First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

The prognostic relevance of full-thickness burns on ABSI.

INTRODUCTION: The Abbreviated Burn Severity Index (ABSI) by Tobiasen, which is commonly used to estimate the mortality risk of severely burned patients, calculates an additional point for the existence of full-thickness (third-degree) burns. [1] However, the score does not consider the extent of the body surface affected by third-degree burns. To understand whether there is a way to improve ABSI prediction power, this study aims to determine the influence of full-thickness burns on survival rates and how it affects the predictive precision of the ABSI. MATERIAL AND METHODS: In this study, the statistical evaluation of 2538 patients collected prospectively in the context of the German Burn Registry was carried out. A linear regression analysis was carried out to show the prognostic relevance of full-thickness burns. Age, sex, total body surface area burned (TBSA), and the presence of inhalation injury were also observed as further influencing factors. RESULTS: Among the 2538 patients meeting our inclusion criteria, full-thickness burns were found in 1233 patients. In patients with a TBSA below 20 %, the extent of full-thickness burns is not relevant to the prognosis in terms of survival probability (p = 0.124). With more than 20 % TBSA, the extent of third-degree burns is of significant relevance (p = 0.000). In patients without full-thickness burns and calculated ABSI values ≥ 12 the survival rate of 46 % was noticeably better than the predicted survival rate of < 10 % according to the ABSI Score, whereas the predicted survival rate in patients with third-degree burns (< 10 %), closely matched the observed survival rate of 11 %. CONCLUSION: For patients with a TBSA < 20 %, the presence of full-thickness burns is not relevant for survival. In contrast to this observation, the percentage of full-thickness burns is of crucial prognostic importance for patients with a TBSA of > 20 %. By adjusting the ABSI and taking into account the exact percentage of third-degree burns, an improvement in the prognostic precision of the score could be achieved.

Supporting patients with heart failure with digital therapeutics-A pilot study in Germany.

Objective: Continuous monitoring and targeted behavioral interventions have been shown to improve health status and quality of life for heart failure patients. Digital therapeutics offer the possibility to make more frequent monitoring and targeted behavioral interventions available for more people. Methods: We conduct a pilot study with 71 patients who were given a smartphone app and wearables for a 3-month period. Clinical indicators as well as patient-reported outcomes were collected at entry and exit examinations. Results: The New York Heart Association class remained stable or improved. Most quantitative outcome measures improved (6-minute walk test distance + 21 m, Kansas City Cardiomyopathy Questionnaire summary score + 6.0 points, European Heard Failure Self-care Behavior Scale summary score + 6.6 points, correct answers in the Atlanta Heart Failure Knowledge Test + 2.1), although the changes were mainly not significantly different from zero. There was no change in EQ-5D weight and 9-item Shared Decision-Making Questionnaire summary score. Conclusions: This before-after comparison shows that an app-based intervention can work as a digital therapeutic for heart failure patients.

Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors.

BACKGROUND: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. PATIENTS AND METHODS: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion. RESULTS: The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. CONCLUSIONS: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.

Response to medical treatment in patients with Crohn's disease: the role of NOD2/CRAD15, disease phenotype, and age of diagnosis.

PURPOSE: Factors influencing response to medications in Crohn's disease (CD) patients are not fully understood. We aimed to evaluate the relationships between NOD2/CARD15 mutations, disease phenotype and age of CD diagnosis and response to medical treatment with systemic steroids, azathioprine (AZA) or 6-mercaptopurine (6-MP), and infliximab. METHODS: A retrospective medical records analysis was made of patients previously tested for the CD-associated NOD2/CARD15 mutations. Harvey- Bradshaw score was used to assess remission or response to therapy. RESULTS: CD-associated NOD2/CARD15 mutations were not related to the rate of steroids dependency or clinical response to AZA/6-MP and infliximab. Steroid dependency was associated with colonic involvement. Thirty-three of 127 (26%) patients with colonic disease were steroid dependent, compared with 7/72 (9.7%) patients with isolated small bowel disease (ISBD), (p = 0.009). ISBD was mildly associated with a better remission/response to AZA/6-MP treatment. Disease behavior and age of diagnosis were not related to response to therapy. CONCLUSIONS: Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: results of a phase I trial.

