Tumor Susceptibility Gene 101 (TSG101) Is a Novel Binding-Partner for the Class II Rab11-FIPs

The Rab11-FIPs (Rab11-family interacting proteins; henceforth, FIPs) are a family of Rab11a/Rab11b/Rab25 GTPase effector proteins implicated in an assortment of intracellular trafficking processes. Through proteomic screening, we have identified TSG101 (tumor susceptibility gene 101), a component of the ESCRT-I (endosomal sorting complex required for transport) complex, as a novel FIP4-binding protein, which we find can also bind FIP3. We show that α-helical coiled-coil regions of both TSG101 and FIP4 mediate the interaction with the cognate protein, and that point mutations in the coiled-coil regions of both TSG101 and FIP4 abrogate the interaction. We find that expression of TSG101 and FIP4 mutants cause cytokinesis defects, but that the TSG101-FIP4 interaction is not required for localisation of TSG101 to the midbody/Flemming body during abscission. Together, these data suggest functional overlap between Rab11-controlled processes and components of the ESCRT pathway

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24

Meckel-Gruber syndrome (MKS), the most common monogenic cause of neural tube defects, is an autosomal recessive disorder characterised by a combination of renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalcoele), hepatic ductal dysplasia and cysts, and polydactyly. Locus heterogeneity has been demonstrated by the mapping of the MKS1 locus to 17q21-24 in Finnish kindreds, and of MKS2 to 11q13 in North African-Middle Eastern cohorts. In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2. We report the localisation of a third MKS locus (MKS3) to chromosome 8q24 in this cohort by a genome-wide linkage search using autozygosity mapping. We identified a 26-cM region of autozygosity between D8S586 and D8S1108 with a maximum cumulative two-point LOD score at D8S1179 (Z(max)=3.04 at theta=0.06). A heterogeneity test provided evidence of one unlinked family. Exclusion of this family from multipoint analysis maximised the cumulative multipoint LOD score at locus D8S1128 (Z(max)=5.65). Furthermore, a heterozygous SNP in DDEF1, a putative candidate gene, suggested that MKS3 mapped within a 15-cM interval. Comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3-linked families

Temperature variability implies greater economic damages from climate change

A number of influential assessments of the economic cost of climate change rely on just a small number of coupled climate–economy models. A central feature of these assessments is their accounting of the economic cost of epistemic uncertainty—that part of our uncertainty stemming from our inability to precisely estimate key model parameters, such as the Equilibrium Climate Sensitivity. However, these models fail to account for the cost of aleatory uncertainty—the irreducible uncertainty that remains even when the true parameter values are known. We show how to account for this second source of uncertainty in a physically well-founded and tractable way, and we demonstrate that even modest variability implies trillions of dollars of previously unaccounted for economic damages

The Oslo definitions for coeliac disease and related terms.

ObjectiveThe literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten.DesignA multidisciplinary task force of 16 physicians from seven countries used the electronic database PubMed to review the literature for CD-related terms up to January 2011. Teams of physicians then suggested a definition for each term, followed by feedback of these definitions through a web survey on definitions, discussions during a meeting in Oslo and phone conferences. In addition to 'CD', the following descriptors of CD were evaluated (in alphabetical order): asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity and gliadin-specific antibodies.ResultsCD was defined as 'a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals'. Classical CD was defined as 'CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.' 'Gluten-related disorders' is the suggested umbrella term for all diseases triggered by gluten and the term gluten intolerance should not to be used. Other definitions are presented in the paper.ConclusionThis paper presents the Oslo definitions for CD-related terms

Decline in Clostridium difficile-associated disease rates in Singapore public hospitals, 2006 to 2008

