hepatitis A 2 months before the outbreak; the employee was reported to have been jaundiced 3 to 4 weeks before the peak of the outbreak. The administration of immune globulin had an efficacy of 100% (95% confidence limits 69, 100%) in preventing hepatitis A among household contacts of primary cases. Similar beverages are sold by convenience markets and many other businesses nationwide. It is important to ensure that safe food-handling practices are followed by such establishments.


Autoimmune disease and the nervous system. Biochemical, molecular, and clinical update. Autoimmunity in the central and peripheral nervous system can manifest as the result of cellular or humoral immune responses to autoantigens. There is evidence that multiple sclerosis is a cell-mediated autoimmune disease of the central nervous system in which both myelin and the cell that produces the myelin are destroyed. Diseases such as acute inflammatory demyelinating polyneuropathy (also called Guillain-Barré syndrome) and myasthenia gravis are considered antibody-mediated diseases of the peripheral nervous system and neuromuscular junctions, respectively. We review these diseases and explore mechanisms of immune-mediated destruction of these nervous system components. We specifically focus on one effective therapy aimed at countering the immune attack, that of thymectomy in patients with myasthenia gravis.


[Structure of borderline depressive conditions]. Overall 502 workers of a scientific-industrial association were examined in order to study the prevalence and structure of affective disorders. Anxiety appeared the most frequently occurring disorder (289 subjects); depression was revealed in 175, and elements of apathy in 94 persons. In 131 cases, the conditions was assessed as depressive, with the level of depression being subclinical in the majority of them. The structure of depressive disorders, their relation to the demographic characteristics of the examined are considered in detail. The necessity of more active identification and prevention of the " pre-nosological " forms of depression is discussed.


[Experimental model of depression: neurochemical changes and the effects of imipramine and citalopram]. A study was made of the influence of the antidepressants imipramine and citalopram (10 mg/kg, chronic administration, i.p.) on the depression-like condition in submissive male rats. The above condition developed under the effect of chronic emotional stress because of successive experience of defeat in social confrontations (Kudryavtseva, Bakshtanovskaya, 1988). Imipramine rather than citalopram exerted a remarkable antidepressive effect recorded by the Porsolt's test. Measurements of the content of serotonin, dopamine and noradrenaline in brain structures have demonstrated changes in the serotoninergic and catecholaminergic systems in males with the depressive symptomatology in relation to intact animals. It should be mentioned that at different stages of pathological process formation, the role of certain structures and mediator systems underwent definite changes.


[Status of cerebral and central hemodynamics in patients with ischemic stroke]. Overall 30 patients who suffered ischemic brain stroke were examined for cerebral and central hemodynamics by radiocerebrography (RC) with the aid of the radiopharmaceutical preparation Tx-99 and by radiocardiography (RCG) using 131I. These methods were employed simultaneously with computer-aided tomography, cerebral angiography, rheoencephalography. The control group was made up of 18 patients suffering from peripheral nervous diseases. In 11 patients with a favourable outcome of ischemic brain stroke and the recovery of work fitness, the RC and RCG readings did not practically differ from those in the controls. The remaining 19 patients with disability due to brain stroke demonstrated deceleration of the cerebral blood flow, most pronounced on the side of brain infarction. Asymmetry of the cerebral blood flow and deceleration of blood supply in the main and intracerebral vessels as shown by the RC readings turned out the signs of the hemodynamically significant stenosis of one of the internal carotid arteries, even in lack of the changes on the angiogram. A correlation was established between deterioration of central hemodynamics and deceleration of the cerebral blood flow, as was a possibility of an increase of the blood inflow to the brain after administering drugs that make the RCG readings return to normal.


[The role of endogenous and exogenous factors in the development of paroxysmal schizophrenia]. Clinical and epidemiological examinations of 347 patients with attack-like schizophrenia and their relatives of the first degree kinship (2688 persons) have demonstrated that the lack of hereditary load and pathological character traits in the premorbid period, and the middle age at which the disease becomes manifest are favourable factors of the development of this pathology debut. The following factors are unfavourable: hereditary load with regard to schizophrenia, the schizoid type of the premorbid condition, the presence of "exogenous" provocation" and early disease onset.


[Comparative catamnestic studies of newly hospitalized patients with schizophrenia associated with alcoholism]. The authors analyze the destiny of 289 patients with associated schizophrenia and alcoholism. For the first time they were admitted to the psychiatric hospital in 1948-1951 (period I); 1959-1961 (period II); 1969-1971 (period III), and in 1979-1981 (period IV). The five-year catamnesis has demonstrated that schizophrenic patients abusing alcohol are often admitted to the hospital with paranoid symptomatology, retaining, however, a high enough level of social and labour adaptation, emotions, communicability for a long time. In the course of transition from the first to the fourth period, this group patients demonstrated an increase of the crime rate.


[Personality characteristics of patients with prosopalgias]. The MMPI test, Hornblow and Kidson's visual-analog anxiety scale and two types of the painful "questionnaires" suggested by the authors were used to examine the status of emotional personality sphere in 61 patients with prosopalgias due to typical trigeminal neuralgia (n = 39), dental plexalgia (n = 13) and pulpitis (n = 9). It has been revealed that patients with typical trigeminal neuralgia demonstrate the predominance of the depressive syndrome, whereas dental plexalgia is mostly characterized by anxiety. Analysis of the semantic tests is very instrumental in helping the physician to deepen the idea of the structure of subjective sensations in facial pain. Meanwhile the indicators of the "daily pain scale" promote administration of the drugs from the standpoint of chronotherapy.


[Magnetic resonance tomography in the diagnosis and differentiation of cerebral stroke]. Assessment of the MRT with an ultra-low magnetic intensity (0.04 Tesla) in 112 patients with different brain strokes has demonstrated the method to be of high information content from the standpoint of the diagnosis and differentiation of foci of injury. MRT is of special importance for detection of lacunar and mixed infarction and foci of stem localization. The use of MRT in the course of the disease permits estimation of the physicochemical and biological processes that occur in ischemia and hemorrhage together with the quality of the treatment given to the patients.