BACKGROUND: Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity. METHODS: This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m(-2). RESULTS: The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased gamma-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m(-2)). The MTD of weekly sagopilone was therefore established as 5.3 mg m(-2). Stable disease was the best overall response (n=3). Microtubule bundle formation in peripheral blood mononuclear cells increased post-treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release. CONCLUSION: Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials.

Depressive symptoms, impaired glucose metabolism, high visceral fat, and high systolic blood pressure in a subgroup of women with recent gestational diabetes.

Women with gestational diabetes (GDM) are a high risk group for early type 2 diabetes (T2D). Depression is a risk factor for T2D in the general population. We investigated in women after a recent pregnancy with GDM and without a clinical diagnosis of depression, whether mild to moderate depressive symptoms associate with pathologic glucose metabolism. In a cross-sectional analysis, we examined 173 women, 9 ± 3 months after delivery with several psychopathological assessments, 5-point oral glucose tolerance test with insulin, anthropometrics, and laboratory chemistry. In a subgroup of 101 women, abdominal visceral fat was quantified by magnetic resonance imaging (MRI). A total of 22 women (13%) showed mild to moderate depressive symptoms, and the proportion of women with pathologic glucose metabolism (impaired fasting glucose, impaired glucose tolerance, or T2D) was higher in this group than in the women without depressive symptoms (59.1% vs. 33.1%, p = 0.018). Women with depressive symptoms also had higher body mass index (BMI), systolic blood pressure, plasma leptin, plasma resistin, and abdominal visceral fat volume. Pathologic glucose metabolism (OR = 2.594, 95% CI: 1.021-6.592), systolic blood pressure (OR = 1.076, 95% CI: 1.027-1.128), and abdominal visceral fat volume (OR = 2.491, 95% CI: 1.142-5.433) remained, even after adjustment for BMI, associated with the presence of depressive symptoms. Taken together, we found depressive symptoms at a level not generally diagnosed in clinical practice in a subgroup of women with recent GDM. This subgroup also showed an unfavorable metabolic profile. Mild to moderate depressive symptoms may therefore help to identify this special subgroup.

Physical fitness and plasma leptin in women with recent gestational diabetes.

AIMS/HYPOTHESIS: Low physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass. METHODS: Cross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3-16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011-16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann-Whitney U and t -test, Spearman correlation coefficient, multiple linear regression. RESULTS: Women pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3-29.9) vs. 30.0(26.6-34.1)ml/min/kg; total VO2peak: 1733(1552-2005) vs. 1970(1767-2238)ml/min; p<0.0001 for both), and maximum workload (122.5(105.5-136.5) vs. 141.0(128.5-159.5)W; p<0.0001). Fasting plasma leptin correlated inversely with PF (VO2peak/kg ρ = -0.72 p<0.0001; VO2peak ρ = -0.16 p = 0.015; max. load ρ = -0.35 p<0.0001). These associations remained significant with adjustment for body mass index, or for body fat mass (BIA and MRI). CONCLUSIONS/INTERPRETATION: Women with a recent history of GDM were less fit than control subjects. Low PF may therefore contribute to the risk for T2D after GDM. This should be tested in intervention studies. Low PF also associated with increased leptin levels-independently of body fat. PF may therefore influence leptin levels and signaling. This hypothesis requires further investigation.

The origin of MDMA ("ecstasy")--separating the facts from the myth.

MDMA (3,4-methylenedioxy-N-methylamphetamine), better known as "Ecstasy", is a synthetic drug with psychedelic and stimulant effects which has gained great popularity. It is closely tied to the underground scene, but has also been used therapeutically as an adjunct to psychotherapy. Both scientific as well as newspaper articles communicate faulty or incomplete information on the origin of MDMA and the role of the German pharmaceutical-chemical company Merck in its development. One of the most common misconceptions is that the substance was synthesized with the goal of creating an anorectic but was not marketed by Merck because of side effects. It was our aim to clarify the circumstances of MDMA's discovery at Merck. An interdisciplinary working group conducted a comprehensive analysis of the original documents in Merck's historical archive in Darmstadt, Germany. It could be revealed that MDMA was in fact mentioned for the first time in files from 1912, but not under this name. In the lab journals it was called "Methylsafrylamin". In a patent certificate it was mentioned only with its chemical structure. Merck applied for this patent to protect an alternative chemical method for synthesizing the styptic hydrastinine, not appetite suppressants. MDMA was not the key substance in this patent, only a precursor. Archive documents revealed that Merck's scientists did not perform basic pharmacological tests with MDMA (now called "Safrylmethylamin") before 1927. These tests were halted for economic reasons. In the 1950s, primitive toxicological studies were conducted but MDMA was not tested in humans.

