The unexplored role of sedentary time and physical activity in glucose and lipid metabolism-related placental mRNAs in pregnant women who are obese: the DALI lifestyle randomised controlled trial.

OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.

Hemostasis Techniques for Non-variceal Upper GI Hemorrhage: Beyond Injection and Cautery.

B. Nulsen D. M. Jensen.

Metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes.

AIMS: To describe the metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes. METHODS: We performed a post hoc analysis using data from the Vitamin D And Lifestyle Intervention for gestational diabetes prevention (DALI) trial conducted across nine European countries (2012-2014). In women with a BMI ≥29 kg/m2 , insulin resistance and secretion were estimated from the oral glucose tolerance test values performed before 20 weeks, using homeostatic model assessment of insulin resistance and Stumvoll first-phase indices, respectively. Women with early gestational diabetes, defined by the International Association of Diabetes and Pregnancy Study Groups criteria, were classified into three groups: GDM-R (above-median insulin resistance alone), GDM-S (below-median insulin secretion alone), and GDM-B (combination of both) and the few remaining women were excluded. RESULTS: Compared with women in the normal glucose tolerance group (n = 651), women in the GDM-R group (n = 143) had higher fasting and post-load glucose values and insulin levels, with a greater risk of having large-for-gestational age babies [adjusted odds ratio 3.30 (95% CI 1.50-7.50)] and caesarean section [adjusted odds ratio 2.30 (95% CI 1.20-4.40)]. Women in the GDM-S (n = 37) and GDM-B (n = 56) groups had comparable pregnancy outcomes with those in the normal glucose tolerance group. CONCLUSIONS: In overweight and obese women with early gestational diabetes, higher degree of insulin resistance alone was more likely to be associated with adverse pregnancy outcomes than lower insulin secretion alone or a combination of both.

Outcomes in Severe Upper GI Hemorrhage from Dieulafoy's Lesion with Monitoring of Arterial Blood Flow.

BACKGROUND: Dieulafoy's lesion (DL) is a rare but increasingly recognized cause of severe upper GI hemorrhage (SUGIH). There is little consensus regarding the endoscopic approach to management of bleeding from DL. AIMS: Our purposes were to compare 30-day outcomes of patients with SUGIH from DL with Doppler endoscopic probe (DEP) monitoring of blood flow and guided treatment versus standard visually guided hemostasis (VG). METHODS: Eighty-two consecutive DL patients with SUGIH were identified in a large CURE Hemostasis database from previous prospective cohort studies and two recent RCTs at two university-based medical centers. 30-day outcomes including rebleeding, surgery, angiography, death, and severe medical complications were compared between the two treatment groups. RESULTS: 40.2% of DL bleeds occurred in inpatients. 43.9% of patients had cardiovascular disease, and 48.7% were taking medications associated with bleeding. For the entire cohort, 41.3% (26/63) of patients treated with VG had a composite 30-day outcome as compared to 10.5% (2/19) of patients treated with DEP (p = 0.017). Rebleeding occurred within 30 days in 33.3% and 10.5% of those treated with VG and DEP, respectively (p = 0.051). After propensity score matching, the adjusted 30-day composite outcome occurred in 39.0% in the VG group compared to 2.6% in the DEP group (p < 0.001). Adjusted 30-day rebleeding occurred in 25.3% in the VG group versus 2.6% in the DEP group (p < 0.001). DISCUSSION: DL patients with SUGIH were frequently inpatients and had severe cardiovascular comorbidities and recurrent bleeding. Lesion arterial blood flow monitoring and obliteration are an effective way to treat bleeding from DL which reduces negative 30-day clinical outcomes.

Clinical impact of treatment timing for chronic hepatitis C infection: a decision model.

