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Background: The role of testosterone in the development of behaviors presaging cannabis use and subsequently cannabis use disorder was investigated in a prospective study of 208 boys. It was theorized that adverse neighborhood correlates with testosterone level that in turn potentiates behaviors predisposing to cannabis consumption and subsequently diagnosis of cannabis use disorder., Methods: Proportion of boarded-up dwellings in the 1990 census tract and testosterone level were recorded at baseline (ages 10-12), followed by assessments of assaultiveness and testosterone level (ages 12-14), social dominance/norm-violating behavior (SDNVB) (age 16), cannabis use (age 19), and cannabis use disorder (age 22)., Results: Percent of vacant dwellings correlates with testosterone level that in turn predicts assaultive behavior sequentially leading to SDNVB, cannabis use, and cannabis use disorder. Externalizing behaviors and cannabis use disorder are not directly predicted by neighborhood quality., Conclusions: Elevated testosterone level intermediates the association between neighborhood adversity and aggressive socially deviant behaviors presaging cannabis use and cannabis use disorder.

With the introduction of interferon therapy for liver disease due to chronic viral hepatitis, it has become important to test individuals thought to have hepatitis C virus disease for the presence of the virus. Moreover, the current goal of therapy for hepatitis C virus-positive liver disease is to render the individual patient HCV-RNA negative. Recently, it has been reported that as many as one-third of the patients with hepatitis C virus liver disease test positive for the presence of mixed cryoglobulins. Few of these cryoglobulin-positive patients have overt disease manifestations of cryoglobulinemia, such as nephropathy, peripheral neuropathy and vasculitis. Because the cryoglobulins in patients with hepatitis C virus-positive disease are directed at hepatitis C virus epitopes, the precipitation of cryoglobulins from serum samples also effectively removes virus. When the viral carriage rate is low in terms of the number of genomes/unit serum, as occurs in cases that are partially treated, the serum can test negative for hepatitis C virus even by polymerase chain reaction, despite the presence of persistent viremia, if precautions preventing the precipitation of cryoglobulins prior to the removal of the sample for polymerase chain reaction testing are taken. From a group of 75 patients with hepatitis C virus-positive hepatitis seen at our institution in the last year (all HCV-RNA positive), 35% were found to test positive for the presence of cryoglobulins. Importantly, in all cases, the cryoglobulins collected tested strongly positive for HCV-RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal hepatitis is a syndrome of unknown etiology occurring in children with viral liver disease, as well as children with unidentified disorders of bile salt synthesis and other poorly understood metabolic diseases. It is characterized by jaundice, giant cell hepatitis and rare liver failure necessitating liver transplantation. In the present investigation, the outcome of liver transplantation performed in 16 children with neonatal hepatitis at the investigators' institution was determined from 1 January 1989 to 31 December 1991. The results were compared to those obtained in 288 children transplanted for biliary atresia and 66 children transplanted for recognized metabolic liver disease. The children transplanted for neonatal hepatitis (4.1 +/- 1.3 years) and metabolic liver disease (5.8 +/- 0.6 years) were older than those transplanted for biliary atresia (3.3 +/- 0.2 years) (p < 0.01), but did not differ in terms of sex, ABO type, UNOS status or year in which the transplant procedure was performed. Interestingly, first allograft survival was equal in the children with neonatal hepatitis (74%) and those with metabolic liver disease (74%), but was greater than that for children transplanted for biliary atresia (68%) (p < 0.01). Despite this significant difference in first graft survival, no differences in 5-year survival were seen for the three groups (81% for neonatal hepatitis, 68% for biliary atresia and 79% for metabolic liver disease).(ABSTRACT TRUNCATED AT 250 WORDS)

In patients with end-stage liver disease complicated with hypersplenism, neutropenia and thrombocytopenia are risk factors for systemic sepsis and spontaneous bleeding. Granulocyte-macrophage colony-stimulating factor is a naturally occurring cytokine that promotes proliferation and differentiation of granulocyte and monocyte progeny cells. In addition, it is reported to promote the proliferation of megakaryocytes. Its use as an intravenous infusion is Federal Drug Authority (USA) approved for the enhancement of myeloid recovery following autologous bone-marrow transplantation. The present study was initiated to determine whether granulocyte-macrophage colony-stimulating factor could be used to increase the white blood cell and platelet count in patients with cirrhosis and hypersplenism and to determine whether the more convenient subcutaneous route can be used with the same efficacy as the recommended intravenous route. Nine patients with cirrhosis and hypersplenism manifested by a reduced absolute neutrophil count (mean value of 1300 +/- 200/mm3) were studied. In eight patients, Indium white blood cell splenic sequestration scans were obtained before and after the administration of granulocyte-macrophage colony-stimulating factor intravenous infusion or subcutaneously for 7 days. One patient had to discontinue the therapy due to a reaction to granulocyte-macrophage colony-stimulating factor. Following intravenous infusion of granulocyte-macrophage colony-stimulating factor, the mean absolute neutrophil count increased to 2600 +/- 1100/mm3. Following subcutaneous administration, the mean absolute neutrophil count increased to 4100 +/- 200/mm3. No significant change in platelet count occurred with either route of administration. Indium scans obtained before and after the treatment period revealed no significant difference in the splenic uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventy-nine subjects (19 women and 60 men) with chronic viral hepatitis were studied to determine the role of hepatic iron and its biochemical correlates in determining response to interferon alpha therapy. Each subject was treated for 6 months with interferon alpha. A total of 45 (57%) subjects achieved either a full or partial response. No differences between responders and non-responders were evident for the type of hepatitis, age, initial alanine aminotransferase, serum iron, total iron binding capacity, %sat, or ferritin. In contrast, the hepatic iron content of non-responders was almost twice that of responders (1156 +/- 283 micrograms/g dry weight vs. 638 +/- 118; p < 0.05). Hepatic iron correlated with total iron binding capacity (r = 0.435) and ferritin (r = 0.585). This study showed that: 1) the hepatic iron content of responders is less than that of non-responders, 2) the relationships of hepatic iron with %sat and ferritin in patients with viral hepatitis are weak, and 3) hepatic iron content predicts a response to interferon therapy.

Using a rat model, the effect of pre-treatment with FK 506 on hepatic ischemia/reperfusion injury was investigated. All control animals died within 72 h of the ischemia/reperfusion injury. Pre-treatment of the animals with FK 506 (0.3 mg/kg in 0.5 ml saline) administered intravenously improved survival. The most striking protection against fatal ischemia/reperfusion injury was achieved in rats that were given FK 506 6 and 24 h prior to the induction of the hepatic ischemic insult (70% and 80% 10-day survival rates, respectively). The hepatoprotective effect of FK 506 was assessed further in a second experiment in which the serum levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were measured. These results suggest that a 60-min period of hepatic ischemia and subsequent reperfusion triggers the release of both TNF and IL-6, and that FK 506 pre-treatment (6 h before the ischemic episode) significantly inhibits the production and/or release of these two cytokines compared to untreated controls. These data provide additional information concerning the immunosuppressive and hepatoprotective activities of FK 506. Based upon these data, it is probable that FK 506 attenuates hepatic ischemia/reperfusion injury, at least in part, by reducing TNF and IL-6 levels.

The prevalence and bacteriology of bacteriuria was studied in 140 patients with cirrhosis of the liver, referred to the University of Pittsburgh Medical Center for evaluation for liver transplantation (72 males and 68 females; mean age 46 years). Urine samples were obtained for cultures within 24 h after admission. Significant bacteriuria (SB) (> 10(5) bacteria/ml) was present in 25 patients (18%), the most common being E. coli (36%) and coagulase-negative staphylococcus (20%). SB was more common in females than in males (32 vs. 4%, p < 0.001), and was seen in every category of cirrhosis. The occurrence of bacteriuria did not correlate with the severity of the underlying liver disease or with the age of the patient. Based upon these results, it can be concluded that: (1) bacteriuria is common in patients with advanced liver disease and occurs in approximately 20% of the cases; (2) it is more common in females than in males; and (3) its prevalence in patients with primary biliary cirrhosis is similar to that in other types of chronic advanced liver disease.

