Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

Staff happiness and work satisfaction in a tertiary psychiatric centre.

BACKGROUND: Mental health professionals are at a high risk of burnout. Positive psychology outcomes of staff in acute in-patient psychiatric wards are poorly researched and unclear. AIMS: To quantify the satisfaction with life and work-life satisfaction of mental health staff at a large university-affiliated tertiary psychiatric centre. METHODS: We utilized the Satisfaction with Life Scale (SWLS) and the Work-Life Satisfaction Questionnaire (WLSQ). RESULTS: Two hundred and nine out of 450 staff members (46%) participated; mean age 48.2 + 9.9 years; 63% were male. On average the participants had been practising their speciality for 21.1 + 9.8 years (range: 2-48). The mean total SWLS scores differed significantly between professions (P < 0.05). The highest levels of happiness were reported by psychologists and social workers, followed by the administrative staff, the psychiatrists and finally the nursing staff. Staff scored the highest for work as a 'calling' followed by work as a 'career' and the lowest rating for work as a 'job'. The mean total WLSQ score differed between professions, (P < 0.01). The highest levels of work as a calling were reported by psychiatrists (mean 2.87 of possible 5.0), followed by psychologists and social workers, nursing staff and finally administrative staff. CONCLUSIONS: Satisfaction with life and work orientation do not correlate among mental health professionals. Although highly motivated and perceiving psychiatry as a 'calling' psychiatrists score low on levels of satisfaction with life. Improving staff happiness may contribute to increase in moral and counter burnout.

Hepatitis B viral infection of hepatic progenitor cells. Resolving unresolved questions?

Accumulated data to date do not entirely explain the; propensity of the hepatitis B virus (HBV) to cause chronic infections in newborns; failure of antiviral agents to resolve infections or precise mechanism whereby HBV causes hepatocellular carcinoma (HCC). Based on the increased numbers of hepatic stem/progenitor cells (HPCs) present within the neonatal liver, the refractoriness of these cells to the effects of interferons and xenobiotics and their ability to undergo malignant transformation, we hypothesize that HBV infection of HPCs could explain these and perhaps other clinical features of chronic HBV.

The effect of glucose administration on perceived fetal movements in women with decreased fetal movement, a double-blinded placebo-controlled trial.

OBJECTIVE: To assess the effect of maternal glucose administration on perceived fetal movements. STUDY DESIGN: This was a randomized, double-blinded placebo-controlled trial. Patients 28-41 weeks singleton gestation complaining of decreased fetal movements (DFM) were assigned to receive either 500 cc dextrose 5% (group A) or 500 cc normal saline (group B) intravenously. Primary outcome was number of fetal movements recorded during the following 30 min. Secondary outcomes included need for admission or induction of labor owing to persistent DFM. Maternal glucose levels were taken before and after intervention. A sample size of 50 patients was planned in order to detect a 30% increase in fetal movements in group A. RESULTS: Between February 2011 and April 2013, 50 patients were recruited. Demographic characteristics were similar among groups. There was no difference in the number of fetal movements recorded (7±6 vs 8.8±6 movements/30 min, group A and B, respectively, P=0.39). Similar number of patients had persistent DFM that required admission (8 vs 10 patients, P=0.77, OR 1.4, confidence interval (CI) 0.38-5.3); of those admitted, similar number of patients had induction of labor (3 vs 6 patients, P=0.64, OR 0.4, CI 0.03-3.8). Maternal glucose levels were similar at recruitment (88±19 vs 83±15 mg dl(-1) P=0.36) but were significantly higher in group A (161±37 vs 75±15 mg dl(-1) P<0.0001) after intervention. CONCLUSION: In women with DFM, maternal glucose administration has no effect on perceived fetal movement and its clinical use is questionable.

Fulminant non--A-G viral hepatitis leading to liver transplantation.

