Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis.

CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.

Local regulators of seasonal reproduction processes in uterus masculinus of an adult male European bison (Bison bonasus, Linnaeus 1758).

Growth factors, hypoxia-inducible factor 1-alpha (HIF-1α) and klotho protein all have very important functions in the male reproduction; however their role in the regulation of seasonal reproductive processes in the male European bison remains unclear. Similarly, although the uterus masculinus is very frequently found in the bison, its importance and functions remain unknown. It is likely that, this organ may have secretory functions and thus be a target for various regulatory factors. Therefore, the aim of this study was to investigate expression and activity of several factors: vascular endothelial growth factor (VEGF-A), fibroblast growth factor (FGF-2), transforming growth factor ß1 (TGF-ß1), nerve growth factor (NGF), insulin-like growth factor receptor (IGF-IR ß), hypoxia-inducible factor 1 alpha (HIF-1α), and klotho protein in the uterus masculinus, immediately after the season of the reproductive activity (November and December). Our study reveals that the growth factor expression levels are significantly higher in November, when compared to December, while expression of HIF-1α and klotho was higher in December. These results provide novel data on differences in the expression levels of several factors in the uterus maculinus of European bison bulls after the breeding season. The described factors may, therefore, be potent regulators of the seasonal reproduction.

Palliative pharmaceutical care: a randomized, prospective study of telephone-based prescription and medication counseling services for treating chronic pain.

OBJECTIVE: To evaluate the effects of providing a unique telephone-based pharmaceutical care program to a sample of patients enrolled at a university pain clinic in Philadelphia, Pa. We hypothesized that in comparison to routine pharmaceutical care, the telephone-based pharmaceutical care program would have a positive impact on delivery of medication, quality of life, and overall satisfaction with the pain clinic program. PATIENTS: One hundred seven pain clinic patients were randomly assigned to the control and intervention groups. Seventy-four patients (control group, n = 36; intervention group, n = 38) met inclusion criteria. METHOD: The control group continued to receive care and prescription services through the same means as prior to the study. There were 2 components to the pharmaceutical care program offered to the intervention group. The first component consisted of a palliative care pharmacy company, PainRxperts, providing specialized prescription services tailored to the needs of a pain medicine clinical practice. The second component involved the palliative-trained pharmacist's proactive monitoring of patient pharmacotherapy for potential or actual drug related problems (DRPs). RESULTS: Intervention patients perceived that they had better access to medication, more efficient processing of prescriptions, and fewer stigmatizing experiences. They also endorsed pharmacists' behavioral interventions such as medication counseling, availability to answer medication-related questions, and non-judgmental attitudes when managing opioid prescriptions. CONCLUSION: This study suggests that the palliative-trained pharmacist can play an important collaborative role in managing chronic pain. Application of the pharmaceutical care model in pain medicine centers can improve satisfaction and remove some of the barriers to good pharmaceutical care facing patients with chronic pain disorders

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids.

Calcium influx through store-operated calcium release-activated calcium channels (CRAC) is required for T cell activation, cytokine synthesis, and proliferation. The CD95 (Apo-1/Fas) receptor plays a role in self-tolerance and tumor immune escape, and it mediates apoptosis in activated T cells. In this paper we show that CD95-stimulation blocks CRAC and Ca(2+) influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca(2+) entry is lacking in CD95-defective lpr lymphocytes as well as in ASM-defective cells and can be restored by retransfection of ASM. C2 ceramide, C6 ceramide, and sphingosine block CRAC reversibly, whereas the inactive dihydroceramide has no effect. CD95-stimulation or the addition of ceramide prevents store-operated Ca(2+) influx, activation of the transcriptional regulator NFAT, and IL-2 synthesis. The block of CRAC by sphingomyelinase metabolites adds a function to the repertoire of the CD95 receptor inhibiting T cell activation signals.

Microsensors and mobile laboratory as instruments for computer-based health management in a pork-production chain.

Diseases are directly associated with production in regard to product quality and quantity. The purpose of health-management programs is to prevent mortality and morbidity during production. Within the European Community, there are several concepts for management and health-control programs. The most important part is the collection and interpretation of data, which can be used at the farm level and down the production chain. Collecting data electronically by use of sensors, identification systems and tests can enhance a human's ability to achieve this.

Examination of self-crosslinked gelatin as a hydrogel for controlled release.

A gelatin matrix crosslinked by extensive dehydration was examined for use in controlled drug delivery in this preliminary investigation. Crosslinking is necessary to prevent gelatin dissolution and immediate drug release at body temperature. Treatment at 105 degrees C and reduced pressure induced crosslinking in discs prepared from Type B gelatin. Crosslinking was evaluated by determining changes in gelatin solubility at 37 degrees C in a USP paddle dissolution apparatus. The crosslinking treatment was reproducible and resulted in 90% of the original gelatin mass remaining after 12 h in water and in phosphate buffer solutions of pH 3 and 6.4. The treated gelatin discs remained intact for greater than 24 h at pH 6.4. Chlorpromazine.HCl (CPZ) was incorporated as a model drug by soaking the treated gelatin discs in an aqueous solution of the drug. Release of CPZ at 37 degrees C in the dissolution apparatus was fitted to an empirical equation. A coefficient of this equation was used as the initial release rate for comparison between different release profiles. The roles of drug solubility, matrix swelling and erosion, and potential drug-matrix interactions were examined by conducting release studies at pH values of 3, 4, 6.4, and 7.4. The insoluble, un-ionized form of the drug had the slowest release rate. The soluble, ionized form under conditions of maximum swelling and a possible drug-matrix repulsive interaction had the fastest release rate. General electrostatic drug-matrix interactions were noted which could influence the drug release rate depending on conditions of the study. The times for 50% release of CPZ ranged from 1.8 to 11.3 h.