The role of ceramide trihexoside (globotriaosylceramide) in the diagnosis and follow-up of the efficacy of treatment of Fabry disease: a review of the literature.

Fabry disease is caused by a deficiency of a-galactosidase A which leads to the progressive intra-lysosomal accumulation of ceramide trihexoside (CTH), also known as globotriaosylceramide (Gb3), in different cell types and body fluids. The clinical manifestations are multisystemic and predominantly affect the heart, kidney and central nervous system. The role of CTH in the pathophysiological process of Fabry disease is not established, and the link between the degree of accumulation and disease manifestations is not systematic. The use of CTH as a diagnostic tool has been proposed for several decades. The recent introduction of a specific treatment for Fabry disease in the form of enzyme replacement therapy (ERT) has led to the need for a biological marker, in place of a clinical sign, for evaluating the efficacy of treatment and also as a tool for following the long term effects of treatment. The ideal biomarker must adhere to strict criteria, and there should be a correlation between the degree of clinical efficacy of treatment and a change in its concentration. This review of the literature assesses the utility of CTH as a diagnostic tool and as a marker of the efficacy of ERT in patients with Fabry disease. Several techniques have been developed for measuring CTH; the principles and the sensitivity thresholds of these methods and the units used to express the results should be taken into consideration when interpreting data. The use of CTH measurement in Fabry disease should be re-evaluated in light of recent published data.

Study of Schistosoma mansoni isolates from patients with failure of treatment with oxamniquine

After three successive treatments with oxamniquine the continuing elimination of Schistosoma mansoni eggs was observed in patients, who came from various regions of Brazil, with different clinical forms of schistosomiasis. The objective of the present study was to determine the experimental behaviour of five different S. mansoni isolates in Swiss Webster mice that were submitted to treatment with the same drug. The experimental group with failure of treatment showed higher mean number of surviving male worms when it was compared to the group without failure of treatment. These date suggest the possibility of resistance to oxamniquine.

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

IMPORTANCE: New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE: To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS: Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE: After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Treatment of chronic hepatitis C genotype 1 with triple therapy comprising telaprevir or boceprevir.

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Two first-generation protease inhibitors, telaprevir and boceprevir, have recently been approved for the treatment of chronic hepatitis C genotype 1. Triple therapy comprising pegylated interferon-α, ribavirin and telaprevir or boceprevir increases sustained virological response rates to ~70% and allows to shorten treatment duration in ~½ of treatment-naïve patients with chronic hepatitis C genotype 1. Sustained virological response rates in treatment-experienced patients depend on the response to previous treatment, ranging from >80% in previous relapsers to ~30% in previous null responders. These advances come at the expense of new adverse effects and increased cost. In addition, treatment of chronic hepatitis C will become more complex. In these times of changing medical practice, the present expert opinion statement by the Swiss Association for the Study of the Liver shall provide guidance on the treatment of chronic hepatitis C with triple therapy comprising telaprevir or boceprevir.

Anesthesia of Biomphalaria spp. (Mollusca, Gastropoda): sodium pentobarbital is the drug of choice

The anesthetic effect of some water-soluble anesthesic or narcotic drugs currently used in mice was tested in molluscs of the Biomphalaria genus. Sodium thiopental was very toxic to the snails resulting in high rates of mortality in all the treatment schedules tested. Cetamine base, at concentration of 0.25 mg/ml of water, resulted in partial snail anesthesia (40% of snails were anesthetized) only after 20 h of exposition. The association of Cetamine base with Tiazine chloridrate did not improve the anesthesic effect, and higher concentrations of these drugs were toxic to the snails. Sodium pentobarbital at 0.4 mg/ml in water for 8 h was the best treatment schedule to anesthetize Biomphalaria snails. In this schedule, the snails were anesthetized without any toxic effect. The procedure provides a powerful tool for in vivo studies that demande a complete state of snail anesthesia.

Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model.

