tbuckley/cabot-search huggingface dataset:
C<scp>OMMON</scp> E<scp>NDOCRINE</scp> C<scp>ONTROL OF</scp> B<scp>ODY</scp> W<scp>EIGHT</scp>, R<scp>EPRODUCTION</scp>, <scp>AND</scp> B<scp>ONE</scp> M<scp>ASS</scp>
Authors: Shu Takeda, Florent Elefteriou, Gerard Karsenty
Journal: Annual Review of Nutrition (2003)

Bone mass is maintained constant between puberty and menopause by the balance between osteoblast and osteoclast activity. The existence of a hormonal control of osteoblast activity has been speculated for years by analogy to osteoclast biology. Through the search for such humoral signal(s) regulating bone formation, leptin has been identified as a strong inhibitor of bone formation. Furthermore, intracerebroventricular infusion of leptin has shown that the effect of this adipocyte-derived hormone on bone is mediated via a brain relay. Subsequent studies have led to the identification of hypothalamic groups of neurons involved in leptin's antiosteogenic function. In addition, those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Finally, the peripheral mediator of leptin's antiosteogenic function has been identified as the sympathetic nervous system. Sympathomimetics administered to mice decreased bone formation and bone mass. Conversely, beta-blockers increased bone formation and bone mass and blunted the bone loss induced by ovariectomy.
Therapeutic Potential of Janus-activated Kinase-2 Inhibitors for the Management of Myelofibrosis
Authors: Srdan Verstovsek
Journal: Clinical Cancer Research (2010)

Abstract Myelofibrosis (either primary or postpolycythemia vera/essential thrombocythemia) is a chronic and debilitating myeloproliferative neoplasm for which there is no well-accepted standard of care. Clinical manifestations of this disease (e.g., cytopenias, splenomegaly, bone marrow fibrosis) and constitutional symptoms (e.g., hypercatabolic state, fatigue, night sweats, fever) create significant treatment challenges. For example, progressive splenomegaly increases the risk for more serious clinical sequelae (e.g., portal hypertension, splenic infarction). Myelofibrosis arises from hematopoietic stem cells or early progenitor cells. However, the molecular mechanisms underlying its pathogenesis and clinical presentation are poorly understood, delaying the development of effective and targeted treatments. Recent studies have implicated mutations that directly or indirectly lead to the deregulated activation of Janus-activated kinase 2 (JAK2). Appreciation for the activation of JAK2 and the importance of increased levels of circulating proinflammatory cytokines in the pathogenesis and clinical manifestations of myelofibrosis has led to novel therapeutic agents targeting JAKs. This review will briefly discuss the origins of the JAK2 hypothesis, the clinical relevance of JAK2 mutations in myelofibrosis, and recent clinical progress in targeting JAKs as a therapeutic intervention for patients with this chronic and debilitating disease. Clin Cancer Res; 16(7); 1988–96. ©2010 AACR.
Evidence-based and complementary medicine
Authors: J. Main
Journal: Journal of the Royal Society of Medicine (2004)

Dr Butterworth (March 2004 JRSM1) describes how a relative of his was diagnosed as hypertensive and put on a succession of medicines with near disastrous consequences. This chain of events had nothing to do with the vogue for evidence-based medicine. Rather, it reflects the enormous difficulty of practising good and safe medicine in the era of effective but dangerous drugs. The proliferation of life-prolonging as opposed to symptom-reducing drugs makes clinical medicine complex and time consuming—though no-one would guess this from the mass of guidelines and protocols and the devolution of traditional medical tasks to non-doctors, all based on a fundamentally faulty world view where everything is either right or wrong, good or bad, black or white. Such reductionist inanity now extends to assessments of massive hospitals or even the whole NHS.

It was not what clinical trials have told us about treating hypertension that poisoned Dr Butterworth's relative. Whether he met any standard criteria for hypertension requiring drug treatment is not clear. To treat consequent dizziness with another drug appears simply crass; life, however, is complex, and we do not know the patient's blood pressure at the time this decision was made. Under-treated as well as over-treated hypertension can cause dizziness. The wise old general practitioner who took him off all medications may well have saved this man, but for all we know has over the years missed the opportunity to prevent dozens of strokes by adopting a ‘common sense’ approach to the management of hypertension in the asymptomatic elderly. Common sense, like evidence-based medicine, should be used only when appropriate.