[Diagnosis, clinical course and prognosis of parenchymatous- ventricular hemorrhages]. As many as 61 patients with hemorrhagic brain stroke and blood penetration in the ventricular system were subjected to a clinical analysis. Based on the data available, attempts were made to predict an outcome of brain stroke. The authors describe the results of studying different aspects of the diagnostic algorithm of parenchymatous ventricular hemorrhages. In accordance with the clinical and computer-aided tomography data, consciousness disturbances, occlusion hydrocephalus, secondary stem syndrome as well as the localization, volume of hematomas and the degree of the blood filling of the ventricular system may serve as diagnostic predictors of brain hemorrhages. The authors' observations correspond with the conclusions made by foreign scientists that ventricular hemorrhages are not always fatal. Parenchymatous ventricular hemorrhages are likely to eventuate in a favourable outcome owing to the drug treatment.


[Clinical aspects and pathogenesis of infarction of the brain stem]. Clinical and hemodynamic studies were carried out in 75 patients with stem brain infarction in the acute period, including repeated infarctions. The total rupture of the autoregulatory mechanisms of the brain blood flow was discovered, leading to the development of different phenomena of "brain steal" determining the clinical course of stem brain infarction. In the given pathology, the acute period is characterized by the development of the vicious circle of hemodynamic disorders, which is coupled with pathological dissociation in coagulation hemostasis. The progression of the hemodynamic changes requires pathogenetic correction of central and cerebral circulation.


[Carotid artery hemodynamics during increased arterial blood pressure]. Ultrasonic duplex scanning was used to measure the volumetric rate of the blood flow (VRBF) in the common carotid artery (CCA) during arterial pressure (AP) rise in 46 patients suffering from arterial hypertension. The group of patients (n = 27) with a moderate rise of AP (by 10-20% of the common AP values) did not manifest any changes in the VRBF in the CCA during AP rise. In the group of patients with a considerable rise of AP (by more than 20% of the common AP values), there was a significant (p less than 0.01) decrease of the total VRBF in both CCA to 747.6 +/- 34.6 ml/min in AP rise as compared with the VRBF in common AP values--815.6 +/- 37.2 ml/min. Apparently, cerebral complaints in the majority of cases of AP rise are not due to excess blood inflow to the brain; the rise of vascular cerebral resistance associated with AP elevation may be of importance.


[Asymmetry of arterial blood pressure in the brachial artery in patients with cerebrovascular pathology]. Twenty-five patients suffering from cerebrovascular pathology coupled with arterial pressure (AP) asymmetry in the brachial arteries underwent an analysis including studies of the clinical picture, angiographic and rheographic readings (REG and RVG of the forearms and hands). It is demonstrated that revelation of a steady and well-defined asymmetry of AP in the brachial arteries associated with pulse weakening or disappearance in the radial artery on the side of AP decrease combined with pronounced asymmetry of the RVG readings for the forearms and hands is an important diagnostic and prognostic sign that points to the involvement into the process (occlusion or stenosis) of the subclavian artery. As a rule, this is coupled with lesions of the other main arteries of the head and may provoke impairment of the cerebral circulation, occurring more frequently in the arteries of the vertebrobasilar system. The emphasis is laid on the importance and necessity of bilateral measurements of AP from the brachial arteries in patients suffering from cerebrovascular pathology.


[Clinico-neurophysiological studies of the conductive affective and effective systems of the brain in the acute period of ischemic stroke]. As many as 43 patients aged 44 to 79 years with acute ischemic brain stroke of hemispheric (n = 30) and stem (n = 13) localization underwent clinical and neurophysiological examinations including noninvasive transcutaneous cortical pacing and investigation of short-latent somatosensory evoked brain potentials. This made it possible to exercise objective dynamic control over the motor and sensitive conductive brain systems. Certain common regularities were revealed in the functional reconstruction of motor (pyramid) and sensitive conductors in the acute period of brain stroke. Quantitative criteria for estimating the degree of the functional motor and sensitive defect were determined together with those for predicting its recovery.


[Cerebral hemodynamics in patients with circulatory encephalopathy]. Overall 130 patients with circulatory (atherosclerotic) encephalopathy were examined for the clinical picture, cerebral hemodynamics, specific features of the treatment and catamnesis at different disease stages. Use was made of ultrasound, rheographic and radionuclide research methods for intracranial arterial and venous blood flow. The data thus obtained were compared to the computer-aided tomography of the brain data. It has been discovered that cerebral hemodynamic disorders and brain atrophy are related to insufficiency of circulation via the main intracranial arteries and blood circulatory disorders in the microvessels. The clinical and hemodynamic efficacy of vasoactive and metabolic therapy (cavinton, piracetam, stugeron combined with complamine++) varied depending on the disease stage.


[Correlations of cognition disorders and the EEG data in elderly patients with circulatory encephalopathy]. The possibilities of the use of electroencephalography for evaluating intellectual-mnemonic disorders in elderly patients with cerebral atherosclerosis have been studied. The study included 95 subjects aged 60 to 74 years with varying intensity of circulatory atherosclerotic encephalopathy (without brain stroke). The psychological tests were performed according to Wechsler's methods. To evaluate the EEG, visual and automatic spectral analyses were employed. The data obtained were analyzed by means of discriminant, correlation and regression methods. A certain relationship was found between the results of the psychological tests and the EEG readings. The method of automatic EEG analysis is proposed, which allows revealing intellectual disorders in patients suffering from cerebral atherosclerosis. Its comparability with the data obtained by means of visual EEG analysis is discussed.


[Status of the nonspecific systems of the brain in initial manifestations of insufficiency of cerebral blood supply and circulatory encephalopathy]. Function of the nonspecific brain structures (NBS) was examined in 49 patients distributed into two groups: with initial manifestations of brain blood supply insufficiency (IMBBSI) (n = 28) and atherosclerotic encephalopathy (n = 21). Use was made of an approach with the use of autonomic and psychological techniques as well as of a polygraphic recording of the electrophysiological parameters of nocturnal sleep. It has been established that both groups patients manifest NBS dysfunction. However, its qualitative characteristics were found to differ noticeably in IMBBSI and AE. The patients with DE demonstrate more remarkable inhibition of the synchronous mechanisms that regulate both phases of nocturnal sleep and reciprocal enhancement of the activity of the systems of the ascending nonspecific brain activation. The autonomic and psychological data agree with the electrophysiological data obtained. The conclusion is drawn that in patients with cerebrovascular insufficiency, the NBS systems are first of all involved in the pathological process. This is of importance for both the diagnosis and further studies into the pathogenesis of different forms of cerebrovascular insufficiency.