BACKGROUND: All hepatotropic viruses are known to cause fulminant hepatic failure (FHF). However, in 30% to 40% of patients with FHF, the precise cause remains unknown. We aimed to better define this subgroup. METHODS: We evaluated the clinical course and outcome of 7 patients admitted during a 22-month period with fulminant viral hepatitis leading to liver transplantation; none had serologic or molecular evidence of hepatitis A, B, C, D, E, or G viral infection, thus the term non-A-G viral hepatitis. All known etiologies of FHF were excluded. RESULTS: All patients had prodromal symptoms suggestive of viral causes. Mean age was 30 years. The interval between onset of jaundice and appearance of encephalopathy was 23 days (range, 4-50 days). Five patients had grade III/IV encephalopathy. Serum alanine aminotransferase levels showed a single peak of activity. The duration between first symptoms and liver transplantation was 28 days (range, 12-71 days). Results of histological study of the explanted liver showed submassive (4 patients) or massive (3 patients) hepatocyte necrosis. In all patients, results of polymerase chain reaction analysis did not detect hepatitis B virus DNA, hepatitis C virus RNA, or hepatitis G virus RNA in the explanted liver. After transplantation, 2 patients showed (6 months later) increased liver enzyme levels of undetermined cause, and results of a liver biopsy showed mild lobular hepatitis; 1 patient had lymphoproliferative disorder (Epstein-Barr virus-originated); and 1 patient, aplastic anemia, which is known to be associated with seronegative viral hepatitis. The latter patient died, whereas the other 6 patients are alive (survival rate, 86%). CONCLUSIONS: Our patients with non-A-G viral hepatitis had a severe acute onset with progressive FHF requiring liver transplantation. There is some suggestion of recurrent viral disease after transplantation implicating other unknown viruses in the etiology.

Decreased serum growth hormone-binding protein in patients with liver cirrhosis.

The recently characterized GH-binding protein (GH-BP) has an amino acid sequence identical to the extracellular domain of the GH receptor. Serum GH-BP reflects the amount of GH receptors, and the liver seems to be their main source. To evaluate the effect of liver disease on GH-BP, 52 patients with liver cirrhosis were studied. Serum GH-BP was measured by a binding assay with dextran-coated charcoal separation. Levels of GH-BP were correlated against the clinical state, assessed by Pugh's score. The GH-BP of 31 Pugh's class A patients was 9.7 +/- 0.5%/50 microL serum, and that of 21 Pugh's class B and C patients was 7.2 +/- 0.5%/50 microL serum compared to 11.3 +/- 0.5%/50 microL serum in age-matched controls. GH-BP correlated negatively with Pugh's score and serum bilirubin, and positively with serum albumin. It did not correlate with serum liver enzymes or serum insulin-like growth factor-I. Scatchard analysis of GH binding to the GH-BP revealed similar binding affinities in Pugh's A, B, and C patients and controls. The binding capacity in cirrhosis was significantly lower than that in controls. We conclude that serum GH-BP is controlled mainly by the liver and can provide an additional measure of disease severity in liver cirrhosis.

Increased concentration of high density lipoprotein in plasma and decreased platelet aggregation in primary biliary cirrhosis.

Plasma lipoprotein concentration and composition were studied in 7 female patients with primary biliary cirrhosis and compared with 6 normal, age-matched controls. The effect of the lipoproteins derived from these patients on the function of normal platelets was also tested. High levels of plasma cholesterol and phospholipids and a raised free/esterified cholesterol ratio were found. In 4 of the patients, both HDL cholesterol and HDL protein were increased, and high levels of plasma apoprotein A-I and A-II were evident. This abnormal HDL did not contain excess apolipoprotein E. The VLDL and LDL fractions were also abnormal, as evidenced by a high cholesterol/protein ratio. Little correlation between lipoprotein disorders and clinical condition was found. Platelet function was reduced in all patients. LDL from the patients reduced aggregation of normal platelets, whereas HDL had a minimal effect. The abnormal lipoproteins in these patients may contribute to their abnormal in vitro platelet aggregation.

The turnover of growth hormone (GH)-binding protein and GH receptor in rabbit and rat.

