tbuckley/cabot-search huggingface dataset:
Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes
Authors: Toshimasa Yamauchi, Hironori Waki, Junji Kamon, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Hiroshi Miki, Naoto Kubota, Yasuo Terauchi, Atsuko Tsuchida, Nobuyo Tsuboyama-Kasaoka, Naoko Yamauchi, Tomohiro Ide, Wataru Hori, Shigeaki Kato, Masashi Fukayama, Yasuo Akanuma, Osamu Ezaki, Akiko Itai, Ryozo Nagai, Satoshi Kimura, Kazuyuki Tobe, Hiroyuki Kagechika, Koichi Shudo, Takashi Kadowaki
Journal: Journal of Clinical Investigation (2001)

PPARγ is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARγ by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARγ activity observed in heterozygous PPARγ-deficient mice or the Pro12Ala polymorphism in human PPARγ, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARγ/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARγ antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARγ-deficient mice with an RXR antagonist or a PPARγ antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARγ/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.
Low plasma cortisol concentrations during late asthmatic responses.
Authors: T Nakazawa, Y Umegae, S Matsui, S Kobayashi
Journal: BMJ (1985)

13 malades asthmatiques, non traites par corticoides, sont soumis a des epreuves d'inhalation d'allergene. Ils presentent des reponses asthmatiques soit tardives, soit precoces, soit des 2 types. Les taux plasmatiques de cortisol sont significativement plus bas dans les cas de reponse tardive
Factors Correlating With Improved A1C in Children Using Continuous Subcutaneous Insulin Infusion
Authors: Jennifer J.F. McVean, Jens C. Eickhoff, Michael J. MacDonald
Journal: Diabetes Care (2007)

The Diabetes Control and Complications Trial demonstrated that tight metabolic control in patients with type 1 diabetes reduces the risk of microvascular complications (1). Subsequently, the use of continuous subcutaneous insulin infusion (CSII) to achieve strict metabolic control increased exponentially. The advantages of CSII over multiple daily injections include increased lifestyle flexibility, variable basal infusion rates with boluses given before meals, and only one injection for insulin administration every few days (2). CSII in children lowers A1C and decreases hypoglycemia (3,4). The American Diabetes Association recommended A1C treatment goals for pediatric patients of 7.5–8.5% for those aged <6 years, ≤8% for those aged 6–12 years, <7.5% for those aged 13–19 years, and <7% for those aged 19–22 years (5), but few children and adolescents reach these goals. The reason for this remains unclear. We conducted this study to determine the percentage of children using CSII who reached their A1C goal and to identify differences between children who met their goal and those who did not.

Medical records of all patients (aged 2–22 years, n = 236) with type 1 diabetes for ≥1 year using CSII for ≥6 months who were followed at the University of Wisconsin pediatric diabetes clinic were reviewed. Data from the time of initiation of CSII were analyzed. Age, duration of diabetes, …
A Model for Predicting Development of Overt Hepatic Encephalopathy in Patients With Cirrhosis
Authors: Oliviero Riggio, Piero Amodio, Alessio Farcomeni, Manuela Merli, Silvia Nardelli, Chiara Pasquale, Ilaria Pentassuglio, Stefania Gioia, Eugenia Onori, Nicole Piazza, Michele De Rui, Sami Schiff, Sara Montagnese
Journal: Clinical Gastroenterology and Hepatology (2015)
Corrigendum to “Robotic gastric resection of large gastrointestinal stromal tumors” [Int J Surg 11 (2013) 191–196]
Authors: Jacopo Desiderio, Stefano Trastulli, Roberto Cirocchi, Carlo Boselli, Giuseppe Noya, Amilcare Parisi, Davide Cavaliere
Journal: International Journal of Surgery (2013)
Inappropriate prescribing is "treatable"
Authors: R. C Tallis
Journal: BMJ (1995)

EDITOR,--I read R E Ferner's editorial on drug errors with mixed feelings.1 Over a decade ago Gosney and I drew attention to inappropriate prescribing (the prescribing of contraindicated drugs and drugs with adverse interactions) for elderly patients admitted to hospital.2 We subsequently extended our surveys to patients seen in accident and emergency departments,3 patients in long term care wards, and patients in residential homes. We suggested that the conventional explanation …
Unexpected Island Effects at an Extreme: Reduced Y Chromosome and Mitochondrial DNA Diversity in Nias
Authors: M. van Oven, J. M. Hammerle, M. van Schoor, G. Kushnick, P. Pennekamp, I. Zega, O. Lao, L. Brown, I. Kennerknecht, M. Kayser
Journal: Molecular Biology and Evolution (2010)

