Contribution of the cyclic nucleotide gated channel subunit, CNG-3, to olfactory plasticity in Caenorhabditis elegans.

In Caenorhabditis elegans, the AWC neurons are thought to deploy a cGMP signaling cascade in the detection of and response to AWC sensed odors. Prolonged exposure to an AWC sensed odor in the absence of food leads to reversible decreases in the animal's attraction to that odor. This adaptation exhibits two stages referred to as short-term and long-term adaptation. Previously, the protein kinase G (PKG), EGL-4/PKG-1, was shown necessary for both stages of adaptation and phosphorylation of its target, the beta-type cyclic nucleotide gated (CNG) channel subunit, TAX-2, was implicated in the short term stage. Here we uncover a novel role for the CNG channel subunit, CNG-3, in short term adaptation. We demonstrate that CNG-3 is required in the AWC for adaptation to short (thirty minute) exposures of odor, and contains a candidate PKG phosphorylation site required to tune odor sensitivity. We also provide in vivo data suggesting that CNG-3 forms a complex with both TAX-2 and TAX-4 CNG channel subunits in AWC. Finally, we examine the physiology of different CNG channel subunit combinations

The communication of a secondary care diagnosis of autoimmune hepatitis to primary care practitioners: a population-based study

Background Autoimmune Hepatitis is a chronic liver disease which affects young people and can result in liver failure leading to death or transplantation yet there is a lack of information on the incidence and prevalence of this disease and its natural history in the UK. A means of obtaining this information is via the use of clinical databases formed of electronic primary care records. How reliably the diagnosis is coded in such records is however unknown. The aim of this study therefore was to assess the proportion of consultant hepatologist diagnoses of Autoimmune Hepatitis which were accurately recorded in General Practice computerised records. Methods Our study population were patients with Autoimmune Hepatitis diagnosed by consultant hepatologists in the Queens Medical Centre, Nottingham University Hospitals (UK) between 2004 and 2009. We wrote to the general practitioners of these patients to obtain the percentage of patients who had a valid READ code specific for Autoimmune Hepatitis. Results We examined the electronic records of 51 patients who had biopsy evidence and a possible diagnosis of Autoimmune Hepatitis. Forty two of these patients had a confirmed clinical diagnosis of Autoimmune Hepatitis by a consultant hepatologist: we contacted the General Practitioners of these patients obtaining a response rate of 90.5% (39/42 GPs). 37/39 of these GPs responded with coding information and 89% of these patients (33/37) used Read code J638.00 (Autoimmune Hepatitis) to record a diagnosis. Conclusions The diagnosis of Autoimmune Hepatitis made by a Consultant Hepatologist is accurately communicated to and electronically recorded by primary care in the UK. As a large proportion of cases of Autoimmune Hepatitis are recorded in primary care, this minimises the risk of introducing selection bias and therefore selecting cases using these data will be a valid method of conducting population based studies on Autoimmune Hepatitis

In pursuit of excellence for patients with cancer: the Scottish Cancer Therapy Network model

The Scottish Cancer Therapy Network (SCTN) was created against a background of rising concerns about perceived variation in the quality of care available to patients with cancer. SCTN has established itself as a major organization with the necessary recognition and infrastructure to provide leadership, support and impetus in the field of clinical guidelines, clinical audit and clinical trials of cancer therapy in Scotland. Since being formed in 1993, SCTN has been instrumental in the development of three evidence-based, clinical guidelines and in the completion of detailed, national, retrospective audits of the treatment of five major tumour sites. The infrastructure has been used successfully to support and encourage trial participation. Challenges for the future are a re-orientation towards prospective audit, widening the constituency and sense of ownership of SCTN as a resource for practising clinicians, and further increasing recruitment into clinical trials. © 1999 Cancer Research Campaig

Impaired RNA incorporation and dimerization in live attenuated leader-variants of SIV(mac239)