Acute hemorrhagic pancreatic necrosis (AHPN) is induced in young female mice fed fo 4 days a choline-deficient diet containing diet 0.5% DL-ethionine (CDE). Contrary to females, male mice do not develop AHPN when fed the same diet. For determination of whether estrogens are involved in the induction of AHPN, estradiol-treated male mice were fed the CDE diet. In such estrogen-treated male mice, the mortality rate, incidence of AHPN, and alterations in biochemical parameters of the pancreas and of serum were similar to those induced by the CDE diet in females.

The adverse effects of ethyl alcohol on the hypothalamic pituitary gonadal axes of men and women are discussed with particular attention being given to effects of alcohol upon reproduction. Data obtained from acute and chronic alcohol exposure studies are presented. The putative pathophysiologic mechanisms responsible for disturbed reproductive performances in alcohol abusing individuals are discussed where sufficient data are available.

The pathophysiologic factors which either document or which have been shown to be responsible for not only the hypogonadism and feminization of chronic alcoholic men but also the loss of gonadal function with resultant defeminization of chronic alcoholic women are reviewed. Evidence is presented which suggests that alcohol abuse is associated with the production of a primary form of hypogonadism characterized by loss of endocrine and reproductive function of the gonads. Moreover, evidence is presented which suggests that alcohol abuse is associated with the production of an associated hypothalamic-pituitary defect in gonadotropin secretion which prevents appropriate enhancement of gonadotropin secretion in response to the primary gonadal injury. Finally, the factors which have been found to partially explain the feminization often seen in chronic alcoholic men with advanced liver disease are discussed individually and a composite mechanism incorporating each is presented.

Prolactin, administered exogenously, has been shown to be trophic to the liver, causing increases in the liver weight-to-body weight ratio. In ornithine decarboxylase activity, and in thymidine kinase activity. To investigate the effect of endogenous hyperprolactinemia on hepatic regeneration, pituitary isografts were placed beneath the renal capsule in rats 2 weeks before the rats underwent a two-thirds partial hepatectomy. Prolactin levels 2 weeks after the transplant were greater in the animals with the pituitary isografts compared with levels in controls. The increase in the liver weight-to-body weight ratio after hepatectomy was similar in the rats with pituitary transplant and the controls. However, chronic hyperprolactinemia was associated with increased basal levels of ornithine decarboxylase activity and thymidine kinase activity. Both ornithine decarboxylase activity and thymidine kinase activity increased after partial hepatectomy, and the magnitude of the changes was similar for both groups of animals. The levels of estrogen receptor activity before the partial hepatectomy and the reduction in receptor activity that follows partial hepatectomy were similar in the two groups of animals. Moreover, the levels of androgen receptor activity within the liver before partial hepatectomy and the increase in receptor activity after hepatectomy were similar in the two groups of animals. Thus, chronic sustained hyperprolactinemia has no beneficial effect on the hepatic regenerative response, despite induction of both basal ornithine decarboxylase and thymidine kinase activities.

Ultrastructural morphometric studies were employed to compare the morphology of Leydig cells found in the testes of rats fed ethanol, accounting for 36% of total calories for 6 weeks, and those found in the testes of rats isocalorically fed a diet in which ethanol was isocalorically replaced with dextrimaltose. The testes of alcohol-fed rats weighed significantly less (p less than 0.01) than those of the isocaloric controls. Moreover, plasma testosterone in the alcohol-fed animals was reduced (p less than 0.01), as compared to the controls. Morphologically, two main differences were encountered between the Leydig cells of alcohol-fed animals and those of the isocalorically-fed controls. These were: (1) an increase in the number of elongated and cup-shaped mitochondria; and (2) an increase in cytoplasmic protrusions in the form of pseudopods. Using morphometric techniques, the Leydig cells of alcohol-fed animals were smaller (p less than 0.05), had less cytoplasm (p less than 0.05), larger mitochondria (p less than 0.01), and less smooth endoplasmic reticulum (p less than 0.05) than did those of the isocaloric controls. These morphologic characteristics of Leydig cells of alcohol-fed animals are similar to those reported to occur in the liver and suggest that the biochemical mechanisms responsible for alcohol-induced cellular injury are similar in the testes and the liver.