The present study was undertaken to further explore the comparative dynamics of growth hormone-binding protein (GH-BP) in relation to the turnover of the GH-receptor (GH-R) in vivo in rabbits and rats. The strategy used was to examine the time course of hepatic GH-R turnover over a 3 h period after cycloheximide treatment, with simultaneous measurements of serum GH-BP level. In the rabbit we sampled multiple liver biopsies and serum samples consecutively from each animal. In the rat, experiments on individual animals were conducted for each time point. In the rat, both liver GH-R and serum GH-BP declined after cycloheximide injection following first-order kinetics. The t 1/2 values for GH-R and GH-BP were 29.7-44.5 and 82.7-119.5 min (95% confidence limits), respectively. A significant positive correlation was found between rat liver GH-R and serum GH-BP (r = 0.85; p < 0.001). In contrast, the decline in rabbit liver GH-R, following cycloheximide treatment was accompanied by simultaneous time-dependent accumulation of serum GH-BP. The t 1/2 for rabbit serum GH-BP accumulation was 30.4-67.6 min. Scatchard analysis of [125I]hGH binding to rabbit GH-BP indicated that the binding capacity increased from 2818 +/- 538 fmol/ml, at time zero, to 5236 +/- 419 fmol/ml following 60 min cycloheximide treatment (p < 0.05). No significant changes in affinity were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Fechtner syndrome: clinical and genetic aspects.

Fechtner syndrome, a variant of Alport syndrome, was first reported by Peterson et al. [1985]. It is characterized by nephritis, hearing loss, eye abnormalities, macrothrombocytopenia, and leucocyte inclusions, present in varying combinations in several members of the same family. This is the second family reported; 16 relatives are affected. The clinical manifestations of the syndrome are delineated. The pattern of inheritance is autosomal dominant. The hematologic abnormalities are similar to those detected in May Hegglin anomaly. They are present in every affected relative and may be present at birth. The feasibility of prenatal diagnosis is discussed.

Gonadotropin-releasing hormone analogues for dysfunctional bleeding in women after liver transplantation: a new application.

A new clinical indication for GnRH agonists treatment seems to exist in addition to the many indications known so far (4, 5). These previously mentioned indications include: uterine fibroids, precocious puberty, endometriosis, polycystic ovarian disease, ovulation induction for assisted fertilization (in vitro or in vivo), treatment of various tumors such as prostatic, breast, pancreatic, ovarian, and pituitary tumors, and various catamenial disorders such as premenstrual syndrome and porphyria. Women after liver transplantation, who are in the reproductive age and who experience menometrorrhagia or dysfunctional bleeding, seem to be a new indication for application of these useful GnRH analogues. This application may prevent the potential hepatotoxicity or cholestasis of E-P combinations usually used for treatment of dysfunctional bleeding. The recommended treatment is of relatively short duration (3 to 6 months), within the first 2 years of the transplantation, after which a more prolonged treatment should be considered. This treatment may also spare the need for contraception during its administration because both oral contraceptives and intrauterine device are relatively contraindicated in these patients (the latter because of the immunocompromised state). We believe this application to become more common because of increasing numbers of liver transplantations and improved survival rate. It may be looked at as a "new application of a relatively new drug for a new and enlarging situation."

Leukocyte adhesiveness/aggregation and neuroleptic drug treatment.

Leukocyte adhesiveness/aggregation as measured by the leukergy test was studied in peripheral citrated blood of two groups of schizophrenic patients treated with neuroleptic drugs. In the first group (N = 25) leukergy test was performed before and after commencement of neuroleptic treatment to acutely psychotic hospitalized patients. The second group studied (N = 25) were stabilized outpatients receiving long term neuroleptic medications for at least 3 months. There was a significant rise in leukergy rates between the drug free period and the subsequent measurements performed after 1 and 7 days of neuroleptic treatment in the first group (p less than 0.001). Similar high leukergy rates were noted in the second group of remitted patients. High leukergy rates were related to neuroleptic therapy and not to the psychotic state of the patients.

Basal and post-methionine serum homocysteine and lipoprotein abnormalities in patients with chronic liver disease.

