Miracle-dz/UniFAR-FTUs huggingface dataset:
Exon skipping and severe childhood‐onset obesity caused by a leptin receptor mutation

Obesity is a chronic disorder that is believed to be due to numerous interacting genetic and non-genetic factors as typically found in multifactorial diseases [Walley et al., 2009]. The prevalence of childhood obesity has strongly increased during the last decades, most dramatically in high-income countries and urban areas [Han et al., 2010]. Childhood obesity is less prevalent in low-income countries; for example, in Pakistan its current prevalence has been estimated to be 4–8% [Warraich et al., 2009; Mushtaq et al., 2012], as compared to >10% in most European and North American countries [Jackson-Leach and Lobstein, 2006; Lobstein and Jackson-Leach, 2007; Sinha and Kling, 2009]. Although monogenic obesity due to highly penetrant mutations accounts for a small proportion of childhood-onset obesity only, research into these forms has contributed to a better understanding of biological pathways underlying energy balance and weight control, such as the leptin–melanocortin system, a potential target for pharmacological intervention [Heymsfield et al., 1999; Feng et al., in press]. Leptin is a peptide hormone secreted by white adipocytes that plays a key role in energy control [Mantzoros et al., 2011]. Biallelic mutations of the genes encoding leptin (LEP) and its receptor (LEPR) have been identified in individuals presenting with severe obesity due to hyperphagia starting in infancy [Montague et al., 1997; Strobel et al., 1998; Clément et al., 1998]. LEPRmutations are further associated with short stature due to the lack of a pubertal growth spurt, alterations in immune function, and hypogonadotropic hypogonadism leading to delayed puberty [Farooqi et al., 2007]. Conversely, LEPRmutations are usually not associated with intellectual disability or congenital malformations. We have studied a large Pakistani family with multiple consanguinity loops in which five individuals (four males, one female) in four branches had severe autosomal recessive early-onset obesity (Fig. 1A). Pregnancy, delivery and motor and cognitive developmentwere unremarkable in the proband (Individual VII: 6; Fig. 1A, B), but from his first years of life a compulsive food-seeking behavior led to accelerated weight gain. On examination at age 15 years he was obese with a weight of 66 kg. He had short stature with a height of 146 cm. Thus, his body-mass index (BMI) was 31.0 kg/m (98th centile according to CDC growth charts; http:// www.cdc.gov/growthcharts). Intelligence was normal and there were no congenital anomalies and no dysmorphic facial features. Routine blood chemistry including lipid profiling was normal, as
Selection and evolution of virulence in bacteria: an ecumenical excursion and modest suggestion

Summary Why do parasites kill their hosts? During this past decade, research in three different areas; evolutionary ecology, medical microbiology, and population genetics has provided theory and data that address this and related questions of selection and the evolution and maintenance of parasite virulence. A general theory of parasite–host coevolution and the conditions for selection to favour parasite virulence has been put forth. Considerable advances have been made in elucidating the mechanisms of pathogenicity and inheritance of virulence in bacteria. The population genetic structure and the relation ship between pathogenic and non-pathogenic forms has been determined for a number of species of bacteria. We critically review these developments and their implications for questions of selection and the evolution and maintenance of virulence in bacteria. We postulate how selection may operate on specific types of bacterial virulence and present a general protocol to experimentally test hypotheses concerning selection and the evolution of virulence in bacteria.
Six-year progression of retinopathy and associated risk factors in African American patients with type 1 diabetes mellitus: the New Jersey 725.

