tbuckley/cabot-search huggingface dataset:
APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection
Authors: Marjorie Pion, Angela Granelli-Piperno, Bastien Mangeat, Romaine Stalder, Rafael Correa, Ralph M. Steinman, Vincent Piguet
Journal: The Journal of Experimental Medicine (2006)

HIV-1 infects immature dendritic cells (iDCs), but infection is inefficient compared with activated CD4+ T cells and only involves a small subset of iDCs. We analyzed whether this could be attributed to specific cellular restrictions during the viral life cycle. To study env-independent restriction to HIV-1 infection, we used a single-round infection assay with HIV-1 pseudotyped with vesicular stomatitis virus G protein (HIV-VSVG). Small interfering RNA–mediated depletion of APOBEC3G/3F (A3G/3F), but not TRIM5α, enhanced HIV-1 infection of iDCs, indicating that A3G/3F controls the sensitivity of iDCs to HIV-1 infection. Furthermore, sequences of HIV reverse transcripts revealed G-to-A hypermutation of HIV genomes during iDC infection, demonstrating A3G/3F cytidine deaminase activity in iDCs. When we separated the fraction of iDCs that was susceptible to HIV, we found the cells to be deficient in A3G messenger RNA and protein. We also noted that during DC maturation, which further reduces susceptibility to infection, A3G levels increased. These findings highlight a role for A3G/3F in explaining the resistance of most DCs to HIV-1 infection, as well as the susceptibility of a fraction of iDCs. An increase in the A3G/3F-mediated intrinsic resistance of iDCs could result in a block of HIV infection at its mucosal point of entry.
International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na<sup>+</sup>Channel
Authors: Stephan Kellenberger, Laurent Schild
Journal: Pharmacological Reviews (2014)

The epithelial Na<sup>+</sup> channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na<sup>+</sup> channels. ENaC mediates transepithelial Na<sup>+</sup> transport, thereby contributing to Na<sup>+</sup> homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H<sup>+</sup>-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.
Individual- Versus Group-Based Financial Incentives for Weight Loss
Authors: Jeffrey T. Kullgren, Andrea B. Troxel, George Loewenstein, David A. Asch, Laurie A. Norton, Lisa Wesby, Yuanyuan Tao, Jingsan Zhu, Kevin G. Volpp
Journal: Annals of Internal Medicine (2013)

Chinese translation Background: Data on the effectiveness of employer-sponsored financial incentives for employee weight loss are limited. Objective: To test the effectiveness of 2 financial incentive designs for promoting weight loss among obese employees. Design: Randomized, controlled trial. (ClinicalTrials.gov: NCT01208350) Setting: Children's Hospital of Philadelphia. Participants: 105 employees with a body mass index between 30 and 40 kg/m2. Intervention: 24 weeks of monthly weigh-ins (control group; n = 35); individual incentive, designed as $100 per person per month for meeting or exceeding weight-loss goals (n = 35); and group incentive, designed as $500 per month split among participants within groups of 5 who met or exceeded weight-loss goals (n = 35). Measurements: Weight loss after 24 weeks (primary outcome) and 36 weeks and changes in behavioral mediators of weight loss (secondary outcomes). Results: Group-incentive participants lost more weight than control participants (mean between-group difference, 4.4 kg [95% CI, 2.0 to 6.7 kg]; P < 0.001) and individual-incentive participants (mean between-group difference, 3.2 kg [CI, 0.9 to 5.5 kg]; P = 0.008). Twelve weeks after incentives ended and after adjustment for 3-group comparisons, group-incentive participants maintained greater weight loss than control group participants (mean between-group difference, 2.9 kg [CI, 0.5 to 5.3 kg]; P = 0.016) but not greater than individual-incentive participants (mean between-group difference, 2.7 kg [CI, 0.4 to 5.0 kg]; P = 0.024). Limitation: Single employer and short follow-up. Conclusion: A group-based financial incentive was more effective than an individual incentive and monthly weigh-ins at promoting weight loss among obese employees at 24 weeks. Primary Funding Source: National Institute on Aging.
Expectations About the Effectiveness of Radiation Therapy Among Patients With Incurable Lung Cancer
Authors: Aileen B. Chen, Angel Cronin, Jane C. Weeks, Elizabeth A. Chrischilles, Jennifer Malin, James A. Hayman, Deborah Schrag
Journal: Journal of Clinical Oncology (2013)

