Treatment of severe recurrent hepatitis C after liver transplantation in HIV infected patients using sofosbuvir-based therapy.

BACKGROUND: For liver transplant recipients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection, recurrence after LT is associated with a higher risk of graft loss than for HCV mono-infected patients. Prior HCV treatment options were limited by side effects and drug-drug interactions. AIM: To evaluate treatment outcomes with sofosbuvir (SOF)-based therapy among HIV/HCV coinfected liver transplant recipients. METHODS: Access to SOF and ribavirin (RBV) prior to regulatory approval was attained via an international compassionate access program for transplant recipients with a life expectancy of 1 year or less in the absence of HCV treatment. This report focuses on the short and longer term outcomes in HCV-HIV co-infected liver transplant recipients. RESULTS: Twenty patients were treated, nine with early severe recurrence and 11 with cirrhosis. Eleven patients received SOF and RBV, one SOF, RBV and Peg-interferon, three SOF, RBV and simeprevir and five SOF, RBV and daclatasvir. Of the 18 patients who completed treatment, 16 (89%) achieved sustained virological response 12 weeks after the end of treatment (SVR12). Liver function tests (including bilirubin and albumin) improved significantly over time. Nineteen serious adverse events occurred in eight (40%) patients, none of them related to SOF. Two patients died during treatment and another, 1 year after the end of therapy, due to progressive end-stage liver disease. Importantly, HIV suppression was not compromised. No significant drug-drug interactions were reported. CONCLUSIONS: Sofosbuvir-based regimens are safe, well-tolerated and provide high rates of SVR in HCV-HIV co-infected patients with severe recurrence after-liver transplant.

Maltose-binding protein is a potential carrier for oral immunizations.

Maltose binding protein (MBP) is often fused to a relevant protein to improve its yield and facilitate its purification, but MBP can also enhance the immunogenicity of the fused proteins. Recent data suggest that MBP may potentiate antigen-presenting functions in immunized animals by providing intrinsic maturation stimuli to dendritic cells through TLR4. The aim of this study was to examine if an MBP-specific immune response can be elicited by oral administration of MBP. Therefore, in a first experiment the MBP specific immune response was analyzed after oral immunization with MBP or MBP+CT to piglets and both the systemic and mucosal immune responses were examined Although no high systemic response was observed in the MBP-group, a local mucosal IgM MBP-specific response in the jejunal Peyer's patches was observed. In the second experiment MBPFedF was orally administered to piglets. A significant systemic response against MBP and a weak response against FedF were found after oral administration of MBPFedF+CT. Also the presence of MBP-specific IgA ASC in the lamina propria indicates that a local intestinal immune response against MBP was induced. Our data suggests that MBP can cross the epithelial barrier reaching the gut-associated lymphoid tissue after oral administration to pigs, which implicates that MBP could act as a carrier and delivery system for fused proteins to target the vaccine antigens to intestinal immune cells.

Targeting aminopeptidase N, a newly identified receptor for F4ac fimbriae, enhances the intestinal mucosal immune response.

Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrhea in human and animal. In piglets, ETEC having F4 fimbriae (F4(+) ETEC) induce severe diarrhea, dependent on the presence of receptors for F4 (F4R). In this study, porcine aminopeptidase N (pAPN) was identified as an F4R by comparative proteomic analysis of brush border proteins of F4R(+) and F4R(-) pigs and by adherence/internalization experiments on pAPN-transfected cells. Binding of F4 fimbriae to pAPN depended on sialic acid containing carbohydrate moieties, and resulted in clathrin-mediated endocytosis of the fimbriae. Endocytosis via pAPN was not restricted to F4 fimbriae, but was also observed for anti-pAPN antibodies. Both F4 fimbriae- and pAPN-specific antibodies were taken up in vivo by porcine enterocytes and induced subsequently a rapid immunoglobulin A and G response. In conclusion, we identified pAPN as an endocytotic receptor for F4 fimbriae and highlight the opportunity to target vaccine antigens to this epithelial receptor.