[Vascular component of mental disorders in patients with organic lesions of the brain]. The paper concerns the results of 30 years of investigations of the Kiev Research Institute of Neurosurgery into correlations between syndromes of mental activity reduction (coma, stupor, global and lacunar dementias, Alzheimer-like and Pick-like syndromes, personality changes by the frontal type, stable neurosis-like conditions, Korsakov's syndrome, disturbed consciousness by the amentive type) in patients with organic brain lesions and objectively recordable changes in cerebral hemodynamics. It has been established that the pathological mechanisms of formation of different syndromes of mental activity reduction are naturally related to deceleration of the general and regional volumetric cerebral blood flow (RVCBF) and a decrease of the general and regional reaction of cerebral vessels (RCV). In this respect, the character of the psychopathological syndrome is specified by localization (lobar and interhemispheric) of the primary deceleration of the RVCBF and RCV decrease; by the rate of augmentation of those changes, their intensity and duration, constancy or periodicity; background against which there develops the hypoxic process; as well as by the development of the underlying disease.


[Clinical aspects, pathogenesis and treatment of neurovascular spastic torticollis]. The authors describe the clinical picture and treatment of neurovascular spastic torticollis (NVST) with special reference to 20 patients with ST, who underwent microvascular decompression of the accessory nerves. Postural attenuation of ST served as a criterion for the screening of the patients. The authors describe the results of clinico-anatomic correlations, attesting to the diverse neurological picture of NVST and to the presence of correlations between the nystagmus in ST and compression of nerve XI of the posterior connective artery as well as between facial hyperkineses in ST patients and compression of the accessory nerves by the pathologically involuted vertebral and posteroinferior cerebellar arteries.


[Clinico-morphological characteristics of cardiogenic non-bacterial cerebral embolism]. Clinical and morphological studies were carried out in 194 patients who died in the acute period of ischemic brain stroke. Disorders of the heart rhythm were found to play the leading part in the origin of cardiogenic embolisms of cerebral vessels. It has been recorded that left atrial thrombus formation was prevalent in heart rhythm disorders whereas left ventricular was prevalent in lack of those disorders. In different heart diseases complicated by atrial fibrillation and cerebral thromboembolism, the one-third of cases did not show any heart thromboses. The content of embolisms in cerebral arteries corresponded to the material of their source, whereas the site was specified by mechanical obstruction, with no changes in the vascular wall. It has been disclosed that in the majority of cases, stable embolism precipitates white infarction or white infarction with the hemorrhagic component whereas embolus lysis is responsible for hemorrhagic infarction and (or) a transitory ischemic attack. The clinical manifestations of hemorrhagic infarction differ from white infarction in less gravity and regression of the neurological symptomatology.


[Revising the principles and improving the methods of differential therapy of ischemic stroke]. In accordance with the clinical and coagulographic data on 172 patients with ischemic brain stroke (IBS), the authors developed a method of the use of some medicamentous agents (heparin, platelet inhibitors, fresh-frozen blood plasma, plasminogen activators, proteolytic enzymes), adapted to concrete characteristics of the coagulation status at different stages of brain infarction formation and permitting the rate of lethal outcomes to be reduced. In disseminated intravascular coagulation seen in patients with the gravest patterns of IBS, heparin may be indicated.


[10-year experience with using Cavinton in cerebrovascular disorders]. Cavinton was used for 10 years in 967 patients with different cerebrovascular diseases. The highest effect was seen in patients with early forms and primarily chronic forms: vegetovascular (neurocirculatory) dystonia, initial manifestations of brain blood supply insufficiency, circulatory encephalopathy in the first and second stages. Improvement of the subjective status and a decrease of the intensity of vestibulocerebellar disorders were recorded by the end of the treatment in 75-85% of such patients. In ischemic brain stroke, regress of general cerebral and focal symptoms was more rapid and significant in the adequate reaction type of cerebral hemodynamics to cavinton administration (a rise of pulse blood content of the brain and a reduction of the vascular tone according to the REG data) and was less noticeable in the hypertonic and, in particular, in the hypotonic type. Cavinton should not be used in severe general cerebral hypertensive crises, as well as in elderly or senile patients with acute cardio-cerebral or cerebro-cardiac syndrome, postinfarction cardiosclerosis, marked disorders of heart rhythm.


[Reflexotherapy and carbon dioxide baths in the complex treatment of patients with circulatory encephalopathy of arteriosclerotic etiology]. Overall 106 patients with atherosclerotic cccccccirculatory encephalopathy (DE) were examined for changes in the EEG, REG and in certain psychological parameters (attention, memory, "associative" thinking) before and after acupuncture and carbon dioxide baths. In patients with stage I and stage II DE (in 93 and 80%, respectively), the clinical improvement was accompanied by positive changes such as a rise of alpha-activity, decrease of pathological waves and frequencies on the EEG, decline of the vascular tone and improvement of the blood content on the REG in addition to the shortening of the time required for the search for numbers according to Schulte's tables, a decrease of errors made during calculation, an increase of words and the family of words in the memorization and "associative" thinking tests. The data obtained may attest to the amelioration of cerebral function and hemodynamics because of the rehabilitation treatment.


[Magnetotherapy of initial manifestations of cerebrovascular disorders in hypertension]. The paper is concerned with the data on 147 subjects who underwent magnetotherapy with the unit "Magniter-AMT-01" applied to the cervical area. The main group included 102 subjects, 45 person served as control. The purpose of the work was to base the application of MT under inpatient and home conditions with the use of the above-indicated unit. In view of this fact, a study was made of cerebral hemo- and thermodynamics with the aid of rheoencephalography and encephaloradiothermography under the action of different modes of the functioning of the unit "Magniter-AMT-01" (pulse and variable magnet induction fields 12-15 mTl and 30-35 mTl). A method of measuring magnetosensitivity of patients depending on the temperature reaction of the brain to a single MT session was elaborated. The greatest clinical effect was attained with the use of pulse magnetic field 15 mTl. Magnetotherapy with the use of the unit "Magniter-AMT-01" provided good results under inpatient and home conditions. The magnetosensitive patients demonstrated the highest effect.


[Comparative evaluation of various forms of Parkinson disease in middle-aged and elderly patients (clinical, neuropsychological and computerized-tomographic studies)]. The clinical, neuropsychological and computer-aided tomography data were compared in elderly and senile patients suffering from trembling and akinetic rigid forms of parkinsonism. 12 patients with trembling and 21 with akinetic rigid parkinsonism were examined. The groups did not differ in age or sex. The results of computer-aided tomography of the brain were evaluated using linear, volumetric and densitometric parameters. The akinetic rigid pattern was found to be associated with a more diverse clinical and neuropsychological symptomatology, by more manifest cerebral atrophy. The gravity of the status of patients with trembling parkinsonism is largely determined by the intensity of the hyperkinetic syndrome, that of patients with akinetic rigid parkinsonism not only by amyostatic disturbances but also by the presence and severity of incoordination , pseudobulbar and mnemonic intellectual disorders. The disorders identified in patients with akinetic rigid parkinsonism often attest to dysfunction of the frontal parts of the brain. The nosological heterogeneity of both patterns of parkinsonism is assumed.


