Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers.

BACKGROUND: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver. METHODS: We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation. RESULTS: GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected. CONCLUSIONS: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.     

Complications and immunological studies of measles virus infection in antithymocyte-treated hamsters.

A study was done to investigate possible late central nervous system (CNS) complications of latent measles infection in hamsters. Signs of CNS disease, consisting of myoclonus and paralysis, occurred in some weanling hamsters inoculated intraperitoneally at 3 or 9 days of age with antithymocyte serum (ATS) and measles virus, but no late complications in adult life attributable to measles virus were seen. A single series of ATS injections plus an injection of measles virus resulted in sustained antibody formation postulated due to establishment of a latent viral infection, whereas similar treatment with normal rabbit serum plus virus caused no or minimal antibody response. The majority of hamsters receiving ATS as newborns and ATS plus virus as weanlings also did not produce antibody. This differential effect of ATS may be due to combined elimination of suppressor and helper cells in the latter ATS-treated group and of suppressor cells only in the former ATS-treated group. Cellular immunity could not be evaluated since lymphocytes from inoculated and uninoculated hamsters released equal and variable amounts of 51Cr for both infected and noninfected labeled, allogeneic hamster target cells.     

Fetal Electrocardiogram Extraction and Analysis Using Adaptive Noise Cancellation and Wavelet Transformation Techniques

Birth defect-related demise is mainly due to congenital heart defects. In the earlier stage of pregnancy, fetus problem can be identified by finding information about the fetus to avoid stillbirths. The gold standard used to monitor the health status of the fetus is by Cardiotachography(CTG), cannot be used for long durations and continuous monitoring. There is a need for continuous and long duration monitoring of fetal ECG signals to study the progressive health status of the fetus using portable devices. The non-invasive method of electrocardiogram recording is one of the best method used to diagnose fetal cardiac problem rather than the invasive methods.The monitoring of the fECG requires development of a miniaturized hardware and a efficient signal processing algorithms to extract the fECG embedded in the mother ECG. The paper discusses a prototype hardware developed to monitor and record the raw mother ECG signal containing the fECG and a signal processing algorithm to extract the fetal Electro Cardiogram signal. We have proposed two methods of signal processing, first is based on the Least Mean Square (LMS) Adaptive Noise Cancellation technique and the other method is based on the Wavelet Transformation technique. A prototype hardware was designed and developed to acquire the raw ECG signal containing the mother and fetal ECG and the signal processing techniques were used to eliminate the noises and extract the fetal ECG and the fetal Heart Rate Variability was studied. Both the methods were evaluated with the signal acquired from a fetal ECG simulator, from the Physionet database and that acquired from the subject. Both the methods are evaluated by finding heart rate and its variability, amplitude spectrum and mean value of extracted fetal ECG. Also the accuracy, sensitivity and positive predictive value are also determined for fetal QRS detection technique. In this paper adaptive filtering technique uses Sign-sign LMS algorithm and wavelet techniques with Daubechies wavelet, employed along with de noising techniques for the extraction of fetal Electrocardiogram.Both the methods are having good sensitivity and accuracy. In adaptive method the sensitivity is 96.83, accuracy 89.87, wavelet sensitivity is 95.97 and accuracy is 88.5. Additionally, time domain parameters from the plot of heart rate variability of mother and fetus are analyzed.     

Lysosomal phospholipase A2: A novel player in host immunity to Mycobacterium tuberculosis

Phospholipases catalyze the cleavage of membrane phospholipids into smaller bioactive molecules. The lysosomal phospholipase A₂ (LPLA₂) is specifically expressed in macrophages. LPLA₂ gene deletion in mice causes lysosomal phospholipid accumulation in tissue macrophages leading to phospholipidosis. This phenotype becomes most prominent in alveolar macrophages where LPLA₂ contributes to surfactant phospholipid degradation. High expression of LPLA₂ in alveolar macrophages prompted us to investigate its role in host immunity against the respiratory pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis. Here we report that adaptive immune responses to M. tuberculosis were impaired in LPLA₂ deficient mice. Upon aerosol infection with M. tuberculosis, LPLA₂ deficient mice showed enhanced mycobacterial counts but less lung immunopathology and pulmonary inflammatory responses. Compromised T‐cell priming in the lymph nodes was associated with impaired pulmonary T‐cell recruitment and activation. Together with reduced Th1 type cytokine production, these results indicate that LPLA₂ is indispensable for the induction of adaptive T‐cell immunity to M. tuberculosis. Taken together, we identified an unexpected and novel function of a lysosomal phospholipid‐degrading enzyme.     

