Partial splenic embolization as pretreatment for antiviral therapy in hepatitis C virus infection

Chronic hepatitis C virus infection is frequently complicated by cirrhosis and hypersplenism, which together with several other factors, such as reduced thrombopoietin synthesis in the liver, cause cytopenia. The antiviral combination therapy with pegylated interferon and ribavirin itself is impaired by haematological toxicity. Partial splenic embolization (PSE) by the injection of microspheres via a catheter comprising approximately 30-70% of the splenic parenchyma is now a safe method, which significantly reduces the cytopenia induced by hypersplenism, especially thrombocytopenia. The effect is long lasting up to 20 years and has been documented in a variety of disorders. PSE is now carefully described in a combination modality as a pretreatment to reduce cytopenia in hepatitis C virus-induced cirrhosis patients with hypersplenism, making antiviral therapy possible per se at higher dosages with a sustained duration.     

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV‐specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T‐cell therapy with donor‐derived HAdV‐specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV‐specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14‐year‐old boy after T‐cell‐depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV‐associated enteritis complicated by acute graft‐versus‐host disease (GvHD). The patient received ten infusions of allogeneic HAdV‐specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon‐γ (IFN‐γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen‐specific T cells against hexon and penton were applied. T‐cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T‐cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV‐specific T‐cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.     

Temperature modulation of growth rates and glucosephosphate isomerase isozyme activity in Trypanosoma cruzi

In an attempt to understand the conditions which might influence the geographical distribution of Trypanosoma cruzi isozyme profiles (zymodemes), the thermal response of different glucosephosphate isomerase (GPI) phenotypes was studied. T. cruzi clones with single- and triple-banded GPI phenotype showed a similar response to temperature with respect to both growth rates and GPI kinetic parameters. However, the relative activity of each GPI isozyme was dependent on parasite incubation temperature. In view of the similar kinetic properties of the isozymes, enzyme regulation is not a consequence of an adaptative response to thermal conditions and the suggestion of a phenotype distribution determined selectively by temperature is not supported by the present study.     

The influence of the diagnostic technique on the histopathological diagnosis in malignant mesothelioma

Summary In the histopathology of malignant mesotheliomas three different types (epithelial, connective tissue and mixed type) are distinguished. Some authors believe all tumours to be of mixed type, but consider that due to inadequate sampling or small biopsies this may be missed frequently. In this study the relationship between the histopathological diagnosis and the amount of tissue examined was investigated. In a series of 124 cases of malignant pleural mesothelioma a high percentage of mixed type tumours was found (55%). In cases where the decisive diagnostic procedure had been an Abrams biopsy (the small-specimen technique) mixed-type histology was found in 36%. If thoracoscopy, thoracotomy or autopsy (the large-specimen techniques) had delivered a definite diagnosis, mixed-type histology was found in 63%. Apparently diagnosing the mixed-type variety depends on the amount of tumour tissue obtained. However, the assumption that all mesotheliomas are of mixed type cannot be confirmed.     

Inhibition of the TRPC5 ion channel protects the kidney filter

An intact kidney filter is vital to retention of essential proteins in the blood and removal of waste from the body. Damage to the filtration barrier results in albumin loss in the urine, a hallmark of cardiovascular disease and kidney failure. Here we found that the ion channel TRPC5 mediates filtration barrier injury. Using Trpc5-KO mice, a small-molecule inhibitor of TRPC5, Ca²⁺ imaging in isolated kidney glomeruli, and live imagining of podocyte actin dynamics, we determined that loss of TRPC5 or its inhibition abrogates podocyte cytoskeletal remodeling. Inhibition or loss of TRPC5 prevented activation of the small GTP-binding protein Rac1 and stabilized synaptopodin. Importantly, genetic deletion or pharmacologic inhibition of TRPC5 protected mice from albuminuria. These data reveal that the Ca²⁺-permeable channel TRPC5 is an important determinant of albuminuria and identify TRPC5 inhibition as a therapeutic strategy for the prevention or treatment of proteinuric kidney disease.