Recent advances in the treatment of hepatitis C virus (HCV) infection have led to the availability of both highly efficacious interferon-containing and interferon-sparing regimens. However, the use of such therapies faces restrictions due to high costs. For patients who are medically eligible to receive interferon, the choice between the two will likely be impacted by preferences surrounding interferon, severity of disease, coverage policies and out-of-pocket costs. We developed a decision model to quantify the trade-offs between immediate, interferon-containing therapy and delayed, interferon-free therapy for patients with chronic, genotype 1 HCV infection. We projected the quality-adjusted life expectancy stratified by the presence or absence of cirrhosis for four strategies: (i) no treatment; (ii) immediate, one-time treatment with an interferon-containing regimen; (iii) immediate treatment as above with the opportunity for retreatment in patients who fail to achieve sustained virologic response with interferon-free therapy in 1 year; and (iv) delayed therapy with interferon-free therapy in 1 year. When compared to one-time immediate treatment with the interferon-containing regimen, delayed treatment with the interferon-free regimen in 1 year resulted in longer life expectancy, with a 0.2 quality-adjusted life year (QALY) increase in noncirrhotic patients, and a 1.1 QALY increase in patients with cirrhosis. This superiority in health benefits was lost when wait time for interferon-free therapy was greater than 3-3.2 years. In this modelling analysis, interferon-free therapy resulted in superior health benefits compared to immediate therapy with interferon until wait time exceeded 3-3.2 years. Such data can inform decision-making regarding treatment initiation for HCV as healthcare financing evolves.

Glutamic acid decarboxylase autoantibody-positivity post-partum is associated with impaired ß-cell function in women with gestational diabetes mellitus.

AIMS: To investigate whether the presence of glutamic acid decarboxylase (GAD) autoantibodies post-partum in women with prior gestational diabetes mellitus was associated with changes in metabolic characteristics, including ß-cell function and insulin sensitivity. METHODS: During 1997-2010, 407 women with gestational diabetes mellitus were offered a 3-month post-partum follow-up including anthropometrics, serum lipid profile, HbA1c and GAD autoantibodies, as well as a 2-h oral glucose tolerance test (OGTT) with blood glucose, serum insulin and C-peptide at 0, 30 and 120 min. Indices of insulin sensitivity and insulin secretion were estimated to assess insulin secretion adjusted for insulin sensitivity, disposition index (DI). RESULTS: Twenty-two (5.4%) women were positive for GAD autoantibodies (GAD+ve) and the remainder (94.6%) were negative for GAD autoantibodies (GAD-ve). The two groups had similar age and prevalence of diabetes mellitus. Women who were GAD+ve had significantly higher 2-h OGTT glucose concentrations during their index-pregnancy (10.5 vs. 9.8 mmol/l, P = 0.001), higher fasting glucose (5.2 vs. 5.0 mmol/l, P = 0.02) and higher 2-h glucose (7.8 vs. 7.1 mmol/l, P = 0.05) post-partum. Fasting levels of C-peptide and insulin were lower in GAD+ve women compared with GAD-ve women (520 vs. 761 pmol/l, P = 0.02 and 33 vs. 53 pmol/l, P = 0.05) Indices of insulin sensitivity were similar in GAD+ve and GAD-ve women, whereas all estimates of DI were significantly reduced in GAD+ve women. CONCLUSION: GAD+ve women had higher glucose levels and impaired insulin secretion adjusted for insulin sensitivity (DI) compared with GAD-ve women. The combination of OGTT and GAD autoantibodies post-partum identify women with impaired ß-cell function. These women should be followed with special focus on development of Type 1 diabetes.

Metabolic effects of lifestyle intervention in obese pregnant women. Results from the randomized controlled trial 'Lifestyle in Pregnancy' (LiP).