[Attention and associative memory in patients with sequelae of ischemic stroke]. To study social and adaptation potentialities of 56 patients with a history of ischemic brain stroke, they were examined for attention and associative memory (AM). Use was made of neuropsychological techniques and phonooscillography of latent conditions of AM. The patients manifested deceleration and instability of all the time parameters of the process of attention (tempo, rate, quality, productivity, accuracy), its depletion (in hemispheric foci) and instability (in stem derangement), as well as a decrease of the level of active attention and of the capability of its switching over (especially in pathology of the left cerebral hemisphere). This evidences restricted potentialities of postinsult patients in adaptation. Examination of AM revealed not only a decline of the scope and deceleration of the time processes of its organization but also showed the dominant hemisphere to play an essential part in the retention (memory scope) and extraction (latent period) of mnemonic associations.


[Cerebrospinal fluid therapy in patients with central motor disorders]. The authors relate new concepts of the mechanisms of the pathogenesis and compensation of central motor disorders of organic origin, based on experimental exploits of the I.P. Pavlov Physiological Department of the Institute of Experimental Medicine. It is shown that in these mechanisms, of paramount importance is the neurochemical component determining a considerable part of the symptomatology of neurological disorders and process of disturbed functions recovery. Based on the regularities discovered and studies of the properties of the convalescents" CSF, a method of its use has been developed in order to treat residual phenomena after brain stroke or craniocerebral injury. The authors describe the results of the clinical testing of that method, demonstrating its effectiveness in the treatment of chronic neurological patients.


[Clinico-epidemiological characteristics of the ambulatory group of elderly patients with endogenous affective psychoses]. The studies were carried out on the basis of the Gerontopsychiatry Center servicing patients aged 60 and more years in one of the districts of Moscow. 163 persons suffering from endogenous affective diseases were identified. The disease prevalence was 3.75 per 1000 population and the incidence 32.2 per 100,000 population. The data were obtained, indicating the rise of the disease prevalence and incidence with age (mainly at the expense of women). In the majority of patients (71.8%), different psychopathological disturbances were detected. 37.4% manifested affective disorders within the structure of the successive disease attack. The number of inpatients was only 4.3%. These data point to the necessity of the development of outpatient specialized forms of gerontopsychiatric assistance.


[Individual prognosis in endogenous affective and schizoaffective psychoses: clinical predictors]. The purpose of the work was to search for predictors for early individual prognosis of the clinical characteristics of affective and schizoaffective psychoses and forecasting treatment responses to the tricyclic antidepressants and prevention with lithium salts. 285 patients (190 with affective and 95 with schizoaffective pathology) were examined. The mean disease standing was about 15 years, the mean duration of the follow-up amounted to over 4 years. More than 40 clinical and therapeutic signs were taken into account on the whole. The data were processed by EC-1036 computer. A number of coefficients indicating the intensity of interrelations between the study signs were computed. Based on the magnitudes of the above coefficients, the lists of the clinical predictor signs and protector signs were compiled to be used in psychiatric practice.


[Individual prognosis in endogenous affective and schizoaffective psychoses: biological predictors]. A study was made of the distribution of a complex of biological markers: HLA antigens, loci A and B, ABO blood groups, haptoglobin phenotypes, acetylator status, indicators of anthropometry and dermatoglyphics, and marital radius of the parents in 285 patients with affective and schizoaffective psychoses--representatives of the Byelorussian population. The mean time of the clinical follow-up was over 4 years. The magnitudes of relative risk (RR) were computed with regard to the indicated biological signs to estimate their relation to the disease and to some characteristics thereof: polarity of affective disorders, the type of the course, age of manifestation, the presence of homonomous hereditary aggravation, late outcome as well as the efficacy of tricyclic antidepressants and lithium prevention. The data obtained are discussed from the standpoint of their practical use.


[Clinical characteristics and typological classification of endogenous depression resistant to treatment]. Overall 47 patients suffering from treatment-resistant endogenous depressions were examined. In accordance with psychopathological manifestations, structure and dynamics of the given conditions, typological differentiation was performed. Three main variants, designated as reactive neurotic, endomorphous vital and heteronomic, were described. Differences were shown between resistant and curable endogenous depressions in terms of some clinical, psychopathological and structural signs. A varying character of treatment response under conditions of routine treatment by antidepressants combined with antioxidants is discussed in different clinical varieties of treatment-resistant endogenous depressions.


[Interhemispheric correlations of electric activity of the brain in late depression]. A chronometric EEG analysis was made in 60 patients aged 50 to 86 years with affective psychosis in different stages of the depressive phase. It has been demonstrated that the development of depressive conditions gives rise not only to changes in the frequency and amplitude characteristics of the EEG but also in the ratios of interhemispheric asymmetry of the parameters of brain electric activity, attesting to a higher tone of the right hemisphere. This interhemispheric asymmetry was determined to a considerable measure by the presence in the reference EEG of generalized discharges of slow-wave activity. The use of the dipolar analysis of the EEG permitted detecting foci of maximum generation of discharges in the left temporal area and brain stem structures. These areas of generation were preserved after removing the depressive symptomatology with antidepressants. It is suggested that the superstem generators of discharges exert a more appreciable effect on right hemisphere function, which is specified by cortico-diencephalic relations.


[Dynamics of ECG changes during the treatment of depressive conditions with different variants of the course of endogenous affective psychosis]. The ECG parameters were studied and compared in normal subjects and patients suffering from affective psychosis running bi- and monopolar course during the development of the depressive phase and after its removal. At the prodromal stage before treatment, the patients manifested sinus tachycardia, changes in the ST configuration and QRS complex. On the histograms of RR intervals distribution, the modal value was shifted to the area of short intervals, the mode amplitude was higher whereas the variation range was more narrow than in the healthy subjects. Intergroup comparisons of the changes in the ECG parameters have shown that the disturbances were more remarkable in the patients with bipolar psychosis. At the initial stage of the treatment with antidepressants, the disorders were either unchanged or got intensified. The initial positive changes in the study parameters were seen only in the presence of the initial clinical improvement. However, the intergroup differences increased at the same time. The removal or appreciable reduction of the psychopathological symptomatology revealed a reversible nature of the changes in myocardial depolarization and disorders of conduction within the system of His bundle crura, seen before treatment. Still, the patients continued manifesting sinus tachycardia and changes in the cardiointerval histograms, particularly those with monopolar depressive psychosis.