Although radiation therapy (RT) can palliate symptoms and may prolong life, it is not curative for patients with metastatic lung cancer. We investigated patient expectations about the goals of RT for incurable lung cancers.The Cancer Care Outcomes Research and Surveillance Consortium enrolled a population- and health system-based cohort of patients diagnosed with lung cancer from 2003 to 2005. We identified patients with stage wet IIIB or IV lung cancer who received RT and answered questions on their expectations about RT. We assessed patient expectations about the goals of RT and identified factors associated with inaccurate beliefs about cure.In all, 384 patients completed surveys on their expectations about RT. Seventy-eight percent of patients believed that RT was very or somewhat likely to help them live longer, and 67% believed that RT was very or somewhat likely to help them with problems related to their cancer. However, 64% did not understand that RT was not at all likely to cure them. Older patients and nonwhites were more likely to have inaccurate beliefs, and patients whose surveys were completed by surrogates were less likely to have inaccurate beliefs. Ninety-two percent of patients with inaccurate beliefs about cure from RT also had inaccurate beliefs about chemotherapy.Although patients receiving RT for incurable lung cancer believe it will help them, most do not understand that it is not at all likely to cure their disease. This indicates a need to improve communication regarding the goals and limitations of palliative RT.
Surveillance for skeletal toxicity of children treated with etretinate
Authors: M.T. GLOVER, A.M. PETERS, D.J. ATHERTON
Journal: British Journal of Dermatology (1987)

Following recent reports of the development of skeletal abnormalities in patients treated with etretinate (Tigason®), we have examined 19 children and adolescents on long‐term treatment with etretinate, using 99mtechnetium methylene diphosphonate (99mTcMDP) whole body bone scans and musculoskeletal assessment. No significant bony abnormalities were detected. We believe that the available evidence does not warrant alarm, and that long‐term etretinate therapy can probably be given with a low risk of musculoskeletal toxicity if certain precautions are taken, in particular the use of low maintenance dose levels, early investigation of symptoms of musculoskeletal pain or stiffness, and regular 99mTcMDP bone scans.
<i>IL28B</i>polymorphisms do not predict response to therapy in chronic hepatitis C with HCV genotype 5: Table 1
Authors: Nabil Antaki, Stéphanie Bibert, Kamel Kebbewar, Fouad Asaad, Osama Baroudi, Sawsan Alideeb, Milad Hadad, Dirar Abboud, Houda Sabah, Pierre-Yves Bochud, Francesco Negro
Journal: Gut (2012)

<h3>Objective</h3> Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (&gt;650) hexanucleotide GGCCTG repeat expansion in the first intron of the <i>NOP56</i> gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. <h3>Methods</h3> The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. <h3>Results</h3> Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. <h3>Conclusions</h3> SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms.
New strategies to control inflammatory synovitis: interleukin 15 and beyond
Authors: I B McInnes
Journal: Annals of the Rheumatic Diseases (2003)

