Miracle-dz/UniFAR-FTUs huggingface dataset:
Lessons learned from recent hypertension trials about kidney disease.

This article reviews BP trials with primary or secondary cardiovascular (CV) or renal end points. It focuses on how results of recent trials have influenced guidelines and clinical practice with specific reference to two issues: ( 1 ) Achievement of goal BP in patients with chronic kidney disease and ( 2 ) emerging data on the importance of decreasing proteinuria to prevent CV events and slow kidney disease progression. Each study is evaluated on its strengths and weaknesses as well as extrapolation of findings to the general population. The tenants of this article are that the baseline level of proteinuria and the magnitude of proteinuria reduction are important determinants of renal outcome in addition to lowering BP and should be consider in all future trials. Second, comparing trials of people with different stages of nephropathy and unknown or differing levels of proteinuria is limited in generalizing the CV or renal outcome to a more global population. As a preamble to this article, two observations are noteworthy: First, use of antihypertensive therapy in those with stage 3 nephropathy, i.e. , GFR of <60 ml/min, will not slow the rate of decline in kidney function to the same extent as in patients with normal kidney function (stage 1). Studies to address the aforementioned questions will not be performed, however, because of low event rates, relatively higher numbers of participants, and longer duration of follow-up, hence, higher cost than currently completed studies. Thus, we are faced with extrapolating from studies to clinical practice that may not be very appropriate. Second, observations from a number of clinical studies suggest that both risk for kidney disease progression as well as CV events may be inversely related to the level of kidney function and directly related to the amount of proteinuria (macroalbuminuria), defined as >300 mg/d of protein (1– …
The significance of attachment security for children’s social competence with peers: a meta-analytic study

This meta-analytic review examines the association between attachment during the early life course and social competence with peers during childhood, and compares the strength of this association with those for externalizing and internalizing symptomatology. Based on 80 independent samples (N = 4441), the association between security and peer competence was significant (d = 0.39, CI 0.32; 0.47) and not moderated by the age at which peer competence was assessed. Avoidance (d = 0.17, CI 0.05; 0.30), resistance (d = 0.29, CI 0.09; 0.48), and disorganization (d = 0.25, CI 0.10; 0.40) were significantly associated with lower peer competence. Attachment security was significantly more strongly associated with peer competence than internalizing (but not externalizing) symptomatology. Discussion focuses on the significance of early attachment for the development of peer competence versus externalizing and internalizing psychopathology.
On the optimal synthesis of shaped beam sparse arrays having uniform amplitude excitations

By exploiting not widely diffused results in the synthesis of shaped beams by means of fixed geometry linear arrays, as well as recent results in the synthesis of pencil beams by means of sparse arrays, we set a frame for a deterministic and hence fast synthesis of shaped beams through sparse arrays having an uniform amplitude. Preliminary results, supporting the effectiveness of the proposed strategies, are also presented.
Sources of Stress: Perceptions of South African TESOL Teachers.

This paper presents the findings of a qualitative study investigating which factors inside and outside the classroom result in feelings of stress for TESOL teachers working at private language schools in South Africa. Using in-depth semi-structured interviews, the findings reveal three main areas that cause stress for TESOL teachers: the job of teaching, relationships at work and organisational and TESOL-related issues. These three areas of stress can be further divided into various sub-themes. Stress resulting from the job of teaching includes the sub-themes of work overload, inadequate training and gaps in subject knowledge, time pressure and student behaviour. Stress resulting from relationships at work includes the sub-themes of negative relationships with colleagues, administrators and management. Stress resulting from organisational and TESOL-related issues includes the sub-themes of working conditions, lack of teaching resources, shared spaces and lack of professional development and career advancement. There has not yet been an investigation into the causes of stress among South African TESOL teachers. This paper is thus an attempt at laying the foundation for further research. The results provide valuable information for TESOL teacher trainers, TESOL co-ordinators and the management of private language schools.
A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control

The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing.
Identifying injection drug users at risk of nonfatal overdose.

