Genetic polymorphism of IL28B in hepatitis C-infected haemophilia patients in Israel.

Single-nucleotide polymorphisms (SNPs) near the IL28B gene were identified as major predictors of treatment response (sustained virologic response--SVR) and spontaneous clearance of HCV. Haemophilia patients have the highest prevalence of HCV, and are a unique target for genetic studies. The Israeli population is ethnically heterogeneous; therefore, genetic variability is anticipated. To determine the IL28B haplotypes in HCV-infected haemophilia patients and association with SVR and spontaneous viral clearance. IL28B polymorphism at SNPs rs12979860 and rs8099917 was determined in sera obtained from 130 HCV-infected haemophilia patients. The frequency of the various haplotypes was analysed according to treatment response, spontaneous HCV clearance, viral load and degree of fibrosis. The CC haplotype at SNP rs12979860 was found in 31% of patients, whereas the TT genotype at SNP rs8099917 was detected in 57% of cases. SVR was achieved in 70% of patients carrying the CC haplotype (P = 0.0196 vs. CT/TT), and 50% of the TT genotype at SNP rs8099917 (P = 0.0227 vs. TG/GG). Thirty-five percent of patients carrying the CC haplotype and 26% with the TT genotype at SNP rs8099917 showed spontaneous clearance of HCV infection (P = 0.00262 vs. CT/TT; and P = 0.00371 vs. TG/GG respectively). The C-allele frequency was exceptionally high (71%) in immigrants from the Asian republics of Russia. In HCV-infected haemophilia patients, SVR was more commonly achieved among patients who had the CC (rs12979860) or TT (rs8099917) genotype. Likewise, patients who possess harbour the CC or TT genotypes were more likely to clear HCV infection spontaneously. A unique distribution of the CC genotype was observed in some ethnic groups.

Fibrotest or Fibroscan for evaluation of liver fibrosis in haemophilia patients infected with hepatitis C.

Non-invasive modalities to estimate fibrosis stage are desirable in hepatitis C-infected haemophilia patients. Previous studies found a high rate of significant fibrosis both by Fibrotest (FT) and Fibroscan (FS) in these patients. To estimate liver fibrosis and to assess the concordance between FT and FS in hepatitis C-infected haemophilia patients. FT and FS were performed at different laboratories and were unaware of the results of the alternative test. Three successive liver stiffness measurements (LSM) were performed at different sites on the liver. Two-validated algorithms were used to improve evaluation of fibrosis by non-invasive methods. Fifty-seven hepatitis C-infected haemophilia patients were evaluated by FT and FS. Acquisition of LSMs was not feasible in two patients: obesity--one, surgical scars--one. Fibrosis stage > or=F2, > or =F3 or =F4 were estimated in about a half, about a third and in 15-20% of the evaluated patients by FS and FT respectively. The corresponding concordance rates and kappa score for fibrosis stage > or =F2, > or =F3 or =F4 between FT and FS were 62%, 69%, 85% and 0.24, 0.32, 0.44 respectively. Using the two aforementioned algorithms, additional 14 patients could be reliably estimated for fibrosis stage > or =F2. High proportion hepatitis C-infected haemophilia patients were estimated with significant or advanced stages of liver fibrosis using both tests. Nevertheless, the agreement between modalities was only fair and improved with more advanced stages of fibrosis. Practical algorithms for the accuracy of FT and FS may improve reliable evaluation of fibrosis in this population.

Testosterone, androstenedione, and 5alpha-dihydrotestosterone on male sexual behavior and penile spines in the hamster.