A broad range of strategies to target inflammatory synovitis is currently being explored. Most approaches require the identification of a single molecule/pathway that is tractable to modulation in the clinic. In general, molecular activities with relevant biological effects are sought within the appropriate target lesion—namely, the synovium. Thereafter, such an activity may be targeted in rodent models of arthritis and the effects on inflammation and articular destruction measured. A moiety with plausible biology and bioactivity in model systems may then move to phase I “proof of concept” studies and thereafter to clinical development (fig 1). The successful targeting of tumour necrosis factor α (TNFα) represents an example of such an approach whereby an effective therapeutic agent has been derived.1,2 However, even after TNF blockade, unmet clinical need clearly persists in inflammatory arthritis. Major challenges remain, in particular the identification of therapeutic responders a priori, and the rational choice of additional targets, either as independent primary therapeutic targets or as synergistic biological targets for future combination applications. This short review will test interleukin 15 (IL15) in this model of new biological development to evaluate its therapeutic potential. Thereafter, an alternative approach will be considered for comparative purposes, whereby a model in which multiple pathways within the synovium are targeted simultaneously using a strategy borrowed from the host-parasite relationship arising from evolutionary pressures over millennia (fig 1).



 Figure 1  
Alternative model approaches, resulting in “proof of concept” clinical studies to target synovitis.



Our group has recently sought mechanisms whereby innate and acquired immune responses interact during chronic inflammation, with particular emphasis on cytokine biology. Many cytokines present within the synovium derive from macrophages and synovial fibroblasts.3 IL15, a cytokine with structural similarities to IL2,4 is produced primarily by macrophages and as such attracted our attention at an early stage as …
In memoriam: Dr Joseph Barnett Kirsner
Authors: Stephen B Hanauer, David T Rubin
Journal: Gut (2012)

![Graphic][1]</img> This figure is only reproduced in colour in the online version. Joseph B Kirsner (Dr Joe to his patients) was a Zeus among the gods of gastroenterology and was almost immortal, living to the age of nearly 103. As our colleague Dr Eugene Chang stated, ‘he was here (at the University of Chicago) for two lifetimes’. To say that Dr Kirsner devoted his life to medicine is an understatement and is an insufficient description of the depth and breadth of his 75-year commitment to his patients, students, and colleagues throughout the world. Dr Kirsner had a remarkably productive and fulfilled career, and in fact he continued to serve and represent the GI Section and Department of Medicine until the last weeks of his life. He saw patients until the age of 95 years and what could be considered the culmination of his academic life occurred at the age of 100 years, when he stood to give a 1-hour Department of Medicine Grand Rounds on the history of gastroenterology, which earned a prolonged ovation by the standing room–only crowd of fellow faculty, housestaff, and students. The oldest of five children, Joseph Barnett Kirsner was born in Boston on 21 September 1909, to Ukrainian Jewish parents who had immigrated to the USA. He grew up in Boston's East End neighbourhood, a foothold for recent immigrants. Throughout his adolescence, Kirsner held multiple jobs, delivering newspapers, stocking a grocery store, and working as a library clerk. He then worked his way through a 6-year programme at Tufts University that combined college and medical school. Reflecting on his parents’ difficult lives, he commented that he chose a career in medicine and derived his work ethic ‘to make them proud’. He entered medical school in 1929 and graduated in 1933. Planning a career as a general practitioner, he … [1]: /embed/inline-graphic-1.gif
A 5-Year Randomized Controlled Study of Learning, Problem Solving Ability, and Quality of Life Modifications in People With Type 2 Diabetes Managed by Group Care
Authors: Marina Trento, Pietro Passera, Enrica Borgo, Marco Tomalino, Marina Bajardi, Franco Cavallo, Massimo Porta
Journal: Diabetes Care (2004)