[Changes in circadian rhythm of various physiological functions in depression]. Analysis of the daily dynamics of some physiological and psychoemotional characteristics in healthy subjects and depressed patients has demonstrated the patients to have circadian rhythm disorders in functions, namely inversion of the daily gradient with the shift of the function optimum to the second half of the day. The depressed patients manifested a high daily variability of the physiological parameters. It should be mentioned that curable conditions were marked by a higher variability as compared to those resistant to the treatment. The latter circumstance permits regarding the ratio of function variability as a potential predictor.


[Significance of various enzymes of mediator metabolism for evaluation of depression and therapeutic prognosis]. The purpose of the work was to specify the possibilities of the use of the enzymes of mediator metabolism: monoamine oxidase (MAO) of platelets, amine oxidase (AO) of serum and acetyl cholinesterase (ACE) of red blood cells to estimate the structure of depressions and to predict their therapeutic dynamics. 32 patients in the depressive phase of MDP were examined. There were 28 women and 4 men aged 22 to 50 years. The monopolar type was recorded in 28 patients, the bipolar one in 4 (all women). The total disease duration amounts to 0.5-17 years; depression may last from 2 months to 4 years. Depending on the type of the dominant affect the patients were distributed into 2 groups (10 persons had melancholic and 22 anxious depression). It has been shown that activity of platelet MAO and serum AO was significantly higher in anxious than in melancholic depression. An interrelationship was established between activity of these enzymes before treatment and prognosis of the treatment with tricyclic antidepressants. Activation of the enzymes during therapy was parallelled by positive clinical changes. Activity of platelet MAO turned out most significant in terms of prognosis. The data obtained are analyzed from the standpoint of regarding depression as a stressful condition, with the participation of the neurohormonal axis: the hypothalamus, pituitary, and adrenal cortex.


Effect of dietary phosphate deprivation and supplementation of recipient mice on bone formation by transplanted cells from normal and X-linked hypophosphatemic mice. The hypophosphatemic (Hyp) mouse is the murine homolog for human hypophosphatemic vitamin D-resistant rickets. We previously reported that bone cells isolated from normal and Hyp mice produced abnormal bone when transplanted intramuscularly into mutant mice. To assess the role of hypophosphatemia on bone formation in transplants, normal and Hyp mouse periostea were pair transplanted into control or phosphate (P)-supplemented Hyp mice and into control or P-deprived normal mice. The bone nodules formed in transplants after 2 weeks were characterized by measuring the thickness of the surrounding osteoid seams and the relative osteoid volume. P restriction in normal recipient mice impaired bone formation by transplanted normal cells and aggravated the defective bone formation by Hyp cells. The osteoid thickness and volume remained significantly higher in Hyp transplants than in normal cotransplants, however. P supplementation of Hyp recipient mice normalized bone formation by transplanted normal cells but not by Hyp cells. However, a marked decrease in osteoid thickness and volume was observed in Hyp transplants down to values observed in normal recipient mice. These results indicate that hypophosphatemia is not the only cause of abnormal bone formation in the Hyp mouse but that an osteoblast dysfunction contributes to the bone disease. These observations further support the concept that the osteoblast may be an important target for the Hyp mutation.


Specific binding of parathyroid hormone to living osteoclasts. We show that osteoclasts bind parathyroid hormone (PTH) in a manner that displays the properties of receptor-dependent hormone binding, that is, saturability, time dependence, temperature dependence, and hormone specificity. Osteoclasts were isolated from the endosteum of 2 to 3 week chick tibiae and maintained in culture for 4-6 days. Bovine PTH-(1-84) was biotinylated with N-hydroxysuccinimidobiotin. Biotinyl-PTH (btPTH, 10(-5)-10(-11) M) was added to the cultured osteoclasts for 2-20 minutes. After rinsing away unbound btPTH, fluorescein isothiocyanate-labeled avidin (FITC-avidin) at a concentration of 66 micrograms/ml was applied. Receptor binding characteristics were assessed: (1) saturation occurred at around 10(-6) M btPTH; (2) competition of excess unlabeled PTH was found, namely, a 10-fold excess abolished fluorescence; (3) specificity was shown by adding other polypeptide hormones (insulin, glucagon, and calcitonin) in 10- to 100-fold excess--no effect on PTH binding was observed; and (4) affinity of btPTH for its binding site was indicated by half-maximal binding approximately equal to 10(-7) M for both osteoclasts and osteoblasts. Biotin (10(-5) M) or FITC-avidin (66 micrograms/ml) alone did not cause fluorescence. The time course of btPTH on the cell exterior was short: at 2 and 5 minutes dots of fluorescence were randomly dispersed over the cell surface, by 10 minutes most of the fluorescence was clustered in one region of the membrane, and by 20 minutes most of the hormone was no longer present on the surface of the cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of transforming growth factor beta on parathyroid hormone receptor binding and cAMP formation in rat osteosarcoma cells. Transforming growth factor beta (TGF-beta) is now recognized as an important growth regulator and modulator in bone, where it apparently acts in an autocrine or paracrine fashion. In an effort to help elucidate how TGF-beta may interact with parathyroid hormone (PTH) to influence bone turnover, we examined the idea that TGF-beta might alter the number or affinity of PTH receptors in osteoblastic bone cells, PTH receptor binding was assessed in cultured ROS 17/2.8 cells using [125I]PTHrP-(1-34) as labeled ligand. Specific binding to intact cells was measured in the presence of up to 1 microM unlabeled rPTH-(1-34), and cAMP in cell extracts was determined by RIA. Incubation of ROS cells with 2 ng/ml of TGF-beta for the maximally effective time of 3 days increased the number of PTH binding sites (Bmax) by 47 +/- 13%, with no change in the KD (3 nM). TGF-beta also increased the intracellular cAMP response to 0.3 nM rPTH-(1-34) (ED50) by 53 +/- 22%. Both effects were dose dependent, with 1-4 ng/ml of TGF-beta producing maximal effects, and both effects were blocked by the protein synthesis inhibitor cycloheximide (2-5 microM). Since TGF-beta induced comparable increases in both PTH binding and cAMP formation, the findings suggest that TGF-beta can increase the number of functional PTH receptors in cultured ROS 17/2.8 cells. This effect may reflect an action of TGF-beta to slow replication and promote differentiated functions in these cells.


