Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes (PNS) are often characterized by the presence of antineuronal antibodies in patient serum or cerebrospinal fluid. The detection of antineuronal antibodies has proven to be a useful tool in PNS diagnosis and the search for an underlying tumor. Here, we describe three patients with autoantibodies to several epitopes of the axon initial segment protein tripartite motif 46 (TRIM46). We show that anti-TRIM46 antibodies are easy to detect in routine immunohistochemistry screening and can be confirmed by western blotting and cell-based assay. Anti-TRIM46 antibodies can occur in patients with diverse neurological syndromes and are associated with small-cell lung carcinoma

Osmium and lithium isotope evidence for weathering feedbacks linked to orbitally paced organic carbon burial and Silurian glaciations

The Ordovician (∼487 to 443 Ma) ended with the formation of extensive Southern Hemisphere ice sheets, known as the Hirnantian glaciation, and the second largest mass extinction in Earth History. It was followed by the Silurian (∼443 to 419 Ma), one of the most climatically unstable periods of the Phanerozoic as evidenced by several large scale (> 5‰) carbon isotope (δ13C) perturbations associated with further extinction events. Despite several decades of research, the cause of these environmental instabilities remains enigmatic. Here, we provide osmium (187Os/188Os) and lithium (δ7Li) isotope measurements of marine sedimentary rocks that cover four Silurian δ13C excursions. Osmium and Li isotope records resemble those previously recorded for the Hirnantian glaciation suggesting a similar causal mechanism. When combined with a new dynamic carbon-osmium-lithium biogeochemical model we suggest that astronomical forcing of the marine organic carbon cycle, as opposed to a decline in volcanic arc degassing or the rise of early land plants, resulted in drawdown of atmospheric CO2, triggering continental scale glaciation, intense global cooling and eustatic sea-level lows recognised in the geological record. Lower atmospheric pCO2 and temperatures during the Hirnantian and Silurian glaciations suppressed CO2 removal by silicate weathering, driving 187Os/188Os and δ7Li variability, supporting the existence of climate-regulating feedbacks

Initial United States experience with the Paracor HeartNet⁎⁎Paracor Medical, Inc, Sunnyvale, Calif. myocardial constraint device for heart failure

ObjectiveThis study was undertaken to review the initial results and surgical safety data for the US Food and Drug Administration safety and feasibility trial of the Paracor HeartNet (Paracor Medical, Inc, Sunnyvale, Calif.) myocardial constraint device.MethodsPatients with New York Heart Association functional class II or III heart failure underwent device implantation (n = 21) through a left minithoracotomy.ResultsThe average age was 53 years (31–72 years). There were 18 men and 3 women, and 17 patients had nonischemic etiology of heart failure. Mean heart failure duration was 8.3 years (1.4-18.8 years). Average ejection fraction was 22% (11%-33%), with an average left ventricular end-diastolic dimension of 74 mm (55-94 mm). Previous medical therapy included angiotensin-converting enzyme inhibitors, β-blockers, diuretics, digoxin, and aldosterone receptor blockers. At implantation, 17 patients had implantable electronic devices: 1 biventricular pacemaker, 11 biventricular pacemakers with cardioverter-defibrillators, and 5 implantable cardioverter-defibrillators. Patient comorbidities included hypertension in 10 cases, diabetes mellitus in 8, myocardial infarction in 1, and ventricular tachycardia in 8. Mean operative time was 68 minutes (42–102 minutes), and implantation time averaged 15 minutes (5–51 minutes). The average time to ambulation was 1.6 days (1–4 days). The intensive care unit stay averaged 3.3 days (1–16 days), and hospital stay averaged 6.3 days (4–16 days). Atrial fibrillation occurred in 2 patients, and there were 2 in-hospital deaths.ConclusionsThe Paracor device can be implanted in patients with heart failure and reduced left ventricular function with a high degree of success. Significant surgical complications were infrequent. The initial US experience supports the conduct of a randomized, controlled, pivotal trial