OBJECTIVES: The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions. METHODS: Human mesothelioma xenografts (H-meso-1) were grown in the dorsal skinfold chambers of 28 nude mice. By intravital microscopy, the rolling and recruitment of leukocytes were assessed in tumour vessels following PDT (Visudyne(®) 400 μg/kg, fluence rate 200 mW/cm(2) and fluence 60 J/cm(2)) using intravital microscopy. Likewise, the distribution of fluorescently labelled macromolecular dextran (FITC-dextran, MW 2000 kDa) was determined after PDT. Study groups included no PDT, PDT, PDT plus a functionally blocking anti-pan-selectin antibody cocktail and PDT plus isotype control antibody. RESULTS: PDT significantly enhanced the extravascular accumulation of FITC-dextran in mesothelioma xenografts, but not in normal tissue. PDT significantly increased leukocyte-endothelial cell interaction in tumour. While PDT-induced leukocyte recruitment was significantly blunted by the anti-pan-selectin antibodies in the tumour xenograft, this manipulation did not affect the PDT-induced extravasation of FITC-dextran. CONCLUSIONS: Low-level PDT pre-treatment selectively enhances the uptake of systemically circulating macromolecular drugs in malignant mesothelioma, but not in normal tissue. Leukocyte-endothelial cell interaction is not required for PDT-induced drug delivery to malignant mesothelioma.

Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone

Chloroquine has been the mainstay of malaria chemotherapy for the past five decades, but resistance is now widespread. Pyrimethamine or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chloroquine resistance. Both pyrimethamine and proguanil are dihydrofolate reductase (DHFR) inhibitors, the proguanil acting primarily through its major metabolite cycloguanil. Resistance to these drugs arises due to specific point mutations in the dhfr gene. Cross resistance between cycloguanil and pyrimethamine is not absolute. It is, therefore, important to investigate mutation rates in P. falciparum for pyrimethamine and proguanil so that DHFR inhibitor with less mutation rate is favored in drug combinations. Hence, we have compared mutation rates in P. falciparum genome for pyrimethamine and cycloguanil. Using erythrocytic stages of P. falciparum cultures, progressively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence. Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil. It enhances the degree of genomic polymorphism leading to diversity of natural parasite population which in turn is predisposes the parasites for faster selection of resistance to some other antimalarial drugs.

Outpatient treatment of pulmonary embolism.

Pulmonary embolism (PE) is traditionally treated in hospital. Growing evidence from non randomized prospective studies suggests that a substantial proportion of patients with non-massive PE might be safely treated in the outpatient setting using low molecular weight heparins. Based on this evidence, professional societies started to recommend outpatient care for selected patients with non-massive PE. Despite these recommendations, outpatient treatment of non-massive PE appears to be uncommon in clinical practice. The major barriers to PE outpatient care are, firstly, the uncertainty as how to identify low risk patients with PE who are candidates for outpatient care and secondly the lack of high quality evidence from randomized trials demonstrating the safety of PE outpatient care compared to traditional inpatient management. Also, although clinical prognostic models, echocardiography and cardiac biomarkers accurately identify low risk patients with PE in prospective studies, the benefit of risk stratification strategies based on these instruments should be demonstrated in prospective management studies and clinical trials before they can be implemented as decision aids to guide PE outpatient treatment. Before high quality evidence documenting the safety of an outpatient treatment approach is published, outpatient management of non-massive PE cannot be generally recommended.

Female asylum seekers with musculoskeletal pain: the importance of diagnosis and treatment of hypovitaminosis D.