Thank goodness we live in the era of dangerous and powerful drugs. Though the public may think that brain surgeons or heart surgeons have the most challenging jobs in medicine, in future the most difficult tasks will be polypharmacy in the elderly with multiple medical problems, to achieve the best combination of wellbeing and longevity. To master those arts will require lifelong education, natural empathy and most importantly, time and desire to think before prescribing. It is not the concept of evidence-based medicine we need fear, it is that of immediately demonstrable value for money.
Metabolic Syndrome in Normal-Weight Americans
Authors: Marie-Pierre St-Onge, Ian Janssen, Steven B. Heymsfield
Journal: Diabetes Care (2004)

OBJECTIVE—To determine the prevalence rates and likelihood of the metabolic syndrome and its individual components in normal-weight and slightly overweight individuals (BMI 18.5–26.9 kg/m2). RESEARCH DESIGN AND METHODS—There were a total of 7,602 adult participants of the Third National Health and Nutrition Examination Survey, a nationally representative cross-sectional survey. Prevalence and odds ratios (ORs) of the metabolic syndrome, defined according to National Cholesterol Education Program Adult Treatment Panel III criteria, were computed according to 2.0- to 2.5-unit increments in BMI. RESULTS—Depending on ethnicity and sex, the prevalence of the metabolic syndrome increased in a graded fashion from 0.9–3.0% at BMI 18.5–20.9 kg/m2 to 9.6–22.5% at BMI 25.0–26.9 kg/m2. Compared with men with BMI 18.5–20.9 kg/m2, the odds for the metabolic syndrome were 4.13 (95% CI 1.57–10.87) for men with BMI 21–22.9 kg/m2, 5.35 (2.41–11.86) for men with BMI 23–24.9 kg/m2, and 9.08 (4.23–19.52) for men with BMI 25–26.9 kg/m2 after controlling for age, ethnicity, education, income, physical activity, smoking status, and alcohol and total fat, saturated fat, carbohydrate, and fiber intakes. The corresponding ORs in women were 4.34 (2.08–9.07), 7.77 (3.95–15.26), and 17.34 (9.29–32.38). CONCLUSIONS—Individuals in the upper normal-weight and slightly overweight BMI range have a relatively high prevalence and are at increased risk of having the metabolic syndrome. Therefore, screening in individuals with normal or slightly elevated BMI is important in the prevention of diabetes and cardiovascular disease.
Localization of BDNF mRNA with the Huntington's disease protein in rat brain
Authors: Bin Ma, Brady P Culver, Gabriele Baj, Enrico Tongiorgi, Moses V Chao, Naoko Tanese
Journal: Molecular Neurodegeneration (2010)

Studies have implicated reduced levels of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Huntington's disease. Mutant huntingtin (Htt) protein was previously reported to decrease BDNF gene transcription and axonal transport of BDNF. We recently showed that wild-type Htt is associated with the Argonaute 2 microRNA-processing enzyme involved in gene silencing. In dendrites, Htt co-localizes with components of neuronal granules and mRNAs, indicating that it might play a role in post-transcriptional processing/transport of dendritic mRNAs.We conducted imaging experiments in cultured cortical neurons to demonstrate the co-localization of endogenous Htt and BDNF mRNA in fixed cells, and co-trafficking of BDNF 3'UTR mRNA with endogenous and fluorescently tagged Htt in live neurons. We used an enhanced technique that combines FISH and immunofluorescent staining to co-localize BDNF mRNA with Htt, Ago2, CPEB and dynein in thick vibratome sections of the rat cortex.In cultured neurons and sections of the rat cortex, we found BDNF mRNA associated with Htt and components of neuronal RNA granules, which are centers for regulating RNA transport and local translation. Htt may play a role in post-transcriptional transport/targeting of mRNA for BDNF, thus contributing to neurotrophic support and neuron survival.
Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice
Authors: Bo Wang, Sarmila Majumder, Gerard Nuovo, Huban Kutay, Stefano Volinia, Tushar Patel, Thomas D. Schmittgen, Carlo Croce, Kalpana Ghoshal, Samson T. Jacob
Journal: Hepatology (2009)