Renal Na(+)-phosphate cotransport in X-linked Hyp mice responds appropriately to Na+ gradient, membrane potential, and pH. To investigate the mechanism for the 50% decrease in Vmax of the high-affinity phosphate transport system in the renal brush-border membrane of X-linked Hyp mice, we compared the effects of external Na+ concentration, membrane potential, pH, phosphonoformic acid (PFA), and arsenate on Na(+)-Pi cotransport in brush-border membrane vesicles prepared from normal mice and Hyp littermates. The affinity of the Na(+)-Pi cotransport system for Na+ (apparent Km = 60 +/- 7 and 64 +/- 2 mM for normal and Hyp mice, respectively) and the Na(+)-Pi stoichiometry estimated from Hill plots (2.5 +/- 0.2 and 2.9 +/- 0.6 for normal and Hyp mice, respectively) were similar in brush-border membranes of both strains. Inside-negative membrane potential, generated by anions of different permeabilities, stimulated Na(+)-Pi cotransport and inside-positive membrane potential generated by valinomycin, and a K+ gradient (outside greater than inside) inhibited Na(+)-Pi cotransport to the same extent in brush-border membranes derived from normal mice and Hyp littermates. The pH dependence of Na(+)-Pi cotransport was similar in brush-border membrane vesicles of normal and Hyp mice. The ratio of Na(+)-Pi cotransport measured at pH 7.5 relative to that at pH 6.5 was 2.9 +/- 0.6 in normal mice and 2.9 +/- 0.7 in Hyp mice. PFA was a competitive inhibitor of Na(+)-Pi cotransport in brush-border membranes of both normal and Hyp mice. However, the apparent Ki for PFA was significantly lower in Hyp mice (0.31 +/- 0.01 and 0.19 +/- 0.02 mM in normal and Hyp mice, respectively, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Neurosurgical experience with tumours of the pineal region at Clinica Puerta de Hierro. The clinicopathological experience with 50 cases of pineal region tumours at Clinica Puerta de Hierro is presented. In this series, 88% of the patients were evaluated by CT-scan. Pineal region tumours make up approximately 0.7% of the intracranial expansive processes in the Spanish population. The largest group of lesions appearing in this localization is that of the germinomas (38%), followed by nontumoural lesions (20%) and tumours generally considered to be of the vicinity, such as meningiomas, gliomas and metastases (18%), tumours of the pineal parenchyma (14%), and non-germinoma germinal tumours (10%). In our series, in addition to an intracranial hypertension syndrome, an ophthalmological and, to a minor degree, an endocrinological syndrome predominate in germ-cell tumours, with a cerebellar syndrome appearing in gliomas of the pineal region. All the patients in the series diagnosed as having a germinoma and treated by irradiation are alive, and free of disease, after follow-up ranging from 2 to 20 years (mean: 8 years). The experience obtained with the present series supports the opinion that, in radiosensitive tumours, surgical resection adds no therapeutic benefit to treatment with radiotherapy alone. We suggest that when dealing with a tumour of the pineal region, CT-scan and clinical assessment now permit an initial selection of patients susceptible to surgery as a first therapeutic option, indicating those patients who, because they are considered to have either a "probable germinoma" or a "tumour of uncertain diagnosis", should undergo stereotaxic biopsy or trial radiotherapy and, only when this has proved a failure, should be subjected to open surgery.


Gastrointestinal microvillus inclusion disease. A 3-year-old girl of Navajo heritage had intractable diarrhea beginning at 4 days of age and resulting in long-term hyperalimentation. Investigation before multivisceral transplantation included biopsies of the rectum, stomach, duodenum, and liver. The diagnosis of microvillus inclusion disease was established by documentation of microvillus inclusions in duodenal epithelial cells. A trial of somatostatin therapy was ineffective in controlling the diarrhea. Subsequently, a multivisceral organ transplant provided a unique opportunity to establish the gastrointestinal extent of involvement of this disease. Ultrastructural microvillus inclusions were identified in the duodenum, jejunum, ileum, and colon, but not in the gallbladder. A few inclusions also were documented in gastric antral epithelial cells. Alkaline phosphatase stains performed on paraffin-embedded material showed a few inclusions in the antrum of the stomach and many inclusions throughout the small intestine, primarily in surface epithelial cells but also in upper crypt cells.


Spontaneous regression of hepatocellular carcinoma. We report a 65-yr-old man with hepatitis B virus-related liver cirrhosis and biopsy-proven hepatocellular carcinoma who has undergone spontaneous regression. The tumor became impalpable, and was no longer detectable by ultrasonography and computed axial tomography, 5 and 30 months later. The alpha-fetoprotein level also decreased to normal range. The clinical course is silent, and the patient is alive and well 37 months after the initial diagnosis.


Activated neutrophils inhibit Na(+)-K(+)-ATPase in canine renal basolateral membrane. To examine the effects of activated neutrophils (PMNs) on Na(+)-K(+)-ATPase, phorbol 12-myristate 13-acetate (PMA)-stimulated PMNs were incubated with canine renal cortical basolateral membrane (BLM), and BLM ouabain-sensitive Na(+)-K(+)-ATPase activity was subsequently quantified. Na(+)-K(+)-ATPase activity decreased to 40.0 +/- 8.7% (SE) of control in the presence of activated PMNs, from 0.89 +/- 0.12 to 0.34 +/- 0.05 mumol Pi.mg protein-1.min-1. This inhibition coincided with a decrease in the apparent Michaelis constant (Km) for ATP from 0.18 +/- 0.02 to 0.05 +/- 0.01 mM. Inclusion of catalase (CAT) and superoxide dismutase (SOD) in the BLM/PMN/PMA incubation mixture resulted in partial preservation of enzyme activity, with an increase to 57.0 +/- 4.6% of control with CAT alone and to 70.0 +/- 5.3% with both CAT and SOD. SOD alone had no protective effect. Neither the myeloperoxidase inhibitor azide nor the hypochlorous acid scavenger L-methionine preserved enzyme activity. Hydroxyl radical scavengers and iron chelators were also ineffective in attenuating Na(+)-K(+)-ATPase inhibition by activated PMNs. These results indicate that activated PMNs mediate a decrease in BLM Na(+)-K(+)-ATPase activity characterized by a reduction in maximum velocity and Km for ATP that appears to be mediated in part by reactive oxygen metabolites.


