Miracle-dz/UniFAR-FTUs huggingface dataset:
WT1 and BCR-ABL specific small interfering RNA have additive effects in the induction of apoptosis in leukemic cells.

BACKGROUND AND OBJECTIVES The Wilms' tumor gene (WT1) is aberrantly over-expressed in leukemic cells. Therefore, we wanted to study the effect of small interfering (siRNA) targeting WT1 in leukemic cells and normal CD34-positive cells with regard to proliferation, induction of apoptosis, and cell differentiation. Furthermore, we wanted to evaluate whether the additional use of BCR-ABL siRNA could increase the anti-leukemic effects of WT1 siRNA in chronic myeloid leukemia (CML) cells. DESIGN AND METHODS We measured WT1 expression by reverse transcription polymerase chain reaction (RT-PCR) in various cell lines and in leukemic cells from patients, then transfected the cells with WT1-specific and BCR-ABL-specific siRNA before carrying out microarray analysis. We used the tunnel assay to measure apoptotic cells. RESULTS We observed a reduction of WT1 gene expression, measured by real-time RT-PCR, in all studied cell lines: K-562, Kasumi-1, MV 4-11 and NB-4, as well as in cells of AML and CML patients. The results also demonstrated that WT1 siRNA significantly induced apoptosis and inhibited proliferation in MV4-11 cells, NB-4 cells, Kasumi-1 cells (p<0.01) and in K-562 cells (p<0.02) versus controls. In normal CD34-positive cells, the proliferation was only slightly inhibited (by about 20%) and no induction of apoptosis was found. Combined transfection with WT1 and BCR-ABL siRNA together in K-562 cells increased the inhibition of the rate of proliferation and the rate of induced apoptosis compared to transfection with BCR-ABL siRNA or WT1 siRNA alone (p<0.01). We found that most genes involved in cell signaling and protein metabolism were regulated by the WT1 gene in K-562 cells in a microarray analysis. INTERPRETATION AND CONCLUSIONS In conclusion, WT1 might be a suitable target for new therapeutic strategies using siRNAs in leukemic cells.
Ophthalmological findings in children born after intracytoplasmic sperm injection.

PURPOSE To investigate visual function and ocular morphology in children born after intracytoplasmic sperm injection (ICSI) and compare them with visual function and ocular morphology in matched children born after spontaneous conception. METHODS A total of 137 children born after ICSI and 159 control children were examined at the age of 5 years in a blinded study. The two groups were matched for age, gender and maternal age. The children underwent a detailed ophthalmological investigation by an ophthalmologist and an orthoptist. RESULTS A total of 90.4% of the ICSI children had a visual acuity (VA) in the better eye of >or= 0.8, compared with 93.7% of the controls (NS). No significant differences were found between ICSI children and controls with regard to hyperopia, myopia, astigmatism, heterotropia, stereoscopic vision and convergence. One child with Goldenhar syndrome and one with Marcus Gunn syndrome were observed in the ICSI group. One child in the ICSI group was treated for retinopathy of prematurity. CONCLUSION In this limited study group, no significant differences in visual function and/or ocular morphology were found between children born after ICSI and matched control children at the age of 5 years.
Assessing a quality model for the social sector: an empirical study of the EQUASS model

Although the recent publication of a few scholarly papers has contributed to shorten the research-practice gap, there is still a shortage of empirical studies on quality management (QM) in the social sector. In particular, the study of the causal relationships incorporated in quality models that are specifically tailored to this sector remains to be examined. This research addresses this gap by (i) empirically analysing the fitness of the model underlying European Quality in Social Services (EQUASS), a QM and excellence programme for European social services, and (ii) proposing a model with an improved fit. It uses a structural equation modelling approach on a sample of 339 external audits from 32 European organisations that were awarded an EQUASS recognition or certification between 2012 and 2015. Results reveal that the EQUASS model (2012 version) does not fit with the sample collected. An improved model with seven constructs is proposed, which shows excellent psychometric properties and good fit indexes. This research provides a better understanding of the causal relationships between QM practices embedded in the EQUASS model, along with a simpler alternative model that is especially suited to small- and medium-sized providers, which represent the majority of the organisations in the social sector.
Assessment of dosimetrical performance in 11 Varian a-Si500 electronic portal imaging devices

