Miracle-dz/UniFAR-FTUs huggingface dataset:
Resveratrol Inhibits Angiotensin II- and Epidermal Growth Factor-Mediated Akt Activation: Role of Gab1 and Shp2

trans-Resveratrol (RV), a polyphenolic stilbene derivative found in grape skin and other food products, has been proposed to exert beneficial effects in cardiovascular disease. Our group has shown previously that RV inhibits angiotensin II (Ang II)-induced Akt activation and, consequently, vascular smooth muscle cell (VSMC) hypertrophy. In this work, to identify the molecular target of RV, we investigated the impact of RV on early signaling cascades in rat aortic VSMCs triggered by Ang II and epidermal growth factor (EGF). We show that RV does not influence Ang II-mediated transactivation of EGF-receptor but potently inhibits EGF-induced phosphorylation of Akt kinase, suggesting that RV acts downstream of EGF-receptor transactivation in VSMCs. Recent evidence indicates that the adapter molecule Gab1, together with the protein tyrosine phosphatase Shp2, is critically involved in regulating the strength and duration of phosphatidylinositol-3-kinase (PI3K) and Akt activation upon EGF stimulation in fibroblasts. Our results show that stimulation of VSMCs with EGF as well as Ang II leads to a rapid tyrosine phosphorylation of Gab1 and its association with the p85 subunit of PI3K. RV attenuates these processes. Experiments performed in Shp2-deficient fibroblasts revealed that RV does not inhibit EGF-stimulated Akt activation in these cells, suggesting that Shp2 is necessary for the inhibitory effect of RV on the PI3K/Akt pathway. Furthermore, RV treatment activates Shp2. We therefore propose that RV blocks Akt activation in Ang II- and EGF-stimulated VSMCs by activating Shp2, thus preventing interaction between Gab1 and PI3K that is necessary for further signal transduction.
High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis

Introduction The molecular mechanisms of syndesmophyte formation in ankylosing spondylitis (AS) are yet to be characterised. Molecules involved in bone formation such as Wnt proteins and their antagonists probably drive syndesmophyte formation in AS. Methods This study investigated sequential serum levels of functional dickkopf-1 (Dkk1), a potent Wnt antagonist involved in bone formation in arthritis, by capture ELISA with its receptor LRP6 in 65 AS patients from the German Spondyloarthritis Inception Cohort. Dkk1 levels were then related to structural progression (syndesmophyte formation) as well as sclerostin and C-reactive protein (CRP) levels. Results Functional Dkk1 levels were significantly (p=0.025) higher in patients with no syndesmophyte growth (6.78±5.48 pg/ml) compared with those with syndesmophyte growth (4.13±2.10 pg/ml). Dkk1 levels were highly correlated to serum sclerostin levels (r=0.71, 95% CI 0.53 to 0.82; p<0.001) but not to CRP (r=0.15, 95% CI −0.10 to 0.38; p=0.23). Conclusion AS patients with no syndesmophyte formation show significantly higher functional Dkk1 levels suggesting that blunted Wnt signalling suppresses new bone formation and consequently syndesmophyte growth and spinal ankylosis. Similar to serum sclerostin levels, the functional Dkk1 level thus emerges as a potential biomarker for structural progression in patients with AS
Voiding dysfunction following suburethral tape

Summary Voiding dysfunction (VD) is relatively common following suburethral tape insertion. Our study aimed to identify perioperative variables that predict VD. Women who underwent suburethral tapes (TVTTM and TVT-OTM), either as sole procedure or with a concomitant prolapse repair, were studied retrospectively. The primary outcome was women requiring catheterisation and/or re-catheterisation in the postoperative period. A total of 319 women underwent suburethral tapes within the study period: 256 case notes (80.2%) were available for review and 40/256 women (15.6%) developed postoperative VD. No preoperative urinary symptoms were associated with postoperative VD. Univariate analysis demonstrated three variables associated with VD: average flow rate (Q-ave) ≤5th centile (odds ratio (OR) 2.3, 95% CI 1.2–6.5, p = 0.016), a combination of Q-ave and maximum flow rate (Q-max) ≤5th centile (OR 2.8, 95% CI 1.1–6.9, p = 0.030) and concomitant prolapse procedure (OR 3.6, 95% CI 1.5–8.9, p = 0.005). Following multivariate logistic regression Q-ave ≤5th centile and concomitant prolapse procedure showed the strongest association with VD.
Histone H2AX phosphorylation is associated with most meiotic events in grasshopper