<p>Abstract</p> <p>Background</p> <p><it>Clostridium difficile </it>is the major cause of pseudomembranous colitis associated with antibiotic use, and the spread of the hypervirulent epidemic ribotype 027/NAP-1 strain across hospitals worldwide has re-focused attention on this nosocomial pathogen. The overall incidence and trend of <it>C. difficile</it>-associated disease (CDAD) in Singapore is unknown, and a surveillance program to determine these via formal laboratory-based reporting was established.</p> <p>Findings</p> <p>Laboratory and pharmacy data were collated from one tertiary and two secondary hospitals on a quarterly basis between 2006 and 2008. All hospitals tested for <it>C. difficile </it>using Immunocard Toxins A&B (Meridian Bioscience Inc., Cincinnati, OH) during this period. Duplicate positive <it>C. difficile </it>results within a 14-day period were removed. The CDAD results were compared with trends in hospital-based prescription of major classes of antibiotics.</p> <p>Overall CDAD incidence-density decreased from 5.16 (95%CI: 4.73 - 5.62) cases per 10,000 inpatient-days in 2006 to 2.99 (95%CI: 2.67 to 3.33) cases per 10,000 inpatient-days in 2008 (<it>p </it>< 0.001), while overall rates for <it>C. difficile </it>testing increased significantly (<it>p </it>< 0.001) within the same period. These trends were mirrored at the individual hospital level. Evaluation of antibiotic prescription data at all hospitals showed increasing use of carbapenems and fluoroquinolones, while cephalosporin and clindamycin prescription remained stable.</p> <p>Conclusions</p> <p>Our results demonstrate a real decline of CDAD rates in three large local hospitals. The cause is unclear and is not associated with improved infection control measures or reduction in antibiotic prescription. Lack of <it>C. difficile </it>stool cultures as part of routine testing precluded determination of the decline of a major clone as a potential explanation. For more accurate epidemiological trending of CDAD and early detection of epidemic clones, data collection will have to be expanded and resources set in place for reference laboratory culture and typing.</p

Results of paclitaxel (day 1 and 8) and carboplatin given on every three weeks in advanced (stage III-IV) non-small cell lung cancer

BACKGROUND: Both paclitaxel (P) and carboplatin (C) have significant activity in non-small cell lung cancer (NSCLC). The weekly administration of P is active, dose intense, and has a favorable toxicity profile. We retrospectively reviewed the data of 51 consecutive patients receiving C and day 1 and 8 P chemotherapy (CT) regimen in advanced stage NSCLC to evaluate the efficacy and toxicity. METHODS: Patients treated in our institutions having pathologically proven NSCLC, no CNS metastases, adequate organ function and performance status (PS) ECOG 0–2 were given P 112.5 mg/m(2 )intravenously (IV) over 1 hour on day 1 and 8, followed by C AUC 5 IV over 1 hour, repeated in every three weeks. PC was given for maximum of 6 cycles. RESULTS: Median age was 58 (age range 39–77) and 41 patients (80%) were male. PS was 0/1/2 in 29/17/5 patients and stage was IIIA/IIIB/IV in 3/14/34 patients respectively. The median number of cycles administered was 3 (1–6). Seven patients (14%) did not complete the first 3 cycles either due to death, progression, grade 3 hypersensitivity reactions to P or lost to follow up. Best evaluable response was partial response (PR) in 45% and stable disease (SD) in 18%. Twelve patients (24%) received local RT. Thirteen patients (25%) received 2nd line CT at progression. At a median follow-up of 7 months (range, 1–20), 25 (49%) patients died and 35 patients (69%) progressed. Median overall survival (OS) was 11 ± 2 months (95% CI; 6 to 16), 1-year OS ratio was 44%. Median time to progression (TTP) was 6 ± 1 months (95% CI; 4 to 8), 1-year progression free survival (PFS) ratio was 20%. We observed following grade 3 toxicities: asthenia (10%), neuropathy (4%), anorexia (4%), anemia (4%), hypersensitivity to P (2%), nausea/vomiting (2%), diarrhea (2%) and neutropenia (2%). Two patients (4%) died of febrile neutropenia. Doses of CT were reduced or delayed in 12 patients (24%). CONCLUSIONS: P on day 1 and 8 and C every three weeks is practical and fairly well tolerated outpatient regimen. This regimen seems to be comparably active to regimens given once in every three weeks