The expression of masculine sexual behavior (MSB) in male hamsters is optimally stimulated by aromatizable androgens like androstenedione (AD) and testosterone (T), while the non-aromatizable androgen, 5alpha-dihydrotestosterone (DHT), exerting potent androgenic peripheral effects, only in high doses maintains MSB after castration. No data exist on the ability of these androgens to restore long intromissions after castration. In this study, AD, T, and DHT were administered to four-week gonadectomized, sexually experienced male hamsters, for three weeks, in doses of 25 microg/day or up to 1000 microg/day to compare their potency in restoring MSB, penile size, and penile spines growth. Plasma levels of these steroids and the metabolites estrone and estradiol, were determined at the end of the treatment period. Gonadectomy completely suppressed MSB and induced a regression of penile spines. AD was more potent than T in restoring MSB, ejaculatory behavior being displayed by most castrated subjects with a lower dose of AD (50 microg/day) than of T (300 microg/day), and long intromissions being shown by all AD-treated castrated hamsters but only by 20% of T-treated ones, when doses of 1000 microg/day were given. DHT did not stimulate any copulatory response. The three androgens, even at the lowest dose, partially stimulated penis and penile epithelium growth, DHT showing the highest potency. Treatment of castrated hamsters with AD (50 microg/day), restored steroid levels to similar values as those of intact animals. These results show that AD and T restored MSB even with a partial stimulation of penile spines growth, AD being more potent than T. In contrast, DHT did not restore MSB in the hamster in spite of its peripheral androgenic potency.

Pesticides re-entry dermal exposure of workers in greenhouses.

This research has the aim to evaluate the risk of pesticide dermal exposure for workers in greenhouses. We considered the following crops: tomato, cucumber and strawberry, largely spread in Bracciano lake district. The pesticides monitored were: tetradifon on strawberry: metalaxyl, azoxystrobin and fenarimol on cucumber; acrinathrin, azoxystrobin and chlorpyrifos ethyl on tomato. The dermal exposure was evaluated by Dislodgeable Foliar Residue (DFR) measurements employing transfer coefficients got from literature. For risk evaluation, we have compared the dermal exposures with Acceptable Operator Exposure Levels (AOEL). The re-entry time were obtained intercepting the dose decay curves with AOEL values. The re-entry times result higher than two days in the cases of chlorpyrifos on tomato (re-entry time: 3 days), azoxystrobin on tomato (4 days), and tetradifon on strawberry (8 days). The need of measuring specific transfer coefficients is pointed out.

Hormone-like behavioral effects of levonorgestrel and its metabolites in the male rat.

Levonorgestrel (LNG), a contraceptive progestin, exhibits, besides its progestational activity, other hormone-like effects at the peripheral level. To assess whether LNG and its metabolites exert androgenic and/or estrogenic actions at the central nervous system (CNS), their effects on male sexual behavior in castrated rats were examined. LNG, 5alpha-dihydro LNG (5alphaLNG), and the 3alpha,5alpha- and 3beta,5alpha-tetrahydro derivatives of LNG (3alphaLNG and 3betaLNG, respectively) were administered for 3 weeks either alone (1000 microg/day) or in combination (300 microg/day) with 5alpha-dihydrotestosterone (DHT, 300 microg/day) or with estradiol-17beta (E(2), 5 microg/day). Copulatory behavior was assessed twice per week and sex accessory organs weights recorded at the end of treatments. LNG restored full copulatory behavior comparable to that of testosterone treated animals, although with a slight delay, whereas 5alphaLNG induced male sexual behavior in a significantly lower number of subjects. 3betaLNG and 3alphaLNG induced mounting but failed to restore intromission and ejaculation. Combined LNG+E(2) treatment fully activated mounting and intromission, but ejaculation was only partially restored. Combined 5alphaLNG+E(2) treatment and the combinations of 3alphaLNG or 3betaLNG with E(2) were significantly less effective, activating fewer intromissions and ejaculations. 3alphaLNG and 5alphaLNG, in combination with DHT, restored male sexual behavior. LNG, but not its metabolites, induced a significant increase on the weight of sex accessory organs. The overall results demonstrated that high doses of LNG induce a potent androgen agonistic behavioral effect and that its A-ring reduction diminishes this potency and enables a shift towards a weak estrogen-like effect.

Cardioversion-induced fulminant ischaemic hepatitis.

Ischaemic hepatitis, although infrequent, should be considered as a cause of fulminant hepatitis in patients with congestive heart failure. Ischaemic hepatitis is characterized by a marked rise in transaminases occurring within 24-48 h of circulatory failure. Cardioversion of atrial fibrillation to sinus rhythm is associated with an increase in cardiac output in most patients; however, a transient reduction in cardiac output may occur in more than one-third of patients, and may therefore induce ischaemic hepatitis. This is the first report of fulminant ischaemic hepatitis as a complication of cardioversion of atrial fibrillation.

Acute liver failure as the sole manifestation of relapsing non-Hodgkin's lymphoma.

Acute liver failure due to hepatic involvement by haematological malignancies is very rare, and usually has a rapidly fatal prognosis. We describe the case of a man who was treated for diffuse large B-cell lymphoma, and achieved a complete remission after eight courses of chemotherapy. He then presented with acute liver failure. Transjugular liver biopsy revealed massive infiltration by lymphomatous cells, with extensive necrosis. A CT scan did not show any evidence of extrahepatic lymphoma. The patient recovered from the liver failure following combined immuno-chemotherapy. Recurrence of the disease should be included in the differential diagnosis of patients with haematological malignancies and acute liver failure, even without evidence of extrahepatic involvement.

A pregnant woman with hepatitis A and Guillain-Barré.

Guillain-Barré syndrome (GBS) is often preceded by an infectious disease. A case of GBS after hepatitis A in a pregnant woman is described. The patient was treated with intravenous immunoglobulin and had full recovery with no neurologic sequelae. She gave birth in term to a healthy baby. This is the first reported case in the English literature of a triple condition of hepatitis A, GBS, and pregnancy.

Progesterone: protective effects on the cat hippocampal neuronal damage due to acute global cerebral ischemia.

BACKGROUND: Barbiturates, benzodiazepines, and synthetic steroids having anesthetic properties, by enhancing the inhibitory GABAergic neurotransmission to the neuronal circuits of cerebral structures vulnerable to ischemia, reduce the damage induced by this condition. Some endogenous steroids resulting from progesterone (P4) biotransformation in the brain exert GABAergic effects, thus inhibiting neuronal excitability. Hence, P4 administration both before and after an experimentally induced ischemic episode may prevent or decrease the ischemic cerebral damage. METHODS: Ovariectomized adult cats were treated s.c. with either P4 (10 mg/kg/day) or corn oil during 7 days before and 7 days after being subjected to a period of acute global cerebral ischemia by 15 min of cardiorespiratory arrest followed by 4 min of reanimation. After 14 days of survival, animals were sacrificed and the brains perfused in situ and formalin-fixed for histological examination. RESULTS: Acute global cerebral ischemia resulted in a severe loss of neurons (54-85%), mainly in CA1 and CA2 subfields of oil-treated cats. Progesterone significantly reduced the neuronal loss in those areas (21-49%). CONCLUSIONS: Overall results suggest that progesterone exerts protective effects against the neuronal cerebral damage induced by acute global cerebral ischemia.

Characteristic frequency bands of the cortico-frontal EEG during the sexual interaction of the male rat as a result of factorial analysis.

The electrocorticogram (ECoG) from the prefrontal cortex was simultaneously recorded with the accelerometric signals of pelvic thrusting performed by male rats during sexual behavior. The changes in the prefrontal ECoG were precisely correlated in time with well defined elements of male rat copulation. Principal component analysis allowed to identify three distinct bands of frequencies in the frontal ECoG: the absolute power (AP) of the 4-16 Hz band was increased in the 500-ms periods before, during, and after the execution of pelvic thrusting in mount, intromission and ejaculation responses; the AP of the 18-24 Hz band was selectively increased during the execution of pelvic thrusting at the three copulatory responses, whereas the AP of the 26-32 Hz band was increased only during the pelvic moments of mount and intromission responses. These results show that the electroencephalographic activity of the prefrontal cortex of the male rat is related to the performance of sexual behavior, supporting the concept that this cortical area is involved in the organization of sequential behaviors, as sexual behavior.

Computer programs to analyze brain electrical activity during copulatory pelvic thrusting in male rats.

