tbuckley/cabot-search huggingface dataset:
Biology of Bone
Authors: Reginald R. Cooper
Journal: JAMA (1972)

Although this relatively brief readable monograph portrays bone "as seen by a histologist," the author takes every opportunity to stress functional implications of structure. A liberal sprinkling of up-to-date references in each short chapter directs the efforts of those who would go deeper into any subject covered. After a condensed survey of bone function and the history of methods applied to the investigation of bone, the author discusses the traditionally defined varieties of bone. A terse review of matrix and mineral structure and chemistry precedes an enlightening synopsis of bone evolution. The sections on bone deposition and calcification (a term chosen deliberately over the more accurate term "mineralization") place modern views of bone metabolism against the appropriate structural background. Those interested in justice for the often disregarded and probably vitally important osteocyte will praise the author for his separate albeit short chapter calling attention to this cell. A summary of
Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial
Authors: N. van Herwaarden, A. van der Maas, M. J. M. Minten, F. H. J. van den Hoogen, W. Kievit, R. F. van Vollenhoven, J. W. J. Bijlsma, B. J. F. van den Bemt, A. A. den Broeder
Journal: BMJ (2015)

<b>Objective</b> To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. <b>Design</b> Randomised controlled, open label, non-inferiority strategy trial. <b>Setting</b> Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. <b>Participants</b> 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. <b>Interventions</b> Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. <b>Main outcome measures</b> Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. <b>Results</b> Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% <i>v</i> 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% <i>v</i> 27%) and minimal radiographic progression (32% <i>v</i> 15%) were more frequent in dose reduction than usual care. <b>Conclusions</b> A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients. <b>Trial registration</b> Dutch trial register (www.trialregister.nl), NTR 3216.
S2. Therapeutic strategies based on overcoming immune resistance mechanisms within the melanoma tumour microenvironment
Authors: T Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Two major categories of melanoma metastases have been observed based on gene expression profiling and confirmatory assays. One subgroup of patients has an inflamed phenotype that includes expression of chemokines, T cell markers, and other immunoregulatory factors. In contrast,
Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
Authors: R G Haller, K G Henriksson, L Jorfeldt, E Hultman, R Wibom, K Sahlin, N H Areskog, M Gunder, K Ayyad, C G Blomqvist
Journal: Journal of Clinical Investigation (1991)

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.
Vibrio Fetus Isolated from a Patient with Localized Septic Arthritis
Authors: Sylvia King
Journal: JAMA (1961)

A 74-year-old man was hospitalized because of fever accompanied by a painful swelling and marked limitation of motion in the right knee. Aspiration of the joint yielded 20 cc. of serosanguineous fluid from which a culture ofVibrio fetuswas obtained. Treatment with 1 gm. of chloramphenicol daily and local applications of heat were followed within 3 days by restoration of normal temperature and marked relief of local symptoms. After a week of therapy, serosanguineous fluid was again obtained by aspiration from the joint, but no further growth ofVibrio fetuswas obtained. The organism is gram negative, assumes straight or curved forms up to 7μ in length, and has single polar flagella. It causes infections in animals as well as in man.
Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide–HLA-GFP complexes: analysis of T-cell phenotype and function in chronic viral infections
Authors: Utano Tomaru, Yoshihisa Yamano, Masahiro Nagai, Dragan Maric, Previn T.P. Kaumaya, William Biddison, Steven Jacobson
Journal: Nature Medicine (2003)
Role of Height and Glycosylated Hemoglobin in Abnormal Nerve Conduction in Pediatric Patients With Type I Diabetes Mellitus After 4–9 yr of Disease
Authors: Stephen C Duck, Feifei F Wei, Julie Parke, Herbert M Swick
Journal: Diabetes Care (1991)

To determine the role of height and glycosylated hemoglobin in abnormal nerve conduction in pediatric patients with insulin-dependent (type I) diabetes mellitus.Sixty-six pediatric patients (aged 6.3-18.2 yr) with a duration of diabetes from 4 to 8.5 yr but free of clinical neuropathy were evaluated for abnormal nerve conduction.Mean HbA1 values for 1 and 2 yr before study were available. Electroneurographic findings were significantly different from control subjects in upper and lower extremities and included all five measured velocities, three sensory latencies, and one amplitude. Stepwise regression analysis identified an adverse effect of height on latency (5 of 6) and of mean HbA1 concentration on decreasing velocity (4 of 5). The data analysis from 52 patients who were restudied and who had a duration of diabetes from 5.3 to 9.6 yr confirmed that all velocity values slowed; one of five values did so significantly. The coefficients associated with mean HbA1 concentration usually increased in both upper- and lower-extremity velocity analyses at the follow-up examination. The change in peroneal motor velocity between the first and last examinations was significantly related to the increasing time interval between examinations.Prospective evaluation of nerve conduction parameters in pediatric patients with diabetes should include both height (the most significant independent variable in latency analysis) and mean glycemic control (the most consistent variable in velocity analyses) as variables in the assessment of the natural history of evolving peripheral neuropathy.
Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features
Authors: Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw, Philippe Froguel
Journal: Journal of Clinical Investigation (2013)