OBJECTIVES Drug overdose is the second leading cause of accidental deaths among U.S. adults aged 15-64 years. Emergency physicians have a unique opportunity to provide overdose prevention interventions, because habitual drug users are in frequent need of medical care. The authors evaluated associations between individual-level risk factors and experiencing an overdose in the past six months to determine which characteristics and behaviors may be most predictive of overdose. METHODS The authors used data from a sample of street-recruited habitual drug users who participated in face-to-face interviews about overdose from November 2001 to February 2004. This analysis was restricted to 772 respondents who had been injecting for at least one year and who had injected heroin within the past two months. RESULTS A total of 16.6% of participants had overdosed in the past six months. Characteristics and behaviors that were independently associated with an increased risk of a recent overdose were having had a prior overdose (odds ratio [OR], 28.58; 95% confidence interval [CI] = 14.10 to 57.96), using cocaine/crack in the past six months (OR, 2.07; 95% CI = 1.25 to 3.45), using alcohol in the past six months (OR, 1.90; 95% CI = 1.01 to 3.57), experiencing serious withdrawal symptoms in the past two months (OR, 2.70; 95% CI = 1.58 to 4.61), and younger age. CONCLUSIONS Drug users who have previously experienced a nonfatal overdose are at very high risk of experiencing future overdoses. Further longitudinal studies are needed to identify robust predictors of overdose risk over time in habitual drug users, but these data suggest that drug users who have overdosed warrant aggressive prevention efforts such as agonist maintenance treatment or provision of take-home naloxone.
THE DAILY URINARY EXCRETION OF ESTROGENIC AND ANDROGENIC SUBSTANCES BY NORMAL MEN AND WOMEN.

It is well established that normal men and women excrete estrogenic and androgenic substances in the urine. Qualitatively speaking, it is also well established that at least a part of the androgenic activity in men's urine is due to androsterone and dehydro-androsterone (1, 2, 3), but we do not know the exact chemical nature of the androgenic material in women's urine. Furthermore, we do not know the true chemical nature of the estrogenic substances found in the urine of normal men and non-pregnant normal women. Comparative biological and chemical studies by Dorfman, Gallagher and Koch (4) indicate that the estrogenic activity of men's urine is not theelol but very likely theelin. Quantitative information on the distribution of these activities in adult human urine is even less satisfactory. In most cases the extractions have been incomplete, and the assays are based on too few animals or have not been properly compared with pure standards. The brief review below reveals the striking extremes reported thus far and the impossibility of interpreting most of the data in terms of common standards of known purity. Funk and Harrow (5) employed concentrated alcoholic extracts from concentrated human urines and concluded that the urines from men 70 to 80 years of age do not contain enough androgenic material to be detected by the comb-growth method. Siebke (6) reported the daily excretion of 0 to 1 capon unit of androgens in young women's urine and that it requires 2.5 to 10 liters to yield 1 capon unit. He did not acidify the urine, and his extraction probably was very incomplete. Ogata and Ito (7) from studies by chloroform extraction of urine concluded that the excretion in normal man varies with the season. Buhler (8) prepared benzene extracts of the alkaline urine. He reports daily excretions of 0 to 2
A new approach for analyzing the vibro-acoustic characteristics of a semi-submerged cylindrical shell

In this work, a new approach is developed for predicting the vibro-acoustic characteristics of a semi-submerged cylindrical shell on the basis of the Flügge shell theory and sound-structure coupling theory. The effect of fluid free surface is taken into account by satisfying the sound pressure release boundary condition. The wave propagation method is utilized to derive the sound-structure coupling equation. Modal coupling phenomenon is noted due to the existence of fluid free surface. A new approach, diagonal coupling acoustic radiation model (DCAAM), is put forward to deal with the modal coupling effect. Then, the far-field sound pressure is predicted by making use of the stationary image method and structural vibration response. The results from DCAAM is compared with recent works. It's verified that the new approach, DCAAM, has good accuracy and costs less time. DCARM can also be applied to study the vibro-acoustic characteristics of a partially immersed cylindrical shell.
Polycyclic aromatic hydrocarbon exposure in oesophageal tissue and risk of oesophageal squamous cell carcinoma in north-eastern Iran.

Objective To evaluate the association between polycyclic aromatic hydrocarbon (PAH) exposure in oesophageal epithelial tissue and oesophageal squamous cell carcinoma (ESCC) case status in an ESCC case-control study in a high-risk population in north-eastern Iran. Methods Tissue microarrays (TMAs) of non-tumoral oesophageal biopsies from patients with biopsy-proven ESCC and gastrointestinal clinic patients with no endoscopic or biopsy evidence of ESCC (control subjects) in a rural region in north-eastern Iran were immunohistochemically stained. Immunohistochemistry was performed using monoclonal antibodies 8E11 and 5D11 raised against benzo[a] pyrene (B[a]P) diol epoxide (BPDE)-I-modi ed guanosine and BPDE-I-modi ed DNA, respectively. Staining intensity was quanti ed by image analysis and the average staining in three replicates was calculated. The main outcome measure was adjusted ORs* with 95% CIs** for the association between antibody staining intensity and ESCC case status. Results Cultured ESCC cells exposed to B[a]P in vitro showed dose-dependent staining with 8E11 but not with 5D11. With 8E11, suf cient epithelial tissue was available in the TMA cores to analyse 91 cases and 103 controls. Compared with the lowest quintile of 8E11 staining in the controls, adjusted ORs for the 2nd to 5th quintiles were 2.42, 5.77, 11.3, and 26.6 (95% CI 5.21 to 135), respectively (p for trend <0.001). With 5D11, 89 cases and 101 controls were analysed. No association between staining and case status was observed (ORs for the 2nd to 5th quintiles were 1.26, 0.88, 1.06, and 1.63 (95% CI 0.63 to 4.21), p for trend=0.40). Conclusions Dramatically higher levels of 8E11 staining were observed in non-tumoral oesophageal epithelium from patients with ESCC than from control subjects. This nding strengthens the evidence for a causal role for PAHs in oesophageal carcinogenesis in north-eastern Iran. [*OR=Odds ratio, **CI=Con dence interval] Source: Abedi-Ardekani B, Kamangar F, Hewitt SM, Hainaut P, Sotoudeh M, Abnet CC, Taylor PR, Boffetta P, Malekzadeh R, Dawsey SM. Gut. 2010 Jun 28. [Epub ahead of print]
Electroconvulsive Therapy Improves Clinical Manifestation with Plasma BDNF Levels Unchanged in Treatment-Resistant Depression Patients

Electroconvulsive therapy (ECT) is the most effective treatment in treatment-resistant depression; it may modulate intracellular processes in such patients. This study aimed to investigate the association between changes in plasma brain-derived neurotrophic factor (BDNF) levels and the clinical improvements after ECT for patients with treatment-resistant depression. Fifty-five inpatients with treatment-resistant depression were recruited. The severity of depression was measured using the 17-item Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression-Severity (CGI-S) before ECT, after every 3 sessions of ECT, and at the end of ECT. Plasma BDNF levels were measured in all subjects before and after ECT. The severity of depression was significantly reduced on the HAMD-17 (p < 0.001) and the CGI-S (p < 0.001) after the end of ECT. There were no significant differences in plasma BDNF levels after ECT (p = 0.615). No significant correlation was found between changes in plasma BDNF levels and changes in HAMD-17 scores (r = 0.188, p = 0.169). Our results do not support the hypothesis that improvements in treatment-resistant depression patients after ECT are due to changes in BDNF levels.
Alternative Splicing as a Molecular Switch for Ca2+/Calmodulin-Dependent Facilitation of P/Q-Type Ca2+ Channels

Alternative splicing of the P/Q-type channel (CaV2.1) promises customization of the computational repertoire of neurons. Here we report that concerted splicing of its main α1A subunit, at both an EF-hand-like domain and the channel C terminus, controls the form of Ca2+-dependent facilitation (CDF), an activity-dependent enhancement of channel opening that is triggered by calmodulin. In recombinant channels, such alternative splicing switches CDF among three modes: (1) completely “ON” and driven by local Ca2+ influx through individual channels, (2) completely “OFF,” and (3) partially OFF but inducible by elevated global Ca2+ influx. Conversion from modes 1 to 3 represents an unprecedented dimension of control. The physiological function of these variants is likely important, because we find that the distribution of EF-hand splice variants is strikingly heterogeneous in the human brain, varying both across regions and during development.
Alcohol’s Contribution to Compromised Immunity

Alcoholics frequently suffer from infectious diseases and have increased rates of some cancers, indicating that alcohol impairs the immune system, which protects the body against this type of damage. Alcohol interferes with the functions of many of the cells and molecules that are part of the immune system. For example, alcohol inhibits the functions of the cells that ingest and destroy invading microorganisms (i.e., neutrophils, monocytes, and macrophages). Both acute and chronic alcohol exposure also alter the production of signaling molecules that help coordinate the immune response (i.e., cytokines). Finally, alcohol adversely affects the functions of the cells that mediate the immune response against specific microorganisms and long-term immunity (i.e., T cells and B cells). As a result, alcoholics have an increased susceptibility to diseases caused by bacterial infections, such as tuberculosis and pneumonia. Alcoholics also may be more susceptible to infections from the virus that causes AIDS. In addition, alcohol intoxication can exacerbate the immune suppression that occurs after traumatic injuries.
Genomic Analysis of Adaptive Differentiation in Drosophila melanogaster

Drosophila melanogaster shows clinal variation along latitudinal transects on multiple continents for several phenotypes, allozyme variants, sequence variants, and chromosome inversions. Previous investigation suggests that many such clines are due to spatially varying selection rather than demographic history, but the genomic extent of such selection is unknown. To map differentiation throughout the genome, we hybridized DNA from temperate and subtropical populations to Affymetrix tiling arrays. The dense genomic sampling of variants and low level of linkage disequilibrium in D. melanogaster enabled identification of many small, differentiated regions. Many regions are differentiated in parallel in the United States and Australia, strongly supporting the idea that they are influenced by spatially varying selection. Genomic differentiation is distributed nonrandomly with respect to gene function, even in regions differentiated on only one continent, providing further evidence for the role of selection. These data provide candidate genes for phenotypes known to vary clinally and implicate interesting new processes in genotype-by-environment interactions, including chorion proteins, proteins regulating meiotic recombination and segregation, gustatory and olfactory receptors, and proteins affecting synaptic function and behavior. This portrait of differentiation provides a genomic perspective on adaptation and the maintenance of variation through spatially varying selection.
Reinforcement Learning Models of Risky Choice and the Promotion of Risk-Taking by Losses Disguised as Wins in Rats