Dosimetrical characteristics of 11 Varian a-Si-500 electronic portal imaging devices (EPIDs) in clinical use for periods ranging between 10 and 86 months were investigated for consistency of performance and portal dosimetry implications. Properties studied include short-term reproducibility, signal linearity with monitor units, response to reference beam, signal uniformity across the detector panel, signal dependence on field size, dose-rate influence, memory effects and image profiles as a function of monitor units. The EPID measurements were also compared with those of the ionization chambers' to ensure stability of the linear accelerators. Depending on their clinical installation date, the EPIDs were interfaced with one of the two different acquisition control software packages, IAS2/IDU-II or IAS3/IDU-20. Both the EPID age and image acquisition system influenced the dosimetric characteristics with the newer version (IAS3 with IDU-20) giving better data reproducibility and linearity fit than the older version (IAS2 with IDU-II). The relative signal response (uniformity) after 50 MU was better than 95% of the central value and independent of detector. Sensitivity for all EPIDs reduced continuously with increasing dose rates for the newer image acquisition software. In the dose-rate range 100–600 MU min−1, the maximum variation in sensitivity ranged between 1 and 1.8% for different EPIDs. For memory effects, the increase in the measured signal at the centre of the irradiated field for successive images was within 1.8% and 1.0% for the older and newer acquisition systems, respectively. Image profiles acquired at a lower MU in the radial plane (gun–target) had gradients in measured pixel values of up to 25% for the older system. Detectors with software/hardware versions IAS3/IDU-20 have a high degree of accuracy and are more suitable for routine quantitative IMRT dosimetrical verification.
Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen.

This study examined vascular function and the role of superoxide in mice that chronically express human renin (R+) and human angiotensinogen (A+). Responses of aortas from R+/A+ mice and from their normotensive littermates (RA- mice) were examined in vitro. Endothelium-dependent relaxation to acetylcholine was impaired in vessels from R+/A+ mice (e.g., maximal relaxation to 100 microM acetylcholine was 45 +/- 5% and 65 +/- 3% in R+/A+ and RA- mice, respectively; P < 0.05). Relaxation was also impaired to the endothelium-independent dilators authentic nitric oxide and nitroprusside in vessels from R+/A+ mice. Maximal vasorelaxation to the endothelium-independent, non-nitric oxide dilator papaverine was similar in R+/A+ and RA- mice. Incubation of vessels from R+/A+ mice with Tiron (1 mM), a superoxide scavenger, improved relaxation to acetylcholine, nitric oxide, and nitroprusside. In contrast, incubation with diethyldithiocarbamate (1 mM), an inhibitor of copper-containing SODs, reduced acetylcholine- and nitroprusside-induced relaxation in vessels from both R+/A+ and RA- mice. Basal superoxide levels, measured with lucigenin-enhanced chemiluminescence (5 microM lucigenin) and hydroethidine-based fluorescent confocal microscopy, were higher in vessels from R+/A+ mice and were Tiron and polyethylene glycol-SOD sensitive. These results suggest that increased superoxide contributes to impaired nitric oxide-mediated relaxation in this genetic model of chronic angiotensin II-dependent hypertension.
A 10‐year prognosis for childhood allergic rhinitis

The prognosis of allergic rhinitis was studied in 154 children aged 3‐17 years at diagnosis by means of a detailed questionnaire administered 8‐11 years later. The symptoms had completely disappeared in only 15 (10%) patients. The conjunctival symptoms, however, had disappeared or were controlled successfully by topical drug therapy in almost all, and 77 (50%) were managing without medication for allergic rhinitis. Twenty‐five (23%) of the 110 children with seasonal allergic rhinitis had a perennial disease at follow‐up, in contrast to seven (16%) of 44 with perennial allergic rhinitis originally who had only seasonal symptoms at follow‐up. Asthma or wheezing had developed in 29 cases (19%) and was more common (p < 0.01) among those with perennial allergic rhinitis (15 of 44) than among those with seasonal allergic rhinitis (14 of 110). No significant association was found between age at onset of symptoms, family history of atopic disease or type of treatment for allergic rhinitis and allergic rhinitis still present at follow‐up or development of asthma during the observation period.
A Pharmacotherapeutic Approach to the Management of Chronic Posttraumatic Stress Disorder

Due to relatively recent and ongoing world events (eg, terrorist attacks, wars, and natural disasters), there has been a shift in attention from some of the more common psychiatric illnesses to one of the more elusive, namely, posttraumatic stress disorder (PTSD). PTSD is a severe, and often chronic, condition that can lead to significant morbidity and mortality. Although originally a condition seen primarily among war veterans, PTSD is now becoming more prevalent in the general community. PTSD often presents concurrently with other conditions, such as depression, bipolar, anxiety/panic disorders, and alcohol and drug abuse. Because of this, PTSD often goes unrecognized and is underdiagnosed in clinical practice. Thus, an opportunity for pharmacist intervention exists, both in the institution and in the community. With proper education and training, pharmacists can be efficient in screening for signs and symptoms of PTSD, triaging appropriate patients, and can play an integral role in managing the diverse array of drug therapy options for PTSD.
Population-based estimate of the burden of acute gastrointestinal illness in Jiangsu province, China, 2010–2011