Acute severe asthma

Acute exacerbations of asthma are very common reasons for a presentation to emergency departments. This paper focuses on defining the high‐risk group, consideration of the concept of phenotypes of acute asthma, the assessment of severe and life‐threatening exacerbations and an emphasis on the management of the more severe end of the exacerbation severity. A number of evidence‐based guidelines exist throughout the world and are all slightly different. This reflects the poor evidence base for some of those recommendations. Thus, a large variation of treatment drugs, doses and regimen are used and clearly not standardised. This paper aims to present a summary of the best evidence and discuss some of these controversies. The most important aspect of treating an exacerbation of acute asthma is to review regularly and assess response to treatment. Severe and life‐threatening episodes should be treated with early use of intravenous treatment in a stepwise manner following the local guidelines. Non‐invasive ventilation and high flow nasal cannulae delivery of oxygen in the emergency department are evolving modalities, but evidence for their use is currently limited.     

Population pharmacokinetics of artesunate and dihydroartemisinin during long-term oral administration of artesunate to patients with metastatic breast cancer

Purpose

The purpose of this study were firstly to characterize the population pharmacokinetics of artesunate (ARS) and its active metabolite dihydroartemisinin (DHA) in patients with metastatic breast cancer during long-term (>3 weeks) daily oral ARS administration and secondly to study the relationship between salivary and plasma concentrations of DHA.

Methods

Drug concentration-time data from 23 patients, receiving oral ARS (100, 150, or 200 mg OD), was analyzed using nonlinear mixed effects modeling. A combined drug-metabolite population pharmacokinetic model was developed to describe the plasma pharmacokinetics of ARS and DHA in plasma. Saliva drug concentrations were incorporated as being directly proportional to plasma concentrations.

Results

A first-order absorption model for ARS linked to a combined two-compartment disposition model for ARS and one-compartment disposition model for DHA provided the best fit to the data. No covariates were identified that could explain between-subject variability. A time-dependent increase in apparent elimination clearance of DHA was observed. Salivary DHA concentrations were proportionally correlated with total DHA plasma concentrations, with an estimated slope factor of 0.116.

Conclusions

Population pharmacokinetics of ARS and DHA in patients with breast cancer was well described by a combined drug-metabolite model without any covariates and with an increase in apparent elimination clearance of DHA over time. The estimated DHA saliva/plasma ratio was in good agreement with the reported DHA unbound fraction in human plasma. Saliva ARS concentrations correlated poorly with plasma concentrations. This suggests the use of saliva sampling for therapeutic drug monitoring of DHA. However, further studies are warranted to investigate the robustness of this approach.     

Sonographie und plastinierte Großschnitte des kleinen Beckens

Ohne Zusammenfassung     

Alloimmunization Against Well Defined Polymorphic Major Histocompatibility or Class I MHC Transfected L Cells Antigens Can Prevent Poly IC Induced Fetal Death in Mice

METHOD : It is possible to induce increased fetal resorption in a number of inbred murine matings by injecting Poly (I) Poly (C12U) 3.5 days postconception, a maneuver associated with natural killer-mediated damage to the feto placental unit such as occurs in spontaneous fetal resorptions. RESULTS : We show here that alloimmunization can block this effect. In addition, maternal immune responses induced by alloimmunization against isolated mutant class I or class II, as well as by immunization with class I MHC alloantigens (K^d) transfected L cells are sufficient to restore normal fetal viability. It is not necessary that the maternal immune response be specifically directed against paternal alloantigens fr the fetal protecton to ensue, since the effect occurs in inbred matings when the mother is immunized against unrelated class I or class II alloantigens. As in previous studies conducted in the murine species, not all MHC alloimmunizations are protective. In addition, as control, immunization with a monomorphic class I MHC molecular (37), transfected L cells, sheep red blood cells or hen egg lysozyme is without effect. CONCLUSION : These results indicate that defined MHC antigens can mediate fetal protection from induced fetal resorption, and suggest that one driving force in promoting MHC antigen polymorphism in mammals is their capacity to confer protection from NK mediated fetal demise.