The Oklahoma Postmenopausal Women's Health Study: recruitment and characteristics of American Indian, Asian, Black, Hispanic, and Caucasian women.

Since 1994, the National Institutes of Health has required the inclusion of women and minorities in all of its sponsored clinical research. This study describes a workable recruitment strategy that embraces the National Institutes of Health requirement. We describe the recruitment pattern of the Oklahoma Postmenopausal Women's Study conducted in the general community of Oklahoma City and in surrounding areas that are both urban and rural. For the period 1994 through 1997, 491 postmenopausal women from all racial/ethnic groups in the community have participated in this study. Over 4 years of recruitment, the percentage of minority women in the study population has risen annually from 31% in 1994 to 81% in 1997. The overall percentage of minority women in the study population is currently 63.3%: American Indian, 21.8%; Asian, 3.7%; Black, 14.9%; Hispanic, 9.4%; White/American Indian Blend, 13.6%; and White, 36.7%. The recruitment approach described may be implemented in a variety of research settings. Specific recruitment approaches are described, as well as the distribution of sociodemographic and health behaviors across and within ethnic/racial groups.

Alcoholic beverages as a source of estrogens.

Alcoholic beverages contain not only alcohol but also numerous other substances (i.e., congeners) that may contribute to the beverages' physiological effects. Plants used to produce alcoholic beverages contain estrogenlike substances (i.e., phytoestrogens). Observations that men with alcoholic cirrhosis often show testicular failure and symptoms of feminization have suggested that alcoholic beverages may contain biologically active phytoestrogens as congeners. Biochemical analyses have identified several phytoestrogens in the congeners of bourbon, beer, and wine. Studies using subjects who produced no estrogen themselves (i.e., rats whose ovaries had been removed and postmenopausal women) demonstrated that phytoestrogens in alcoholic beverage congeners exerted estrogenlike effects in both animals and humans. Those effects were observed even at moderate drinking levels.

Effects of ethanol on rat Sertoli cell function: studies in vitro and in vivo.

Chronic alcohol administration to male animals is associated with testicular atrophy and gonadal failure. The Sertoli cell seems to be the first testicular cell injured as a result of alcohol exposure. To investigate the adverse effects of ethanol on testicular and particularly Sertoli cell function, the consequences of in vivo and in vitro ethanol exposure on rat Sertoli cell mRNA and protein levels of transferrin and ornithine decarboxylase were investigated. In vivo, ethanol exposure enhanced the levels of both hepatic and testicular (Sertoli cell) transferrin protein and mRNA. Ethanol exposure also enhanced testicular, but not hepatic, levels of ornithine decarboxylase protein and mRNA. These in vivo findings were confirmed when isolated Sertoli cells were studied in vitro. Specifically, ethanol exposure increased Sertoli cell transferrin protein and mRNA levels. Ethanol exposure increased Sertoli cell ornithine decarboxylase mRNA and protein when cultured in serum-free media, but not when cultured in the presence of serum. These studies demonstrate that ethanol exposure of rat Sertoli cells is associated with alterations in the levels of mRNA and protein that are known to be important in the process of spermatogenesis. These findings add to the body of evidence that suggests that, within the testes, the Sertoli cell may be an important target for ethanol-induced gonadal injury.

Endotoxemia is associated with renal dysfunction in liver transplantation recipients during the first postoperative week.

The effect of endotoxemia on renal function was studied in 76 orthotopic liver transplant patients. In the preoperative period, a high preoperative serum creatinine level (> 2.0 mg/dl) was significantly associated with postoperative endotoxemia. The serum total bilirubin level was significantly greater in the patients with high serum creatinine levels than in those with lower serum creatinine levels (< 2.0 mg/dl). On the 7th postoperative day (POD), the serum creatinine level was significantly associated with an increased plasma endotoxin level. The serum total bilirubin and AST levels did not differ significantly between the patients with high and those with low serum creatinine levels. Based upon these data postoperative endotoxemia is suspected as being the principal cause of early postoperative renal dysfunction. A synergistic effect on renal function between cyclosporine and endotoxin may be important in the pathogenesis of the renal dysfunction seen after successful liver transplantation.

Cryoglobulinemia: a cause for false negative polymerase chain reaction results in patients with hepatitis C virus positive chronic liver disease.

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)

The phytoestrogen congeners of alcoholic beverages: current status.

The idea that alcoholic beverages might contain biologically active phytoestrogenic congeners stemmed from findings of overt feminization observed in alcoholic men with alcohol-induced cirrhosis. Specifically, in addition to being hypogonadal, these chronically alcohol-abusing men with cirrhosis frequently manifest gynecomastia, palmar erythema, spider angiomata, and a female escutcheon. These physical signs of exposure to active estrogen occur in the presence of normal or only minimally elevated levels of endogenous steroid estrogens. Because levels of circulating steroid hormones failed to provide a satisfactory explanation for the feminization observed, alternate explanations were considered. If the estrogenization observed was not entirely a function of tissue expose to steroid estrogens produced endogenously, then perhaps tissues were being exposed to exogenous estrogenic substances from dietary sources. Given the degree of alcohol abuse in the population in which hypotheses for feminization were being formed, alcoholic beverages became a prime candidate as a dietary source of exogenous estrogenic substances.