Risky decisions are inherently characterized by the potential to receive gains or incur losses, and these outcomes have distinct effects on subsequent decision-making. One important factor is that individuals engage in loss-chasing, in which the reception of a loss is followed by relatively increased risk-taking. Unfortunately, the mechanisms of loss-chasing are poorly understood, despite the potential importance for understanding pathological choice behavior. The goal of the present experiment was to illuminate the mechanisms governing individual differences in loss-chasing and risky-choice behaviors. Rats chose between a low-uncertainty outcome that always delivered a variable amount of reward and a high-uncertainty outcome that probabilistically delivered reward. Loss-processing and loss-chasing were assessed in the context of losses disguised as wins (LDWs), which are loss outcomes that are presented along with gain-related stimuli. LDWs have been suggested to interfere with adaptive decision-making in humans and thus potentially increase loss-making. Here, the rats presented with LDWs were riskier, in that they made more choices for the high-uncertainty outcome. A series of nonlinear models were fit to individual rats’ data to elucidate the possible psychological mechanisms that best account for individual differences in high-uncertainty choices and loss-chasing behaviors. The models suggested that the rats presented with LDWs were more prone to showing a stay bias following high-uncertainty outcomes compared to rats not presented with LDWs. These results collectively suggest that LDWs acquire conditioned reinforcement properties that encourage continued risk-taking and increase loss-chasing following previous high-risk decisions.
Case report of extensive metabolism by aldehyde oxidase in humans: Pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans

We describe the preclinical and clinical pharmacokinetic profiles of FK3453 [6-(2-amino-4-phenylpyrimidin-5-yl)-2-isopropylpyridazin-3(2H)-one] and the mechanism responsible for poor oral exposure of FK3453 in humans. FK3453 showed favourable profiles in preclinical pharmacokinetic studies, including satisfactory absolute bioavailability and total body clearance in animals (30.5%–41.4%, 54.7%–68.2%, and 71.3%–93.4% and 10.8–17.6, 1.9–17.1, and 5.0 mL/min/kg in male rats, female rats, and dogs, respectively), and good metabolic stability in liver microsomes (42.3, 14.5, and 1.1 mL/min/kg in male rats, dogs, and humans, respectively). However, despite these promising preclinical findings, plasma concentrations of FK3453 in humans were extremely low, with the oxidative metabolite of the aminopyrimidine moiety (M4) identified as a major metabolite. Given that aldehyde oxidase (AO) and xanthine oxidase (XO) were presumed to be the enzymes responsible for M4 formation, we investigated the mechanism of M4 formation using human liver subcellular fractions. M4 was detected in the incubation mixture with S9 and cytosol but not with microsomes, and M4 formation was inhibited by AO inhibitors (menadione, isovanillin) but not by cytochrome P-450 inhibitor (1-aminobenzotiazole) or XO inhibitor (allopurinol). These results suggest M4 formation is catalyzed by AO, and therefore, its poor exposure in humans was attributed to extensive AO metabolism.
TccP is an enterohaemorrhagic Escherichia coli O157:H7 type III effector protein that couples Tir to the actin‐cytoskeleton †

Subversion of host cell actin microfilaments is the hallmark of enterohaemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli infections. Both pathogens translocate the trans‐membrane receptor protein – translocated intimin receptor (Tir), which links the extracellular bacterium to the cell cytoskeleton. While both converge on neural Wiskott–Aldrich syndrome protein (N‐WASP), Tir‐mediated actin accretion by EPEC and EHEC differ in that TirEPEC requires both tyrosine phosphorylation and the host adaptor protein Nck, whereas TirEHEC is not phosphorylated and utilizes an unidentified linker. Here we report the identification of Tir‐cytoskeleton coupling protein (TccP), a novel EHEC effector that displays an Nck‐like coupling activity following translocation into host cells. A tccP mutant did not affect Tir translocation and focusing but failed to recruit α‐actinin, Arp3, N‐WASP and actin to the site of bacterial adhesion. When expressed in EPEC, bacterial‐derived TccP restored actin polymerization activity following infection of an Nck‐deficient cell line. TccP has a similar biological activity on infected human intestinal explants ex vivo. Purified TccP activates N‐WASP stimulating, in the presence of Arp2/3, actin polymerization in vitro. These results show that EHEC translocates both its own receptor (Tir) and an Nck‐like protein (TccP) to facilitate actin polymerization.