Cocaine dependence with and without PTSD among subjects in the National Institute on Drug Abuse Collaborative Cocaine Treatment Study.

OBJECTIVE: This study examined the prevalence of lifetime traumatic events and current symptoms of posttraumatic stress disorder (PTSD) among treatment-seeking cocaine-dependent outpatients and compared patients with and without PTSD on current substance use, psychopathology, and sociodemographic characteristics. METHOD: The subjects were 122 adult cocaine-dependent outpatients participating in a treatment outcome study of psychosocial therapy. In addition to standard self-report and interview measures of psychopathology and substance use, the subjects completed the Trauma History Questionnaire and the PTSD Checklist before entering treatment. RESULTS: These patients experienced a large number of lifetime traumatic events (mean = 5.7); men experienced more general disasters and crime-related traumas than women, and women experienced more physical and sexual abuse than men. According to self-report measures, 20.5% of the subjects currently met the DSM-III-R criteria for PTSD; the rate of PTSD was 30.2% among women and 15.2% among men. Patients with PTSD had significantly higher rates of co-occurring axis I and axis II disorders, interpersonal problems, medical problems, resistance to treatment, and psychopathology symptoms than patients without PTSD. Psychopathology symptoms represented the most consistent difference between the two groups and provided the best prediction of PTSD status in a logistic regression. However, the groups did not differ significantly in current substance use or sociodemographic characteristics. CONCLUSIONS: These findings underscore the value of screening substance abusers for PTSD, because it can identify a small but substantial number who might require additional treatment. Further studies of the relationship between PTSD and substance abuse appear warranted.

Immunopathology of hyperacute xenograft rejection in a swine-to-primate model.

Hyperacute rejection is the inevitable consequence of the transplantation of vascularized organs between phylogenetically distant species. The nature of the incompatibility and the pathogenetic mechanisms that lead to hyperacute xenograft rejection are incompletely understood. We investigated these issues by the immunopathological analysis of tissues from swine renal and cardiac xenografts placed in rhesus monkeys. Hyperacute rejection was associated with deposition of recipient IgM and classic but not alternative complement pathway components along endothelial surfaces, the formation of platelet and fibrin thrombi, and the infiltration of neutrophils. In animals from which natural antibody was temporarily depleted by organ perfusion, rejection was observed at 3 days to 5 days posttransplant. The immunopathology of rejection in these tissues revealed focal vascular changes similar to those observed in hyperacute rejection. A xenograft functioning for a prolonged period in a recipient temporarily depleted of circulating natural antibody contained recipient IgM along endothelial surfaces but no evidence for significant deposition of complement, formation of platelet and fibrin thrombi, or infiltration of neutrophils. These results suggest that rhesus IgM contributes significantly to the development of hyperacute rejection in the swine to Rhesus model and that the fixation of complement is a critical factor in the recruitment of the coagulation cascade and platelet aggregation--and possibly in the adherence and infiltration of PMN.

The immunopathology of cardiac xenograft rejection in the guinea pig-to-rat model.