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.
The Structure of Psychiatric Science
Authors: Kenneth S. Kendler
Journal: American Journal of Psychiatry (2014)

This essay addresses two interrelated questions: What is the structure of current psychiatric science and what should its goals be? The author analyzed all studies addressing the etiology of psychiatric disorders in the first four 2013 issues of 12 psychiatry and psychology journals. He classified the resulting 197 articles by the risk factors examined using five biological, four psychological, and three environmental levels. The risk factors were widely dispersed across levels, suggesting that our field is inherently multilevel and already practicing empirically based pluralism. However, over two-thirds of the studies had a within-level focus. Two cross-level patterns emerged between 1) systems neuroscience and neuropsychology and 2) molecular or latent genetic factors and environmental risks. The author suggests three fundamental goals for etiological psychiatric research. The first is an eclectic effort to clarify risk factors regardless of level, including those assessed using imaginative understanding, with careful attention to causal inference. An interventionist framework focusing on isolating causal effects is recommended for this effort. The second goal is to clarify mechanisms of illness that will require tracing causal pathways across levels downward to biological neuroscience and upward to social factors, thereby elucidating the important cross-level interactions. Here the philosophy of biology literature on mechanisms can be a useful guide. Third, we have to trace the effects of these causal pathways back up into the mental realm, moving from the Jasperian level of explanation to that of understanding. This final effort will help us expand our empathic abilities to better understand how symptoms are experienced in the minds of our patients.
Sudden Death as a Complication of Anomalous Left Coronary Origin From the Anterior Sinus of Valsalva
Authors: MELVIN D. CHEITLIN, CARLOS M. DE CASTRO, HUGH A. MCALLISTER
Journal: Circulation (1974)

Both coronary arteries arising as a single or double vessel from the same sinus of Valsalva has been considered a minor congenital anomaly not affecting longevity. There are rare case reports in the literature of sudden death in young males with this anomaly of coronary origin. We have reviewed 51 such cases from the Armed Forces Institute of Pathology congenital heart disease accessions. There were 33 patients in whom both coronaries arose from the anterior sinus of Valsalva either as a single or double vessel and 18 in whom they arose from the left coronary sinus of Valsalva. Out of the 33 patients in whom the coronaries arose from the anterior sinus of Valsalva, 9 (27.3%) died sudden, unexplained deaths. There were no sudden unexplained deaths among the patients in whom both coronaries arose from the left sinus of Valsalva. It is evident that where the left coronary artery does not pass acutely posterior and leftward between the pulmonary artery and the aorta there is no risk of sudden death. All patients who died suddenly were male. The suggested mechanism for sudden death in these cases is that the acute leftward passage of the coronary artery along the aortic wall causes the entrance into the left coronary svstem to be slit-like. Under circumstances of increased cardiac activity with increased expansion of the pulmonary artery and aorta with exercise, there is stretching of the left coronary artery and a flap-like closure of the orifice of the left coronary with sudden, fatal myocardial ischemia. We also present the first case where this anomaly was recognized in a 14-year-old boy and a surgical attempt was made to correct the problem by creating a non-collapsible funnel-like opening into the left coronary artery.
Successful Treatment of Postpeak Stage Patients with Class II Division 1 Malocclusion Using Non‐extraction and Multiloop Edgewise Archwire Therapy: A Report on 16 Cases
Authors: Jun Liu, Ling Zou, Zhi‐he Zhao, Neala Welburn, Pu Yang, Tian Tang, Yu Li
Journal: International Journal of Oral Science (2009)

To determine cephalometrically the mechanism of the treatment effects of non‐extraction and multiloop edgewise archwire (MEAW) technique on postpeak Class II Division 1 patients. In this retrospective study, 16 postpeak Class II Division 1 patients successfully corrected using a non‐extraction and MEAW technique were cephalometrically evaluated and compared with 16 matched control subjects treated using an extraction technique. Using CorelDRAW® software, standardized digital cephalograms pre‐ and post‐active treatments were traced and a reference grid was set up. The superimpositions were based on the cranial base, the mandibular and the maxilla regions,and skeletal and dental changes were measured. Changes following treatment were evaluated using the paired‐sample t‐test. Student's t‐test for unpaired samples was used to assess the differences in changes between the MEAW and the extraction control groups. The correction of the molar relationships comprised 54% skeletal change (mainly the advancement of the mandible) and 46% dental change. Correction of the anterior teeth relationships comprised 30% skeletal change and 70% dental change. The MEAW technique can produce the desired vertical and sagittal movement of the tooth segment and then effectively stimulate mandibular advancement by utilizing the residual growth potential of the condyle.
Acute effects of catecholamines on function of the rat right heart
Authors: M. Irlbeck, H.-G. Zimmer
Journal: Cardiovascular Research (1993)

Journal Article Acute effects of catecholamines on function of the rat right heart Get access Michael Irlbeck, Michael Irlbeck Department of Physiology. University of Munich, Pettenkoferstrasse 12, 80336, Munchen, Germany: M Irlbeck, H-G Zimmer. Correspondence to Professor Zimmer. Search for other works by this author on: Oxford Academic PubMed Google Scholar Heinz-Gerd Zimmer Heinz-Gerd Zimmer Department of Physiology. University of Munich, Pettenkoferstrasse 12, 80336, Munchen, Germany: M Irlbeck, H-G Zimmer. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 27, Issue 12, December 1993, Pages 2146–2151, https://doi.org/10.1093/cvr/27.12.2146 Published: 01 December 1993
Hunt promises to reduce NHS bureaucracy by a third
Authors: H. Jaques
Journal: BMJ (2013)

The secretary of state for health for England, Jeremy Hunt, has commissioned Mike Farrar, chief executive of the NHS Confederation, to look at how to reduce “bureaucratic burdens” in the NHS by a third.