The amount of genetic diversity in a population is determined by demographic and selection events in its history. Human populations which exhibit greatly reduced overall genetic diversity, presumably resulting from severe bottlenecks or founder events, are particularly interesting, not least because of their potential to serve as valuable resources for health studies. Here, we present an unexpected case, the human population of Nias Island in Indonesia, that exhibits severely reduced Y chromosome (non-recombining portion of the Y chromosome [NRY]) and to a lesser extent also reduced mitochondrial DNA (mtDNA) diversity as compared with most other populations from the Asia/Oceania region. Our genetic data, collected from more than 400 individuals from across the island, suggest a strong previously undetected bottleneck or founder event in the human population history of Nias, more pronounced for males than for females, followed by subsequent genetic isolation. Our findings are unexpected given the island's geographic proximity to the genetically highly diverse Southeast Asian world, as well as our previous knowledge about the human history of Nias. Furthermore, all NRY and virtually all mtDNA haplogroups observed in Nias can be attributed to the Austronesian expansion, in line with linguistic data, and in contrast with archaeological evidence for a pre-Austronesian occupation of Nias that, as we show here, left no significant genetic footprints in the contemporary population. Our work underlines the importance of human genetic diversity studies not only for a better understanding of human population history but also because of the potential relevance for genetic disease–mapping studies.
Immunohistochemical study of angiotensin receptors in human anagen hair follicles and basal cell carcinoma
Authors: H. Takeda, Y. Katagata, S. Kondo
Journal: British Journal of Dermatology (2002)

Angiotensin receptors are the specific receptors of angiotensin II of the renin-angiotensin system. However, expression of the receptors in hair follicles has not been determined.To clarify the expression and localization of angiotensin receptors in human anagen hair follicles and basal cell carcinomas.We studied immunohistochemically the expression of angiotensin type 1(AT1) and type 2 (AT2) receptors in human anagen hair follicles and in 16 cases of basal cell carcinoma (BCC) (nine of solid BCC of the circumscribed type, two of adenoid BCC, five of BCC with follicular differentiation).Our experiments demonstrated the localization of AT1 in the inner root sheath and the inner layers of the outer root sheath. In BCC, positive staining with AT1 was revealed in the tumour cells of basal cell carcinoma with follicular differentiation.AT1 may have a role in association with follicular keratinization. Studying AT1 distribution may be useful in understanding the pathophysiology of human hair follicles and the hair follicle-associated tumours.
Characterization of two hepatitis B virus populations isolated from a hepatitis B surface antigen-negative patient
Authors: Damien Jeantet, Isabelle Chemin, Bernard Mandrand, Fabien Zoulim, Christian Trepo, Alan Kay
Journal: Hepatology (2002)

In a study of surface antigen-negative, but weakly hepatitis B virus (HBV) DNA-positive, patients, we were able to amplify and clone whole HBV genomes from the serum of a cirrhotic patient. Sequencing showed that the patient harbored two different HBV populations, one of genotype A and the other of genotype D, with the genotype D genome apparently predominating. The surface antigen of the genotype A virus is heavily mutated, especially in the extracellular ≪ determinant a ≫ region, with several mutations that have not been previously described. The genotype D virus is a precore mutant. Both genomes possess the common A1762T-G1764A double mutation of the basal core promoter (BCP), and the genotype D virus is also mutated in the ≪ TATA box ≫ of the large surface antigen promoter. Biological characterization showed that the genotype A genome was fully replication-competent, whereas the genotype D genome replicated poorly. The small surface antigen of the genotype A virus was only very weakly recognized by commercial tests. The small surface antigen of the genotype D virus could be recognized by the tests, but it was mainly retained within transfected cells, probably because of an excess of large surface antigen. In conclusion, the cryptic nature of this double HBV infection is characterized by the predominance of the replication-deficient genotype D virus over the replication-competent genotype A virus.
Adrenalectomy and hypophysectomy for carcinoma of the prostate
Authors: J. T. Grayback
Journal: JAMA (1969)