BACKGROUND: The 5' untranslated region (UTR) or leader sequence of simian immunodeficiency virus (SIV(mac239)) is multifunctional and harbors the regulatory elements for viral replication, persistence, gene translation, expression, and the packaging and dimerization of viral genomic RNA (vRNA). We have constructed a series of deletions in the SIV(mac239 )leader sequence in order to determine the involvement of this region in both the packaging and dimerization of viral genomic RNA. We also assessed the impact of these deletions upon viral infectiousness, replication kinetics and gene expression in cell lines and monkey peripheral blood mononuclear cells (PBMC). RESULTS: Regions on both sides of the major splice donor (SD) were found to be necessary for the efficiency and specificity of viral genome packaging. However, stem-loop1 is critical for both RNA encapsidation and dimerization. Downstream elements between the splice donor and the initiation site of SIV-Gag have additive effects on RNA packaging and contribute to a lesser degree to RNA dimerization. The targeted disruption of structures on both sides of the SD also severely impacts viral infectiousness, gene expression and replication in both CEMx174 cells and rhesus PBMC. CONCLUSION: In the leader region of SIV(mac239), stem-loop1 functions as the primary determinant for both RNA encapsidation and dimerization. Downstream elements between the splice donor and the translational initiation site of SIV-Gag are classified as secondary determinants and play a role in dimerization. Collectively, these data signify a linkage between the primary encapsidation determinant of SIV(mac239 )and RNA dimerization

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p Z 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4e4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3e1.6) for placebo (HR Z 0.64, 95% CI: 0.38e1.07; p Z 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6e4.2) months for brivanib and 2.0 months (95% CI: 1.2e2.7) for placebo (HR: 0.56, 95% CI: 0.26e1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6e4.2) and was 2.0 months (95% CI: 1.2e2.7) in those randomised to placebo (HR Z 0.54, 95% CI: 0.25e1.17; p Z 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib

The Murid Herpesvirus-4 gH/gL Binds to Glycosaminoglycans

The first contact a virus makes with cells is an important determinant of its tropism. Murid Herpesvirus-4 (MuHV-4) is highly dependent on glycosaminoglycans (GAGs) for cell binding. Its first contact is therefore likely to involve a GAG-binding virion glycoprotein. We have previously identified two such proteins, gp70 and gp150. Gp70 binds strongly to GAGs. However, deleting it makes little difference to MuHV-4 cell binding or GAG-dependence. Deleting gp150, by contrast, frees MuHV-4 from GAG dependence. This implies that GAGs normally displace gp150 to allow GAG-independent cell binding. But the gp150 GAG interaction is weak, and so would seem unlikely to make an effective first contact. Since neither gp70 nor gp150 matches the expected profile of a first contact glycoprotein, our understanding of MuHV-4 GAG interactions must be incomplete. Here we relate the seemingly disconnected gp70 and gp150 GAG interactions by showing that the MuHV-4 gH/gL also binds to GAGs. gH/gL-blocking and gp70-blocking antibodies individually had little effect on cell binding, but together were strongly inhibitory. Thus, there was redundancy in GAG binding between gp70 and gH/gL. Gp150-deficient MuHV-4 largely resisted blocks to gp70 and gH/gL binding, consistent with its GAG independence. The failure of wild-type MuHV-4 to do the same argues that gp150 is normally engaged only down-stream of gp70 or gH/gL. MuHV-4 GAG dependence is consequently two-fold: gp70 or gH/gL binding provides virions with a vital first foothold, and gp150 is then engaged to reveal GAG-independent binding

Iliotibial band release as an adjunct to the surgical management of patellar stress fracture in the athlete: a case report and review of the literature

Stress fracture of the patella is rare. In this report, a case of patellar stress fracture occurring in an amateur athlete is presented, and an operative adjunct to the surgical management of this condition is proposed

Regional spread of HIV-1 M subtype B in middle-aged patients by random env-C2V4 region sequencing

A transmission cluster of HIV-1 M:B was identified in 11 patients with a median age of 52 (range 26–65) in North-East Germany by C2V4 region sequencing of the env gene of HIV-1, who—except of one—were not aware of any risky behaviour. The 10 male and 1 female patients deteriorated immunologically, according to their information made available, within 4 years after a putative HIV acquisition. Nucleic acid sequence analysis showed a R5 virus in all patients and in 7 of 11 a crown motif of the V3 loop, GPGSALFTT, which is found rarely. Analysis of formation of this cluster showed that there is still a huge discrepancy between awareness and behaviour regarding HIV transmission in middle-aged patients, and that a local outbreak can be detected by nucleic acid analysis of the hypervariable env region

Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways.

Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic-METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c-Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment