bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity
Authors: Wither Joan , Cai Yong-chun , Lim Sooyeol , McKenzie Tamara , Roslin Nicole , Claudio Jaime O , Cooper Glinda S , Hudson Thomas J , Paterson Andrew D , Greenwood Celia MT , Gladman Dafna , Pope Janet , Pineau Christian A , Smith C Douglas , Hanly John G , Peschken Christine , Boire Gilles ,   CaNIOS Investigators, Fortin Paul R 
Published: September 2008

Abstract
Introduction
Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives.

Methods
Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.

Results
We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait.

Conclusions
The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.
The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas
Authors: Herschkowitz Jason I , He Xiaping , Fan Cheng , Perou Charles M 
Published: September 2008

Abstract
Introduction
Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in prognosis. One of these groups, the basal-like subtype, is poorly differentiated, highly metastatic, genomically unstable, and contains specific genetic alterations such as the loss of tumour protein 53 (TP53). The loss of the retinoblastoma tumour suppressor encoded by the RB1 locus is a well-characterised occurrence in many tumour types; however, its role in breast cancer is less clear with many reports demonstrating a loss of heterozygosity that does not correlate with a loss of RB1 protein expression.

Methods
We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples.

Results
RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy.

Conclusions
These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses.
Effects of inhaled iloprost on right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence: a randomized placebo-controlled trial in an experimental model of acute pulmonary hypertension
Authors: Rex Steffen , Missant Carlo , Claus Piet , Buhre Wolfgang , Wouters Patrick F 
Published: September 2008

AbstractIntroductionProstacyclin inhalation is increasingly used to treat acute pulmonary hypertension and right ventricular failure, although its pharmacodynamic properties remain controversial. Prostacyclins not only affect vasomotor tone but may also have cAMP-mediated positive inotropic effects and modulate autonomic nervous system tone. We studied the role of these different mechanisms in the overall haemodynamic effects produced by iloprost inhalation in an experimental model of acute pulmonary hypertension.MethodsIn this prospective, randomized, placebo-controlled animal study, twenty-six pigs (mean weight 35 ± 2 kg) were instrumented with biventricular conductance catheters, a pulmonary artery flow probe and a high-fidelity pulmonary artery pressure catheter. The effects of inhaled iloprost (50 μg) were studied in the following groups: animals with acute hypoxia-induced pulmonary hypertension, and healthy animals with and without blockade of the autonomic nervous system.ResultsDuring pulmonary hypertension, inhalation of iloprost resulted in a 51% increase in cardiac output compared with placebo (5.6 ± 0.7 versus 3.7 ± 0.8 l/minute;P= 0.0013), a selective reduction in right ventricular afterload (effective pulmonary arterial elastance: 0.6 ± 0.3 versus 1.2 ± 0.5 mmHg/ml;P= 0.0005) and a significant increase in left ventricular end-diastolic volume (91 ± 12 versus 70 ± 20 ml;P= 0.006). Interestingly, right ventricular contractility was reduced after iloprost-treatment (slope of preload recruitable stroke work: 2.2 ± 0.5 versus 3.4 ± 0.8 mWatt·s/ml;P= 0.0002), whereas ventriculo-vascular coupling remained essentially preserved (ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance: 0.97 ± 0.33 versus 1.03 ± 0.15). In healthy animals, inhaled iloprost had only minimal haemodynamic effects and produced no direct effects on myocardial contractility, even after pharmacological blockade of the autonomic nervous system.ConclusionsIn animals with acute pulmonary hypertension, inhaled iloprost improved global haemodynamics primarily via selective pulmonary vasodilatation and restoration of left ventricular preload. The reduction in right ventricular afterload is associated with a paradoxical decrease in right ventricular contractility. Our data suggest that this reflects an indirect mechanism by which ventriculo-vascular coupling is maintained at the lowest possible energetic cost. We found no evidence for a direct negative inotropic effect of iloprost.
Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo
Authors: Bosisio Daniela , Vulcano Marisa , Del Prete Annalisa , Sironi Marina , Salvi Valentina , Salogni Laura , Riboldi Elena , Leoni Flavio , Dinarello Charles A , Girolomoni Giampiero , Sozzani Silvano 
Published: September 2008