The mechanisms underlying rejection by rats of vascularized guinea pig xenografts have been controversial. The aim of this study was to define, using sequential immunopathologic analysis, the contributions of xenoreactive antibody, complement, and effector cells to the rejection of guinea pig cardiac xenografts by Lewis rats. In untreated recipients, hyperacute rejection of guinea pig cardiac xenografts occurred in 20 +/- 10.2 min and was characterized by focal endothelial deposition of IgM and by diffuse deposition of C3. IgG was not localized to endothelial surfaces, but was present in the same locations as albumin, suggesting that the accumulation of IgG might reflect nonspecific leakage of plasma proteins from blood vessels. No polymorphonuclear or monocytic infiltrate was observed. Depletion from rats of xenoreactive antibody to undetectable levels prolonged the survival of guinea pig cardiac xenografts, but did not prevent hyperacute rejection; the rejected xenografts contained deposits of C3 along the microvasculature but no deposits of IgM or IgG. No cellular infiltrate was observed. Depletion of complement with cobra venom factor prolonged the survival of xenografts up to 96 hr. Xenograft tissues from complement-depleted animals had diffuse deposits of IgM along the microvasculature, but no detectable deposits of C3 or IgG were noted. Graft tissues obtained at various times after transplantation into complement-depleted animals revealed cellular infiltrates consisting of granulocytes, monocytes, and lymphocytes, but few cells bearing an NK cell phenotype. Our findings are consistent with the concept that complement activation is essential for the hyperacute rejection of discordant xenografts, and that in this particular model complement activation can proceed without the involvement of antibody. However, our findings also suggest that xenoreactive antibody contributes to hyperacute rejection and, along with effector cells, contributes to the later rejection of a xenograft when hyperacute rejection has been averted. Finally, we show that when hyperacute rejection is avoided, a form of vascular rejection occurs in which certain of the pathologic features--i.e., interstitial hemorrhage, interstitial edema, and thrombosis--are very similar to those observed in hyperacute rejection. Whether this form of rejection is a delayed form of the process that leads to hyperacute rejection or a novel pathologic process of graft rejection has yet to be determined.

The efficacy of omeprazole-based short-term triple therapy in Helicobacter pylori-positive older patients with dyspepsia.

OBJECTIVE: To evaluate the efficacy of 1-week triple therapy with omeprazole, clarithromycin,and tinidazole (OCT) in Helicobacter pylori-positive older patients with dyspepsia. DESIGN: A prospective, nonrandomized therapeutic study. SETTING: The primary care and referral center of a gastroenterological outpatient clinic at a central university hospital serving an urban population (>1 million) in Israel. PARTICIPANTS: The study group consisted of 134 patients (71 men, and 63 women) more than 60 years old who were referred for evaluation of symptoms of dyspepsia and were endoscopically diagnosed as H. pylori positive. The patients were divided into two groups: those who received their first course of anti-H. Pylori therapy during this study (Group 1) and those who had previously received standard metronidazole and bismuth combination therapies that failed to eradicate the H. pylori (Group 2). MEASUREMENTS: All the patients underwent upper gastrointestinal endoscopy, and H. pylori infection was confirmed by a rapid urease test (CUTest) and/or histological staining. Therapeutic efficacy was assessed by a 13C-urea breath test 4 weeks after completion of treatment. RESULTS: The mean age of the study population was 68.8 years (range 60-87). There were 112 patients in Group 1 and 22 patients in Group 2. Endoscopic findings were: gastritis (in 46), gastric ulcer (8), duodenal ulcer (52), and duodenitis (28). The H. pylori eradication rate was significantly higher in Group 1 patients (104/112, 92.9%) than in patients of Group 2 (15/22, 68.2%). There was no difference in the eradication rate in relation to gender, endoscopic diagnosis, more advanced age, place of birth, or smoking habits. The compliance in both groups was equally good, and no major side effects were recorded. CONCLUSIONS: A 1-week OCT triple therapy is well tolerated and effective as first line therapy for H. pylori among older people. It is less effective in patients previously treated.

Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients.

PURPOSE: To compare etoposide pharmacokinetics following administration of high-dose etoposide and etoposide phosphate, a water-soluble prodrug of etoposide. Bioequivalence was assessed using a two-treatment randomized crossover design. METHODS: Ten patients with high-risk or relapsed lymphoma were treated with a sequential high-dose chemotherapy. They were randomized to receive either 3 x 400 mg/m2 etoposide or an equimolar amount of etoposide phosphate (as 1-h infusions on three consecutive days) in the first course and the alternative drug in the second course. Serial plasma and ultrafiltered plasma samples were collected and analysed for etoposide by a reversed-phase HPLC method with UV and electrochemical detection. Pharmacokinetic parameters were estimated using a two-compartment model. Bioequivalence was assessed calculating the 90% confidence intervals (CI) for the ratios of the geometric means of AUC(0-infinity) and additionally of Cmax of etoposide derived from etoposide phosphate relative to etoposide in plasma and ultrafiltered plasma as point estimates (level of significance alpha < 0.05). RESULTS: Pharmacokinetic parameters of etoposide were comparable in both treatment arms except that terminal half-life was significantly shorter and apparent Vss in ultrafiltered plasma was significantly larger following administration of the prodrug. The point estimates for AUC(0-infinity) of etoposide derived from etoposide phosphate relative to etoposide were 102.9% and 88.4% for plasma and ultrafiltered plasma, respectively. The 90% CIs were in the range from 80% to 125% where bioequivalence can be assumed. The point estimates of Cmax on day 3 of chemotherapy were 96.5% and 81.7% in plasma and ultrafiltrate with the 90% CI in ultrafiltered plasma being out of the range from 80% to 125%. CONCLUSION: With respect to total drug exposure, represented by AUC(0-infinity), high-dose etoposide phosphate is bioequivalent to high-dose etoposide.

