tbuckley/cabot-search huggingface dataset:
PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding
Authors: Lihong Long, Chitoku Toda, Jing Kwon Jeong, Tamas L. Horvath, Sabrina Diano
Journal: Journal of Clinical Investigation (2014)

Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.
GA<sup>2</sup>LEN/EAACI pocket guide for allergen‐specific immunotherapy for allergic rhinitis and asthma
Authors: T. Zuberbier, C. Bachert, P. J. Bousquet, G. Passalacqua, G. Walter Canonica, H. Merk, M. Worm, U. Wahn, J. Bousquet
Journal: Allergy (2010)

To cite this article: Zuberbier T, Bachert C, Bousquet PJ, Passalacqua G, Walter Canonica G, Merk H, Worm M, Wahn U, Bousquet J. GA 2 LEN/EAACI pocket guide for allergen‐specific immunotherapy for allergic rhinitis and asthma. Allergy 2010; 65 : 1525–1530. Abstract This pocket guide is the result of a consensus reached during several GA 2 LEN and EAACI meetings. The aim of the current pocket guide is to offer a comprehensive set of recommendations on the use of immunotherapy in allergic rhinoconjunctivitis and asthma in daily practice. This pocket guide is meant to give simple answers to the most frequent questions of practitioners in Europe, including ‘practising allergists’, general practitioners and any other physicians with special interest in allergen‐specific immunotherapy (SIT). It is not a long or detailed scientific review of the topic. However, the recommendations in this pocket guide were compiled following an in‐depth review of existing guidelines and publications, including the 1998 EAACI position paper, the 1998 WHO Position Paper on SIT and the 2001 Allergic Rhinitis and its Impact on Asthma (ARIA). It is also based on the ARIA update 2008 (prepared in collaboration with GA 2 LEN), the ‘Sub‐lingual Immunotherapy: WAO Position Paper 2009’ (from the World Allergy Organisation) and the Methodology paper of ARIA. The recommendations cover patient selection, allergen extract to be used, route of administration of SIT (in particular, sublingual and subcutaneous immunotherapy), and necessary precautions to be followed in using SIT.
Dermoscopic Findings in Cutaneous Metastases
Authors: Karen A. Chernoff, Ashfaq A. Marghoob, Mario E. Lacouture, Liang Deng, Klaus J. Busam, Patricia L. Myskowski
Journal: JAMA Dermatology (2014)

Cutaneous metastases rarely develop in patients with cancer but have important implications for prognosis and treatment. While dermoscopy is useful for many skin lesions, few data exist regarding dermoscopic findings in cutaneous metastases.We reviewed high-quality dermoscopic images of 20 outpatients with biopsy-proven cutaneous metastases and known diagnosis of underlying visceral malignancy and correlated these findings with clinical and histologic data. Most lesions were pink or flesh-colored, but 3 of 20 were pigmented. All 17 nonpigmented lesions demonstrated a vascular pattern on dermoscopy, with 15 of 17 (88%) having discrete vessels and 2 of 17 (12%) showing pink homogeneous structureless areas. Serpentine, or linear irregular, vessels were most common. In the 3 pigmented lesions (all metastatic breast carcinoma), various melanocytic patterns were observed.Dermoscopically visible vascular structures within a cutaneous nodule in patients with a known cancer diagnosis should raise suspicion for cutaneous metastasis. Pigmentation in such lesions, in the absence of a history of melanoma, suggests a primary breast carcinoma. The high prevalence of vascular structures among cutaneous metastases may suggest a role for angiogenesis in their pathogenesis. These findings support the use of dermoscopy in the evaluation of suspected skin metastases or in the assessment of lesions of unknown origin in patients with cancer.
Rats Transgenic for Human Renin and Human Angiotensinogen as a Model for Gestational Hypertension
Authors: JU[Combining Diaeresis]RGEN BOHLENDER, DETLEV GANTEN, FRIEDRICH C. LUFT
Journal: Journal of the American Society of Nephrology (2000)