The available evidence which suggests that ethanol is a Leydig cell toxin is presented. Both in vivo and in vitro data are reviewed. The minor differences obtained in vitro as compared to those obtained in vivo are discussed. As a result of information obtained during the last decade, there can be little doubt that ethanol and possibly acetaldehyde are clinically important environmental Leydig cell toxins.

Thiazide diuretics are used commonly to treat hypertension. Unfortunately, they also are known to elevate serum cholesterol levels. Because serum lipid fraction levels differ between the sexes, possible sex-related differences in thiazide-induced changes in serum total cholesterol (TC), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) levels were examined. Four groups of male and female hamsters were treated for a minimum of 3 months with hydrochlorothiazide (HCTZ) at zero, 1, 2 or 4 mg/kg/day. At zero dose, there was no difference in TG levels between the sexes; however, females had significantly higher TG concentrations than did males at 1, 2 and 4 mg HCTZ (all p less than 0.05). Females demonstrate a significant dose response with HCL-C levels increasing with increasing doses of HCTZ, (r = 0.983; p less than 0.02); in contrast males had a similar increase in HDL-C at all dose levels (all p less than 0.05) thus there was no demonstrable dose response (r = 0.539). Total cholesterol concentrations were significantly higher in the females than in males (p less than 0.05) at all 3 dose levels as well as at zero dose. Further, the females demonstrated a direct dose response in TC levels (r = 0.986; p less than 0.02) while the males showed no such dose response (r = 0.824; p less than 0.01). Based on these findings we conclude that: 1) HCTZ increases TG, TC and HDL-C levels in both male and female hamsters; 2) TC levels are higher in females than in males regardless of HCTZ dose; 3) only females show a dose-dependent increase in HCL-C and TC in response to HCTZ. These sex-related changes in lipid fractions occurring with HCTZ treatment, if they occur in humans, may contribute to sex-related differences in rates and severity of atherosclerosis in HCTZ-treated populations.

During designated sampling periods, all patients presenting at an urban hospital Emergency Room with complaints meeting nonurgent criteria were interviewed in an effort to examine patterns of Emergency Room usage and to characterize those patients utilizing the Emergency Room inappropriately. Each such patient's stated number of visits to an Emergency Room during the previous year, including the present visit, was used as an indicator in assessing inappropriate Emergency Room use. Statistical analysis showed no significant differences when the variable was race; in contrast, significant differences were seen when the variables were type of medical insurance coverage and personal physician status. Based on these data, we suggest that the true problem is not one of how to control inappropriate Emergency Room use, but rather one of how to improve the health care delivery system for the urban poor.