Farrar’s project will involve working with the national regulatory bodies to focus inspections on the outcomes that “matter most” to clinical success and patient care. Other approaches in the project will include ensuring that …
Abstract 460: The role of Cdc42 in cancer cell perineural invasion
Authors: Natalya Chernichenko, Tatiana Omelchenko, Sylvie Deborde, Richard Bakst, Shuangba He, Chun-Hao Chen, Alan Hall, Richard J. Wong
Journal: Cancer Research (2012)

Abstract Perineural invasion (PNI) is the ability of cancer cells to invade in, around, and along nerves. PNI is widely recognized as an adverse pathologic feature of many malignancies. Glial-derived neurotrophic factor (GDNF) is secreted by nerve and glial cells, and is important in neural development. We previously showed that GDNF activation of the RET/GFR-alpha tyrosine kinase in cancer cells induces chemotaxis towards nerves and PNI. Cdc42 is a member of the Rho family of G proteins and a key regulator of cell polarity. We demonstrate here that GDNF-mediated activation of RET/GFR-alpha leads to activation of Cdc42 as a mediator of cancer cell chemotaxis and PNI. Exposure of MiaPaCa2 cells to GDNF or dorsal root ganglia (DRG) activates Cdc42. SiRNA inhibition of Cdc42 impairs MiaPaCa2 chemotaxis towards GDNF or DRG in Boyden chamber assays. SiRNA inhibition of RET decreases Cdc42 activity under GDNF stimulation and MiaPaCa2 chemotaxis. To study dynamic interactions between nerves and cancer cells in vitro, we used a DRG and cancer cell co-culture model of PNI in matrigel. Analysis of individual cell trajectories reveals that cell velocity remains unchanged, while directional migration is disrupted with shRNA inhibition of Cdc42. The disruption of directional response impairs the ability of shRNA Cdc42 MiaPaCa2 cells to migrate along neurites, as visualized by time lapse microscopy and measured by area of PNI. MRI imaging of live mice with sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells reveals significantly diminished length and volume of PNI as compared with injected shRNA control cancer cells when matched for equivalent overall tumor volume. Murine sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells exhibited preserved hindlimb and hind paw neurologic function, and diminished perineural invasion by histopathologic examination as compared with shRNA control MiaPaCa2. To identify potential activators of Cdc42 in this model, we performed a comprehensive siRNA screen of guanine nucleotide exchange factors (GEFs), identifying specific GEFs which are necessary for MiaPaCa2 migration towards DRG in Boyden chambers. We identified and validated six GEFs (FLJ10521, DOCK9, ARHGEF7, RASGRF1, ARHGEF5, PLEKHG1) that impair chemotaxis without affecting proliferation. These findings provide novel insights into the molecular mechanisms underlying cancer cell perineural invasion. The RET-GEF-Cdc42 axis may be an attractive target for novel therapies that may potentially interrupt perineural invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 460. doi:1538-7445.AM2012-460
Glutathione depletion in epithelial lining fluid of lung allograft patients.
Authors: M A Baz, V F Tapson, V L Roggli, P Van Trigt, C A Piantadosi
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

The lower respiratory tract is protected against reactive oxygen species (ROS) by a complex antioxidant system. In the epithelial lining fluid (ELF), glutathione (L-alpha-glutamyl-L-cysteinylglycine, GSH) is essential for adequate protection of pneumocytes from potential toxicity mediated by extracellular hydrogen peroxide (H2O2). We assessed the concentration of total GSH in bronchoalveolar lavage fluid (BALF) in lung allograft patients in the absence and presence of acute rejection. Bronchoalveolar lavage (BAL) and biopsies were performed concurrently on 36 occasions in 17 patients who had undergone lung transplantation. BALF samples were divided into two groups on the basis of presence or absence of acute lung rejection on transbronchial biopsy. Seven BALF samples were obtained from control subjects for comparison. The BALF data demonstrated significantly lymphocyte recruitment and evidence of lung injury during acute rejection episodes. Transplant allografts without rejection showed significant depletion of total GSH in the ELF as compared with that of normal volunteers (94.0 +/- 9.7 microM versus 302.6 +/- 40.8 microM, p < 0.01). Transplant allografts with acute rejection had a slightly higher GSH concentration in their ELF (179.8 +/- 34.7), but this was still lower than control values. The deficiency of total GSH in the alveolar fluid may predispose lung allografts to extracellular H2O2-mediated toxicity.