OBJECTIVE To report the 6-year progression of diabetic retinopathy (DR) and associated risk factors among African American patients with type 1 (insulin-dependent) diabetes mellitus. METHODS Participants from the New Jersey 725 included 483 African American patients with type 1 diabetes who underwent reexamination as part of a 6-year follow-up. Evaluations included a structured clinical interview, ocular examination, 7 stereoscopic fundus photographs, and blood pressure measurements. Severity of DR was determined via masked grading of fundus photographs. Biological evaluation included blood and urine assays. RESULTS During the 6-year period, 56.1% of patients at risk showed progression of DR; 15.0% showed progression to proliferative DR; and 15.9% developed macular edema. A baseline high glycosylated hemoglobin level and systemic hypertension were significant risk factors for progression of DR, progression to proliferative DR, and incidence of macular edema. Progression to proliferative DR was significantly associated with baseline older age, renal disease, and severity of DR. The incidence of macular edema was significantly associated with baseline older age, low socioeconomic status, severity of DR, and total serum cholesterol level. CONCLUSIONS Six-year progression of DR is high in African American patients with type 1 diabetes. Improving glycemic and blood pressure control may reduce the ocular morbidity of diabetes in African Americans.
Articular tissues expressing the env-pX transgene are required for generation of arthritogenic T cells in human T cell leukemia virus type I transgenic rats.

OBJECTIVE Human T cell leukemia virus type I env-pX transgenic rats (env-pX rats) were used to investigate the pathogenesis of arthritis. METHODS Phenotype of cells infiltrated into arthritic joints in env-pX rats was analyzed using flow cytometry and cell-transfer experiments were done using env-pX and wild-type WKAH rats. RESULTS The majority of T cells infiltrated into arthritic joints in env-pX rats exhibited a CD4 and activated phenotype. Transfer of these T cells into articular space in wild-type WKAH rats succeeded to induce arthritis similarly seen in env-pX rats. However, injection of the cells into sites other than joints did not induce inflammation. Transfer of in vitro-stimulated lymph node cells from disease-free env-pX rats into articular space did not induce arthritis in wild-type WKAH rats. CONCLUSION These findings suggest that articular tissues carrying the env-pX transgene are required for generation of arthritogenic T cells in env-pX rats. However, the constitutive antigens other than the transgene products are recognized as immunological targets by the arthritogenic T cells in the advanced arthritic joints. Molecules expressed specifically in articular tissues may be needed to maintain the inflammatory cell infiltration.
A benefit–risk assessment of class III antiarrhythmic agents

The prevalence of arrhythmia in the population is increasing as more people survive for longer with cardiovascular disease. It was once thought that antiarrhythmic therapy could save life, however, it is now evident that antiarrhythmic therapy should be administrated with the purpose of symptomatic relief. Since many patients experience a decrease in physical performance as well as a diminished quality of life during arrhythmia there is still a need for antiarrhythmic drug therapy. The development of new antiarrhythmic agents has changed the focus from class I to class III agents since it became evident that with class I drug therapy the prevalence of mortality is considerably higher. This review focuses on the benefits and risks of known and newer class III antiarrhythmic agents. The benefits discussed include the ability to maintain sinus rhythm in persistent atrial fibrillation patients, and reducing the need for implantable cardioverter defibrillator shock/antitachycardia therapy, since no class III antiarrhythmic agents have proven survival benefit. The risks discussed mainly focus on pro-arrhythmia as torsade de pointes ventricular tachycardia.
Xanthine Oxidoreductase and Translational Potential Enhanced Vasodilator Activity of Nitrite in Hypertension : Critical Role for Erythrocytic

Nigel Alexandra B. Milsom, Rayomand Khambata, Sheiva Maleki-Toyserkani, Mubeen Yousuf, Suborno M. Ghosh, Vikas Kapil, Isabel Fuentes-Calvo, Kristen J. Bubb, Vanessa Pearl, Xanthine Oxidoreductase and Translational Potential Enhanced Vasodilator Activity of Nitrite in Hypertension : Critical Role for Erythrocytic Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 2013 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Hypertension doi: 10.1161/HYPERTENSIONAHA.111. 00933 2013;61:1091-1102; originally published online April 15, 2013; Hypertension. http://hyper.ahajournals. org/content/61/5/1091 World Wide Web at: The online version of this article, along with updated information and services, is located on the
Jason-1/Jason-2 Metocean Comparisons and Monitoring