Animal models of gestational hypertension are problematic. A novel mouse model was described earlier. The dams in that study were transgenic for human angiotensinogen and the sires for human renin; human renin was expressed in and produced by the placenta. This model was adapted to the rat, which has greater utility in terms of chronic instrumentation and physiologic measurements. Female rats transgenic for human angiotensinogen were mated with rats transgenic for human renin. Telemetry BP increased on day 5 of pregnancy from 110/80 mmHg to as high as 180/140 mmHg, while heart rate increased slightly. The renin transgene was expressed in the placenta, which resulted in increased human plasma renin concentration from 0 to 937 +/- 800 ng angiotensin I ml/h; the values returned to 0 after delivery. Female rats transgenic for human renin that were mated with male rats transgenic for human angiotensinogen in contrast exhibited a decrease in BP. In these rats, human angiotensinogen in plasma remained undetectable. Double transgenic offspring of these transgenic rats developed hypertension and end-organ damage, regardless of the source of the transgenes. The conclusion is that transgenic rats that bear human renin and angiotensinogen genes make an attractive model for gestational hypertension. The rat model will have greater utility than the mouse model.
Shear Stress Causes Nuclear Localization of Endothelial Glucocorticoid Receptor and Expression From the GRE Promoter
Authors: Julie Y. Ji, Huiyan Jing, Scott L. Diamond
Journal: Circulation Research (2003)

We tested the hypothesis that steady laminar shear stress activates the glucocorticoid receptor (GR) and its transcriptional signaling pathway in an effort to investigate the potential involvement of GR in shear stress-induced antiatherosclerosis actions in the vasculature. In both bovine aortic endothelial cells (BAECs) and NIH3T3 cells expressing GFP-GR chimeric protein, wall shear stress of 10 or 25 dynes/cm2 caused a marked nuclear localization of GFP-GR within 1 hour to an extent comparable to induction with 25 micromol/L dexamethasone. The shear mediated nuclear localization of GFP-GR was significantly reduced by 25 micromol/L of the MEK1 inhibitor (PD098059) or the PI 3-kinase inhibitor (LY294002). Also, Western blots demonstrated translocation of endogenous GR into nucleus of sheared BAECs. Promoter construct studies using glucocorticoid response element (GRE)-driven expression of secreted alkaline phosphatase (SEAP) indicated that BAECs exposed to shear stress of 10 and 25 dynes/cm2 for 8 hours produced >9-fold more SEAP (n=6; P<0.005) than control cells, a level comparable to that observed with dexamethasone. Shear stress enhanced SEAP expression at 6 hours was reduced 50% (n=5; P<0.005) by MEK1/2 or PI 3-kinase inhibitors, but not by the NO inhibitor, L-NAME. Finally, in human internal mammary artery, endothelial GR is found to be highly nuclear localized. We report a new shear responsive transcriptional element, GRE. The finding that hemodynamic forces can be as potent as high dose glucocorticoid steroid in activating GR and GRE-regulated expression correlates with the atheroprotective responses of endothelial cells to unidirectional arterial shear stress.
Aggressive granulomatous mycosis fungoides with clinical pulmonary and thyroid involvement
Authors: E. Gómez-De La Fuente, P.L. Ortiz, F. Vanaclocha, J.L. Rodriguez-Peralto, L. Iglesias
Journal: British Journal of Dermatology (2000)

We report a patient with granulomatous mycosis fungoides (MF) that progressed to a tumoral pattern and finally developed clinical pulmonary and thyroid involvement, despite multiple and intensive treatments. We emphasize the visceral involvement in this case, which was manifest as dyspnoea simulating pneumonia and by palpable thyroid nodules. These features are very unusual even in classic MF, and this is the first case in our knowledge of thyroid involvement in granulomatous MF.
The origin of urinary angiotensins in humans.
Authors: P F Vos, P Boer, B Braam, H A Koomans
Journal: Journal of the American Society of Nephrology (1994)