BACKGROUND: Lipoprotein abnormalities are commonly found in chronic liver diseases (CLDs), particularly hypercholesterolemia in primary biliary cirrhosis (PBC). However, affected patients may not be at increased risk of coronary heart disease. Cirrhotic patients display impaired methionine clearance, and an increased level of homocysteine, a methionine metabolite, is an independent risk factor for coronary heart disease. Thus, we hypothesized that the low risk of coronary heart disease in patients with CLD may be related to low serum levels of homocysteine. The aim of this study was to test this hypothesis after methionine load and to describe the serum lipoprotein profile in patients with PBC and in patients with hepatocellular liver disease. METHODS: Fifteen female patients (mean age, 58.2 +/- 11.7 years) with PBC, 15 female patients (mean age, 54.5 +/- 9.6 years) with other causes of CLD, and 15 healthy sex- and age-matched controls were given L-methionine (50 mg/kg of ideal body weight). Basal fasting serum homocysteine level and 2, 4, and 6 hours of post-methionine load were determined using high-performance liquid chromatography with a fluorometric detector. Levels of fasting serum cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), lipoprotein (a) (Lp(a)), and apoprotein B were also determined. RESULTS: Results showed that mean basal and post-methionine load (6 hours) serum homocysteine levels were statistically significantly higher in the patients with PBC and with CLD than in the control group (P=0.04) and that levels of serum cholesterol, LDL, HDL, and apoprotein B were significantly higher in the PBC patients than in the other two groups (P < or = 0.05). There was no correlation between any of these parameters and the severity of liver disease. Serum HDL was significantly lower in the CLD group (P < or = 0.05) and correlated with severity of liver disease. There was no significant difference in serum cholesterol, LDL, or apoprotein B between the CLD group and the controls. Serum triglyceride and Lp(a) levels were similar for all three groups. CONCLUSIONS: In contrast to previous reports, the site of the methionine metabolic impairment was found to be below the homocysteine synthesis level. For most patients with CLD, factors other than serum homocysteine or Lp(a) are responsible for the reduction in the risk of coronary heart disease. Further studies with larger samples are needed.

Periodontal changes in liver cirrhosis and post-transplantation patients. I: clinical findings.

BACKGROUND: Cyclosporin A (CsA) is widely used to prevent liver transplantation failure. CsA-induced gingival overgrowth is a common side effect. However, the effect of cirrhotic liver disease, liver transplantation, and immunosuppressive therapy on the periodontium is yet unclear. The aim of the present cross-sectional study was to examine the effect of liver cirrhosis, transplantation, and immunosuppressive therapy on the periodontium. METHODS: The experimental group (LC) consisted of 13 liver cirrhosis patients. A second experimental group (PT) included 24 patients, post-liver transplantation, receiving immunosuppressive therapy. Seventeen healthy subjects formed a control group. The Ramfjord index teeth were recorded for plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL), and gingival overgrowth (GO). RESULTS: Mean PI and mean GI for the LC, PT, and C groups were not statistically different (P >0.05). Mean PD for the LC (3.32+/-0.24 mm) and PT group (3.41+/-0.13 mm) was significantly higher (P = 0.0001, ANOVA) compared to the C group (2.45+/-0.16 mm). Likewise, CAL for the LC (4.89+/-0.47 mm) and PT group (4.68+/-0.47 mm) was significantly higher (P = 0.001, ANOVA) than the C group (2.78+/-0.23 mm). Patients in the PT group exhibited the greatest mean GO scores (0.88+/-0.09) compared to the LC group (0.37+/-0.07) and the C group (0.09+/-0.02). All 3 groups were significantly different from each other (P = 0.0001) despite great variability within the groups. GO in the CsA-treated patients (1.1+/-0.09) was significantly higher (P = 0.0001) than in those treated with tacrolimus (0.57+/-0.1). CONCLUSIONS: Liver cirrhosis patients demonstrated greater pocketing and attachment loss compared to healthy matched controls. These same differences were observed in patients post-transplantation. Gingival overgrowth occurred as a result of the immunosuppressive therapy with CsA, while to a lesser degree with tacrolimus. Replacement of CsA by tacrolimus in patients manifesting gingival overgrowth might be recommended whenever possible to overcome this problem.