MicroRNAs (miRs) are conserved, small (20-25 nucleotide) noncoding RNAs that negatively regulate expression of messenger RNAs (mRNAs) at the posttranscriptional level. Aberrant expression of certain microRNAs plays a causal role in tumorigenesis. Here, we report identification of hepatic microRNAs that are dysregulated at early stages of feeding C57BL/6 mice choline-deficient and amino acid–defined (CDAA) diet that is known to promote nonalcoholic steatohepatitis (NASH)-induced hepatocarcinogenesis after 84 weeks. Microarray analysis identified 30 hepatic microRNAs that are significantly ( P ≤ 0.01) altered in mice fed CDAA diet for 6, 18, 32, and 65 weeks compared with those fed choline-sufficient and amino acid–defined (CSAA) diet. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis demonstrated up-regulation of oncogenic miR-155, miR-221/222, and miR-21 and down-regulation of the most abundant liver-specific miR-122 at early stages of hepatocarcinogenesis. Western blot analysis showed reduced expression of hepatic phosphatase and tensin homolog (PTEN) and CCAAT/enhancer binding protein beta (C/EBPβ), respective targets of miR-21 and miR-155, in these mice at early stages. DNA binding activity of nuclear factor kappa B (NF-κB) that transactivates miR-155 gene was significantly ( P = 0.002) elevated in the liver nuclear extract of mice fed CDAA diet. Furthermore, the expression of miR-155, as measured by in situ hybridization and real-time RT-PCR, correlated with diet-induced histopathological changes in the liver. Ectopic expression of miR-155 promoted growth of hepatocellular carcinoma (HCC) cells, whereas its depletion inhibited cell growth. Notably, miR-155 was significantly ( P = 0.0004) up-regulated in primary human HCCs with a concomitant decrease ( P = 0.02) in C/EBPβ level compared with matching liver tissues. Conclusion: Temporal changes in microRNA profile occur at early stages of CDAA diet-induced hepatocarcinogenesis. Reciprocal regulation of specific oncomirs and their tumor suppressor targets implicate their role in NASH-induced hepatocarcinogenesis and suggest their use in the diagnosis, prognosis, and therapy of liver cancer. (Hepatology 2009.)
Corticosteroid Insufficiency in Acutely Ill Patients
Authors: Mark S. Cooper, Paul M. Stewart
Journal: New England Journal of Medicine (2003)

Recent studies report benefits from corticosteroid treatment in patients with septic shock. This review summarizes the physiology of the corticosteroid response in acute illness. The authors present an updated, practical approach to the diagnosis and treatment of hypoadrenalism in acutely ill patients. Supplemental corticosteroid treatment may be beneficial in many critical illnesses.
Bacillary dysentery from World War 1 and NCTC1, the first bacterial isolate in the National Collection
Authors: Alison E Mather, Kate S Baker, Hannah McGregor, Paul Coupland, Pamela L Mather, Ana Deheer-Graham, Julian Parkhill, Philippa Bracegirdle, Julie E Russell, Nicholas R Thomson
Journal: The Lancet (2014)
BMA urges caution over MPs' request to collect data on patients addicted to prescription drugs
Authors: A. O'Dowd
Journal: BMJ (2013)

Tough action is needed to tackle the growing problems of patients addicted to prescription drugs and of deaths linked to psychoactive substances, MPs have said.

In a report published on 20 December by the home affairs select committee, MPs warned that the United Kingdom was facing an “epidemic” of psychoactive substances such as mephedrone, with the number of deaths rising by 79% in the past year from 29 in 2011 to 52 in 2012.

There was also a serious and underestimated problem with more than 1.5 million people addicted to prescription drugs in the UK, the report said, which should be dealt with by asking GPs to start collecting anonymous data on patients with an addiction.

The …
Nontraditional Risk Factors and Biomarkers for Cardiovascular Disease: Mechanistic, Research, and Clinical Considerations for Youth
Authors: Prabhakaran (Babu) Balagopal, Sarah D. de Ferranti, Stephen Cook, Stephen R. Daniels, Samuel S. Gidding, Laura L. Hayman, Brian W. McCrindle, Michele L. Mietus-Snyder, Julia Steinberger
Journal: Circulation (2011)

The rapid increase in the prevalence and severity of obesity in children is likely to lower the age of onset and increase the incidence of cardiovascular disease worldwide. Understanding the pathophysiology and improving the clinical management of cardiovascular disease involve a knowledge of novel risk factors and biomarkers. The clinical and mechanistic roles of these novel biological factors during childhood are currently being investigated. The goals of this scientific statement are to present the existing knowledge and theoretical framework of nontraditional risk factors for cardiovascular disease as they relate to children and adolescents, to describe the relevance and weight of available experimental and clinical evidence and the therapeutic implications pertaining to nontraditional risk factors in the pediatric population, and to stimulate further research with a goal of developing valid and reliable approaches to identify and validate novel risk factors that will aid in the clinical evaluation and perhaps prediction of cardiovascular disease in the pediatric population. Although several biomarkers are promising, substantial research is required before nontraditional risk factors can be used to identify and reduce cardiovascular disease risk in children and adolescents.
The Immunology of Fibrosis
Authors: Georg Wick, Cecilia Grundtman, Christina Mayerl, Thomas-Florian Wimpissinger, Johann Feichtinger, Bettina Zelger, Roswitha Sgonc, Dolores Wolfram
Journal: Annual Review of Immunology (2013)