It is widely accepted that the H2AX histone in its phosphorylated form (γ-H2AX) is related to the repair of DNA double-strand breaks (DSBs). In several organisms, γ-H2AX presence has been demonstrated in meiotic processes such as recombination and sex chromosome inactivation during prophase I (from leptotene to pachytene). To test whether γ-H2AX is present beyond pachytene, we have analysed the complete sequence of changes in H2AX phosphorylation during meiosis in grasshopper, a model organism for meiotic studies at the cytological level. We show the presence of phosphorylated H2AX during most of meiosis, with the exception only of diplotene and the end of each meiotic division. During the first meiotic division, γ-H2AX is associated with i) recombination, as deduced from its presence in leptotene-zygotene over all chromosome length, ii) X chromosome inactivation, since at pachytene γ-H2AX is present in the X chromosome only, and iii) chromosome segregation, as deduced from γ-H2AX presence in centromere regions at first metaphase-anaphase. During second meiotic division, γ-H2AX was very abundant at most chromosome lengths from metaphase to telophase, suggesting its possible association with the maintenance of chromosome condensation and segregation.
Algorithm for reducing the number of constraints of POD-based predictive controllers

This paper introduces an algorithm for reducing the number of temperature constraints of a POD-based predictive controller for a non-isothermal tubular reactor. Apart from keeping the process operating around some nominal conditions, the control system has to maintain the temperature inside the reactor below a certain limit in order to avoid undesirable side reactions. The controller uses a reduced order model of the process, which is derived by means of the proper orthogonal decomposition (POD) and Galerkin projection techniques. The use of a reduced order model is necessary due to the high dimensionality of the discretized system used to approximate the partial differential equations (PDEs) that model the reactor. Although a big order reduction can be obtained with the POD technique, this technique does not reduce the number of temperature constraints which is typically very large. The algorithm proposed in this paper reduces dramatically the number of temperature constraints, and consequently the memory needed for storing them and the time required for solving the optimization of the predictive controller.
Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial.

CONTEXT Many people with diabetes experience lower-limb ulcers. Footwear has been implicated as a primary cause of foot ulcers, yet research is limited on the efficacy of shoe and insert combinations to prevent reulceration. OBJECTIVE To determine whether extra-depth and -width therapeutic shoes used with 2 types of inserts reduce reulceration in diabetic individuals with a history of foot ulcer. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 400 diabetes patients with history of foot ulcer in 2 Washington State health care organizations who did not require custom shoes for foot deformity and were enrolled between August 1997 and December 1998 and followed up for 2 years. Data collected at regular intervals documented physical, foot, and diabetes characteristics; footwear use; foot lesions; and ulcers. INTERVENTIONS Participants were randomly assigned to receive 3 pairs of therapeutic shoes and 3 pairs of customized medium-density cork inserts with a neoprene closed-cell cover (n = 121); to receive 3 pairs of therapeutic shoes and 3 pairs of prefabricated, tapered polyurethane inserts with a brushed nylon cover (n = 119); or to wear their usual footwear (controls; n = 160). MAIN OUTCOME MEASURE Foot reulceration, compared among the 3 groups. RESULTS Two-year cumulative reulceration incidence across the 3 groups was low: 15% in the cork-insert group, 14% in the prefabricated-insert group, and 17% in controls. In the intent-to-treat analysis, patients assigned to therapeutic shoes did not have a significantly lower risk of reulceration compared with controls (risk ratio [RR] for the cork-insert group, 0.88; 95% confidence interval [CI], 0.51-1.52 and RR the for prefabricated-insert group, 0.85; 95% CI, 0.48-1.48). All ulcer episodes in patients assigned to therapeutic shoes and 88% wearing nonstudy shoes occurred in patients with foot insensitivity. CONCLUSIONS This study of persons without severe foot deformity does not provide evidence to support widespread dispensing of therapeutic shoes and inserts to diabetic patients with a history of foot ulcer. Study shoes and custom cork or preformed polyurethane inserts conferred no significant ulcer reduction compared with control footwear. This study suggests that careful attention to foot care by health care professionals may be more important than therapeutic footwear but does not negate the possibility that special footwear is beneficial in persons with diabetes who do not receive such close attention to foot care by their health care providers or in individuals with severe foot deformities.
Oxidized phospholipids and lipoprotein-associated phospholipase A2 as important determinants of Lp(a) functionality and pathophysiological role