Two microcomputer programs have been developed to simultaneously record and analyze the brain electrical activity: multiple unit activity (MUA) and electroencephalogram (EEG), and the accelerometric signals generated in relation to the pelvic thrusting that performs the male rat during the copulatory responses of mount, intromission, and ejaculation. CAPTUMUL is a program allowing the on line capture of the different signals and the further off line delimitation of the brain signals occurring in exact temporal relation with the accelerometric record of motor responses. The ANAMUA program allows the off line analysis of the neuronal firing rate in MUA records at different discrimination levels according to the amplitude of the neuronal spikes, and compare these data in various behavioral situations. The use of these programs provides a way of correlating in time the changes of brain electrical activity occurring in animals in free-movement with the brief motor events of copulation as well as with other behaviors (i.e., genital grooming, sniffing, running, walking). Advantages of this software include the recording of sequential events, a better and rapid handling of data and a reliable method to analyze the MUA with different discrimination levels according to the amplitude of the neuronal spikes.

Subcortical multiple unit activity changes during rat male sexual behavior.

Multiple unit activity (MUA) was recorded from the ventral tegmental area (VTA) and mesencephalic locomotor region (MLR) during copulatory behavior of freely moving male rats. Simultaneous accelerometric recordings of the copulatory pelvic thrusting performed by the male rat were taken to precisely correlate in time the changes in MUA with well defined elements of copulation. The baseline MUA firing rates recorded in the quiet-alert condition in the VTA and in the MLR were significantly increased during pursuit of the female by the male; significantly higher MUA firing rates were found in the VTA at the 500 ms periods before and during the execution of pelvic thrusting in mount, intromission, and ejaculation responses as compared to the baseline, and returned to this value when these responses ended. The maximum MUA firing rate in the MLR was obtained during the execution of pelvic thrusting in each copulatory response, and it remained significantly elevated, as compared to the baseline, after thrusting and at the postintromission and postejaculatory genital grooming, then decreasing to basal values at the initial part of the postejaculatory interval. The fact that the highest changes in MUA were related to pelvic thrusting suggests a major participation of both structures in the execution of motor copulatory responses.

Characteristics of the motor and genital copulatory responses of the male hamster.

The temporal and dynamic characteristics (duration, frequency, rhythmicity, and vigor) of pelvic thrusting displayed by 17 male golden hamsters during their copulatory behavioral responses: mounts, intromissions, ejaculations, and long intromissions, as well as their temporal correlation with the genital contacts established by intravaginal penile insertion, were studied by an accelerometric and polygraphic technique. Pelvic thrusting in all copulatory behavioral responses appeared as series or trains of rhythmical, synchronic, vigorous movements. The various pelvic thrusting trains lasted around 1 s on average, but those of mounts were significantly longer than the trains displayed in the other behavioral responses. The frequencies of pelvic thrusting were similar in all responses (around 15 thrusts per s) excepting mounts which had lower values. In intromission, ejaculation, and long intromission responses, when penile insertion occurred, pelvic thrusting either was interrupted or showed changes in its characteristics: penile insertion was related to a period without thrusting in intromissions, to a series of intravaginal thrusting of higher frequency (16.4 thrusts per s) and lower vigor in ejaculations, and to a prolonged period of 6 to 25 s of slow intravaginal pelvic thrusting (1-2 thrusts per s) in long intromissions. Penile insertion lasted longer in ejaculations than in intromissions and it was significantly shorter in both of these responses than in long intromissions. These results provide information about some dynamic aspects of sexual behavior in hamsters, as well as a temporal correlation between the motor and genital components of this behavior.

Inhibition of sexual behavior in male mice infected with Taenia crassiceps cysticerci.