Alcohol effects on hormone levels in normal postmenopausal women and in postmenopausal women with alcohol-induced cirrhosis.

The effects of alcoholic beverage consumption on the hormonal status of postmenopausal women will be reviewed. Focused attention on the effect of social drinking 244 normal postmenopausal women has revealed that moderate alcohol intake exerts a major influence not only on estradiol, testosterone, and the estimate of aromatization of testosterone to estradiol but also on the estrogen-responsive pituitary hormones in normal postmenopausal women. The hormonal status of 66 postmenopausal women with alcohol-induced cirrhosis is compared with normal alcohol-abstaining control women. As expected, there are significant differences in levels of all hormones; furthermore, hormonal interrelationships are also disrupted. Of major interest are findings that hormone levels in alcoholic cirrhotic postmenopausal women are related to the severity of liver disease. This observation supports a role for cirrhosis per se in the hormonal disruptions noted. Of further interest are findings that hormone levels may have prognostic value in postmenopausal women with alcohol-induced liver disease.

Liver transplantation for neonatal hepatitis as compared to the other two leading indications for liver transplantation in children.

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)

The use of granulocyte-macrophage colony-stimulating factor to enhance hematologic parameters of patients with cirrhosis and hypersplenism.

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)

Treatment of putative non-A, non-B, non-C hepatitis with alpha interferon: a preliminary trial.

Chronic hepatitis due to putative non-A, non-B, non-C hepatitis occurring in an individual who is negative for HBV and HCV markers has been identifiable only recently. Little or nothing is known about its natural history or response to interferon therapy. In the present study, 13 subjects with chronic non-A, non-B, non-C hepatitis were treated with interferon for 6 months (5 million units, three times per week). Prior to and after 6 months of therapy and again 6 weeks after discontinuing interferon therapy, each subject underwent a liver biopsy. These tissues were used to define the histopathology, the character of the cellular infiltrate within the liver, and the changes in histopathology and inflammatory infiltrate achieved in response to interferon therapy and withdrawal. No differences for age, gender, initial AST, bilirubin, histopathology, or Knodell score were evident between responders (n = 7) and non-responders (n = 6). Only the number of NK cells was altered significantly as a result of IFN treatment and distinguished responders from non-responders. These data demonstrate that: (1) chronic non-A, non-B, non-hepatitis can be treated with interferon; (2) interferon activates NK cells and enhances hepatocyte expression of Class II MHC antigens; and (3) interferon also increases the number of CD3, CD4, and CD8 cells found within the liver but these changes do not distinguish between responders and non-responders.

Unusual indications for liver transplantation.

This paper is an attempt to present some of the unusual indications for OLTx that are occasionally seen at transplant centers. It is not an all-encompassing treatise but rather an attempt to present the more usual of the unusual indications for OLTx. As such, it is a framework to which readers could add any we do not mention as and when they are encountered in their own practice.

Intrahepatic mononuclear cell populations and MHC antigen expression in patients with chronic hepatitis C [correction of B]: effect of interferon-alpha.

Twenty-four subjects with chronic HCV infection were treated with IFN for six months. Liver biopsies were obtained before and after therapy. The number of mononuclear cells staining for CD3, CD4, CD8, 3G8, and the number of mononuclear cells, liver cells, and bile duct cells staining for class I and II MHC antigens in the biopsies was determined. NK cells increased from 16 +/- 3 to 28 +/- 3 cells per 5 high-power fields (HFP) (P < or = 0.03). The number of bile duct cells expressing class I and II MHC Ag and liver cells expressing class II MHC Ag increased (all P < or = 0.03). The only parameter that distinguished responders from nonresponders was the number of NK cells. Following IFN withdrawal, expression of these antigens declined. Based upon these data, it is concluded that IFN treatment of HCV increases: (1) the NK cells number; (2) the expression of class I MHC Ag on bile duct cells and the expression of class II MHC Ag on liver and bile duct cells; and (3) with IFN withdrawal, these changes disappear.

Sexuality of alcoholic postmenopausal women: effects of duration of alcohol abstinence.

Little is known about the sexuality of alcoholic postmenopausal women, and even less is known about the influence of abstinence on self-assessed measures of sexual function. We now report findings in 60 postmenopausal women to whom a standardized questionnaire was administered. The responses provided information related to not only perceptions of sexuality, but also sexual behavior and performance. Women were categorized as alcohol abstinent (AA) for > 1 year (long AA, n = 33) or < 1 year (short AA, n = 27). There were no differences between the groups in age, age at menarche, age at menopause, or age at onset of heavy drinking and alcohol dependence. The mean response rate to 12 sexuality-related questions was comparable in the long AA and short AA groups (83.8% and 85.6%, respectively), and reflected the prevalence of having a regular sexual partner (76% and 85%, respectively). There were statistical differences between the two groups with respect to sexual desire, arousability, and responsiveness during alcohol abstinence, but not during alcohol dependence. Further, there were significant differences with respect to measures of current sexuality: higher proportions of long AA women reported sex being important, as well as their sexual life and intercourse being satisfying. Taken together, these findings suggest that alcoholic postmenopausal women abstinent from alcohol for longer than 1 year report greater satisfaction with the sexual aspects of their lives than women abstinent for a shorter period of time.