The initial tandem phase of the Jason-2 mission is important for the calibration of the entire altimetric system, not just the records of sea surface height. As well as allowing a bulk comparison of metocean parameters such as wave height and backscatter strength (used to infer wind speed), the tandem phase also affords a more detailed opportunity to understand the artefacts within each instrument. The wave height comparison shows no bias between the instruments, with the mismatch error of consecutive points independent of one another. The backscatter difference is not a simple offset but also has a trend with weak nonlinear variations. The technique for backscatter monitoring using Ku-/C-band differences is validated during the tandem phase, and extended to show ∼59-day oscillations throughout the Jason-1 mission. This effect, which is predominantly in the C-band, is related to changing solar exposure due to the fraction of orbit in eclipse varying as the orbit precesses. Such anomalies were partially present in TOPEX-B data but are not noticeable for Jason-2. It is recommended that all TOPEX, Jason-1, and Jason-2 data be transformed to a consistent scale, allowing for the bias and trend terms in the offsets between instruments, and correcting for any long-period drifts in individual calibration; this will enable a single wind speed algorithm to be applied to the combined satellite data.
PSO-based Linear SVM Classifier Selection for Credit Risk Evaluation Modeling Process

A research on credit risk evaluation modelling using linear Support Vector Machines (SVM) classifiers is proposed in this paper. The classifier selection is automated using Particle Swarm Optimization technique. Sliding window approach is applied for testing classifier performance, together with other techniques such as discriminant analysis based scoring for evaluation of financial instances and correlation-based feature selection. The developed classifier is applied and tested on real bankruptcy data showing promising results.
UN condemns Australian plans for “safe injecting rooms”

The first medically supervised injecting room for heroin users will open in Sydney in May 2000 despite last week's condemnation by the United Nations International Narcotics Control Board and opposition from John Howard, the Australian prime minister. The supervised facility will have 10 bays in which users can inject, supervised by two health professionals, and clients will be offered supportive counselling and primary health care. The UN is so opposed to the development that it …
A 52-to-67 GHz dual-core push-push VCO in 40-nm CMOS

We present a continuously tunable 52-to-67 GHz push-push dual-core voltage-controlled oscillator (VCO) in a 40 nm bulk CMOS technology. The circuit is suitable for 60 GHz FMCW radar applications requiring a continuously tunable ultra-wide modulation bandwidth. The LC-tank inductor is used to couple the two VCO cores. The fundamental frequency of the VCO can be tuned from 26 GHz to 33.5 GHz, which corresponds to a frequency tuning range (FTR) of 25%. The second harmonic is extracted in a non-invasive way using a transformer. The primary side acts simultaneously as a second harmonic filter. The VCO achieves in measurement a low phase noise of −91.8 dBc/Hz at 1 MHz offset at 62 GHz and an output power of −20 dBm. The VCO including buffers dissipates in the dual-core operation mode 60 mA from a single 1.1 V supply and consumes a chip area of 0.58 mm2.
Blood free radical antioxidant enzymes and lipid peroxides following long-distance and lactacidemic performances in highly trained aerobic and sprint athletes.

OBJECTIVE We have determined the differences of the influence of prolonged exercise or higher intensity lactacidemic exercise, on plasma lipid peroxidation and on erythrocyte antioxidant enzymatic defence system. EXPERIMENTAL DESIGN We measured plasma indices of lipid peroxidation, conjugated dienes (CD) and malondialdehyde (MDA) and erythrocyte enzymes superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT). The biochemical evaluations were performed in six healthy control males (C) and twelve athletes: six marathon runners (MR) and six sprint-trained athletes (STA) at rest and after a half-marathon (MR) and a training session of 6 x 150 m (STA). RESULTS In resting conditions MDA was higher in STA and MR than in C (p < 0.01), while only the MR showed significantly elevated levels of CD (p < 0.05). In STA the enzymatic scavenging capacity showed a significantly higher SOD (p < 0.01) and GSHPx (p < 0.01), while CAT was lower than in controls (p < 0.05). In MR only SOD (p < 0.01) was significantly higher than in C. It increased significantly immediately after half-marathon, while CAT decreased 24 and 48 hours postexercise respectively. In these athletes the lipoperoxidative indices increased in the early postexercise phase, while at 24 and 48 hrs both CD and MDA levels decreased. In STA enzyme activities were not modified by anaerobic performance while CD showed a peak 6 hrs postexercise and the MDA showed a progressive increase until 48 hrs afterwards. CONCLUSIONS Both strenuous long duration exercise and exhaustive sprint training overwhelm our capacity to detoxify ROS, producing oxidative stress. Thus an adequate supply of antioxidants could be appropriate.
Comparison of myocardial fractional flow reserve and intravascular ultrasound for the assessment of slotted‐tube stents

Intravascular ultrasound (IVUS) and myocardial fractional flow reserve (FFR) have been reported to provide similar results for assessment of coil stent deployment. Their relative value in slotted‐tube stents has not been investigated. Fourteen patients subjected to coronary angioplasty and IVUS‐guided elective stenting with a slotted‐tube stent underwent IVUS assessment and FFR measurement following stent implantation at inflation pressures of 12 and 18 atm. FFR values (mean ± SD) preangioplasty, postangioplasty, and poststenting at 12 atm and 18 atm, were 0.58 ± 0.07, 0.83 ± 0.05, 0.94 ± 0.02, and 0.94 ± 0.02, respectively. After inflation at 12 atm, the area under the receiver operating characteristic (ROC) curve for the concordance of IVUS and FFR measurements was 0.89 (P = 0.02). Six patients had either an abnormal IVUS (n = 2) or FFR < 0.94 (n = 1) or both abnormal IVUS and FFR < 0.94 (n = 3) after the first inflation and had a second inflation at 18 atm. The area under the ROC curve for the concordance between IVUS and FFR final measurements was 0.855 (P = 0.10). Perfect concordance between IVUS and FFR was seen only for FFR values less than 0.91 or larger than 0.94. Overall, IVUS and FFR have substantial concordance with respect to slotted‐tube stent deployment. However, FFR values between 0.91 and 0.94 after inflation are difficult to interpret. Cathet Cardiovasc Intervent 2001;52:322–326. © 2001 Wiley‐Liss, Inc.
An implementation of ROHC for TCP/IPv6

Nowadays, we witness the rapid deployment of networks based on WLAN technologies either in indoor or outdoor configurations. However, wireless links exhibit varying delivery rates, asymmetry, and packet loss, even if fixed deployments are considered. It is well-known that such a link behavior impacts severely the performance of Internet protocols. This paper discusses an implementation of header compression algorithm and protocol for TCP/IPv6 transport over wireless links of slow or medium speed. Our implementation complies to the underway standardization work in the IETF ROHC working group. ROHC TCP reduces the size of TCP/IPv6 headers, thus yielding spatial efficiency, while at the same time, being robust against the packet loss of the wireless link.
Imaging of acute subarachnoid hemorrhage with a fluid-attenuated inversion recovery sequence in an animal model: comparison with non-contrast-enhanced CT.

BACKGROUND AND PURPOSE Fluid-attenuated inversion recovery (FLAIR) MR imaging sequences have been previously described in the evaluation of acute subarachnoid hemorrhage (SAH) in human subjects and have demonstrated good sensitivity. The purpose of this study was to evaluate a FLAIR sequence in an animal model of SAH and to compare the results with those obtained with non-contrast-enhanced CT. METHODS SAH was experimentally induced in 18 New Zealand rabbits by injecting autologous arterial blood into the subarachnoid space of the foramen magnum. Nine animals had high-volume (1-2 mL) injections, and nine animals had low-volume (0.2-0.5 mL) injections. Four control animals were injected with 0.5 mL of saline. The animals were imaged with a FLAIR sequence and standard CT 2-5 hours after injection. Gross pathologic evaluation of seven of the animals was performed. Four blinded readers independently evaluated the CT and FLAIR images for SAH and graded the probability of SAH on a scale of 1 to 5 (1 = no hemorrhage, 5 = definite hemorrhage). RESULTS Overall, the sensitivity of FLAIR was 89%, and the sensitivity of CT was 39% (P <.01). In animals with a high volume of SAH, the sensitivity of FLAIR was 100%, and the sensitivity of CT was 56%. In animals with a low volume of SAH, the sensitivity of FLAIR was 78%, and the sensitivity of CT was 22%. The specificity of FLAIR in animals without SAH was 100%, and the specificity of CT was 100%. The average reader score for FLAIR was 3.8, and that for CT was 2.2 (P <.001). Reader scores for FLAIR were higher than those for CT in 94% (P <.01) of animals with SAH and in 25% of animals without SAH (P >.05). Seven animals underwent gross pathologic examination, and all had blood in the subarachnoid space around the brain stem. CONCLUSION FLAIR was more sensitive than CT in the evaluation of acute SAH in this model, especially when a high volume of SAH was present. This study provides a model for further experimentation with MR imaging in the evaluation of SAH. These findings are consistent with those of current clinical literature, which show FLAIR to be an accurate MR sequence in the diagnosis of SAH.
Neck Pain in the General Population