The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports.

BACKGROUND: Drug-induced liver injury (DILI) profile in most drugs' available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports. AIM: To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting. METHODS: Hepatotoxic drugs were identified from product labelling and classified in high-medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (> or = 3 x ULN) for drug (I(D)) and placebo (I(C)) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. RESULTS: The median I(C) was 10/1000. The high-medium-risk drugs' median I(D) was significantly higher compared with low-risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi-squared test, absolute difference and odds ratio comparing I(D) and I(C) identified 35%, 51% and 77% of high-medium-risk drugs respectively. Less number of case reports were associated with low- than high-medium-risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (I(D) vs. I(C)) was the strongest predictor of published DILI case reports. CONCLUSION: A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.

Primary prophylaxis of esophageal variceal bleeding in cirrhosis.

Variceal bleeding is a common and severe complication of liver cirrhosis. The risk of bleeding increases with the size of varices, red wheal marks and disease severity. Noninvasive tests are not accurate enough for the diagnosis of varices, so all patients with cirrhosis should be screened by endoscopy. Nonselective beta-blockers (propranolol, nadolol) are indicated for primary prophylaxis in patients with medium/large varices, and for those with small varices and red signs or advanced liver failure (Child C). In such patients, beta-blockers have been shown to reduce the risk of bleeding from 25 to 15%. There is no evidence to support using beta-blockers with nitrates or spironolactone. In patients with contraindication or intolerance to beta-blockers, endoscopic band ligations are indicated.

Hospital admissions for human T-cell lymphotropic virus type-1 (HTLV-1) associated diseases in Dominica.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that is endemic in certain regions of the world, and may account for significant morbidity and mortality among hospitalised patients. Sixty six HTLV-1 seropositive patients admitted to hospital with HTLV-1 associated diseases from 1995-99 were studied. HTLV-1 screening was done with ELISA and confirmed on western blot testing. There were 32 females (48.5%) and 34 males (51.5%). The mean age was 56 years and the age range was 9-89 years. The main associated diseases were tropical spastic paraparesis or HTLV-1 associated myelopathy in 18.2% of cases, acute form of adult T-cell leukaemia/lymphoma 7.6%, lymphomas 15.2%, and ectoparasites/endoparasites in 40.9%. HTLV-1 is associated with diseases in Dominica and association with severe forms of strongyloidiasis and scabies is particularly noted.

Severe refractory sarcoidosis in a 64-year-old man with persistent leucopenia.

We present a case of bone marrow granulomas in a 64-year-old West Indian man who presented with severe leucopenia, anaemia, thrombocytopenia, hepatosplenomegaly, hypercalcaemia, hypercalciuria, elevated angiotensin converting enzyme level and reticulo-nodular shadows on chest X-ray. Bone marrow biopsy revealed numerous non-caseating epithelioid granulomas. A diagnosis of sarcoidosis was made and he was treated with prednisolone 60 mg daily for four weeks and the dose was subsequently reduced to 30 mg daily. Eight months follow-up revealed persistent pancytopenia. Bone marrow granulomas are rare and, when they occur, sarcoidosis is an uncommon aetiology. This case illustrates that severe leucopenia may occur in sarcoidosis and may present therapeutic difficulties.

Severe refractory sarcoidosis in a 64-year-old man with persistent leucopenia

We present a case of bone marrow granulomas in a 64-year-old West Indian man who presented with severe leucopenia, anaemia, thrombocytopenia, hepatosplenomegaly, hypercalcaemia, hypercalciuria, elevated angiotensin converting enzyme level and reticulo-nodular shadows on chest X-ray. Bone marrow biopsy revealed numerous non-caseating epithelioid granulomas. A diagnosis of sarcoidosis was made and he was treated with prednisolone 60 mg daily for four weeks and the dose was subsequently reduced to 30 mg daily. Eight months follow-up revealed persistent pancytopenia. Bone marrow granulomas are rare and, when they occur, sarcoidosis is an uncommon aetiology. This case illustrates that severe leucopenia may occur in sarcoidosis and may present therapeutic difficulties

Case study: Fatal strongyloidiasis associated with human T-cell lymphotropic virus type 1 infection.