Lipoprotein(a) [Lp(a)] is composed of a low density lipoprotein (LDL)-like particle to which apolipoprotein (a) [apo(a)] is linked by a single disulfide bridge. Lp(a) is considered a causal risk factor for ischemic cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS). The evidence for a causal role of Lp(a) in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp(a) as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp(a) functionality may be played by its oxidized phospholipids (OxPL) content. Importantly, most of circulating OxPL are associated with Lp(a); however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp(a) over the other lipoproteins, are mostly unknown. Several studies support the hypothesis that the risk of Lp(a) is primarily driven by its OxPL content. An important role in Lp(a) functionality may be played by the lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp(a). The present review article discusses new data on the pathophysiological role of Lp(a) and particularly focuses on the functional role of OxPL and Lp-PLA2 associated with Lp(a).
Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women.

BACKGROUND Flutamide is a pure non-steroidal anti-androgen that may be hepatotoxic, when given in high-dose (750 mg/d). Low- to ultralow-doses (250-62.5 mg/day) have been recently explored in patients with Polycystic Ovary Syndrome (PCOS), and these lower doses were found to confer benefit on multiple PCOS markers. There is a need for evidence on the potential hepatotoxicity of low- and ultralow-dose flutamide therapy. METHODS We assessed circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of hepatotoxicity in a total of 190 hyperandrogenic girls and young women receiving low- or ultralow-dose flutamide because of established (n = 150) or incipient (n = 40) PCOS without obesity. Assessments were performed before start of flutamide, after 3 months, and subsequently at least twice yearly. RESULTS AST and ALT results were normal at baseline, and they remained so on flutamide treatment, including between 3 months and last assessment, which was after a mean time of 19 months on low- or ultralow-dose flutamide (range 3-54 months). None of the AST or ALT levels at any time during flutamide treatment was > or = 45 U/L. CONCLUSION We found no evidence for hepatotoxicity in 190 hyperandrogenic girls or young women receiving low- or ultralow-dose flutamide for up to 54 months. These results may represent a first step in a long process whereby the status of low- and ultralow-dose flutamide may gradually evolve from 'absence of evidence on toxicity' towards 'evidence of absence of hepatic toxicity'. Ultralow-dose flutamide may become a key component within future therapies for hyperandrogenic states in girls and young women.
On the Use of GLS Demeaning in Panel Unit Root Testing

One of the most well-known facts about unit root testing in time series is that the Dickey–Fuller (DF) test based on ordinary least squares (OLS) demeaned data suffers from low power, and that the use of generalized least squares (GLS) demeaning can lead to substantial power gains. Of course, this development has not gone unnoticed in the panel unit root literature. However, while the potential of using GLS demeaning is widely recognized, oddly enough, there are still no theoretical results available to facilitate a formal analysis of such demeaning in the panel data context. The present article can be seen as a reaction to this. The purpose is to evaluate the effect of GLS demeaning when used in conjuncture with the pooled OLS t-test for a unit root, resulting in a panel analog of the time series DF–GLS test. A key finding is that the success of GLS depend critically on the order in which the dependent variable is demeaned and first-differenced. If the variable is demeaned prior to taking first-differences, power is maximized by using GLS demeaning, whereas if the differencing is done first, then OLS demeaning is preferred. Furthermore, even if the former demeaning approach is used, such that GLS is preferred, the asymptotic distribution of the resulting test is independent of the tuning parameters that characterize the local alternative under which the demeaning performed. Hence, the demeaning can just as well be performed under the unit root null hypothesis. In this sense, GLS demeaning under the local alternative is redundant.
Protein Synthesis by Treponema pallidum Extracted from Infected Rabbit Tissue