Hypogonadism is a major manifestation of zinc deficiency in humans and animals, but the mechanisms responsible for this hypogonadism are unclear. We evaluated the pituitary gonadal axis of zinc-deficient rats with basal testosterone, follicle-stimulating hormone, and luteinizing hormone measurements and both luteinizing hormone releasing hormone (GnRH) and human chorionic gonadotropin (HCG) stimulation tests, and we utilized pair-fed (isocalorically fed to zinc deficient), weight-restricted (fed to weigh the same as zinc deficient), and ad libitum-fed controls. Basal testosterone levels were significantly decreased in rats with zinc deficiency (0.6 +/- 0.2 ng/ml) and weight-restricted rats (0.6 +/- 0.1 ng/ml) compared with pair-fed rats (1.2 +/- 0.2 ng/ml) and ad libitum-fed rats (1.6 +/- 0.2 ng/ml, p less than 0.01). Appropriate pituitary response to GnRH were noted in each group of rats. In a final study, zinc-deficient and weight-restricted rats were given injections of 1 U HCG for 5 days. Weight-restricted rats demonstrated a highly significant increase in stimulated testosterone (7.6 +/- 0.9 ng/ml) compared with zinc-deficient rats (2.1 +/- 0.3 ng/ml, p less than 0.0005). We conclude: (1) hypogonadism occurs in both zinc-deficient and weight-restricted rats compared with pair-fed and ad libitum-fed controls; (2) pituitary reserve is intact in zinc-deficient rats; (3) HCG stimulation demonstrates Leydig cell failure in zinc-deficient but not weight-restricted hypogonadal rats; and (4) the hypogonadism in zinc-deficient rats results mainly from Leydig cell failure.

Lower esophageal sphincter pressure (LESP), basal gastric pH, and plasma levels of gastrin, estradiol, and progesterone were determined in ten women known to have normal menstrual cycles. All determinations were performed both during the follicular phase (Days 2 to 8) and during the luteal phase (Days 20 to 30). In addition, an intraluminal pH probe placed 5 cm. above the lower esophageal sphincter was used to test for the presence of acid reflux in response to three provocative procedures. LESP during the follicular phase was 19.0 +/- 1.5 mm. Hg (mean +/- S.E.M.) and during the luteal phase 16.5 +/- 1.3 mm. Hg (p less than 0.01). Basal gastric pH and plasma gastrin levels were similar at both times. Plasma estradiol in the follicular phase (76.1 +/- 7.0 pg. per milliliter) increased twofold during the luteal phase (159.0 +/- 6.0) (p less than 0.01). Plasma progesterone increased from a level of 1.5 +/- 0.8 ng. per milliliter during the follicular phase to 19.2 +/- 4.2 during the luteal phase. Coincident with these changes in LESP and increases in steroid levels, acid reflux was detected in five women during the luteal phase but was present in only one during the follicular phase.

A neuropsychiatric study of individuals who underwent successful liver transplantation an average of 3 years previously was conducted to assess quality of life in terms of cognitive capacity and psychiatric status, as well as social and behavioral functioning. Compared with a control group of patients with Crohn's disease, liver transplant patients did not differ on measures of intelligence, language, attention, concentration, spatial organization, memory, or learning. Performance on these diverse aspects of cognitive functioning was in the normal ranges for both groups when compared with normative or standardized test values. The control and liver transplant patients were not different from each other on measures of psychiatric status or social functioning; however, both groups exhibited some disruption of functioning in these two areas when contrasted with normative values. We conclude that relatively young individuals (mean age in this study, 27.8 years) do not exhibit debilitating long-term neuropsychiatric disability after liver transplantation, although some disturbance in social and psychiatric adjustment was observed.

The nephrotoxic effect of ethanol feeding on renal structure and function was evaluated in rats and compared to that in dextrose-fed isocaloric control animals. Alcohol-fed animals had larger kidneys than their controls. Despite this increase in renal mass, the alcohol-fed animals had a 50% reduction in creatinine clearance and a 67% reduction in osmolar clearance compared to their controls. When specific renal constituents were compared, the alcohol-fed animals were found to have twice the renal protein and a 50% increase in renal lipid. Despite these marked structural and functional differences, the light microscopic appearance of the kidneys of the two groups did not appear significantly different. In contrast, the electron microscopic differences were substantial. The renal epithelial cells, particularly of the distal tubules and Henle's loops, were found to show varying degrees of cellular injury and were observed to be sloughing into the lumens. These electron microscopic observations are similar to those obtained in tubular necrosis due to a variety of nephrotoxic agents. We propose, therefore, that chronic alcohol feeding of rats produces significant renal dysfunction and abnormalities of structure such that ethanol should be considered a true nephrotoxin.