Von Willebrand gene expression in damaged human liver.

BACKGROUND/AIMS: von Willebrand factor (vWf) is an adhesive glycoprotein known to play a role in hemostasis and in tissue injury. It is found in high levels in plasma of patients with acute hepatic failure and chronic liver disease. The aim of this study was to investigate the pattern of tissue vWf in acute liver failure in humans. METHODOLOGY: We studied vWf immunostaining and mRNA expression in the liver of three patients with fulminant liver failure, two patients with chronic liver disease, and two controls. PECAM-1 (CD31) immunostaining and mRNA expression were used as an additional endothelial marker. RESULTS: In chronic liver cirrhosis, vWf deposits were strongly detected at the scar-parenchyma interface. In fulminant hepatic failure, intense deposits were seen in tissue sections in the area of necrosis. A similar pattern of immunostaining was seen with PECAM-1. vWf transcripts were abundant in the liver of patients with chronic disease and minimally expressed in patients with acute hepatic failure and in controls. CONCLUSIONS: vWf is deposited within the liver sinusoids early after liver damage. The factor is only partially produced locally during the acute phase of the disease, but is overproduced in chronic disease states. These changes may suggest a role for vWf in liver injury and repair.

Pregnancy after liver transplantation.

Two patients who became pregnant after liver transplantation for end-stage liver disease were carefully monitored using pulsed Doppler waveform measurements. One patient with Wilson's disease, on triple immunosuppressive therapy including prednisone, azathioprine and low-dose cyclosporin A, delivered a healthy girl weighing 2650 g after 38 weeks' gestation. The other patient, with HBV-related postnecrotic cirrhosis, became pregnant less than 3 months postoperatively, under triple therapy, after being amenorrheic for 6 years. Episodes of elevation in liver enzymes were noted, and severe osteoporosis with low back pain developed. A healthy boy weighing 2975 g was born at 35 weeks' gestation. Our cases add to previous reports of successful pregnancies under cyclosporin A immunosuppression.

Differentiation between major and milder acute mental stress by means of the leukocyte adhesiveness/aggregation test.

Following previous observations that the adhesive state of white blood cells in the peripheral blood increases during stress, we examined 645 volunteers in various conditions of anticipatory anxiety. The volunteer subjects included 465 controls in whom stress was related solely to impending venipuncture, 149 persons under moderate stress (students before delivering a graded lecture, patients before dental treatment, etc), as well as 31 individuals under major stress (eg, before induction of anesthesia in the operating room). The respective values of aggregated leukocytes in the peripheral blood were 5.2 +/- 3.8, 6 +/- 4.2, and 19.3 +/- 9.3% of aggregated cells, with a significant difference (p < .0001) between the third and the other two groups. In both discriminant analysis and multiple regression, the leukocyte adhesiveness/aggregation test (LAAT) was shown to be superior to the white blood cell count for the detection of major stress. The LAAT had a sensitivity of 0.8, compared with only 0.35 for leukocyte count for that purpose. We concluded that the LAAT could be a powerful tool for the diagnosis of major acute mental stress and for discrimination between conditions causing major stress and those conditions that are less stressful.

[Transjugular liver biopsy in patients with bleeding tendency].

Transjugular liver biopsy (TJB) was successful in 14 of 23 patients with chronic liver disease and abnormal coagulation profiles. There were 7 men and 7 women between the ages of 20 and 65. No bleeding followed the procedure, nor were there any other significant complications. The size of the specimens and the number of portal spaces included were compared with those obtained by percutaneous liver biopsy from 12 patients with advanced liver cirrhosis. TJB samples were smaller than those obtained by percutaneous biopsy (0.56 +/- 1.6 cm vs 1.0 +/- 0.05) and contained fewer portal spaces (2.2 +/- 1.6 vs 3.4 +/- 2.3). Despite the smaller size, the contribution of TJB to diagnosis and prognosis was defined as good in 78% of the patients. We conclude that TJB is safe and is an important tool for liver tissue diagnosis in patients with bleeding tendency.