Fibrosis is the production of excessive amounts of connective tissue, i.e., scar formation, in the course of reactive and reparative processes. Fibrosis develops as a consequence of various underlying diseases and presents a major diagnostically and therapeutically unsolved problem. In this review, we postulate that fibrosis is always a sequela of inflammatory processes and that the many different causes of fibrosis all channel into the same final stereotypical pathways. During the inflammatory phase, both innate and adaptive immune mechanisms are operative. This concept is exemplified by fibrotic diseases that develop as a consequence of tissue damage, primary inflammatory diseases, fibrotic alterations induced by foreign body implants, “spontaneous” fibrosis, and tumor-associated fibrotic changes.
P139 Atelectasis following bronchoscopic lung volume reduction (BLVR) is associated with improved survival in COPD
Authors: N. S. Hopkinson, S. V. Kemp, T. P. Toma, D. M. Hansell, D. M. Geddes, P. L. Shah, M. I. Polkey
Journal: Thorax (2010)

<h3>Background</h3> A range of bronchoscopic therapies are being developed to reduce lung volumes in COPD patients, either in order to avoid the morbidity and mortality associated with lung volume reduction surgery, or to extend therapy to patient groups in whom LVRS is not appropriate because of disease pattern or severity. <h3>Aims</h3> Bronchoscopic lung volume reduction (BLVR), using endobronchial valves to target unilateral lobar occlusion in patients with heterogeneous emphysema has been shown to improve lung function and exercise capacity in patients with emphysema. Benefit was most pronounced in, though not confined to, patients where lobar atelectasis occurred. Little data exists on the long-term outcome following BLVR. <h3>Study population</h3> 19 patients (16 males) FEV<sub>1</sub> 28.4 (11.9) underwent BLVR between July 2002 and February 2004. Radiological atelectasis was observed in five patients. Survival data to February 2010 was available for all patients. The age dyspnoea obstruction (ADO) score was used to calculate predicted mortality. <h3>Results</h3> None of the patients in whom atelectasis occurred died during follow up whereas eight out of 14 in the non-atelectasis group died (χ<sup>2</sup> p=0.026) (Abstract P139 Figure 1). There was no significant difference between the groups at baseline in lung function, quality of life, exacerbation rate, exercise capacity (shuttle walk test or cycle ergometry) or CT appearances, although BMI was significantly higher in the atelectasis group 21.6(2.9) vs 28.4 (2.9) kg.m<sup>−2</sup> (p&lt;0.001). Pre treatment CT appearances did not differ significantly between the atelectasis and non-atelectasis groups in terms of degree of emphysema at either the upper or lower parts of the lungs or in heterogeneity (slope) in either the treated or non-treated lung prior to treatment. ADO score, predicted 3 year mortality was 31.1 (10.0)% in the non-atelectasis group and 32.2 (15.1)% in the atelectasis group (p=0.8). Four of the eight deaths occurred within 3 years of the procedure, representing a 29% mortality rate for the non-atelectasis group (ie, close to that predicted). <h3>Conclusions</h3> These data suggest that atelectasis following BLVR is associated with a survival benefit which is not explained by differences at baseline.
Upregulation of 5′-AMP–Activated Protein Kinase Is Responsible for the Increase in Myocardial Fatty Acid Oxidation Rates Following Birth in the Newborn Rabbit
Authors: A-Olufemi Makinde, James Gamble, Gary D. Lopaschuk
Journal: Circulation Research (1997)