Feasibility of multidimensional substance abuse treatment matching: automating the ASAM Patient Placement Criteria. American Society of Addiction Medicine.

UNLABELLED: The Patient Placement Criteria published by the American Society of Addiction Medicine (ASAM Criteria) established a non-proprietary standard for matching substance use disorder patients to treatment settings. METHODS: Data from 593 substance dependent adults who were assessed using the first computerized implementation of the ASAM Criteria were analyzed to determine whether the level of care assignments showed significant differences on a variety of clinical measures. RESULTS: The algorithm showed acceptable discrimination between each of three ASAM Levels of Care across numerous clinical subscales. CONCLUSIONS: It is feasible to implement complex, multidimensional criteria for substance abuse treatment that may improve reliability and facilitate validity studies.

Protein-restricted diet alters concentration of plasma membrane glycoproteins in rat liver.

Malnutrition is known to have adverse effects on the physiology and morphology of the liver. The aim of this investigation was to examine the effect of protein restriction on the content of plasma membrane proteins residing in the sinusoidal and bile canalicular domains of rat liver. Post-weanling rats maintained on low protein isocaloric diets showed marked growth retardation concomitant with reduced liver protein concentration compared to control animals. The content of leucine aminopeptidase, a bile canalicular enzyme, and asialoglycoprotein receptor, a sinusoidal receptor, in livers of protein-restricted rats was 66% and 50%, respectively, of control livers. In contrast, the relative concentrations of dipeptidyl peptidase IV and a cell adhesion molecule (GP 110), both canalicular proteins, were 160% and 121%, respectively, in rat livers upon protein restriction. After a 4-week rehabilitation period, the concentrations of all canalicular membrane proteins were similar to those in control livers, while the sinusoidal receptor was only 68% of control values. Protein restriction was found to adversely affect the concentrations of protein constituents, but not their localization in the hepatocyte plasma membrane. In general, altered concentrations of hepatocyte membrane proteins were reversed on the administration of a normal protein diet.

Evaluation of a new immunochromatographic test for Helicobacter pylori IgG antibodies in elderly symptomatic patients.

AIM: To determine the diagnostic value of a new serum and whole blood serological IgG antibody test, FlexPack HP, for the diagnosis of Helicobacter pylori in elderly symptomatic patients. METHODS: 94 consecutive symptomatic patients who underwent upper endoscopy were studied (mean age, 62.6 years). On endoscopy, the presence of H. pylori infection was examined by biopsies from gastric antrum and body for rapid urease test and histologic examination. Blood was drawn prior to endoscopy and both blood and serum were immediately analyzed for human IgG antibodies to H. pylori by a new commercially available qualitative immunochromatographic method, FlexPack HP. This test incorporates high-molecular weight cell-associated proteins (HM-CAP), which are highly specific for H. pylori IgG antibodies. RESULTS: Overall agreement for FlexPack HP whole blood vs FlexPack HP serum was 100%, and agreement with biopsy results was 71%. The gold standard (detection of H. pylori by histology or urease test) identified H. pylori in 61 patients (65%). Complete agreement was observed between the gold standard test and the serology kit in 72% (68/94) of sera (51 positive and 17 negative). Disagreement was found in sera of 26 patients; 16 sera were negative by the gold standard and positive by FlexPack HP and 10 patients were found negative by serology. The sensitivity of FlexPack HP was 84% and the specificity 52% when compared with the gold standard. CONCLUSIONS: FlexPack HP serum and whole blood test is a simple and reliable method for the detection of H. pylori antibodies, with 100% agreement between the serum and blood results. In the elderly symptomatic patients the sensitivity of FlexPack HP was similar to that of other serologic tests, but the specificity was relatively low, limiting its use in this population.