AIMS: The Lifestyle in Pregnancy intervention in obese pregnant women resulted in significantly lower gestational weight gain compared with the control group, but without improvement in rates of clinical pregnancy complications. The impact of the lifestyle intervention on metabolic measurements in the study participants is now reported. METHODS: The Lifestyle in Pregnancy study was a randomized controlled trial among 360 obese women (BMI 30-45 kg/m²) who were allocated in early pregnancy to lifestyle interventions with diet counselling and physical activities or to the control group. Fasting blood samples, including plasma glucose, insulin, lipid profile and capillary blood glucose during a 2-h oral glucose tolerance test were carried out three times throughout pregnancy. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance. RESULTS: Three hundred and four women (84%) were followed until delivery. Women in the intervention group had a significantly lower change in insulin resistance (HOMA-IR) from randomization to 28-30 weeks' gestation compared with control subjects (mean ± SD: 0.7 ± 1.3 vs. 1.0 ± 1.3, P = 0.02). Despite a significantly lower gestational weight gain in the intervention group, there was no difference between the groups with respect to total cholesterol, HDL, LDL or triglycerides. CONCLUSIONS: Lifestyle intervention in obese pregnant women resulted in attenuation of the physiologic pregnancy-induced insulin resistance. Despite restricted gestational weight gain, there were no changes in glucose or lipid metabolism between the groups.

Infant twin mortality and hospitalisations after the perinatal period - a prospective cohort study from Guinea-Bissau.

OBJECTIVE: To examine mortality and hospitalisations among infant twins and singletons after the perinatal period in Guinea-Bissau. METHODS: The study was conducted from September 2009 to November 2012 by the Bandim Health Project (BHP). Newborn twins and unmatched singleton controls were included at the National Hospital Simão Mendes in the capital Bissau. Children were examined clinically at enrolment. Maternal, pregnancy and obstetric information was collected and HIV testing offered at birth. Follow-up occurred at home at 2, 6 and 12 months and through linkage with the paediatric admission register at the National Hospital. RESULTS: About 495 twins and 333 singletons were alive on day 7 after birth. In total, 36 twins and 12 singletons died during follow-up, the post-perinatal infant mortality rate being 91/1000 person-years for twins and 42/1000 for singletons (HR = 2.11, 95% CI: 1.09-4.07). In a multivariable analysis among twins only, birth weight <2000 g [3.32, (1.36-8.07)], death of the cotwin perinatally [2.54, (1.16-5.57)] and severe maternal illness during pregnancy [2.35, (1.00-5.51)] were significant risk factors for twin death. In the subgroup with available HIV status, maternal HIV infection was strongly associated with twin mortality [3.16, (1.24-8.05)]. Death occurred at home for 60% of twins and 67% of singletons. During follow-up, 90 first-time hospital admissions were registered, with similar rates observed for twins (139/1000) and singletons (143/1000) [0.97, (0.61-1.52)]. CONCLUSION: The post-perinatal infant mortality rate of twins was double that of singletons. No excess in twin hospitalisations was observed, possibly implying obstacles to hospital admission for twins in case of severe illness.

Severe upper gastrointestinal hemorrhage from linear gastric ulcers in large hiatal hernias: a large prospective case series of Cameron ulcers.

We report a case series of all consecutive patients hospitalized in our two tertiary referral medical centers over the past 17 years for Cameron ulcers causing severe upper gastrointestinal hemorrhage (GIH) or severe obscure GIH. Cameron ulcers were diagnosed in 25 of the 3960 screened patients with severe upper GIH or severe obscure GIH (0.6 %). Of these, 21 patients had a prospective follow-up (median time 20.4 months [interquartile range: 8.5 - 31.8]). Patients were more often elderly women with chronic anemia, always had large hiatal hernias, and were usually referred for obscure GIH. Twelve of the 21 patients (57 %) were referred for surgery while being treated with high-dose proton pump inhibitors (PPIs). The other 9 patients (43 %) continued PPIs without any rebleeding during the follow-up. Cameron ulcers in large hiatal hernias are an uncommon cause of severe upper GIH. The choice of medical vs. surgical therapy should be individualized.

Pregestational body mass index is related to neonatal abdominal circumference at birth--a Danish population-based study.

