173 research outputs found

    Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene

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    Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNATyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0–11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNATyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNATyr gene is the causative mutation for SAN

    Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

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    OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHODS: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation

    Nonurgent patients in the emergency department? A French formula to prevent misuse

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    <p>Abstract</p> <p>Background</p> <p>Overcrowding in emergency department (EDs) is partly due to the use of EDs by nonurgent patients. In France, the authorities responded to the problem by creating primary care units (PCUs): alternative structures located near hospitals. The aims of the study were to assess the willingness of nonurgent patients to be reoriented to a PCU and to collect the reasons that prompted them to accept or refuse.</p> <p>Methods</p> <p>We carried out a cross sectional survey on patients' use of EDs. The study was conducted in a French hospital ED. Patients were interviewed about their use of health services, ED visits, referrals, activities of daily living, and insurance coverage status. Patients' medical data were also collected.</p> <p>Results</p> <p>85 patients considered nonurgent by a triage nurse were asked to respond to a questionnaire. Sex ratio was 1.4; mean age was 36.3 +/- 11.7 years.</p> <p>Most patients went to the ED autonomously (76%); one third (31.8%) had consulted a physician. The main reasons for using the ED were difficulty to get an appointment with a general practitioner (22.3%), feelings of pain (68.5%), and the availability of medical services in the ED, like imaging, laboratory tests, and drug prescriptions (37.6%). Traumatisms and wounds were the main medical reasons for going to the ED (43.5%).</p> <p>More than two-thirds of responders (68%) were willing to be reoriented towards PCUs. In the multivariate analysis, only employment and the level of urgency perceived by the patient were associated with the willingness to accept reorientation. Employed persons were 4.5 times more likely to accept reorientation (OR = 4.5 CI (1.6-12.9)). Inversely, persons who perceived a high level of urgency were the least likely to accept reorientation (OR = 0.9 CI (0.8-0.9).</p> <p>Conclusions</p> <p>Our study provides information on the willingness of ED patients to accept reorientation and shows the limits of its feasibility. Alternative structures such as PCUs near the ED seem to respond appropriately to the growing demands of nonurgent patients. Reorientation, however, will be successful only if the new structures adapt their opening hours to the needs of nonurgent patients and if their physicians can perform specific technical skills.</p

    Role of protein kinase C and epidermal growth factor receptor signalling in growth stimulation by neurotensin in colon carcinoma cells

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    <p>Abstract</p> <p>Background</p> <p>Neurotensin has been found to promote colon carcinogenesis in rats and mice, and proliferation of human colon carcinoma cell lines, but the mechanisms involved are not clear. We have examined signalling pathways activated by neurotensin in colorectal and pancreatic carcinoma cells.</p> <p>Methods</p> <p>Colon carcinoma cell lines HCT116 and HT29 and pancreatic adenocarcinoma cell line Panc-1 were cultured and stimulated with neurotensin or epidermal growth factor (EGF). DNA synthesis was determined by incorporation of radiolabelled thymidine into DNA. Levels and phosphorylation of proteins in signalling pathways were assessed by Western blotting.</p> <p>Results</p> <p>Neurotensin stimulated the phosphorylation of both extracellular signal-regulated kinase (ERK) and Akt in all three cell lines, but apparently did so through different pathways. In Panc-1 cells, neurotensin-induced phosphorylation of ERK, but not Akt, was dependent on protein kinase C (PKC), whereas an inhibitor of the Ξ²-isoform of phosphoinositide 3-kinase (PI3K), TGX221, abolished neurotensin-induced Akt phosphorylation in these cells, and there was no evidence of EGF receptor (EGFR) transactivation. In HT29 cells, in contrast, the EGFR tyrosine kinase inhibitor gefitinib blocked neurotensin-stimulated phosphorylation of both ERK and Akt, indicating transactivation of EGFR, independently of PKC. In HCT116 cells, neurotensin induced both a PKC-dependent phosphorylation of ERK and a metalloproteinase-mediated transactivation of EGFR that was associated with a gefitinib-sensitive phosphorylation of the downstream adaptor protein Shc. The activation of Akt was also inhibited by gefitinib, but only partly, suggesting a mechanism in addition to EGFR transactivation. Inhibition of PKC blocked neurotensin-induced DNA synthesis in HCT116 cells.</p> <p>Conclusions</p> <p>While acting predominantly through PKC in Panc-1 cells and via EGFR transactivation in HT29 cells, neurotensin used both these pathways in HCT116 cells. In these cells, neurotensin-induced activation of ERK and stimulation of DNA synthesis was PKC-dependent, whereas activation of the PI3K/Akt pathway was mediated by stimulation of metalloproteinases and subsequent transactivation of the EGFR. Thus, the data show that the signalling mechanisms mediating the effects of neurotensin involve multiple pathways and are cell-dependent.</p

    Habitat selection, facilitation, and biotic settlement cues affect distribution and performance of coral recruits in French Polynesia

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    Habitat selection can determine the distribution and performance of individuals if the precision with which sites are chosen corresponds with exposure to risks or resources. Contrastingly, facilitation can allow persistence of individuals arriving by chance and potentially maladapted to local abiotic conditions. For marine organisms, selection of a permanent attachment site at the end of their larval stage or the presence of a facilitator can be a critical determinant of recruitment success. In coral reef ecosystems, it is well known that settling planula larvae of reef-building corals use coarse environmental cues (i.e., light) for habitat selection. Although laboratory studies suggest that larvae can also use precise biotic cues produced by crustose coralline algae (CCA) to select attachment sites, the ecological consequences of biotic cues for corals are poorly understood in situ. In a field experiment exploring the relative importance of biotic cues and variability in habitat quality to recruitment of hard corals, pocilloporid and acroporid corals recruited more frequently to one species of CCA, Titanoderma prototypum, and significantly less so to other species of CCA; these results are consistent with laboratory assays from other studies. The provision of the biotic cue accurately predicted coral recruitment rates across habitats of varying quality. At the scale of CCA, corals attached to the β€œpreferred” CCA experienced increased survivorship while recruits attached elsewhere had lower colony growth and survivorship. For reef-building corals, the behavioral selection of habitat using chemical cues both reduces the risk of incidental mortality and indicates the presence of a facilitator
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