OBJECTIVE—To study time course changes in knowledge, problem solving ability, and quality of life in patients with type 2 diabetes managed by group compared with individual care and education. RESEARCH DESIGN AND METHODS—We conducted a 5-year randomized controlled clinical trial of continuing systemic education delivered by group versus individual diabetes care in a hospital-based secondary care diabetes unit. There were 120 patients with non–insulin-treated type 2 diabetes enrolled and randomly allocated to group or individual care. Eight did not start and 28 did not complete the study. The main outcome measures were knowledge of diabetes, problem solving ability, quality of life, HbA1c, BMI, and HDL cholesterol. RESULTS—Knowledge of diabetes and problem solving ability improved from year 1 with group care and worsened among control subjects (P &amp;lt; 0.001 for both). Quality of life improved from year 2 with group care but worsened with individual care (P &amp;lt; 0.001). HbA1c level progressively increased over 5 years among control subjects (+1.7%, 95% CI 1.1–2.2) but not group care patients (+0.1%, −0.5 to 0.4), in whom BMI decreased (−1.4, −2.0 to −0.7) and HDL cholesterol increased (+0.14 mmol/l, 0.07–0.22). CONCLUSIONS—Adults with type 2 diabetes can acquire specific knowledge and conscious behaviors if exposed to educational procedures and settings tailored to their needs. Traditional one-to-one care, although delivered according to optimized criteria, is associated with progressive deterioration of knowledge, problem solving ability, and quality of life. Better cognitive and psychosocial results are associated with more favorable clinical outcomes.
Hemodynamic sequelae of regression of experimental atherosclerosis.
Authors: M L Armstrong, D D Heistad, M L Marcus, D J Piegors, F M Abboud
Journal: Journal of Clinical Investigation (1983)

Regression of experimental atherosclerosis is characterized by decreased intimal thickness and luminal enlargement, but intimal fibrosis becomes more dense. We tested the hypothesis that fibrosis of arteries during regression might limit vasodilator capacity and restrict hemodynamic improvement despite luminal improvement. We studied limb, coronary, and cerebral hemodynamics in 11 normal cynomolgus monkeys, 10 monkeys given an atherogenic diet for 20 mo and 8 monkeys given a regression diet for an additional 18 mo. The atherogenic diet induced lesions of moderate severity (50-60% stenosis); owing to characteristic vessel growth during the atherogenic period, luminal size did not decrease correspondingly. Regression monkeys showed typical changes of regression with luminal enlargement but increased fibrosis. The iliac artery was perfused at constant blood flow and maximal vasodilatation was produced with papaverine. Blood flow was measured with microspheres during maximal vasodilatation in the coronary bed (adenosine) and cerebral bed (hypercapnia). In normal monkeys, minimal vascular resistances were 1.95 +/- 0.19 mm Hg/ml/min X 100 g (mean +/- SE) (limb), 0.13 +/- 0.01 (coronary), and 0.44 +/- 0.02 (cerebral). In atherosclerotic monkeys minimal resistance increased (P less than 0.05) 108, 62, and 166% in the limb, coronary, and cerebral beds, respectively. In regression monkeys, minimal resistance increased from values found in atherosclerotic animals in the limb (+22%), decreased inconsistently in the coronary bed (-19%), and decreased significantly in the cerebral bed (-44%, P less than 0.05). Thus morphologic regression was accompanied by significant hemodynamic improvement during maximal dilatation only in cerebral vessels. We conclude that increases in luminal size during regression of atherosclerotic lesions may not be associated with increases in vasodilator capacity, as intimal fibrosis may limit physiologically important hemodynamic improvement.
Pediatric glioblastomas: A histopathological and molecular genetic study
Authors: Vaishali Suri, Prasenjit Das, Ayushi Jain, Mehar Chand Sharma, Sachin Anil Borkar, Ashish Suri, Deepak Gupta, Chitra Sarkar
Journal: Neuro-Oncology (2008)