SUMMARY To determine the burden and distribution of acute gastrointestinal illness (AGI) in the population, a cross-sectional, monthly face-to-face survey of 10 959 residents was conducted in Jiangsu province between July 2010 and June 2011. The adjusted monthly prevalence was 4·7% with 0·63 AGI episodes/person per year. The prevalence was the highest in children aged <5 years and lowest in persons aged ⩾65 years. A bimodal seasonal distribution was observed with peaks in summer and winter. Regional difference of AGI prevalence was substantial [lowest 0·5% in Taicang, highest 15·1% in Xinqu (Wuxi prefecture)]. Healthcare was sought by 38·4% of the ill respondents. The use of antibiotics was reported by 65·2% of the ill respondents and 38·9% took antidiarrhoeals. In the multivariable model, gender, education, season, sentinel site and travel were significant risk factors of being a case of AGI. These results highlight the substantial burden of AGI and the risk factors associated with AGI in Jiangsu province, China.
Modulation of Human Cortical Rolandic Rhythms during Natural Sensorimotor Tasks

We studied modulation of cortical neuromagnetic rhythms in association with left and right median nerve stimulation, during rest, finger movements, and passive tactile hand stimulation, in seven healthy, right-handed adults. In the rest condition, the amplitude of the rhythmic sensorimotor activity decreased immediately after the median nerve stimuli and increased above the prestimulus level within 0.4 s afterward, especially in the 7- to 25-Hz band. The rebound occurred 100-300 ms earlier for 20 (7-15)-than for 10 (15-25)-Hz activity. Suppressions and rebounds were strongest in the contralateral sensorimotor hand area for the 20-Hz, but not for the 10-Hz, activity. The maximum rebound was on average 22-34% stronger in the left than in the right hemisphere. Active exploration of objects abolished rebounds of both 10- and 20-Hz signals in the contralateral hemisphere and markedly diminished them ipsilaterally. Finger movements without touching an object and passive tactile stimulation produced a weaker effect. The sensorimotor rhythms thus show a characteristic suppression and subsequent rebound after electrical median nerve stimulation. The rebound is left-hemisphere dominant in right-handed subjects and its suppression reveals bilateral cortical activation during both motor tasks and passive tactile stimulation, especially for explorative finger movements.
Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.

BACKGROUND Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain. METHODS Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding. RESULTS A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. CONCLUSIONS Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).
Declining Prevalence of Cervicovaginal Human Papillomavirus Infection With Age Is Independent of Other Risk Factors

Background and Objectives: Human papillomavirus (HPV) infection of the female genital tract is the most common sexually transmitted disease. Although the prevalence of HPV in women without detectable cervical disease has been shown to decline with increasing age, the relationship to sexual behavior has not been investigated. Goal: To identify risk factors for, and associated with the age‐dependent decline in, genital HPV infection in women. Study Design: The prevalence of HPV was determined in a cohort of 439 sexually active inner‐city women between the ages of 18 and 50 years recruited in Brooklyn, New York. Cervicovaginal cells were collected by lavage, and HPV was detected by low‐stringent Southern blot hybridization. Results: The prevalence of HPV infection ranged from 36% in women younger than 25 years of age to 2.8% in women 45 years or older. Logistic regression analysis identified an increased risk for cervical HPV infection to be independently associated with number of sex partners in the past year (odds ratio [OR], 1.04 per yearly increase in age; 95% confidence interval [CI], 1.00 to 1.08), younger age (OR, 0.92 per year increase in age; 95% CI, 0.88 to 0.95), and not living with partner (OR, 2.28; 95% CI, 1.40 to 4.22). Conclusions: The lower prevalence of HPV infection in older women compared to younger women was found to be independent of sexual behavior. These results suggest that a biologic effect, such as HPV immunity acquired over time and with multiple exposures, may mediate the inverse relationship between age and HPV prevalence.
Development of single/geminate obstruent discrimination by Japanese infants: early integration of durational and nondurational cues.