Initial attempts to modify the endocrine status of patients with carcinoma of the prostate resulted from acceptance of the assumptions that this neoplasm usually is hormonally controlled and that the response of the malignant prostate to hormonal stimulation is similar to that of normal prostate.<sup>10</sup>The frequently prompt therapeutic response seen following orchiectomy and estrogen administration reinforced these assumptions. The variability in degree and duration of the response to these initial efforts, coupled with the persistent acceptance of the assumptions on which endocrine therapy is based, prompted a search for sources of endogenous hormones which might serve as a continuing stimulus to prostatic growth. Eventually, this focused attention on the adrenals and pituitary and led to utilization of adrenalectomy and hypophysectomy in treating patients with carcinoma of the prostate. Evidence indicating that the adrenals might contribute to stimulation of prostatic growth came from two sources. Studies in animals demonstrated
Comparative airway response to high- versus low-molecular weight agents in occupational asthma
Authors: M-H. Dufour, C. Lemiere, P. Prince, L-P. Boulet
Journal: European Respiratory Journal (2009)

Airway responses to occupational agents in sensitised workers may vary clinically and physiologically. The patterns of change in airway responsiveness, type of response and fall in expiratory flows following laboratory exposure to high- or low-molecular weight agents (HMW and LMW agents, respectively) were compared in sensitised workers. Data on workers who underwent specific inhalation challenges with occupational sensitisers (117 exposed to HMW agents and 130 to LMW agents) were collected from their medical charts. Maximum falls in forced expiratory volume in one second (FEV<sub>1</sub>) were of similar magnitude for both types of agents. Compared with HMW agents, LMW agents induced more frequently late or dual responses and higher increases in airway responsiveness. After exposure to HMW agents, there was a mean±sd reduction in doubling concentrations of methacholine of 0.5±1.7 for early responses, compared with 2.8±1.2 and 1.4±2.0 for late and dual responses, respectively. Isolated early responses were more frequently found in females, smokers, workers with a higher % predicted FEV<sub>1</sub> and higher provocation concentration causing a 20% fall in FEV<sub>1</sub>, and in those with longer asthma duration. Workers' characteristics, as well as the type of agent they are sensitised to, may help to predict the type of response after specific inhalation challenge.
Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin
Authors: Sarah Srodulski, Savita Sharma, Adam B Bachstetter, Jennifer M Brelsfoard, Conrado Pascual, Xinmin Simon Xie, Kathryn E Saatman, Linda J Van Eldik, Florin Despa
Journal: Molecular Neurodegeneration (2014)

We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function. In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. We exploited this fact by comparing rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels. Compared to WT rats, HIP rats show i) reduced exploratory drive, ii) impaired recognition memory and iii) no ability to improve the performance on the rotarod. The development of neurological deficits is associated with amylin accumulation in the brain. The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates is almost double in HIP rats compared with WT littermates (P < 0.05). Large amylin deposits (>50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin alters the brain structure at the molecular level. Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which are clustering in areas positive for amylin infiltration. Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that amylin deposition in the brain induces a neuroinflammatory response. Hyperamylinemia promotes accumulation of oligomerized amylin in the brain leading to neurological deficits through an oligomerized amylin-mediated inflammatory response. Additional studies are needed to determine whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline.
A case of pulmonary AV fistula. Possible involvement of adenosine in hyperventilation.
Authors: S Kobayashi, M Nishimura, Y Nasuhara, K Miyamoto, Y Kawakami
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

A 21-yr-old man with multiple pulmonary AV fistulae presented with moderate hypoxemia with chronic hyperventilation, which continued even after sufficient oxygenation by 100% O2 inhalation. The infusion of aminophylline, an adenosine receptor blocker, not only increased PaCO2 from 35 to 39 mm Hg but also depressed the magnitude of hypoxic ventilatory response (HVR). After a surgical removal of the major fistulae, PaCO2 increased to 42 mm Hg. At this time, aminophylline increased the resting ventilation and slightly augmented the HVR value, which was opposite to the findings of preoperation. Dipyridamole, which potentiates endogenous adenosine by inhibiting its cellular uptake, increased the magnitude of HVR both before and after the operation. We propose that the hyperventilation observed in this case can at least in part be attributed to the ventilatory stimulation by endogenous adenosine, which presumably passed through the fistulae without being metabolized in the pulmonary circulation.
HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis
Authors: Julio Madrigal-Matute, Carlos Ernesto Fernandez-Garcia, Carmen Gomez-Guerrero, Oscar Lopez-Franco, Begoña Muñoz-Garcia, Jesus Egido, Luis Miguel Blanco-Colio, Jose Luis Martin-Ventura
Journal: Cardiovascular Research (2012)

Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis.Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells.Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.
P30 The changing face of pulmonary hypertension: the role of heart and lung disease
Authors: S. Crawley, M. Johnson, A. Peacock
Journal: Thorax (2010)

<h3>Introduction</h3> The advent of disease-targeted therapy for pulmonary arterial hypertension (PAH) has led to an increased awareness of this condition within the general cardiology and respiratory communities. More patients are being referred to specialist centres for diagnostic assessment, however there is concern that many will have pulmonary hypertension (PH) due to underlying lung disease or left heart disease. <h3>Aim</h3> The aim of the study was to review the outcome of diagnostic admissions to the Scottish Pulmonary Vascular Unit (SPVU) before (2003–2005) and after (2006–2009) the introduction of disease-targeted PAH therapy. <h3>Methods</h3> 470 new patients with suspected PH were admitted between January 2003 and December 2009 for diagnostic assessment including right heart catheterisation (RHC). Demographic and haemodynamic data from these patients were retrospectively reviewed. Following RHC patients were diagnosed with: – Group 1. PAH; – Group 2. Pulmonary venous hypertension (PVH) due to left heart disease; – Group 3. PH due to hypoxic lung disease (HLDPH); – Group 4. Chronic thromboembolic PH (CTEPH); – Group 5. PH due to unclear multifactorial mechanisms (PH Misc); – No PH. <h3>Results</h3> In 2003–2005, 114 patients underwent diagnostic assessment, and 112 had PH. Of these 77.7% had PAH and 18.8% had CTEPH. Only 2.7% of patients had PVH and 0.8% had HLDPH. In 2006–2009, 356 patients underwent diagnostic assessment, and 308 had PH. Of these only 51.9% had PAH and 15.9% had CTEPH. However, now 17.9% of patients had PVH, and 10.4% had HLDPH. 48 patients had No PH at the time of RHC (Abstract P30 Figure 1). <h3>Conclusion</h3> Prior to admission all referrals are screened by an SPVU consultant, but despite this there are a significant number of patients proceeding to RHC who will have PH due to left heart or lung disease. This highlights the importance of fully assessing all patients with suspected PH, as per ESC/ERS 2009 guidelines, before instituting expensive and potentially dangerous PAH therapy. We need to improve our non-invasive screening methods so that fewer patients proceed to RHC who do not have PAH.
A Dual Role of CD4 <sup>+</sup> T Cells in Adipose Tissue?
Authors: Christian M. Matter, M. A. Sokrates Stein
Journal: Circulation Research (2009)

R ecent studies project an exponential increase in type 2 diabetes mellitus, obesity, and the metabolic syndrome not only in Western but also in developing countries. 1This perspective suggests an alarming rise in morbidity, mortality, and health care costs associated with these diseases.Thus, for improving prevention, diagnosis, and therapy of these diseases, we need a better understanding of the genetic, molecular, cellular, and environmental interactions that govern these metabolic derangements.Chronic inflammation plays a pivotal role in insulin resistance and obesity that shares many pathogenetic aspects with atherogenesis. 2 Hotamisligil and coworkers were the first to describe a role of proinflammatory cytokines in obesity.They reported an increase in tumor necrosis factor (TNF)␣ in the white adipose tissue of obese mice that correlated with insulin resistance. 3Meanwhile, this notion has been extended from mice to men and to other cytokines such as monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1, and IL-6 that have been found to be involved in obesity and insulin resistance. 4 -6 At the cellular level, most reports have highlighted macrophages as the key directors of this inflammatory concert. 5,6ess is known about the role of adaptive immunity in obesity.Recent studies reveal that obese mice and men also exhibit an increase in adipose tissue T cells and the corresponding chemokines such as RANTES (regulated on activation, normal T-cell expressed and secreted) or cytokines such as interferon (IFN)-␥. 7,8Nevertheless, the relevance of T cells in this context remains to be determined. 9n this issue of Circulation Research, Sultan et al describe the effects of T cell-mediated inflammation in lean atherosclerotic mice focusing on the role of IL-6 on insulin resistance in adipose tissue. 10The authors used ApoE Ϫ/Ϫ CD4dnTGFbR mice that display enhanced T cell activation attributable to disrupted TGF-␤ signaling and observed increased number of macrophages and CD4 ϩ T cells, as well as enhanced expression and secretion of TNF␣, IFN␥, and MCP-1 in adipose tissue.Unexpectedly, IL-6 was not elevated, but lower in ApoE Ϫ/Ϫ CD4dnTGFbR compared with obese ob/ob and even wild-type mice.