Passive smoking in patients with inflammatory bowel disease: an Israeli multicentre case-control study.

BACKGROUND: The association between smoking and inflammatory bowel disease (IBD) is well established. There are, however, no large scale studies of passive smoking in inflammatory bowel disease and this has never been surveyed in the Jewish population of Israel. AIM: To study the passive smoking exposure of Jewish IBD patients in Israel in a large scale multicentre study. METHODS: Patients with established IBD, aged 18-70 years, were interviewed regarding smoking and other habits. Two controls, one clinic and one neighbourhood, matched by age, sex, community group, and education, were sought for each subject. RESULTS: Five hundred and thirty-four patients (273 ulcerative colitis (UC) and 261 Crohn's disease (CD)), 478 clinic controls and 430 community controls were interviewed. There were no significant differences in the passive smoking habits between IBD patients and their controls. Fifty-one percent of UC patients, 50% of the clinic controls and 58% of the community controls were exposed to passive smoking at home (NS); similar results were found among CD patients (50%, 55% and 56%, respectively). When a quantitative exposure index was used UC patients were significantly less exposed to passive smoking than were their community controls (7.46 +/- 8.40 vs 9.36 +/- 9.46, n = 229, P< 0.031). There was no difference in the exposure to passive smoking among CD patients and their controls. No differences in exposure to passive smoking were found when UC patients who had never smoked were compared with their controls. When the quantitative index was used 'never-smoked' CD patients tended to be less exposed to passive smoking at home than their community controls (5.40 +/- 7.60 vs 8.04 +/- 8.72, P < 0.05). CONCLUSION: There is a lack of association between passive smoking and IBD in Jewish patients in Israel. When a quantitative exposure index was used UC patients were found to be less exposed to passive smoking than their community controls.

Measles is more prevalent in Crohn's disease patients. A multicentre Israeli study.

The question whether there is a transmissible pathogenetic agent as a cause for Crohn's disease, remains unanswered. Measles virus has been the subject of many intensive studies, in the attempt to find a role for it in the pathogenesis of inflammatory bowel disease. Whether an early infection with measles virus may predispose to Crohn's disease in later life is still not clear. We conducted a large scale multicentre study, in order to obtain sufficient data to answer this question. To do so, we compared inflammatory bowel disease patients, with Crohn's disease or ulcerative colitis, with two matched control groups: clinical controls, and community controls. A total of 531 patients, 271 with ulcerative colitis and 260 with Crohn's disease were interviewed, as well as 903 matched controls. Blood from 104 inflammatory bowel disease patients and 50 controls was tested for antibodies to measles virus. We did not find any differences related to measles vaccination, either in Crohn's disease or in ulcerative colitis. Exposure to measles in childhood was more frequent in Crohn's disease patients than in their controls, the difference being statistically significant (p < 0.05) in relation to community controls. The presence of IgG antibodies to measles virus was higher in patients with Crohn's disease than in patients with ulcerative colitis or controls (p = 0.084). Another observation of interest was the finding that Crohn's disease patients who had measles in childhood, more frequently had large bowel disease than those who had not had measles. These data lead us to postulate that there may be a role for measles infection in Crohn's disease, even if, at present, this role remains unclear.

Total parenteral nutrition-induced steatosis: reversal by parenteral lipid infusion.

Prolonged use of total parenteral nutrition (TPN) may be associated with hepatic complications, primarily steatosis and cholestasis. A case is reported of an 18-year-old woman with chronic idiopathic intestinal pseudo-obstruction syndrome who was on prolonged home parenteral nutrition without lipid supplementation and developed steatosis. This finding was reversed by addition of lipid emulsion, at a dose of 0.5 g/kg/day, to the parenteral nutrition solution. The lack of lipid supplementation as a possible cause of steatosis, as well as other mechanisms of liver steatosis associated with TPN, are discussed.