To examine whether urinary angiotensin (ANG) I and II excretion responds to changes in plasma ANG I and ANG II, ANG I or ANG II was infused in seven healthy subjects pretreated with a 340-mmol sodium diet and 20 mg of enalapril twice daily. Infusion rates were 4, 8, 16, and 32 pmol/kg per minute for ANG I and 1, 4, and 8 pmol/kg per minute for ANG II. Baseline ANG I and ANG II excretions averaged 10 and 20 fmol/min, respectively, which is approximately 0.3 and 5% of the filtered loads. Despite a 20-fold increase in plasma ANG I during ANG I infusion, urinary ANG I did not increase. Similarly, the 30-fold increase in plasma ANG II during ANG II infusion was not followed by an increase in ANG II excretion, but in fact by a decrease in urinary ANG I and ANG II. In a separate study, urinary ANG I and ANG II were measured before and after the oral administration of 20 mg of enalapril in eight healthy volunteers taking 400, 200, or 20 mmol of NaCl daily. In contrast to the considerable effects on plasma ANG I and ANG II and renal hemodynamics, enalapril had no effect on urinary ANG I and ANG II. Variation of sodium intake had predictable effects on plasma ANG I and ANG II but did not affect urinary ANG I and ANG II. These data suggest that urinary ANG I and ANG II originate from an intrarenal source. The independency of sodium intake and ANG-converting enzyme make the juxtaglomerular apparatus as the site responsible for the production of this ANG unlikely.
Effects of imidapril on NOS expression and myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats
Authors: Naohiko Kobayashi, Teruo Higashi, Kazuyoshi Hara, Hiromichi Shirataki, Hiroaki Matsuoka
Journal: Cardiovascular Research (1999)

Objectives: To elucidate the relationship between renin–angiotensin system and nitric oxide in hypertensive heart failure, we evaluated the effects of long-term treatment with imidapril, an angiotensin-converting enzyme inhibitor, on endothelial-cell nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in the left ventricle (LV) and its relation to myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats (DS) fed a high-salt diet. Methods: In DS rats fed an 8% NaCl diet after the age of 6 weeks, a stage of concentric left ventricular hypertrophy at 11 weeks (DSLVH) was followed by a distinct stage of fatal left ventricular failure with chamber dilatation at 18 weeks (DSCHF). Imidapril (DSCHF-I, n=7, 1 mg/kg/day, subdepressor dose) or vehicle (DSCHF-V, n=7) were given from DSLVH to DSCHF stage for 7 weeks, and age-matched (18 weeks) Dahl salt-resistant rats fed the same diet were served as control group (DR-C, n=7). Results: Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSCHF-V was significantly ameliorated in DSCHF-I using transthoracic echocardiography. The level of eNOS mRNA and protein in the LV was significantly suppressed in DSCHF-V compared with DR-C, and significantly increased in DSCHF-I compared with DR-C and DSCHF-V. The iNOS mRNA and protein and the fibrosis factor expression of type I collagen mRNA were significantly increased in DSCHF-V compared with DR-C, and significantly decreased in DSCHF-I compared with DSCHF-V. DSCHF-V demonstrated a significant increase in wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These changes in the microvasculature were improved significantly by imidapril. Conclusions: Subdepressor dose of imidapril may ameliorate the endothelial damage not only by inhibiting production of angiotensin II but also by promoting eNOS and inhibiting iNOS mRNA and protein expression in the LV, and this increased eNOS mRNA and protein level may have a role in the improvement of congestive heart failure and myocardial remodelling.
Safety of long-acting -agonists: urgent need to clear the air remains
Authors: R. Beasley, F. D. Martinez, A. Hackshaw, K. F. Rabe, P. J. Sterk, R. Djukanovic
Journal: European Respiratory Journal (2008)

The introduction of long-acting β-agonist (LABA) drugs in the 1990s was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life 1, 2. There were also potential safety advantages due to the twice daily, fixed dose usage, which reduced the risk of overuse of β-agonist therapy in the situation of severe exacerbations. The subsequent introduction of the combination of LABA/inhaled corticosteroid (ICS) products had the added potential value of ensuring that the patient received concomitant ICS therapy while improving compliance with ICS therapy 3, 4.

However, concerns about the possible risks associated with LABA therapy were raised soon after their introduction into clinical practice, with the evidence that regular LABA use had the potential to reduce bronchodilator sensitivity to β-agonists 5, 6 and induce tolerance to their bronchoprotective effects 7, which may not be restored by concurrent use of ICS 8. It also became apparent that patients using LABAs may be at risk of severe exacerbations if the symptom control achieved with LABA use led to a discontinuation of ICS therapy 9. There were also concerns about a potential risk of mortality from the Salmeterol Nationwide Surveillance Study 10. In this UK-based study of >25,000 subjects, there was a nonsignificant three-fold increased risk of asthma death in subjects treated with salmeterol compared with regular salbutamol; however, there was no increase in hospital admissions or life-threatening events. This led to the USA-based Salmeterol Multicenter Asthma Research Trial (SMART), a placebo-controlled study of the safety of salmeterol in adults with unstable asthma 11. The trial was stopped after an interim analysis of 26,000 subjects because it showed a statistically significant, four-fold increase in asthma mortality with salmeterol. Unfortunately, due to low …
Trichomonas vaginalis is dependent on uptake and degradation of human low density lipoproteins.
Authors: K M Peterson, J F Alderete
Journal: The Journal of Experimental Medicine (1984)

Human plasma low density lipoprotein uptake by the urogenital pathogen, Trichomonas vaginalis, was examined. Rapid binding and internalization of 125I-labeled low density lipoproteins by live T. vaginalis was observed at 37 degrees C. Data showing parasite degradation of the internalized apoproteins and lipid accumulation following low density lipoprotein uptake was obtained. Acquisition of low density lipoproteins was by a trichomonad surface protein that possessed a molecular weight of greater than 250,000. The receptor is specific for apolipoprotein CIII, a component of high, low, and very low density lipoprotein subfractions. Low density lipoproteins in a semi-defined medium of trypticase, nucleic acid precursors, vitamins, and maltose promoted T. vaginalis growth and multiplication at rates and levels equal to the yeast extract-trypticase-serum complex medium routinely used for culture of trichomonads. HeLa cell membranes as a source of lipids were unable to sustain T. vaginalis organisms. These data demonstrate host lipoprotein internalization by T. vaginalis via a specific uptake mechanism.
Hereditary angio-oedema in Denmark: a nationwide survey
Authors: A. Bygum
Journal: British Journal of Dermatology (2009)

Hereditary angio-oedema (HAE) is a rare disease caused by deficiency of complement C1 inhibitor (C1 inhibitor). The diagnosis is challenging as the disease can have a variety of clinical manifestations. In 2001 a national HAE comprehensive care centre was established and a search for these patients was initiated.To identify and characterize all patients with HAE in Denmark and increase awareness of the disease.Patients were recruited from hospital departments, dermatologists in private practice, Centres for Rare Diseases, the Danish patient organization and the national reference laboratory. Family interviews were conducted and medical records were evaluated. Information was spread through lectures, articles in popular magazines and via television. National guidelines for diagnosis and treatment were published.Eighty-two patients were identified. The mean diagnostic delay was 16.3 years. Five patients had HAE type II. Forty-five patients reported a characteristic serpiginous rash (erythema marginatum). More than 90% of patients had noticed precipitating factors before skin and mucosal swellings. Four patients underwent a total of eight tracheotomies and five families recalled 11 relatives who died of HAE.The minimal prevalence of HAE in Denmark is approximately 1.41 per 100 000 inhabitants. The risk of upper airway obstruction underlines the importance of diagnosing these patients. Precipitating factors, a preceding or concomitant serpiginous erythema and cutaneous swelling and/or abdominal pain attack and/or laryngeal oedema are clues to the diagnosis. As a consequence of this survey, information has been spread to patients, families and physicians.
Relationship Between Maternal Mid Pregnancy Folate Levels and the Risk of Allergic and Respiratory Diseases in Early Childhood: The Mothers and Children's Environmental Health (MOCEH) Study
Authors: Ja Hyeong Kim, Kyoung-Sook Jeong, Eun-Hee Ha, Hye sook Park, Mi na Ha, Yun-Chul Hong, Soo-Young Bhang, Soo-Jeong Lee, Kyung Yeon Lee, Seon-Ho Lee, Yang ho Kim, Ju-Suk Lee, Jin-A. Jung, Nam Soo Chang
Journal: Journal of Allergy and Clinical Immunology (2013)
Can we improve on how we select medical students?
Authors: P. Hughes
Journal: Journal of the Royal Society of Medicine (2002)