Glioblastoma multiforme (GBM) occurs rarely in children. Relatively few studies have been performed on molecular properties of pediatric GBMs. Our objective in this study was to evaluate the genetic alterations in pediatric GBM (age ⩽ 18 years) with special reference to p53, p16, and p27 protein expression, alterations of the epidermal growth factor receptor (EGFR), and deletion of the phosphate and tensin homolog gene (PTEN). Thirty cases of childhood GBMs reported between January 2002 and June 2007 were selected, and slides stained with hematoxylin and eosin were reviewed. Immunohistochemical staining was performed for EGFR, p53, p16, and p27, and tumor proliferation was assessed by calculating the MIB-1 labeling index (LI). Fluorescence in situ hybridization analysis was performed to evaluate for EGFR amplification and PTEN deletion. Histopathological features and MIB-1 LI were similar to adult GBMs. p53 protein expression was observed in 63%. Although EGFR protein overexpression was noted in 23% of cases, corresponding amplification of the EGFR gene was rare (5.5%). Deletion of the PTEN gene was also equally rare (5.5%). One case showed polysomy (chromosomal gains) of chromosomes 7 and 10. Loss of p16 and p27 immunoexpression was observed in 68% and 54% of cases, respectively. In pediatric de novo/primary GBMs, deletion of PTEN and EGFR amplification are rare, while p53 alterations are more frequent compared to primary adult GBMs. Frequency of loss of p16 and p27 immunoexpression is similar to their adult counterparts. This suggests that pediatric malignant gliomas are distinctly different from adult GBMs, highlighting the need for identification of molecular targets that may be adopted for future novel therapeutic strategies.
Response of Intra-acinar Pulmonary Microvessels to Hypoxia, Hypercapnic Acidosis, and Isocapnic Acidosis
Authors: Kazuhiro Yamaguchi, Koichi Suzuki, Katsuhiko Naoki, Kazumi Nishio, Nagato Sato, Kei Takeshita, Hiroyasu Kudo, Takuya Aoki, Yukio Suzuki, Atsushi Miyata, Harukuni Tsumura
Journal: Circulation Research (1998)

Abstract —To elucidate the differential reactivity of pulmonary microvessels in the acini to hypoxia, excessive CO 2 , and increased H + , we investigated changes in the diameter of precapillary arterioles, postcapillary venules, and capillaries in isolated rat lungs on exposure to normocapnic hypoxia (2% O 2 ), normoxic hypercapnia (15% CO 2 ), and isocapnic acidosis (0.01 mol/L HCl). Microvascular diameters were precisely examined using a real-time confocal laser scanning luminescence microscope coupled to a high-sensitivity camera with an image intensifier. Measurements were made under conditions with and without indomethacin or N ω -nitro- l -arginine methyl ester to assess the importance of vasoactive substances produced by cyclooxygenase (COX) or NO synthase (NOS) as it relates to the reactivity of pulmonary microvessels to physiological stimuli. We found that acute hypoxia contracted precapillary arterioles that had diameters of 20 to 30 μm but did not constrict postcapillary venules of similar size. COX- and NOS-related vasoactive substances did not modulate hypoxia-elicited arteriolar constriction. Hypercapnia induced a distinct venular dilatation closely associated with vasodilators produced by COX but not by NOS. Arterioles were appreciably constricted in isocapnic acidosis when NOS, but not COX, was suppressed, whereas venules showed no constrictive response even when both enzymes were inhibited. Capillaries were neither constricted nor dilated under any experimental conditions. These findings suggest that reactivity to hypoxia, CO 2 , and H + is not qualitatively similar among intra-acinar microvessels, in which COX- and NOS-associated vasoactive substances function differently.
Prognostic Utility of Neutrophil Gelatinase-Associated Lipocalin in Predicting Mortality and Cardiovascular Events in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention
Authors: Søren Lindberg, Sune H. Pedersen, Rasmus Mogelvang, Jan Skov Jensen, Allan Flyvbjerg, Søren Galatius, Nils E. Magnusson
Journal: Journal of the American College of Cardiology (2012)
A volcanic disruption
Authors: D. O'Neill
Journal: BMJ (2010)

“If you want to make God laugh tell him your plans,” was a proverb that re-entered common currency in the last week. In common with many conference organisers (and impromptu vulcanologists) I was preparing for the worst on Saturday. I was to chair a long planned national conference on the brain and music, and three international speakers were due to fly in. While we were fortunate to field an excellent local speaker as one substitute, the stellar qualities of the other two speakers were such that we were poised to cancel the meeting. In the event, new technology and the adaptability of enthusiastic delegates saved the day. For a limited period at least, it would appear that Goethe’s dictum “It is when constrained that the master shows himself” holds in …