Neck pain and anxiety do not always go together

Chronic pain and psychosocial distress are generally thought to be associated in chronic musculoskeletal disorders such as non-specific neck pain. However, it is unclear whether a raised level of anxiety is necessarily a feature of longstanding, intense pain amongst patient and general population sub-groups. In a cohort of 70 self-selected female, non-specific neck pain sufferers, we observed relatively high levels of self-reported pain of 4.46 (measured on the 11 point numerical pain rating scale (NRS-101)) and a longstanding duration of symptoms (156 days/year). However, the mean anxiety scores observed (5.49), fell well below the clinically relevant threshold of 21 required by the Beck Anxiety Inventory. The cohort was stratified to further distinguish individuals with higher pain intensity (NRS>6) and longer symptom duration (>90 days). Although a highly statistically significant difference (p = 0.000) was subsequently observed with respect to pain intensity, in the resulting sub-groups, none such a difference was noted with respect to anxiety levels. Our results indicate that chronic, intense pain and anxiety do not always appear to be related. Explanations for these findings may include that anxiety is not triggered in socially functional individuals, that individual coping strategies have come into play or in some instances that a psychological disorder like alexithymia could be a confounder. More studies are needed to clarify the specific role of anxiety in chronic non-specific musculoskeletal pain before general evidence-driven clinical extrapolations can be made

Global Ocean Science Report: The Current Status of Ocean Science around the World

The IOC-UNESCO Global Ocean Science Report (GOSR) aims to provide a status report on ocean science. It identifies and quantifies the elements that drive the productivity and performance of ocean science, including workforce, infrastructure, resources, networks and outputs. The report is intended to facilitate international ocean science cooperation and collaboration. It helps to identify gaps in science organization and capacity and develop options to optimize the use of scientific resources and advance ocean science and technology by sharing expertise and facilities, promoting capacity-building and transferring marine technology. As the first consolidated assessment of global ocean science, the GOSR assists the science-policy interface and supports managers, policy-makers, governments and donors, as well as scientists beyond the ocean community. The GOSR offers decision-makers an unprecedented tool to identify gaps and opportunities to advance international collaboration in ocean science and technology and harness its potential to meet societal needs, address global challenges and drive sustainable development for all

Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells

Virus-specific CD8+ T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon γ assays presently used. Here, we demonstrate that HIV-1–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4+ T cells or addition of interleukin 2–neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4+ T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1–specific CD4+ T helper cell responses. These data demonstrate a loss of HIV-1–specific CD8+ T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1–specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions

Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK Pathways

<p>Abstract</p> <p>Background</p> <p>Curcumin is a principal compound of turmeric, commonly used to treat tumors and other diseases. However, its anti-cancer activity in human acute monocytic leukemia THP-1 cells is not clear. This study aimed to study the anti-cancer effect and action of curcumin on THP-1 cells.</p> <p>Methods</p> <p>THP-1 parental cells and PMA-treated THP-1 cells, were used as <it>in vitro </it>models to evaluate the anti-cancer effect and mechanism of curcumin. Apoptosis and its mechanism were evaluated by WST-1, flow cytometry and Western blotting. MAPK inhibitors were used to further confirm the molecular mechanism of curcumin-induced THP-1 cell apoptosis.</p> <p>Results</p> <p>Curcumin induced cell apoptosis of THP-1 cells as shown by cell viability, cell cycle analysis and caspase activity. Curcumin significantly increased the phosphorylation of ERK, JNK and their downstream molecules (c-Jun and Jun B). Inhibitor of JNK and ERK reduced the pro-apoptotic effect of curcumin on THP-1 cells as evidenced by caspase activity and the activation of ERK/JNK/Jun cascades. On the contrary, the pro-apoptotic effect of curcumin was abolished in the differentiated THP-1 cells mediated by PMA.</p> <p>Conclusions</p> <p>This study demonstrates that curcumin can induce the THP-1 cell apoptosis through the activation of JNK/ERK/AP1 pathways. Besides, our data suggest its novel use as an anti-tumor agent in acute monocytic leukemia.</p

Bupropion Increases Selection of High Effort Activity in Rats Tested on a Progressive Ratio/Chow Feeding Choice Procedure: Implications for Treatment of Effort-Related Motivational Symptoms

Background: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. Methods: Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. Results: Bupropion (10.0–40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. Conclusion: The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans