Adenine induces differentiation of rat hepatic stellate cells.

BACKGROUND AND AIMS: Adenine is a uric acid pathway metabolite of no known function, and has recently been identified as a ligand for a rat G protein-coupled receptor. Due to the known role of other uric acid pathway metabolites in HSC biology, we tested the ability of adenine to induce HSC differentiation. METHODS: RT-PCR was performed for adenine receptor expression in T-6 and primary rat HSC. T-6 and primary rats HSC were cultured with and without adenine, and stellation examined. Next, we examined inhibition of calcium signaling using caged IP(3). To test if adenine inhibits HSC chemotaxis T-6 cells and rat HSCs were cultured with or without adenine for 24 h in a transwell assay with PDGF as the chemoattractant. cDNA was prepared from T-6 and primary HSC for quantification of collagen 1 mRNA using real-time PCR. RESULTS: We found that mRNA for the adenine receptor is expressed in T-6 cells and primary rat HSC. Also, adenine induces HSC stellation and adenine inhibits IP(3) mediated increase in cytosolic [Ca(2+)](i) and inhibits chemotaxis in T-6 cells and primary rat HSC. Adenine was also shown to up-regulate α-SMA and collagen 1, and this effect is lost by using specific si-RNA for the adenine receptor. Finally, adenine inhibits endothelin-1-induced gel contraction. CONCLUSIONS: The adenine receptor is present in T-6 cells and primary rats HSC. Adenine, via the adenine receptor, induces morphological change, and cytosolic calcium signaling, inhibits chemotaxis, and up-regulates collagen 1 mRNA in HSCs.

Role of anticoagulation in the management of pancreatic cancer.

Pancreatic cancer remains a major clinical challenge. Recent advances in chemotherapeutic and targeted agents have offered a modest survival benefit. One of the major complications of pancreatic cancer is venous thromboembolism. Although it is well-known fact that patients with mucinous carcinoma of the pancreas and gastrointestinal tract pose an increased risk of developing thromboembolic complications, scarce data exists regarding the incidence and pathogenesis of venous thromboembolism in pancreatic cancer patients. The incidence of venous thromboembolism in pancreatic cancer patients ranges from 17% to 57%. Clinical data also suggest that the occurrence of venous thromboembolism may be associated with poorer prognosis in such patients. Recent data suggest that anticoagulant treatments may improve cancer patient survival by decreasing thromboembolic complications as well as by anticancer effects. Thromboembolic disease in pancreatic cancer presents a life-threatening complication and is regarded as paraneoplastic manifestation of the disease. Effective management of this risk factor is very important in the management of pancreatic cancer. Given the lack of extensive data and the clinical relevance of this topic for both physicians and basic research scientists, the authors review the incidence, pathogenesis and clinical implications of venous thromboembolism in pancreatic cancer patients.

Flucytosine-induced colitis.

A 52-year-old man with a history of HIV (CD4 count 155, and viral load 154 K), who is on antiretroviral treatment presented in the emergency room with acute onset of headache. The patient had lumbar puncture and found to have elevated intracranial pressure and cryptococcal antigen was positive. The patient was started on flucytosine. After 10 days of treatment, the patient developed watery diarrhoea. An extensive infectious workup was carried out, which did not reveal any infectious aetiology. A colonoscopy was carried out which revealed acute colitis in the colon and the pathology confirmed the colonoscopic findings with severe colitis in the colon. At this time, the patient's diarrhoea was attributed to flucytosine and it was stopped. The patient's diarrhoea improved after 5 days of stopping flucytosine.

Serum sickness-like reaction with clarithromycin.

Serum sickness-like reaction is a rare immunological condition which may develop following exposure to certain drugs such as penicillins, cephalosporins, and trimethoprim-sulfamethoxazole, among many others. It is described classically as a type III hypersensitivity response to heterologous proteins. Its true mechanism is still unclear. We present a case of serum sickness-like reaction to clarithromycin, a commonly prescribed drug for the treatment of respiratory tract infections. The patient had been taking this drug for 3 days when she experienced generalized body aches, rash, arthralgia, and shortness of breath, prompting presentation to the emergency department. Laboratory studies showed decreased C4 and total complement with a slightly elevated sedimentation rate. After exclusion of other possible causes, the diagnosis of serum sickness-like reaction was made. The patient responded well to nonsteroidal antiinflammatory medication, antihistamines, and a short, tapering dose of steroids. To our knowledge, serum sickness-like reaction to clarithromycin has never been reported previously. This case emphasizes the need for increased clinical awareness of such an adverse outcome to clarithromycin use.

Frequency and psychosocial impact of acne on university and college students.

Objectives of the study were to describe the frequency of acne in late adolescent and adult students and to evaluate psychosocial impact of the disease. It was a cross-sectional study conducted in four institutions, from June to August 2008. Questionnaires with Cardiff Acne Disability Index (CADI) were filled by 950 students. They were examined for presence and severity of acne. Age ranged from 17 to 28 years. Frequency of facial acne was 74.6%. Difference between the genders was not statistically significant. Mean ADI score was 2.67 + 5.35, and range was 0-13. The disease had a greater psychosocial impact on females as compared to males.

Inflammasome-mediated regulation of hepatic stellate cells.

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 microg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with alpha-smooth muscle actin and visualized by confocal microscopy, and TGF-beta and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca(2+)) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP(3)). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl(4)) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-beta and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca(2+) via IP(3) in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl(4) and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.