Study Design A randomized cross-sectional questionnaire was used to determine the prevalence of neck pain in Norwegian adults. Objectives The frequency and duration of neck pain were assessed. Summary of Background Data Reliable epidemiologic studies on the prevalence of neck pain in the general population have been sparse. Methods A questionnaire that inquired about neck pain within the last year was sent to a random sample of 10,000 adult Norwegians. Results Overall, 34.4% of the responders had experienced neck pain within the last year. A total of 13.8% reported neck pain that lasted for more than 6 months. Conclusions Chronic neck pain is a frequent symptom in the general population, particularly in women. Although reservations have to be taken as to the interpretation, the reported prevalence of persisting pain after whiplash injuries is of the same magnitude as the prevalence of chronic neck pain in the general population.
Identification of Residues Involved in Neurotensin Binding and Modeling of the Agonist Binding Site in Neurotensin Receptor 1*

The neurotensin receptor 1 (NTR1) subtype belongs to the family of G protein-coupled receptors and mediates most of the known effects of the neuropeptide including modulation of central dopaminergic transmission. This suggested that nonpeptide agonist mimetics acting at the NTR1 might be helpful in the treatment of Parkinson's disease and schizophrenia. Here, we attempted to define the molecular interactions between neurotensin-(8–13), the pharmacophore of neurotensin, and the rat NTR1. Mutagenesis of the NTR1 identified residues that interact with neurotensin. Structure-activity studies with neurotensin-(8–13) analogs identified the peptide residues that interact with the mutated amino acids in the receptor. By taking these data into account, computer-assisted modeling techniques were used to build a tridimensional model of the neurotensin-(8–13)-binding site in which the N-terminal tetrapeptide of neurotensin-(8–13) fits in the third extracellular loop and the C-terminal dipeptide binds to residues at the junction between the extracellular and transmembrane domains of the receptor. Interestingly, the agonist binding site lies on top of the previously described NTR1-binding site for the nonpeptide neurotensin antagonist SR 48692. Our data provide a basis for understanding at the molecular level the agonist and antagonist binding modes and may help design nonpeptide agonist mimetics of the NTR1.
Fingerprinting‐based metabolomic approach with LC‐MS to sleep apnea and hypopnea syndrome: A pilot study

Sleep apnea and hypopnea syndrome (SAHS) is a multicomponent disorder, with associated cardiovascular and metabolic alterations, second in order of frequency among respiratory disorders. Sleep apnea is diagnosed with an overnight sleep test called a polysomnogram, which requires having the patient in hospital. In addition, a more clear classification of patients according to mild and severe presentations would be desirable. The aim of the present study was to assess the relative metabolic changes in SAHS to identify new potential biomarkers for diagnosis, able to evaluate disease severity to establish response to therapeutic interventions and outcomes. For this purpose, metabolic fingerprinting represents a valuable strategy to monitor, in a nontargeted manner, the changes that are at the base of the pathophysiological mechanism of SAHS. Plasma samples of 33 SAHS patients were collected after polysomnography and analyzed with LC coupled to MS (LC‐QTOF‐MS). After data treatment and statistical analysis, signals differentiating nonsevere and severe patients were detected. Putative identification of 14 statistically significant features was obtained and changes that can be related to the episodes of hypoxia/reoxygenation (inflammation) have been highlighted. Among them, the patterns of variation of platelet activating factor and lysophospholipids, together with some compounds related to differential activity of the gut microflora (bile pigments and pipecolic acid) open new lines of research that will benefit our understanding of the alterations, offering new possibilities for adequate monitoring of the stage of the disease.