Erythrocytes from magnesium-deficient hamsters display an enhanced susceptibility to oxidative stress. Previous studies in our laboratory have indicated a role for free radical participation in magnesium deficiency cardiomyopathy. We have demonstrated the ability of various antioxidant drugs and nutrients to protect against magnesium deficiency-induced myocardial injury. In this study, we have examined erythrocytes from normal and magnesium-deficient animals and compared their susceptibility to an in vitro oxidative stress. Syrian male hamsters were placed on either magnesium-deficient or magnesium-supplemented diets. Animals from each group also received vitamin E in doses of 10 and 25 mg as subcutaneous implants. Erythrocytes obtained after 14 days on the diet were exposed to an exogenous hydroxyl (.OH) radical generating system (dihydroxyfumarate not equal to Fe3+ ADP) at 37 degrees C for 20 min. Erythrocyte crenation was observed and quantified by scanning electron microscopy. Lipid peroxidation, hemolysis (%), and intracellular glutathione levels were determined. In addition, serum lipid changes and membrane phospholipids were characterized. Our data demonstrate that erythrocytes from magnesium-deficient animals are more susceptible to free radical injury, supporting our hypothesis that magnesium deficiency reduces the threshold antioxidant capacity.


Determination of Na(+)-K(+)-ATPase alpha- and beta-isoforms and kinetic properties in mammalian liver. While Western blot analysis clearly revealed the presence of the alpha- and beta-subunits of Na(+)-K(+)-ATPase in a variety of rat tissues, beta was not readily detectable in liver. This observation was consistent with a previous report indicating that Na(+)-K(+)-ATPase immunoprecipitated from rat liver gives no clear evidence for the presence of a beta-subunit (Hubert et al. Biochemistry 25: 4156-4163, 1986). However, Western blot analysis of density gradient-purified lamb and rat liver microsomes showed the presence of a protein with an approximate molecular mass of 42 kDa that was immunoreactive with beta-specific polyclonal antibodies as well as beta-directed monoclonal antibodies. Deglycosylation of this protein by N-glycosidase F generated a core protein (beta c, M(r) approximately 32,000) that had the identical electrophoretic mobility as the beta c protein of the purified kidney enzyme. Isoform-specific monoclonal and synthetic peptide-directed polyclonal antibodies were used to demonstrate the presence of only the alpha 1- and beta 1-proteins in the liver and the presence of beta 2 in rat brain. Functional studies then showed that although both rat and lamb liver enzymes had sensitivities to cardiac glycoside inhibition similar to that of their corresponding kidney enzyme, the lamb liver enzyme had higher affinities for Na+, K+, and ATP than the kidney enzyme.


C-25 hydroxylation of vitamin D3 in periportal and perivenous region of hepatic acinus. Many biotransformation activities have absolute or modulated localization within the hepatic acinus. To investigate the intrahepatic acinar zonation of vitamin D3 (D3) metabolism, hepatic D3 extraction was investigated by antegrade or retrograde perfusion of normal livers and livers bearing selective periportal (PP) or perivenous (PV) destruction; D3 C-25 hydroxylation was studied after selective harvesting of PP or PV hepatocytes by digitonin-collagenase perfusion. Data indicate that hepatic D3 extraction is not regioselective and not perturbed by destruction of the proximal (PP) or distal (PV) part of the acinus, indicating that D3 extraction takes place in the most proximal hepatocytes being perfused. These observations suggest that, in vivo, D3 extraction will take place according to its concentration gradient within the hepatic acinus, thus resulting in a preferential PP extraction of the vitamin. D3 C-25 hydroxylation was higher in PP than in PV hepatocytes in the presence of 1.9 mM Ca2+, with 25-hydroxyvitamin D3 [25(OH)D3] formation of 34.6 +/- 3.9 and 24.4 +/- 1.1 fmol.h-1.(10(6) hepatocytes)-1, respectively (P less than 0.05). Modulators of extracellular [ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)] or intracellular Ca2+ (parathyroid hormone, A23187), however, significantly influenced 25(OH)D3 formation with similar decreases in the PP (31%) and PV (26%) areas in the presence of EGTA but with increases in the presence of Ca2+ ionophore A23187 of 189 +/- 16% in PP and of 260 +/- 20% in PV hepatocytes, resulting in similar production in both regions of the acinus.(ABSTRACT TRUNCATED AT 250 WORDS)


Increased plasma FFA uptake and oxidation during prolonged exercise in trained vs. untrained humans. We studied the effect of local muscle adaptations on free fatty acid (FFA) metabolism during prolonged exercise in trained and untrained subjects. Six trained (T) and six untrained (UT) young human males exercised for 3 h at 60% of their individual maximal dynamic knee extension capacity. The contribution of blood and plasma metabolites as well as intramuscular substrates to oxidative metabolism in the thigh was calculated from arteriovenous differences and femoral-venous blood flow as well as from muscle biopsies in subjects that were continuously infused with [1-14C]palmitate. Arterial plasma FFA concentration increased over time in both T and UT. Fractional uptake of FFA across the thigh remained unchanged over time in T (15%) but decreased in UT (from 15 to 7%), especially during the last hour of exercise. Thus FFA uptake increased linearly over time in T (96 +/- 20 to 213 +/- 20 mumol.min-1.kg-1), whereas it leveled off after 2 h in UT (74 +/- 16 to 133 +/- 46) even though FFA delivery increased similarly in T and UT. Percentage oxidation was similar in T and UT; thus total FFA oxidation was higher in T. Glucose uptake increased in both groups over time and was significantly higher in UT during the last hour of exercise. In conclusion, during prolonged knee extension exercise, FFA uptake increases linearly with FFA delivery in the trained thigh, whereas in the untrained thigh uptake becomes saturated with time. This difference partly explains the increased lipid oxidation in T vs. UT and suggests, furthermore, that local muscle adaptations to training are important for the utilization of FFA during prolonged exercise.