A case of fatal strongyloidiasis associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection is described in a 45-year-old West Indian man living in an area endemic for both strongyloidiasis and HTLV-1 infection. Clinical presentation was typical with severe diarrhea, vomiting, and progressive weight loss. Stool microscopy revealed Strongyloides stercoralis rhabditiform larvae. Despite treatment with thiabendazole, the patient died. Autopsy findings revealed severe ileocolitis due to Strongyloides larvae, right subdiaphragmatic pyogenic abscess, and severe pleuritis of the right lower lobe of the lung. This case illustrates that despite effective antihelmintic therapy, mortality is still high in patients with the hyperinfective state of S. stercoralis. Thus, in patients in areas endemic for both Strongyloides infection and HTLV-1, or in immigrants from these areas, repeated stool microscopy is indicated in patients positive for HTLV-1.

An atypical aggressive Kaposi's sarcoma in a HIV-negative bisexual man.

We describe a case of Kaposi's sarcoma in a previously healthy 35-year-old bisexual West Indian man of African descent who was seronegative for the human immunodeficiency virus (HIV) and human T-cell lymphotropic virus-1 (HTLV-1) and who presented with extensive mucocutaneous lesions, weight loss, visceral and generalized lymph node involvement, poor response to combination therapy with vinblastine and interferon alfa-2a, and a short survival of eight months from the onset of illness. This is the first documented case of Kaposi's sarcoma in Dominica. The presentation is unusual in that it is similar to the aggressive and disseminated Kaposi's sarcoma seen only in AIDS and the florid variant of the endemic disease in young men in Equatorial Africa.

An atypical aggressive Kaposi's sarcoma in a HIV-negative bisexual man

We describe a case of Kaposi's sarcoma in a previously healthy 35-year-old bisexual West Indian man of African descent who was seronegative for the human immunodeficiency virus (HIV) and human T-cell lymphotropic virus-1 (HTLV-1) and who presented with extensive mucocutaneous lesions, weight loss, visceral and generalized lymph node involvement, poor response to combination therapy with vinblastine and interferon alfa-2a, and a short survival of eight months from the onset of illness. This is the first documented case of Kaposi's sarcoma in Dominica. The presentation is unusual in that it is similar to the aggressive and disseminated Kaposi's sarcoma seen only in AIDS and the florid variant of the endemic disease in young men in Equatorial Africa.

NMR determination of the Sternheimer antishielding factor of Ca2+.

The experimental determination of the Sternheimer antishielding factor gamma(infinity) for Ca2+ in a sold material is reported for the first time. The gamma(infinity) value was obtained by comparing the quadrupole frequency measured by 43Ca NMR with the electric field gradient calculated in a frame of the point charge approximation in the high-Tc superconducting compound, Tl0.5Pb0.5Sr2CaCu2O7. The deduced value (gamma(infinity)= -6.1+/-.9) is about one-third of that obtained from the quantum mechanical calculations, whereas in the same sample, the gamma(infinity)value for O2- deduced by the same procedure (gamma(infinity)= -13.7+/-2.0) is very close to the calculated one.

[Quality of the information collected during admission to a hospital geriatric service: importance of a structured medical record]. / Qualité du recueil d'information à l'admission en service hospitalier de gériatrie: intérêt d'un dossier médical structuré.