Response to interferon alpha therapy is influenced by the iron content of the liver.

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.

Liver regeneration after partial hepatectomy in the rat. Sequential events monitored by 31P-nuclear magnetic resonance spectroscopy and biochemical studies.

BACKGROUND: Little data exist wherein both the 31P nuclear magnetic resonance (NMR) signals and biochemical changes associated with hepatic regeneration after a 70% hepatic resection have been assessed simultaneously. EXPERIMENTAL DESIGN: Two groups of rats were used: one group underwent a 70% partial hepatectomy and the second underwent a sham operation. Both groups were followed sequentially for 192 hours by in vivo serial 31P-NMR spectroscopy of the liver and its phospholipid extracts. Liver injury and function were assessed by biochemical means. RESULTS: After surgery, a significant reduction in ATP and an increase in the phosphomonoester signal for the hepatectomized animals were noted as compared with the controls (p < 0.05). The phosphodiester content of the liver in the hepatectomized rats declined to nonmeasurable amounts in vivo. The nadir of ATP occurred 72 hours after surgery. The area of the phosphomonoester relative to an external reference of methylenediphosphonic acid peak increased steadily over the first 96 hours, whereas that of the area ratio of the inorganic phosphate/methylenediphosphonic increased over the first 72 hours posthepatectomy. The intracellular pH declined sharply in the first 3 days, followed by a gradual recovery over the next 5 days. Little change in the intracellular pH was observed for the control animals. A significant increase in the area of the phosphorylethanolamine relative to an internal reference of methylenediphosphonic and a reduction in the glycerophosphorylethanolamine and glycerophosphorylcholine peaks were noted during the first four post-hepatectomy days as measured by 31P-NMR of perchloric acid liver extracts (p < 0.05). CONCLUSIONS: It has been found that a concerted reduction in the intracellular ATP and intracellular pH coupled with an increase in inorganic phosphate and high levels of phosphorylethanolamine occur as a result of hepatic regeneration and the physiologic changes induced. These data demonstrated that a coordinated pattern of biochemical changes occur with and after hepatic regeneration. Moreover, NMR spectroscopy demonstrates an increase in phosphomonoesters and a decline in phosphodiesters during hepatic regeneration. These measures and, more specifically, the ratio of these two lipid classes may provide a biochemical snapshot of the regeneration status of the liver.

Upper gastrointestinal endoscopy: its clinical use and safety at a transplant center.

Upper gastrointestinal endoscopy is a widely practiced clinical procedure that has become routine in even the most remote medical environments. Its application at a liver transplant center represents the use of this particular technology at the opposite extreme of medical practice and its use in a unique and severely ill group of patients. The following is a description of the author's experience with upper gastrointestinal endoscopy at the University of Pittsburgh's liver transplant center. Despite the severity of illness of the patients seen at this center, documented by the high frequency of patients seen with abnormal prothrombin times and low platelet counts, upper gastrointestinal endoscopy performed either for diagnostic or therapeutic procedures has been found to be safe. The disease processes that affect transplant patients both before and after transplantation are not seen frequently in the general practice of gastroenterology. Thus the endoscopist at a transplant center has to be able to recognize, identify, and treat the unique problems seen in a transplant population.

Gastrointestinal transit in cirrhotic patients: effect of hepatic encephalopathy and its treatment.

Chronic hepatic encephalopathy is highly responsive to changes in diet, to antibiotic therapy and to ingestion of nondigestible disaccharides. The precise pathophysiology of chronic hepatic encephalopathy in individual cases is highly variable, although ammonia toxicity and production of neurotransmitterlike substances in the gut have been proposed to contribute to the overall syndrome of chronic hepatic encephalopathy. The support for this hypothesis is based on the empiric observation that reduction in protein intake, a catharsis or both are effective treatments for chronic hepatic encephalopathy. This study was performed to evaluate the effect of mild subclinical and low-grade (grade 0 to 1) chronic hepatic encephalopathy on gastric emptying and oral-cecal transit times. Thirty patients were studied. Ten had no evidence of chronic hepatic encephalopathy, as determined with a battery of neuropsychiatric studies (group 1); 10 had subclinical hepatic encephalopathy, as judged on the basis of abnormal neuropsychiatric test performance but normal neurological examination (group 2); and 10 had grade 1 hepatic encephalopathy. Each underwent a liquid gastric emptying study and a lactulose oral-cecal transit time study. No significant differences between groups were evident in the results of the gastric emptying studies. In contrast, the time required for a lactulose load to reach the cecum was significantly greater in the patients with hepatic encephalopathy (p < 0.01) and increased as a function of the hepatic encephalopathy grade.(ABSTRACT TRUNCATED AT 250 WORDS)