OBJECTIVES: To examine the impact of maternal pregestational body mass index (BMI) and smoking on neonatal abdominal circumference (AC) and weight at birth. To define reference curves for birth AC and weight in offspring of healthy, nonsmoking, normal weight women. DESIGN: Population-based study. SETTING: Data from the Danish Medical Birth Registry. POPULATION: All live singletons without congenital malformations in Denmark 2004-10. METHODS: Data on 366,886 singletons at 35(+0) to 41(+6) weeks(+days) of gestation were extracted and analysed using multivariate linear regressions. MAIN OUTCOME MEASURES: Birth AC and weight in relation to pregestational maternal BMI, maternal smoking and medical conditions (any). RESULTS: Birth AC and weight increased with increasing pregestational BMI, and decreased with smoking (P < 0.0001). Reference curves were created for offspring of healthy, nonsmoking mothers with normal pregestational BMI. Mean AC ranged from 30.1 cm and 30.2 cm at 35 weeks of gestation to 33.9 cm and 34.1 cm at 41 weeks of gestation, for girls and boys, respectively. Mean birthweight ranged from 2581 and 2666 g at 35 weeks to 3705 and 3852 g at 41 weeks of gestation for girls and boys, respectively. Pregestational BMI correlated more to the Z score of birthweight than to the Z score of AC (P < 0.0001). CONCLUSION: Birth AC and weight are affected by maternal smoking status and pregestational BMI. Pregestational BMI correlated more to birthweight than to AC. Using data from healthy, nonsmoking mothers with normal pregestational BMI we have provided new reference curves for birth AC and birthweight.

A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C.

The aim of this study is to review clinical trial data on the newly approved protease inhibitors boceprevir and telaprevir to develop consensus recommendations on the optimal use of these agents for the treatment of patients with chronic hepatitis C virus (HCV) infection. An expert panel of seven leading authorities in viral hepatitis was convened to establish and disseminate a practical guide on best practices for incorporating boceprevir and telaprevir into therapy for HCV infection in both treatment-naive and treatment-experienced patients. The topics covered include selecting candidates for boceprevir- or telaprevir-based treatments, predictors of response and early viral kinetics, response-guided therapy approaches, on-treatment management strategies to optimize the likelihood of response and minimize the risk of drug resistance, management of adverse effects during therapy and key considerations for special populations. The expert panel incorporated the best available clinical evidence into recommendations on how boceprevir and telaprevir should be used in the clinical setting. They indicated how treatment regimens may differ according to the baseline factors, such as presence of cirrhosis and when therapy may need to be modified or stopped altogether because of adverse events or poor virologic response. This practical guide will serve as a valuable resource for clinicians embarking on the new treatment paradigm of boceprevir or telaprevir in combination with peginterferon/ribavirin for chronic genotype 1 HCV infection.

Cognitive function in adult offspring of women with Type 1 diabetes.

AIMS: Maternal diabetes may affect offspring cognitive function. The objective of the study was to evaluate cognitive function and potential predictors hereof in adult offspring of women with Type 1 diabetes. METHODS: We conducted a follow-up study of adult offspring of women with Type 1 diabetes (n = 158) and a reference group from the background population (n = 118). The main outcome measure was offspring cognitive function measured by global cognitive score, derived from Raven's Progressive Matrices and three verbal subtests from the Weschler Adult Intelligence Scale. RESULTS: Offspring of women with Type 1 diabetes obtained lower global cognitive scores (94.8 vs. 100.0, P = 0.004) than offspring from the background population. When adjusted for confounders, the groups no longer differed significantly (difference 0.4, 95% CI -3.3 to 4.). Positive predictors of cognitive function in offspring of women with diabetes were family social class, parental educational level, maternal diabetes duration, male gender and offspring age, whereas parity ≥ 1 and gestational age < 34 weeks were negative predictors. We found no association with maternal glycaemia during pregnancy or with neonatal hypoglycaemia. CONCLUSIONS: Impaired cognitive function in adult offspring of women with Type 1 diabetes compared with the background population apparently reflects differences with respect to well-known confounders. However, harmful effects of maternal hyperglycaemia may be mediated through delivery at < 34 weeks.