OBJECTIVES: The medical record (MR) is a key document for hospitalized patients. Several audits have however demonstrated that much important information is often missing in hospital MR. We conducted this survey with the aim of improving the quality of MR in a geriatric unit. PATIENTS AND METHODS: A structured MR was elaborated and implemented in order to guide and record the assessment of patients admitted in our geriatric ward. MR of 54 consecutive patients admitted after implementation of the structured MR were studied and compared to those of 108 consecutive patients admitted on the preceeding year (classical MR). Quality of data collected at admission was assessed using a 33-item guide, proposed by 3 experts in geriatric medicine unaware of the structured MR studies. For each item, a binary score (present/absent) and a precision score were used. A validation study was conducted using the same methods in another geriatric ward which has not participated to development of the structured charts MR studied. RESULTS: For most items studied, information was present in a significantly higher proportion in structured MR than in classical MR. Likewise, the precision score was significantly higher in structured MR. The validation survey found analogous results. CONCLUSION: Use of a structured MR significantly improves the quality of data collection at admission in geriatric units. This improvement appears to be related more to the use of the structured MR than the effect of developing a new tool.

Effect of two French nurses' strikes on mortality in a geriatric hospital.

PURPOSE: To study the influence of the 1988 French nurses' strikes on mortality in a geriatric hospital. MATERIALS AND METHODS: Two nurses' strikes affected the Charles Foix Hospital near Paris from June 29 to July 31 and from September 17 to October 22, 1988. Mortality was studied in nine geriatric wards of this hospital, including two rehabilitation units comprising 187 beds, and seven long-term care units comprising 1,132 beds. Monthly mortality rates were calculated from the hospital's administrative registers and expressed as deaths per 1,000 patient-days. These rates were calculated in each of the aforementioned nine units for the 36 months preceding the first strike (control period) and for the 12 months following it (study period). RESULTS: Over the control period, monthly mortality was significantly higher in rehabilitation units than in long-term care units (2.46 +/- 1.21 versus 0.83 +/- 0.47, p less than 0.001), but mortality rates among rehabilitation units, as well as among long-term care units, were comparable. Also, during the control period, large seasonal fluctuations in monthly mortality rates were observed in both rehabilitation units and long-term care units (peak in winter and nadir in summer). These rates tended to decrease from year to year in rehabilitation units but not in long-term care units. A statistical model based on time-series analysis of the control period data was used to calculate the expected monthly mortality rates for the study period in rehabilitation units and in long-term care units, respectively. Three of the 12 actual monthly mortality rates exceeded the upper limit of the 95% confidence interval of the 12 expected monthly mortality rates, in the units where the more severe care disruption occurred. A detailed analysis of discharge summaries of these units failed to identify a possible link between some of these deaths and a possible absence of care. CONCLUSIONS: The nurses' strikes did not induce a clear-cut increase in mortality in this population of elderly patients. However, we cannot exclude the possibility that these strikes had some negative effects on health. Our results fail to provide answers to the difficult ethical problems created by such stoppages.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced pulmonary fibrosis.

Clinical data are presented on 14 patients undergoing BCNU therapy for a primary intracranial glioma (11 biopsied, 3 suspected) in whom pulmonary fibrosis developed as a consequence of the therapy. Pulmonary diffusion abnormalities, dry hacking cough, and chest x-ray changes herald the onset of the process. Microscopic evaluation of lung specimens revealed a wide spectrum of change including hyaline membrane formation, alveolar septal thickening, interstitial fibrosis, and granuloma formation. It is concluded that BCNU causes pulmonary fibrosis that is primarily but not necessarily dose-related and may not be reversible.

Lymphoepithelioid cellular lymphoma (Lennert's lymphoma) in association with malignant lymphoma, histiocytic type.

The present case is unusual in that it demonstrates the presence of the histologic pattern of Lennert's lymphoma in a patient who had a 14-year history of recurrent reticulum cell sarcoma (histiocytic lymphoma). This particular lesion also exhibits clinical and pathologic similarities to angioimmunoblastic lymphadenopathy and malignant lymphoma of peripheral T-lymphocyte origin. Whether the appearance of Lennert's lymphoma in this patient represents a regression of the previous reticulum cell sarcoma (histiocytic lymphoma) to a more benign form, a response to therapy, an alteration in the immune system, or a new lymphoreticular malignancy remains to be answered.