Insulin receptor function is preserved in a physiological state of hypoinsulinemia and insulin resistance. The suckling period in the rat is characterized by a continuously low plasma insulin concentration and a physiological insulin resistance, particularly in the adipose tissue. This insulin resistance disappears after weaning on the high-carbohydrate adult diet. We have studied the number, structure, and function of adipose tissue insulin receptors during the suckling-weaning transition. The insulin receptor number determined either on intact adipocytes or after partial purification was higher during suckling (15 days), whereas the affinity was similar when compared with weaned rats (30 days). The molecular weight of the alpha- and beta-subunits were identical in both groups and, when analyzed in nonreducing conditions, the alpha 2 beta 2-form was the unique detectable form of the receptor. Neither the basal and insulin-stimulated autophosphorylation of the insulin receptor beta-subunit nor the tyrosine kinase activity toward a synthetic substrate was decreased during the suckling period. Thus, in the adipose tissue of the suckling rat, a marked insulin resistance is concomitant with a normal insulin receptor number and function.


Na+-H+ antiport and monensin effects on cytosolic pH and iodide transport in FRTL-5 rat thyroid cells. Na+-H+ exchange may proceed via an endogenous antiporter or by exposure to the Na+ ionophore monensin. We investigated the characteristics of Na+-H+ exchange induced by antiporter stimulation and by monensin in FRTL-5 rat thyroid cells. We also examined the effects of intracellular pH (pHi) changes on iodide uptake and efflux. pHi was determined using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The resting pHi was 7.33 +/- 0.02 units; this level correlated directly with extracellular pH. In acid-loaded cells, Km for external Na+ activation of the antiporter was 7.1 mM and maximum velocity was 0.3801 delta pH units/min. Dimethylamiloride was 42 times more potent than amiloride in inhibiting sodium-dependent recovery in acidified cells. Metabolic inhibition reduced the initial alkalinization rate. Monensin increased pHi, and this response was dependent on extracellular Na+ and HCO3- but not on antiporter function. Low-dose monensin (1 microM) and 1 mM NH4Cl enhanced 125I uptake. High-dose monensin (100 microM), but not NH4Cl, reduced iodide uptake. Neither NH4Cl nor monensin altered 125I efflux. Thus FRTL-5 cells possess an amiloride-sensitive Na+-H+ exchanger, which is not essential for maintaining basal pHi but is affected by ATP depletion. Monensin also alkalinizes these cells but independently of the antiporter. Iodide uptake, but not efflux, is affected by changes in intracellular Na+ and H+ levels.


Insulin-like growth factor I-dependent tyrosine kinase activity in stromal cells of human endometrium in vitro. The study was undertaken to identify and characterize insulin-like growth factor I (IGF-I) receptors in human endometrial stromal cells in culture and to examine whether these receptors are modulated by estradiol (E2) and/or progesterone (P). We found that partially purified plasma membrane proteins from these cells contain specific high-affinity binding sites for IGF-I (10 fmol/micrograms protein). Chemical cross-linking with 125I-labeled IGF-I and autophosphorylation with [32P]ATP-labeled proteins of relative molecular weight 135,000 and 95,000 correspond to the known Mr values of the alpha- and the beta-subunits of IGF-I receptors. Receptor autophosphorylation and phosphorylation of the substrate poly(Glu,Na4Tyr1) was stimulated in vitro by IGF-I (half-maximally at 1 nM, maximally at 100 nM). After stimulation of intact cells with IGF-I (5 nM) and subsequent partial purification of receptors in the presence of phosphatase inhibitors, a 2.5- to 3.6-fold stimulation of the kinase activity toward poly(Glu,Na4Tyr1) was found. Preincubation of the cells for 16 h with E2, P, and E2 + P did not modify the IGF-I binding characteristics nor the effect of IGF-I (5 nM) on tyrosine kinase stimulation in intact cells. This suggests that, in isolated humans, endometrial cell modulation of IGF-I receptor function by estrogen and P does not occur.


Studies of adrenal steroidogenic enzymes in guinea pigs. In the present study we found that 3 beta-hydroxysteroid dehydrogenase 4-ene-5-ene-isomerase (3 beta-HSD), 17-hydroxylase and 17,20-lyase (P-450c17), and 21-hydroxylase (P-450c21) activities in a suspension of cells from guinea pig zona reticularis (RE) were 10- to 15-fold less than those measured in cells from zona fasciculata-glomerulosa (FG). Whereas the secretion of cortisol and C-19 steroids was remarkably increased during treatment of FG cells with adrenocorticotropic hormone (ACTH), no response could be detected when using cells from zona RE. By contrast, the measurement of a series of C-21 and C-19 steroids shows that the concentrations of several steroids were greater in the zona RE than in the zona FG. In addition, using Northern blot analysis, we have observed that the basal steady-state levels of mRNA for cholesterol side-chain cleavage (P-450scc), 3 beta-HSD, P-450c21, P-450c17, and P-450c11 were in the same range in the two zones and an administration of ACTH caused, in both zona FG and zona RE, a two- to threefold decrease in P-450c17 and P-450c21 steady-state mRNA levels, whereas P-450c11, 3 beta-HSD, and P-450scc steady-state mRNA levels remained unchanged. Our data suggest the presence of some factor(s) capable of rapidly deactivating the steroidogenic enzymes in the zona RE.


Physiological effects of 1,25-dihydroxyvitamin D3 in TM4 Sertoli cell line. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] receptors have been previously described in Sertoli cells. This study was performed to assess biological activity of the receptor in the mouse Sertoli cell line TM4. A 2-h preincubation with 0.01-25 nM 1,25(OH)2D3 resulted in a dose-dependent rapid uptake of 45Ca2+ within 5 min of addition of the isotope to the cells (27 +/- 8%, n = 4 experiments; P less than 0.05). This response was specific for 1,25(OH)2D3, in that it was not induced by 25-hydroxyvitamin D3, estradiol, cortisol, R 5020 (promegestone), or testosterone. However, a combination of testosterone and 1,25(OH)2D3 inhibited uptake by 23 +/- 8% (n = 3 experiments, P less than 0.01). That the mechanism responsible for 1,25(OH)2D3-stimulated uptake may involve 1,25(OH)2D3 receptor interaction is supported by the observation that cycloheximide inhibited the response. Conversely, there was no detectable change in uptake by 1,25(OH)2D3-treated cells after 24-h incubation with 0.1-5 nM 1,25(OH)2D3. Increased levels of DNA and protein content also resulted from a 2-h incubation with the steroid and were sustained up to 24 h without a concomitant increase in cell number or a detectable change in cell morphology. The presence of specific 1,25(OH)2D3 receptor-like binding sites was demonstrated by sucrose gradient analysis and hydroxylapatite assay. These data demonstrate that 1,25(OH)2D3 may play an important role in testicular function through regulation of receptor-mediated events.