In newborn rabbits, fatty acid oxidation rates in the heart significantly increase between 1 and 7 days after birth. This is due in part to a decrease in malonyl coenzyme A (CoA) production by acetyl CoA carboxylase (ACC). In other tissues, 5'-AMP-activated protein kinase (AMPK) can phosphorylate and inhibit ACC activity. In this study, we show that 1- and 7-day-old rabbit hearts have a high AMPK activity, with AMPK expression and activity being greatest in 7-day-old hearts. Hearts were also perfused in the Langendorff mode with Krebs-Henseleit buffer containing 0.4 mmol/L [14C]palmitate and 11 mmol/L glucose +/- 100 microU/mL insulin. In the absence of insulin, fatty acid oxidation rates were significantly higher in 7-day-old hearts compared with 1-day-old hearts. AMPK activity was also greater in 7-day-old hearts compared with 1-day-old hearts (909 +/- 60 and 585 +/- 75 pmol.min-1.mg protein-1, respectively; P < .05). In 1-day-old hearts, the presence of insulin resulted in a significant decrease in AMPK activity, an increase in ACC activity, and a decrease in fatty acid oxidation rates. In 7-day-old hearts, AMPK activity was also decreased by insulin, although ACC activity remained low and fatty acid oxidation rates remained high. Stimulation of AMPK in 7-day-old hearts with 200 mumol/L 5-amino 4-imidazolecarboxamide ribotide resulted in a further decrease in ACC activity and an increase in fatty acid oxidation rates. These data suggest that AMPK, ACC, and fatty acid oxidation are sensitive to insulin in 1-day-old rabbit hearts and that the decrease in circulating insulin levels seen after birth leads to an increased activity of AMPK. This can then lead to a phosphorylation and inhibition of ACC activity, with a resultant increase in fatty acid oxidation rates.
Identifying the Interaction Between Influenza and Pneumococcal Pneumonia Using Incidence Data
Authors: Sourya Shrestha, Betsy Foxman, Daniel M. Weinberger, Claudia Steiner, Cécile Viboud, Pejman Rohani
Journal: Science Translational Medicine (2013)

Influenza virus increases susceptibility to pneumococcal pneumonia in individuals but has only a modest impact on the total population.
Polyurethane or Methacrylate For Arthroplasty
Authors: C. Andrew L. Bassett
Journal: JAMA (1972)

<h3>To the Editor.—</h3> I have just read, with considerable interest and dismay, Dr. Mandarino's reply (219:512, 1972) to Dr. Eftekhar's article on low-friction arthroplasty (218:705, 1971). Dr. Mandarino suggests, if I interpret his remarks properly, that we reconsider the use of polyurethane foam (Ostamer) as a substitute for methylmethacrylate as the "filler" material in low-friction arthroplasty. Should any of your readers, whom he implores to become innovative, decide to follow this approach, they first should determine the incidence of problems with Ostamer. These were adequately documented in the early 1960s, to such a degree that the material no longer is in general use by the orthopedists. Furthermore, they should ascertain the position of the Food and Drug Administration on Ostamer. This is not the place to engage in a detailed discussion of the biological and biomechanical properties of polyurethane vis-à-vis methyl-methacrylate. Suffice it to say, that the latter material has
Classification of Sleep-disordered Breathing
Authors: JEAN-JACQUES HOSSELET, INDU AYAPPA, ROBERT G. NORMAN, ANA C. KRIEGER, DAVID M. RAPOPORT
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Increasing recognition of sleep-disordered breathing (SDB) and its morbidity have prompted reevaluation of techniques to identify respiratory events during sleep. The present study was designed to evaluate the utility of various metrics of SDB and to identify the optimal respiratory metric that objectively correlates to symptoms of excessive daytime somnolence (EDS). Metrics were derived from combinations of conventional apnea/hypopnea, flow limitation events (transient elevated upper airway resistance identified by characteristic flattening on the flow/time tracing, using a noninvasive nasal cannula technique), desaturation, and arousal. A total of 137 subjects underwent clinical evaluation and nocturnal polysomnogram. In 34 randomly selected subjects, the best metrics for discriminating between 13 subjects with no EDS/snoring and 21 patients with EDS and snoring were identified by receiver operator curve analysis. Of the metrics and cut points tested, a total respiratory disturbance index (RDITotal, sum of apneas, hypopnea, and flow limitation events) of 18 events/h was found to have the best discriminant ability (100% sensitivity and 96% specificity). Prospective testing of this metric was then performed with the remaining 103 subjects (14 nonsnoring non-EDS, 21 snoring non-EDS, 68 snoring with EDS). Using this cutoff of 18 events/h, we obtained 71% sensitivity and 60% specificity for identifying subjects with EDS. We conclude that, in subjects with upper airway dysfunction, an index that incorporates all respiratory events provides the best quantitative physiological correlate to EDS.
Liver enzymes and vitamin D levels in metabolically healthy but obese individuals: Korean National Health and Nutrition Examination Survey
Authors: Ho Cheol Hong, Ji-Sung Lee, Hae Yoon Choi, Sae Jeong Yang, Hye Jin Yoo, Ji A Seo, Sin Gon Kim, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi, Kyung Mook Choi
Journal: Metabolism (2013)