AbstractHistone deacetylase (HDAC) inhibitors are small molecules inducing cell-cycle arrest, differentiation, and apoptosis, currently undergoing clinical trials as anticancer drugs. In addition, emerging evidence suggests HDAC inhibitors may have anti-inflammatory and immunomodulatory properties as well, although the molecular mechanisms remain poorly defined. Given the central role of dendritic cells (DC) in the induction and maintenance of the inflammatory and immune response, we investigated the effects of HDAC inhibitors on the maturation and activation of human monocyte-derived DC in the presence of LPS and IFN-γ. Our results show that the production of TH1- and TH17-inducing cytokines, namely IL-12 and IL-23, was inhibited by trichostatin A (72% and 52%, respectively) and suberoylanilide hydroxamic acid (86% and 83%). Strikingly, HDAC inhibitors were effective if added simultaneously as well as after the proinflammatory challenge, and their effect was not associated to a reduction of expression or function of LPS/IFN-γ receptors. These findings were confirmed in two different murine models. In addition, HDAC inhibitors selectively blocked the production of TH1-attracting chemokines CXCL9, CXCL10, and CXCL11. The reduction of TH1- and TH17-inducing cytokines as well as TH1-attracting chemokines may represent relevant mechanisms through which HDAC inhibitors at nonproapoptotic doses exert their immunomodulatory properties.
The frequency of regulatory CD3+CD8+CD28−CD25+ T lymphocytes in human peripheral blood increases with age
Authors: Simone Rita , Zicca Anna , Saverino Daniele 
Published: September 2008

AbstractAging is commonly associated with immune deficiency and dysregulation. The aging of the immune system involves a progressive reduction in naïve T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells. We have investigated frequency, phenotype, and function of CD3+CD8+CD28−CD25+ T cells in healthy volunteers over a wide age range. We demonstrate that the frequency of CD3+CD8+CD28−CD25+ T cells in healthy volunteers increases with age. Peripheral CD3+CD8+CD28−CD25+ T cells share phenotypic and functional features with CD3+CD4+CD25+ regulatory T cells (Tregs): In particular, they strongly express CTLA-4 and forkhead box P3. We observed that in vitro, functional titration assays of CD3+CD8+CD28−CD25+ T cells show equivalent regulatory function in young and elderly donors, with suppression of proliferation and cytokine production in response to polyclonal T cell stimulation. Finally, CD3+CD8+CD28−CD25+ T cells seem to specifically express the CD122 receptor. Altogether, these observations demonstrate an increase in peripheral blood CD8+ Tregs associated with aging.
Prevention and Treatment of Pediatric Obesity: An Endocrine Society Clinical Practice Guideline Based on Expert Opinion
Authors: August Gilbert P. , Caprio Sonia , Fennoy Ilene , Freemark Michael , Kaufman Francine R. , Lustig Robert H. , Silverstein Janet H. , Speiser Phyllis W. , Styne Dennis M. , Montori Victor M. 
Published: September 2008

Objective: Our objective was to formulate practice guidelines for the treatment and prevention of pediatric obesity.Conclusions: We recommend defining overweight as body mass index (BMI) in at least the 85th percentile but &lt; the 95th percentile and obesity as BMI in at least the 95th percentile against routine endocrine studies unless the height velocity is attenuated or inappropriate for the family background or stage of puberty; referring patients to a geneticist if there is evidence of a genetic syndrome; evaluating for obesity-associated comorbidities in children with BMI in at least the 85th percentile; and prescribing and supporting intensive lifestyle (dietary, physical activity, and behavioral) modification as the prerequisite for any treatment. We suggest that pharmacotherapy (in combination with lifestyle modification) be considered in: 1) obese children only after failure of a formal program of intensive lifestyle modification; and 2) overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history of type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions. We suggest bariatric surgery for adolescents with BMI above 50 kg/m2, or BMI above 40 kg/m2 with severe comorbidities in whom lifestyle modifications and/or pharmacotherapy have failed. Candidates for surgery and their families must be psychologically stable and capable of adhering to lifestyle modifications. Access to experienced surgeons and sophisticated multidisciplinary teams who assess the benefits and risks of surgery is obligatory. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. We suggest that clinicians educate children and parents through anticipatory guidance about healthy dietary and activity habits, and we advocate for restricting the availability of unhealthy food choices in schools, policies to ban advertising unhealthy food choices to children, and community redesign to maximize opportunities for safe walking and bike riding to school, athletic activities, and neighborhood shopping.
Influences of Gender on the Interaction between Sympathetic Nerve Traffic and Central Adiposity
Authors: Tank Jens , Heusser Karsten , Diedrich Andre , Hering Dagmara , Luft Friedrich C. , Busjahn Andreas , Narkiewicz Krzysztof , Jordan Jens 
Published: September 2008