The significance of gastric and duodenal histological ischemia reported on endoscopic biopsy.

Although frequently reported, it is unknown whether pathological reports of ischemia obtained from gastroduodenal biopsies suggest a diagnosis, prognosis or a requirement for additional evaluation. The aim of this study was to review the natural history, clinical presentation, endoscopic appearance, treatments, and major clinical outcomes of patients with gastroduodenal ischemia. A case series of 14 patients with variable etiologies (seven gastric and seven duodenal) was obtained from a search of our endoscopic pathological database for reports of histological ischemia. The results were as follows. The most common presentation was upper gastrointestinal bleeding (71 %). Half of the endoscopic lesions appeared very severe (large or circumferential lesions, exudative, pseudomembranous, black or pale mucosa). There were six cases of rebleeding (43 %) and four deaths (29 %). Computed tomography scanning was frequently used (12 cases, 86 %), but led to an underlying diagnosis in only three cases. In our series, patients with underlying vascular pathology have substantial 6-month mortality (29 %).

Factors associated with rapid and early virologic response to peginterferon alfa-2a/ribavirin treatment in HCV genotype 1 patients representative of the general chronic hepatitis C population.

Rapid virologic response (RVR) and complete early virologic response (cEVR) are associated with sustained virologic response to hepatitis C virus (HCV) therapy. We retrospectively examined baseline and on-treatment factors associated with RVR (HCV RNA undetectable at week 4) and cEVR (HCV RNA undetectable at week 12, regardless of week 4 response). The analysis comprised 1550 HCV genotype-1 patients from five clinical trials, including three enriched with difficult-to-treat populations, randomized to peginterferon alfa-2a 180 microg/week plus ribavirin 1000-1200 mg/day. Overall, 15.6% achieved RVR and 54.0% achieved cEVR. Baseline factors predictive of RVR were serum HCV RNA 3 x ULN (OR: 2.01; P < 0.0001), non-cirrhotic status (OR: 1.92; P = 0.0087), age 13 mg/kg/day was predictive of RVR (OR: 1.69; P = 0.005) and cEVR (OR: 1.24; P = 0.09), whereas peginterferon alfa-2a dose reduction was not. Greater decreases in haematologic parameters were observed in patients who achieved cEVR compared with patients who did not. In conclusion, several baseline and on-treatment factors were associated with RVR and cEVR to peginterferon alfa-2a plus ribavirin in difficult-to-treat HCV genotype-1 patients, providing important prognostic information on the antiviral response in a patient cohort that is reflective of the general chronic hepatitis C population.

Independent risk factors of 30-day outcomes in 1264 patients with peptic ulcer bleeding in the USA: large ulcers do worse.

BACKGROUND: Predictors of worse outcomes (rebleeding, surgery and death) of peptic ulcer bleeds (PUBs) are essential indicators because of significant morbidity and mortality rates of PUBs. However those have been infrequently reported since changes in medical therapy (PPI, proton pump inhibitors) and application of newer endoscopic haemostatic technique. AIMS: To determine: (i) independent risk factors for 30-day rebleeding, surgery, and death and (ii) whether ulcer size is an independent predictor of major outcomes in patients with severe PUB after successful endoscopic haemostasis and treatment with optimal medical (high dose IV PPI) vs. prior treatment (high dose IV histamine 2 antagonists - H2RAs). METHODS: A large prospectively followed population of patients hospitalised with severe PUBs between 1993 and 2011 at two US tertiary care academic medical centres, stratified by stigmata of recent haemorrhage (SRH) was studied. Using multivariable logistic regression analyses, independent risk factors for each outcome (rebleeding, surgery and death) up to 30 days were analysed. Effects for medical treatment (H2RA patients 1993-2005 vs. PPIs 2006-2011) were also analysed. RESULTS: A total of 1264 patients were included. For ulcers ≥10 mm, the odds of 30-day rebleeding increased 6% per each 10% increase in ulcer size (OR 1.06, 95% CI 1.02-1.10, P = 0.0053). Other risk factors for 30-day rebleeding were major SRH, in-patient start of bleeding, and prior GI bleeding. Major SRH and ulcer size≥10 mm were predictors of 30-day surgery. Risk factors for 30-day death were major SRH, in-patient bleeding, and any initial platelet transfusion or fresh frozen plasma transfusion ≥2 units. Among patients with major SRH and out-patient start of bleeding, larger ulcer size was also a risk factor for death (OR 1.08 per 10% increase in ulcer size, 95% CI 1.02-1.14, P = 0.0095). Ulcer size was a significant independent variable for both time periods. CONCLUSIONS: Ulcer size is a risk factor for worse outcomes after PUB and should be carefully recorded at initial endoscopy to improve patient triage and management.