BACKGROUND: Hypovitaminosis D is well known in different populations, but may be under diagnosed in certain populations. We aim to determine the first diagnosis considered, the duration and resolution of symptoms, and the predictors of response to treatment in female asylum seekers suffering from hypovitaminosis D. METHODS: Design: A pre- and post-intervention observational study. Setting: A network comprising an academic primary care centre and nurse practitioners. Participants: Consecutive records of 33 female asylum seekers with complaints compatible with osteomalacia and with hypovitaminosis D (serum 25-(OH) vitamin D < 21 nmol/l). Treatment intervention: The patients received either two doses of 300,000 IU intramuscular cholecalciferol as well as 800 IU of cholecalciferol with 1000 mg of calcium orally, or the oral treatment only. Main outcome measures: We recorded the first diagnosis made by the physicians before the correct diagnosis of hypovitaminosis D, the duration of symptoms before diagnosis, the responders and non-responders to treatment, the duration of symptoms after treatment, and the number of medical visits and analgesic drugs prescribed 6 months before and 6 months after diagnosis. Tests: Two-sample t-tests, chi-squared tests, and logistic regression analyses were performed. Analyses were performed using SPSS 10.0. RESULTS: Prior to the discovery of hypovitaminosis D, diagnoses related to somatisation were evoked in 30 patients (90.9%). The mean duration of symptoms before diagnosis was 2.53 years (SD 3.20). Twenty-two patients (66.7%) responded completely to treatment; the remaining patients were considered to be non-responders. After treatment was initiated, the responders' symptoms disappeared completely after 2.84 months. The mean number of emergency medical visits fell from 0.88 (SD 1.08) six months before diagnosis to 0.39 (SD 0.83) after (P = 0.027). The mean number of analgesic drugs that were prescribed also decreased from 1.67 (SD 1.5) to 0.85 (SD 1) (P = 0.001). CONCLUSION: Hypovitaminosis D in female asylum seekers may remain undiagnosed, with a prolonged duration of chronic symptoms. The potential pitfall is a diagnosis of somatisation. Treatment leads to a rapid resolution of symptoms, a reduction in the use of medical services, and the prescription of analgesic drugs in this vulnerable population.

Surgical hepatosplenic mansonic schistosomiasis in adolescents: repercussions of the post-treatment schistosomotic burden on the hepatic functional reserve

Schistosomiasis mansoni affects the hepatic functional reserve. Clinical treatment with oxamniquine is not 100% effective and there has been found strain of this parasite resistant to this drug. The aims of this investigation were: (1) to examine the presence of residual parasite burden after medical and surgical treatment on adolescents with surgical schistosomiasis mansoni and (2) to assess the effect on the hepatic functional reserve in patients with and without residual infection. Twenty nine children with hepatosplenic schistosomiasis mansoni and bleeding esophageal varices were treated with oxamniquine. They underwent splenectomy, ligature of the left gastric vein and autologous implantation of spleen tissue into the greater omentum. After a mean post-operative follow up of five years they underwent rectal biopsy for schistosomotic egg search. They were divided in patients with and without infection. In 20 patients the submucosal egg search was negative, however, in 9 it was positive. The hepatic functional reserve in the patients without infection was as follows: 17 were Child-Pugh A and 3 Child-Pugh B. In the patients who were still infected 6 were Child-Pugh A and 3 Child-Pugh B. The chi2 analysis of the hepatic functional reserve showed chi2 = 3.19 - p= 0.07. From the results the following conclusion can be drawn: residual infection or reinfection in the follow up period had not interfered with the distribution of the hepatic functional reserve of the patients in this series. However, there was a trend for a decrease of this parameter in patients with residual infection.

Methadone maintenance treatment (MMT) in general practice or in specialized centers: profile of patients in the Swiss Canton of Vaud.

We studied profile of patients (n=1782) treated in specialized centers and general practice (GP) enrolled in methadone maintenance treatment (MMT) programs during 2001 in the Swiss Canton of Vaud. We found that GPs treated the majority of patients (76%). Specialized centers treated a higher proportion of patients with uncontrolled intravenous use of cocaine and heroin, and prescribed neuroleptics as concomitant medication three times more frequently than GPs. Patients treated in specialized centers were more likely to undergo screening for HIV, HBV, HCV, and receive complete HBV immunization. In conclusion, specialized centers are more likely to treat severely addicted patients and patients with a poor global assessment (physical, psychiatric, and social).