The Japanese language has single/geminate obstruents characterized by durational difference in closure/frication as part of the phonemic repertoire used to distinguish word meanings. We first evaluated infants' abilities to discriminate naturally uttered single/geminate obstruents (/pata/ and /patta/) using the visual habituation-dishabituation method. The results revealed that 9.5-month-old Japanese infants were able to make this discrimination, t(21) = 2.119, p = . 046, paired t test, whereas 4-month-olds were not, t(25) = 0.395, p = . 696, paired t test. To examine how acoustic correlates (covarying cues) are associated with the contrast discrimination, we tested Japanese infants at 9.5 and 11.5 months of age with 3 combinations of natural and manipulated stimuli. The 11.5-month-olds were able to discriminate the naturally uttered pair (/pata/ vs. /patta/), t(20) = 4.680, p < . 000, paired t test. Neither group discriminated the natural /patta/ from the manipulated /pata/ created from natural /patta/ tokens: For 9.5-month-olds, t(23) = 0.754, p = . 458; for 11.5-month-olds, t(27) = 0.789, p = . 437, paired t tests. Only the 11.5-month-olds discriminated the natural /pata/ and the manipulated /patta/ created from /pata/ tokens: For 9.5-month-olds, t(24) = 0.114, p = . 910; for 11.5-month-olds, t(23) = 2.244, p = . 035, paired t tests. These results suggest that Japanese infants acquire a sensitivity to contrasts of single/geminate obstruents by 9.5 months of age and that certain cues that covary with closure length either facilitate or interfere with contrast discrimination under particular conditions.
Identification of a Conserved N-Capping Box Important for the Structural Autonomy of the Prion α3-Helix: The Disease Associated D202N Mutation Destabilizes the Helical Conformation

Peptides corresponding to three alpha helices present in the C-terminal region of the human prion protein have been synthesized and their structural autonomy analyzed by circular dichroism (CD) and NMR spectroscopy. The results obtained indicate that the protein fragment corresponding to the α3-helix, in contrast to α1 and α2 peptides, shows a complete structural autonomy. The chemical shifts values found for NH and CHa resonances of the isolated α3 peptide, formed by 30 aminoacid residues, were markedly and surprisingly similar to the corresponding values of the α3-helix in the protein. The structural autonomy of the α3-helix is profoundly determined by the presence of the conserved capping box and, in part, by the ionic bond formed between Glu200 and Lys204. On the basis of these observations a novel PrP consensus pattern, centered on the α3-helix region, has been defined. The data indicate that this autonomous and highly conserved region of the PrPc likely plays a critical role in folding and stability. This gives an explanation of why many of pathogenic mutations occur in this part of the molecule, sharing relevant effects on the overall protein conformation. In particular the D202N capping mutation almost completely destabilizes the isolated α3 peptide. While it is well known that the D202N substitution is associated with a GSS disease, the possible structural basis of this fatal pathology has never been investigated. We propose that a lower α3-helical propensity leading to a major destabilization of the PrPc molecule initiates the pathogenic process associated with D202N capping mutation.
Smad3-Dependent Induction of Plasminogen Activator Inhibitor-1 in Astrocytes Mediates Neuroprotective Activity of Transforming Growth Factor-β1 against NMDA-Induced Necrosis

The intravenous injection of the serine protease, tissue-type plasminogen activator (t-PA), has shown to benefit stroke patients by promoting early reperfusion. However, it has recently been suggested that t-PA activity, in the cerebral parenchyma, may also potentiate excitotoxic neuronal death. The present study has dealt with the role of the t-PA inhibitor, PAI-1, in the neuroprotective activity of the cytokine TGF-beta1 and focused on the transduction pathway involved in this effect. We demonstrated that PAI-1, produced by astrocytes, mediates the neuroprotective activity of TGF-beta 1 against N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. This t-PA inhibitor, PAI-1, protected neurons against NMDA-induced neuronal death by modulating the NMDA-evoked calcium influx. Finally, we showed that the activation of the Smad3-dependent transduction pathway mediates the TGF-beta-induced up-regulation of PAI-1 and subsequent neuroprotection. Overall, this study underlines the critical role of the t-PA/PAI-1 axis in the regulation of glutamatergic neurotransmission.
Cerebellar agenesis II: Motor and language functions

In a former study of a patient with cerebellar agenesis (HK) mild motor deficits, problems in delay eyeblink conditioning and mild to moderate deficits in IQ, planning behavior, visuospatial abilities, visual memory, and attention were found. The present study reports additional findings in the same patient. In the motor domain, impairments in fine motor manipulations, trace eyeblink conditioning and motor imagination in a functional magnetic resonance (fMRI) study were found. Based on fMRI findings; however, cortical areas involved in a tapping task did not significantly differ from a healthy control group. In the cognitive domain, deficits in speech comprehension as well as verbal learning and declarative memory were present. No significant affective symptoms were observed. Although problems in executive, visuospatial and language tasks are in agreement with the so-called cerebellar cognitive affective syndrome—other possibilities remain. Non-motor impairments in HK might also be a consequence of lacking motor abilities in development and motor deficits may interfere with the performance of parts of the cognitive tasks. In addition, lack of promotion and learning opportunities in childhood may contribute and mental retardation based on extracerebellar dysfunction cannot be excluded. We would like to thank HK for her time and effort, B. Brol and S. Sturm for conducting the conditioning experiment, B. Müller for providing the MLS, and H.G. Elles for his help in setting up the fMRI-experiment. The study was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG Ti 239/5-1, DFG Ti 239/5-2).