Chronic liver disease manifesting as Waldenström's macroglobulinemia.

A 59-year-old woman was initially seen with anemia, purpura, gastrointestinal tract and vaginal bleeding, pronounced hyperglobulinemia, and an increased serum viscosity, all suggestive of Waldenström's macroglobulinemia. Subsequent investigation, however, indicated that these abnormalities were more likely due to chronic active hepatitis with cirrhosis. The striking similarity of this patient's symptoms to those of Waldenström's macroglobulinemia and the pathophysiologic characteristics of polyclonal hypergammaglobulinemia in chronic liver disease are discussed.

Pancreatic enzymes in chronic renal failure.

Serum was obtained from 55 patients, including 43 with stable chronic renal failure (CRF) (28 receiving chronic hemodialysis [CHD] and 15 receiving chronic ambulatory peritoneal dialysis [CAPD]), nine with peritonitis receiving CAPD, and three with pancreatitis receiving CAPD. Total serum amylase activity, lipase activity, isoamylase fractionation, and lipase concentration were used to measure pancreatic enzymes. Amylase activity was increased in 35 of 43 patients with CRF but was greater than threefold elevated in only three. Pancreatic isoamylase activity was greater than 80% in only one patient with CRF but was greater than 80% in all three patients with pancreatitis receiving CAPD. Lipase activity was increased in 26 patients and lipase concentration was elevated in 27. Peritoneal fluid from three patients with pancreatitis receiving CAPD contained high levels of amylase. Serum amylase and lipase are frequently elevated in patients with CRF in the absence of clinical pancreatitis. However, serum amylase activity greater than threefold elevated or the presence of pancreatic enzymes in the peritoneal fluid may suggest coexistent pancreatitis.

Serum alanine aminotransferase levels and prevalence of hepatitis A, B, and delta in outpatients.

We investigated the relationship between alanine aminotransferase (ALT) levels and the prevalence of serologic markers of hepatitis A, hepatitis B, and delta hepatitis in an outpatient population. Sera submitted for routine biochemical testing from 4669 patients were grouped according to ALT level (normal and 1 to 2.5, 2.5 to 5.0, and more than five times the upper limit of normal). Serologic evidence of acute hepatitis A or acute or chronic hepatitis B was detected in 6.1% of specimens with elevated ALT levels compared with 1.3% with normal ALT levels. Patients with ALT levels greater than 2.5-fold and fivefold elevated were associated with a 9.3% and a 15.1% prevalence, respectively, of markers of acute or chronic hepatitis. Antibody to delta hepatitis was detected in nine subjects, all of whom also had serologic evidence of chronic hepatitis B. A retrospective chart review of 80 patients with serologic evidence of acute or chronic hepatitis revealed that 51% of cases were previously undiagnosed, most of which were in the low ALT groups. Hepatitis serologic testing may be indicated in outpatients with unexplained elevations of the ALT level.