Prominent estrogenization and deandrogenization ensue in male mice as a consequence of experimental intraperitoneal infection with Taenia crassiceps cysticerci. The impact of these endocrine changes upon sexual behavior was explored in a group of infected Balb/c male mice at weekly intervals for 15 wk and compared with the behavior of otherwise paired, nonparasitized male mice. Mounting, intromission, and ejaculation responses markedly declined as infection progressed. Six weeks after infection, none of the infected mice displayed ejaculation, the number of mounts and intromissions gradually decreased, and their latencies increased, until, by the 13th wk, none of the parasitized mice showed any sexual response toward female mice. Fifteen weeks after infection, the number of metacestodes per host increased to a couple of thousand, the mean serum estradiol level was approximately 50 times higher than the normal value, and testosterone fell to 5% of its normal level. To fully assess that the inhibition of sexual behavior resulted from the decrease in testosterone levels, a group of 8-wk-infected mice received testosterone, and complete restoration of their sexual behavior was observed. Inhibition of masculine sexual behavior during the infection period is the result of hormonal changes, estradiol being ineffective in maintaining copulation.

Mechanisms regulating male sexual behavior in the rat: role of 3 alpha- and 3 beta-androstanediols.

To assess whether naturally occurring 5 alpha-androstanediols (5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol) play a role in the regulation of male sexual behavior in the rat, their capability to restore copulatory behavior in castrated animals was evaluated. Androstanediols were chronically administered either alone or in combination with 5 alpha-dihydrotestosterone (DHT) or with estradiol-17 beta (E2). Animals treated with testosterone (T), DHT, E2, and vehicle, either alone or in different combinations, served as controls. The occurrence of mounting, intromission, and ejaculation as well as detailed parameters of copulatory behavior were recorded twice per week for 3 weeks. At the end of treatments, the weights of sex accessory organs were also recorded. When 3 beta, 5 alpha-androstanediol (3 beta-diol; 500 micrograms/day) was administered in combination with DHT (300 micrograms/day), full copulatory behavior was restored in all subjects in a manner similar to that obtained with E2 plus DHT or T plus DHT combinations, thus indicating an estrogen-like behavioral effect of 3 beta-diol. Administration of 3 alpha, 5 alpha-androstanediol (3 alpha-diol; 500 micrograms/day) combined with DHT also restored sexual behavior, though to a lesser extent. When 3 alpha-diol (500 micrograms/day) was simultaneously administered with E2 (5 micrograms/day), the copulatory behavior of castrated animals was fully restored in a fashion similar to that observed after administration of DHT plus E2 and T plus E2 combinations, indicating a potent androgen-like effect of 3 alpha-diol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute lactulose administration on serum acetate levels in cirrhosis.

Lactulose has been used successfully in the treatment of portal-systemic encephalopathy but its exact mechanism of action is not known. The aim of this study was to observe the systemic effects of the colonic fermentation of an acute lactulose dose in cirrhotics and normal subjects. Six cirrhotic patients and 6 normal subjects were placed on 2 identical 2-d metabolic diets, 1 of which was supplemented with lactulose (1 g/100 kcals to a maximum of 28 g/d). Lactulose increased colonic fermentation in cirrhotic and normal subjects as evidenced by higher breath hydrogen and serum acetate levels. The increase in serum acetate levels after lactulose compared to control was similar in cirrhotic compared to normal subjects. However, the mean serum acetate concentration in the cirrhotics was significantly greater than that in the control subjects (p = 0.039), indicating increased endogenous production, or decreased peripheral utilization of acetate by the cirrhotic liver, or both. No change was observed in blood ammonia, glucose, insulin, or free fatty acid levels with lactulose.

Central blood volume in cirrhosis: measurement with radionuclide angiography.

In patients with cirrhosis a diminished effective central arterial blood volume associated with systemic arterial vasodilation has been proposed as the mechanism that initiates renal sodium retention. Furthermore, total central blood volume has recently been reported as reduced in cirrhosis, and the controversy over the stimulus for sodium retention in cirrhosis remains. The aim of this study was to assess the central blood volume with radionuclide angiography to determine whether there is effective arterial underfilling in cirrhosis. Twenty-nine patients (13 with and 16 without ascites) and 10 age- and sex-matched control subjects were studied under metabolic conditions. Radionuclide ventricular volume and total central blood volume were determined from gated images, taking into account the 99Tc count activity per milliliter of blood volume and attenuation. The pulmonary volumes were similarly derived.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intrathecal administration of adrenergic agonists on the frequency of copulatory pelvic thrusting of the male rat.