Drug resistance and genotypes of strains of Mycobacterium tuberculosis isolated from human immunodeficiency virus-infected and non-infected tuberculosis patients in Bauru, São Paulo, Brazil

Little is known about transmission and drug resistance of tuberculosis (TB) in Bauru, State of São Paulo. The objective of this study was to evaluate risk factors for transmission of Mycobacterium tuberculosis strains in this area. Strains were collected from patients attended at ambulatory services in the region and susceptibility towards the main first line antibiotics was determined and fingerprinting performed. A total of 57 strains were submitted to susceptibility testing: 23 (42.6%) were resistant to at least one drug while 3 (13%) were resistant against both rifampicin and isoniazide. Resistant strains had been isolated from patients that had not (n = 13) or had (n = 9) previously been submitted to anti-TB treatment, demonstrating a preoccupying high level of primary resistance in the context of the study. All strains were submitted to IS6110 restriction fragment length polymorphism (IS6110-RFLP) and double repetitive element PCR (DRE-PCR). Using IS6110-RFLP, 26.3% of the strains were clustered and one cluster of 3 patients included 2 HIV-infected individuals that had been hospitalized together during 16 days; clustering of strains of patients from the hospital was however not higher than that of patients attended at health posts. According to DRE-PCR, 55.3% belonged to a cluster, confirming the larger discriminatory power of IS6110-RFLP when compared to DRE-PCR, that should therefore be used as a screening procedure only. No clinical, epidemiological or microbiological characteristics were associated with clustering so risk factors for transmission of TB could not be defined in the present study.

Avancées recentes dans le traitement des carcinomes corticosurrénaliens [Recent advances in the treatment of adrenocortical carcinomas].

Adrenocortical carcinomas are rare and aggressive malignant tumors, with an incidence of 1 to 2 cases per million inhabitants. Their diagnosis is made in three clinical situations: during the work up of a syndrome of hormonal hypersecretion, during the work up of locoregional symptoms, or incidentally during an unrelated radiological procedure. Surgery is usually indicated except in situations of advanced metastatic disease. Adjuvant chemotherapy with mitotane is associated with a significant increase in disease-free survival when the drug is administered at adequate therapeutic dosage. Novel anti-mitotic therapies have recently been described for treating recurrent adrenocortical carcinoma under mitotane treatment, but their overall efficacy remains unsatisfactory.

Mapping HIV-related behavioural surveillance among injecting drug users in Europe, 2008.

The systematic collection of behavioural information is an important component of second-generation HIV surveillance. The extent of behavioural surveillance among injecting drug users (IDUs) in Europe was examined using data collected through a questionnaire sent to all 31 countries of the European Union and European Free Trade Association as part of a European-wide behavioural surveillance mapping study on HIV and other sexually transmitted infections. The questionnaire was returned by 28 countries during August to September 2008: 16 reported behavioural surveillance studies (two provided no further details). A total of 12 countries used repeated surveys for behavioural surveillance and five used their Treatment Demand Indicator system (three used both approaches). The data collected focused on drug use, injecting practices, testing for HIV and hepatitis C virus and access to healthcare. Eight countries had set national indicators: three indicators were each reported by five countries: the sharing any injecting equipment, uptake of HIV testing and uptake of hepatitis C virus testing. The recall periods used varied. Seven countries reported conducting one-off behavioural surveys (in one country without a repeated survey, these resulted an informal surveillance structure). All countries used convenience sampling, with service-based recruitment being the most common approach. Four countries had used respondent-driven sampling. Three fifths of the countries responding (18/28) reported behavioural surveillance activities among IDUs; however, harmonisation of behavioural surveillance indicators is needed.

Prevalence of social phobia in a clinical sample of drug dependent patients.

INTRODUCTION: Social phobia is among the most frequent psychiatric disorders and can be classified into two subtypes, nongeneralized and generalized. Whereas it significantly worsens the morbidity of comorbid substance abuse disorders, and it often is associated with reduced treatment responses, there is still lacking data on its prevalence in clinical populations of drug abusing patients. METHODS: The study sample consisted of 75 inpatients and 75 outpatients meeting DSM-IV criteria for drug dependence. Symptoms of social phobia were assessed with the French-language version of the Liebowitz Social Anxiety Scale (LSAS). RESULTS: Prevalence rate were 20% for the generalized subtype and 42.6% for the nongeneralized subtype. Gender difference emerged in the severity of fear, women reporting significantly greater fear relating to performance situations than men. CONCLUSIONS: An important proportion of patients with substance dependence present a comorbid generalized or nongeneralized social phobia. Early recognition of social phobia and adequate interventions is warranted for these patients in order to improve their treatment response with regard to quality of life and relapse prevention.