Context: Sympathetic activation promotes insulin resistance and arterial hypertension with increasing adiposity. A difference in the relationship between adiposity and sympathetic activity between women and men could contribute to the known gender difference in cardiovascular disease risk.
Objective: We tested whether muscle sympathetic nerve activity (MSNA) is correlated differently with waist circumference, waist to hip ratio (WHR), and body mass index (BMI) in women and men.
Design and Setting: We pooled data from two microneurography centers (Berlin, Germany; Gdansk, Poland) for a cross-sectional study.
Participants: We studied 111 normotensive, healthy Caucasian subjects (70 males and 41 females). Age ranged between 19 and 62 yr and BMI ranged between 18 and 40 kg/m2.
Intervention: No intervention was applied during the study.
Measurements: Supine heart rate, blood pressure, and MSNA were recorded after at least 30 min rest.
Results: MSNA in bursts per minute was age dependent in both sexes [r (male) = 0.56, r (female) = 0.34, P &lt; 0.01]. Controlling for waist and hip circumferences, age dependence remained highly significant in men (r = 0.43) and women (r = 0.43). Adjusting for age, in men, waist circumference (r = 0.29), WHR (r = 0.39), and BMI (r = 0.31) were predictive for MSNA and directly correlated (P &lt; 0.01) but not in women. Adjusting for BMI, in men, only WHR (r = 0.40) remained predictive for MSNA.
Conclusion: These data support the hypothesis of a gender difference in the regulation of the sympathetic nervous system, in which MSNA mainly relates to WHR in men but not women. The phenomenon may contribute to the sexual dimorphism in cardiovascular disease risk.
Changes in Adenosine 5′-Monophosphate-Activated Protein Kinase as a Mechanism of Visceral Obesity in Cushing’s Syndrome
Authors: Kola Blerina , Christ-Crain Mirjam , Lolli Francesca , Arnaldi Giorgio , Giacchetti Gilberta , Boscaro Marco , Grossman Ashley B. , Korbonits Márta 
Published: September 2008

Objective: Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushing’s syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushing’s syndrome.
Methods: AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushing’s syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery.
Results: The patients with Cushing’s syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P &lt; 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushing’s syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol.
Conclusions: Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing’s syndrome.
Effects of Information Disclosure Under First- and Second-Price Auctions in a Supply Chain Setting
Authors: Chen Ying-Ju , Vulcano Gustavo 
Published: September 2008