An analysis of acute changes in interleukin-6 levels after treatment of hepatitis C with consensus interferon.

Cytokine production has been implicated in the antiviral response to interferon-alpha (IFN-alpha) in hepatitis C and in the development of IFN-alpha-related side effects. We characterized acute changes in serum cytokine levels following administration of a single dose of consensus IFN (IFN-con1) and during continuous treatment of chronic hepatitis C patients. Serum samples were collected at baseline, at multiple times early after IFN administration, and weekly thereafter. Viral RNA titers were assessed by RT-PCR, and viral kinetics were followed. ELISA assays were used to measure IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-16. Serum cytokine levels were low at baseline. IL-6 was detected in patients with hepatitis C but not in healthy control subjects by either ELISA or RT-PCR, indicating that low levels of circulating IL-6 were associated with hepatitis C infection. None of the cytokines measured increased significantly after IFN administration except for IL-6. IL-6 levels rose rapidly, peaked at 6-15 h in a dose-dependent manner, and returned to baseline by 48 h in both patients receiving a single dose of IFN and those receiving continuous treatment. This was confirmed by RT-PCR. Pretreatment IL-6 levels were directly correlated with area under the curve (AUC) for IL-6 during the 24 h after IFN dosing (r = 0.611, p = 0.007). Viral titers decreased within 24-48 h after a single dose of IFN-con1. Changes in hepatitis C RNA titers were not significantly associated with pretreatment IL-6 levels or with changes in IL-6 levels. In conclusion, (1) baseline serum cytokine levels, except for IL-6, were low or within the normal range in patients with hepatitis C, (2) IL-6 levels were detected in some patients with hepatitis C before treatment but not in healthy controls, (3) IL-6 levels increased acutely after a single dose of IFN-alpha, and IL-6 induction was related to baseline IL-6 level, and (4) changes in IL-6 levels did not correlate with the early virologic response to IFN.

Economic and health aspects of peptic ulcer disease and H2-receptor antagonists.

The costs of peptic ulcer disease to society are very high. Costs can be expressed as either direct or indirect. Direct costs include hospitalization or clinic visits, physicians' fees, and medication. Indirect costs are loss of productivity due to absenteeism from work or loss of income from death of an employee. The daily cost of different ulcer drugs such as the histamine (H2)-receptor antagonists for intravenous treatment, acute healing, and maintenance can easily be compared. As newer anti-ulcer drugs such as H2-receptor antagonists have been introduced into the marketplace, the number of prescriptions and medication costs have increased rather than decreased. In part, this may be accounted for by the high frequency with which H2 antagonists are prescribed for patients with non-ulcer dyspepsia. Some patients have chronic peptic ulcer disease with multiple painful recurrences or complications such as hemorrhage, perforation, or obstruction. They may require long-term care or drug maintenance, hospitalization, or surgery. For patients with chronic ulcer disease or complications, randomized controlled trials to compare the efficacy, safety, and costs of different forms of therapy (maintenance drugs, surgery, or placebo) have not been reported. However, based upon good efficacy and safety for acute healing and long-term drug maintenance for painful duodenal ulcer disease, long-term maintenance with H2-receptor antagonists is now prescribed for many patients. No controlled randomized trials have been reported to document that long-term maintenance with H2-receptor antagonists actually reduces peptic ulcer complications. However, by current cost estimates, long-term H2-receptor antagonist therapy is less expensive than ulcer surgery for uncomplicated ulcer disease for up to eight years. However, maintenance drug therapy after eight years may be more expensive than elective ulcer surgery in patients with chronic peptic ulcer disease who are good surgical candidates. Patients with complications of peptic ulcer disease seem to represent a different subset than patients with symptomatic ulcer disease. Further studies in these subsets are needed to ascertain the most effective, safest, and least expensive management such as surgery, long-term drug maintenance, or intermittent drug therapy to prevent recurrent ulceration or complications.(ABSTRACT TRUNCATED AT 400 WORDS)