Getting the right policy for admission to medical school is a balancing act: be fair to society by choosing people with the potential to be good doctors; and be fair to the applicants—that diverse group of people who for many reasons want to set out on the long road to a medical career. Selection is not an exact science but we must use what evidence we have to ensure that we do our best by all concerned. There is widespread agreement that we should select future doctors on wider criteria than scores of academic success1,2, though in practice many medical schools have valued pre-admission academic scores at the expense of other considerations3. There are recognized drawbacks to the use of school exam performance even as a measure of intellectual competence. One study has shown that a major causal determinant of A level results is social class, independent of ability4, and some would-be medical students elect to focus on sciences for their school leaving exams because very high marks are more easily achieved in the physical sciences than in the humanities5. The conviction that only exam results give valid and reliable data has been trenchantly dismissed as a ‘seductive but fallacious’ belief in the precision of quantitative tests6. We are reminded that all selective instruments depend on subjective judgments and each must be accountable to the rules of reason, fairness and public scrutiny7. However, if we decide to consider non-cognitive criteria, a legitimate concern is that the many specialties of medicine need diverse skills and they must not be too narrow. We also want to be reassured, if we include noncognitive characteristics, that we can assess them reliably and that such evaluation can predict personal character over years of practice.

While we need to maintain diversity of skills and personality, there are some characteristics which we demand in any doctor. Enough intellectual ability to do the job, plus honesty, integrity and conscientiousness, must be at the heart of good practice8. Helpfulness and willingness to cooperate come close behind8, while patients give high priority to interpersonal skills and empathy2. The personal welfare of the profession is another consideration9. Doctors are more vulnerable than comparable professional groups to alcoholism, drug abuse and suicide10,11. Burnout is well recognized, and has a high cost for the individual, for colleagues and for the quality of service that patients get12. One answer may be better support for psychologically vulnerable doctors12,13 (together with improved working conditions for all doctors), but perhaps we should try to evaluate ability to deal with stress right from the start.
Urinary and Sexual Function After Radical Prostatectomy for Clinically Localized Prostate Cancer
Authors: Janet L. Stanford, Ziding Feng, Ann S. Hamilton, Frank D. Gilliland, Robert A. Stephenson, J. William Eley, Peter C. Albertsen, Linda C. Harlan, Arnold L. Potosky
Journal: JAMA (2000)

ContextPatients with prostate cancer and their physicians need knowledge of treatment options and their potential complications, but limited data on complications are available in unselected population-based cohorts of patients.ObjectiveTo measure changes in urinary and sexual function in men who have undergone radical prostatectomy for clinically localized prostate cancer.DesignThe Prostate Cancer Outcomes Study, a population-based longitudinal cohort study with up to 24 months of follow-up.SettingPopulation-based cancer registries in 6 geographic regions of the United States.ParticipantsA total of 1291 black, white, and Hispanic men aged 39 to 79 years who were diagnosed as having primary prostate cancer between October 1, 1994, and October 31, 1995, and who underwent radical prostatectomy within 6 months of diagnosis for clinically localized disease.Main Outcome MeasuresDistribution of and change in urinary and sexual function measures reported by patients at baseline and 6, 12, and 24 months after diagnosis.ResultsAt 18 or more months following radical prostatectomy, 8.4% of men were incontinent and 59.9% were impotent. Among men who were potent before surgery, the proportion of men reporting impotence at 18 or more months after surgery varied according to whether the procedure was nerve sparing (65.6% of non–nerve-sparing, 58.6% of unilateral, and 56.0% of bilateral nerve–sparing). At 18 or more months after surgery, 41.9% reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age (39.0% of men aged &lt;60 years vs 15.3%-21.7% of older men were potent at ≥18 months [P&lt;.001]; 13.8% of men aged 75-79 years vs 0.7%-3.6% of younger men experienced the highest level of incontinence at ≥18 months [P = .03]), and sexual function also varied by race (38.4% of black men reported firm erections at ≥18 months vs 25.9% of Hispanic and 21.3% of white men; P = .001).ConclusionsOur study suggests that radical prostatectomy is associated with significant erectile dysfunction and some decline in urinary function. These results may be particularly helpful to community-based physicians and their patients with prostate cancer who face difficult treatment decisions.