Virulent Treponema pallidum organisms, extracted from infected rabbit testes, incorporated amino acids into protein. A temperature of 34 C and a pH of 7.6 were optimal for protein synthesis, which was linear during in vitro incubation for 24 h. Selective inhibition of protein synthesis by erythromycin as judged by the incorporation of radiolabeled amino acids and radioautography demonstrated that treponemes were actively synthesizing proteins. Since addition of various sera and ultrafiltrates to the basal incubation mixture did not stimulate the level of protein synthesis, it was uncertain whether treponemes synthesized protein at a maximal or endogenous rate. Based upon the size of the unlabeled amino acid pool contained in infected testicular extract, it appeared that virulent treponemes utilized the majority of amino acids for protein synthesis but at varying efficiency.
Passive protection against rotavirus-induced diarrhea by monoclonal antibodies to surface proteins vp3 and vp7

Monoclonal antibodies directed against two rotavirus surface proteins (vp3 and vp7) as well as a rotavirus inner capsid protein (vp6) were tested for their ability to protect suckling mice against virulent rotavirus challenge. Monoclonal antibodies to two distinct epitopes of vp7 of simian rotavirus strain RRV neutralized RRV in vitro and passively protected suckling mice against RRV challenge. A monoclonal antibody directed against vp3 of porcine rotavirus strain OSU neutralized three distinct serotypes in vitro (OSU, RRV, and UK) and passively protected suckling mice against OSU, RRV, and UK virus-induced diarrhea. The role of vp3 in eliciting protection against heterotypic rotavirus challenge should be considered when developing a vaccine with cloned rotavirus genes. Alternatively, immunization with a reassortant rotavirus containing vp3 and vp7 from two antigenically distinct rotavirus parents might protect against diarrhea induced by two or more rotavirus serotypes.
Technetium-99m-ECD brain SPECT in misery perfusion.

UNLABELLED Discordant findings of 99mTc-methyl cysteinate dimer (99mTc-ECD) brain distribution have been reported when brain tissue is supplied by excess blood flow. We evaluated changes in 99mTc-ECD brain activity in the opposing pathological state, in which cerebral blood flow (CBF) is more profoundly impaired than metabolism, and analyzed the relationship of 99mTc-ECD activity with CBF and metabolism to investigate the dominant regulating factor on 99mTc-ECD distribution. METHODS Twelve patients with unilateral intracranial steno-occlusive diseases were evaluated using dynamic and static 99mTc-ECD SPECT. Relative 99mTc-ECD activities and the retention ratio of the affected and unaffected cortices were compared with CBF and oxygen metabolism obtained by PET. Change in the relationships until 1 hr after tracer injection were also analyzed. RESULTS Relative 99mTc-ECD activity was significantly correlated with CBF, and the highest correlation was obtained for the first minute of imaging (r = 0.674, p < 0.0010. Fifteen minutes after injection, the correlation coefficient with CBF decreased, whereas higher correlation was observed with the parameter of oxygen metabolism (r = 0.758-0.815, p < 0.001). Changes in the retention ratio were dependent on changes in oxygen metabolism, and the retention ratio for the high oxygen extraction fraction (OEF) area was the same as that for the normal OEF area. CONCLUSION In addition to CBF, brain distribution on 99mTc-ECD SPECT images is affected by brain metabolism, especially on delayed images after injection. The degree of discrepancy between CBF and metabolism should be considered when interpreting images of the misery perfusion state.
Neurohospitalists: An emerging model for inpatient neurological care