The effects of the intrathecal perispinal administration of adrenergic agonists on the characteristics of frequency, duration, and vigor of pelvic thrusting displayed by male rats during copulation was assessed by an accelerometric technique. A different dose of one drug (noradrenaline, clonidine or isoproterenol) and saline as control was administered at the lumbosacral level of the spinal cord to sexually active male rats in tests of sexual behavior performed at weekly intervals. The intrathecal administration of noradrenaline (alpha-adrenoceptor agonist) increased the frequency of pelvic thrusting in mount and intromission responses, whereas both the alpha 2-adrenoceptor agonist clonidine (25 micrograms) and the beta-adrenoceptor agonist isoproterenol (40 micrograms) reduced the frequency of pelvic thrusting in these responses as compared to values obtained under the intrathecal administration of saline. On the other hand, the duration of the thrusting trains and the potency or vigor of pelvic thrusting in mounts and intromissions did not differ from values obtained under saline treatment. These findings indicate a possible participation of noradrenaline in the modulation of the spinal mechanisms involved in the generation of rhythmic pelvic thrusting performed by the male rat during copulation.

Induction of male sexual behavior in the rat by 7 alpha-methyl-19-nortestosterone, an androgen that does not undergo 5 alpha-reduction.

The synthetic steroid 7 alpha-methyl-19-nortestosterone (MENT) binds with high affinity to the androgen receptor and exerts biological effects at some peripheral target tissues with a potency greater than that of naturally occurring androgens. In vivo, MENT does not undergo enzymatic 5 alpha-reduction and as a consequence, its biologic action on prostate and other organs of the male reproductive tract is not amplified as is that of testosterone (T). Thus, in castrated rats, a dose of MENT that will maintain normal muscle mass and gonadotropin levels will not maintain normal prostate and seminal vesicle weights. To investigate the ability of MENT to restore male sexual behavior in castrated rats, varying doses of MENT acetate were administered for 4 wk by use of s.c. mini-osmotic pumps. Animals treated with T acetate (200 micrograms/day) and nontreated intact animals served as positive controls, while a group of animals receiving vehicle alone were the negative controls. Steroid acetates are rapidly converted to T and MENT in blood. Appropriate steroid delivery was assessed by measurement of serum androgen concentrations. Male behavioral parameters were recorded twice per week. At the end of treatment, the weights of sex accessory organs were also recorded. The administration of MENT acetate at daily doses of 100 micrograms and 10 micrograms induced full copulatory behavior in a manner similar to that observed with doses of 200 micrograms T acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

Peritoneovenous shunting restores atrial natriuretic factor responsiveness in refractory hepatic ascites.

BACKGROUND: Sodium retention in cirrhosis has been attributed to an imbalance between vasoconstrictive, antinatriuretic forces such as the renin aldosterone angiotensin system and the sympathetic nervous system, and vasodilatory, natriuretic agents such as atrial natriuretic factor (ANF). Patients with diuretic resistant refractory ascites may require peritoneovenous shunting (PVS) to control ascites. METHODS: To study the factors responsible for the improvement in sodium homeostasis post-PVS, we compared the response to ANF infusion before and 1 month after PVS in 6 patients with massive ascites. RESULTS: Before PVS, sodium excretion at baseline and in response to ANF infusion was blunted but became more normal post-PVS. ANF infusion post-PVS induced a significant increase in the glomerular filtration rate and filtration fraction and also in distal delivery of sodium. ANF's distal effect of increasing the fractional excretion of distally delivered sodium was present pre-PVS and was not significantly increased post-PVS. Changes in sodium handling were accompanied by a significant decrease in antinatriuretic forces (baseline aldosterone, 2079 +/- 507 vs. 647 +/- 17 nmol/L; P < 0.04) post-PVS. CONCLUSIONS: The improvement in sodium homeostasis and response to ANF infusion post-PVS appears to be associated with the decrease in antinatriuretic forces with the loss of massive refractory ascites. Thus, PVS restores the balance toward ANF responsiveness.