We study a supply chain where an upstream supplier auctions his inventory or capacity as a bundle. The importance of this setting is twofold: From a practical point of view, there are several examples, both in manufacturing (e.g., auctioning the capacity of a wafer fabrication facility) and service industries (e.g., auctioning the sponsorship of a website), where a supplier's capacity is sold as a single piece; from a theoretical side, it highlights the information asymmetry introduced on the downstream supply chain parties when the auction result is disclosed. We formulate the problem as a two-stage supply chain comprising a single supplier and two resellers. Each reseller receives a signal of the consumer demand and bids for the capacity of the supplier. The supplier announces the winner as well as the auction price. Both resellers can get additional units in a procurement market and then engage in Cournot competition in the consumer market. We analyze the impact of the information elicited by the supplier in the early stage of the game. We characterize sufficient conditions for the existence of equilibrium behavior, derive the equilibrium bidding functions under both first- and second-price auctions, and show that the bidding functions are lower than the corresponding ones for a single-shot auction without resale. Our computational experiments indicate that both the supplier and resellers are better off running a second-price auction and that consumers benefit if the resellers have very different signals on the total demand. Overall, our results suggest that traditional auctions may have a profound impact in the context of a supply chain because of the information disclosure in the upstream stages.
Dexmedetomidine Infusion as Adjunctive Therapy to Benzodiazepines for Acute Alcohol Withdrawal
Authors: Darrouj Jamil , Puri Nitin , Prince Erin , Lomonaco Anthony , Spevetz Antoinette , Gerber David R 
Published: September 2008

Objective: To report a case of alcohol withdrawal and delirium tremens successfully treated with adjunctive dexmedetomidine. Case Summary: A 30–year-old man with a history of alcohol abuse was admitted to the general medical unit because of altered mental status and agitation. He was initially treated for alcohol withdrawal with benzodiazepines; his condition then deteriorated and he was transferred to the intensive care unit. Because of the patient's poor response to benzodiazepines (oxazepam and lorazepam, with midazolam the last one used), intravenous dexmedetomidine was started at an initial dose of 0.2 µg/kg/h and titrated to 0.7 µg/kg/h to the patient's comfort. Midazolam was subsequently tapered to discontinuation due to excessive sedation. In the intensive care unit, the patient's symptoms remained controlled with use of dexmedetomidine alone. He remained in the intensive care unit for 40 hours; dexmedetomidine was then tapered to discontinuation and the patient was transferred back to the general medical unit on oral oxazepam and thiamine, which had been started in the emergency department. He was discharged after 5 days. Discussion: A review of the PubMed database (1989-2007} failed to identify any other instances of dexmedetomidine having been used as the principal agent to treat alcohol withdrawal. The use of sedative to treat delirium tremens Is well documented, with benzodiazepines being the agents of choice. The clinical utility of benzodiazepines is limited by their stimulation of the γ-aminobutyric acid receptors, an effect not shared by dexmedetomidine, a central α2-receptor agonist that induces a state of cooperative sedation and does not suppress respiratory drive. Conclusions: In patients with delirium tremens, dexmedetomidine should be considered as an option for primary treatment. This case illustrates the need for further studies to investigate other potential uses for dexmedetomidine.
Sustained-Release Fampridine for Symptomatic Treatment of Multiple Sclerosis
Authors: Korenke Anne R , Rivey Michael P , Allington Douglas R 
Published: September 2008

Objective: To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of sustained-release (SR) fampridine in patients with multiple sclerosis (MS). Data Sources: An English-language human data search was done using PubMed/MEDLINE (1966-August 2008) to retrieve relevant material using the search terms fampridine-SR, 4-aminopyridine. and multiple sclerosis. References of selected articles and information from the drug developer were used to further identify pertinent trials. Study Selection and Data Extraction: Article selection was based primarily on studies that evaluated the pharmacokinetics, safety, and efficacy of fampridine-SR in patients with MS. Relevant meeting abstracts were also included as part of the analysis. Data Synthesis: Fampridine-SR is a sustained-release, orally administered potassium-channel blocker acting in the central nervous system to enhance conduction in demyelinated axons Several small trials have evaluated the safety and efficacy of fampridine-SR in patients with MS to improve their walking ability. Data from a recent large Phase 3 trial indicated that walking speed improved in 42.9% of patients with MS who were treated with fampridine-SR compared with 9.3% of those who received placebo (p < 0.001), Treatment-related adverse events associated with the use of fampridine-SR include dizziness, insomnia, nausea, and paresthesia. More severe adverse events, such as seizure, have occurred in patients receiving doses higher than those currently recommended. Conclusions: Positive results from 2 Phase 3 clinical trials have put fampridine-SR on the path toward approval as a medication for improving walking speed and tower extremity strength in patients with MS.