Over the past decade, the hospitalist model has become a dominant system for the delivery of general adult and pediatric inpatient care. Similar forces, including national mandates to improve safety and quality and intense pressure to safely reduce length of hospital stays, that led to the remarkable growth of hospitalist medicine are now exerting pressure on neurologists. A neurohospitalist model, in which inpatient neurology specialists deliver high‐quality and efficient care to neurology patients, is emerging to meet these challenges. Benefits of this system may include more frequent, timely neurology consultations in the hospital and emergency department, as well as improved quality of inpatient neurological education for residents and medical students. Challenges will involve defining the relationship of neurohospitalists with primary stroke centers, the economic feasibility of such neurohospitalist systems, and how to train members of this new field. A neurohospitalist model of care is an emerging idea in neurology that would overcome many regulatory, educational, and economic challenges facing neurologists; further research is needed to gauge the effects of this innovative approach. Ann Neurol 2008;63:135–140
Risk factors influencing HIV infection incidence in a rural African population: a nested case-control study.

BACKGROUND Risk factors influencing the incidence of human immunodeficiency virus (HIV) infection were investigated in a case-control study nested within a community-randomized trial of treatment of syndromic sexually transmitted infections (STIs) in rural Tanzania. METHODS Case patients were persons who became HIV positive, and control subjects were randomly selected from among persons who remained HIV negative. For each sex, we obtained adjusted odds ratios (ORs) and population-attributable fractions (PAFs) for biomedical and behavioral factors. RESULTS We analyzed 92 case patients and 903 control subjects. In both sexes, the incidence of HIV infection was significantly higher in subjects with an HIV-positive spouse than in those with HIV-negative spouse (men: OR, 25.1; women: OR, 34.0). The incidence of HIV infection was significantly higher in those who became positive for herpes simplex virus type 2 (HSV-2) (men: OR, 5.60; women: OR, 4.76) and those who were HSV-2-positive at baseline (men: OR, 3.66; women: OR, 2.88) than in subjects who were HSV-2 negative. In women, living elsewhere (OR, 3.22) and never having given birth (OR, 4.27) were significant risk factors. After adjustment, the incidence of HIV infection was not significantly associated with a history of injections or STIs in either sex. CONCLUSION HSV-2 infection was the most important risk factor for HIV infection, which highlights the need for HSV-2 interventions in HIV infection control, and there were particularly strong associations with recent HSV-2 seroconversion. The PAF associated with having an HIV-positive spouse was low, but this is likely to increase during the epidemic.
Stress or drug priming induces reinstatement of extinguished conditioned place preference

To construct a model for the relapse of drug use, we investigated the reinstatement of morphine-induced conditioned place preference (CPP) in rats. After the morphine CPP paradigm was established, rats were left extinguishing for 9 days, then exposed to 15 min of random foot shock or s.c. drug priming with different doses of morphine or amphetamine, respectively. Foot shock or a higher dose (0.25 mg/kg) of both drugs could reinstate the CPP induced by 4 mg/kg of morphine after a 9-day extinction, while a lower dose (0.125 mg/kg) of both drugs had no effect. It is concluded that the CPP extinction-reinstatement paradigm might be used as a model to investigate the mechanism of relapse in addicts.
Evidence for the Asiatic origin of endogenous AKR-type murine leukemia proviruses

A restriction endonuclease cleavage map of the genome of AKV, the endogenous, ecotropic leukemia virus of AKR mice, has been derived. By using this map and analyzing DNA from congenic mice, we have defined four DNA fragments diagnostic for AKV proviruses. Analysis of DNAs from 10 strains of American laboratory mice revealed that all strains carrying inducible, ecotropic murine leukemia viruses yielded DNAs which contained the four DNA fragments diagnostic for AKV. Virus-negative strains lacked these fragments in their DNA. Screening DNA from 23 additional mice revealed that, among these mice, only mice from Asia gave rise to the DNA fragments diagnostic of an AKV provirus. We conclude that all of the endogenous ecotropic murine leukemia proviruses in American laboratory mice are closely related since they share a common set of restriction endonuclease cleavage sites. These proviruses appear to derive from the East Asian ancestors of these mouse strains. Analysis of DNA from six selected mice with an additional restriction endonuclease showed that greater than 97% of the nucleotide sequences in each provirus are contigous and that these endogenous proviruses are indistinguishable from proviruses introduced by exogenous infection.