Skin prick test results of child patients diagnosed with bronchial asthma.
The pathogenesis of asthma is associated with both genetic and environmental factors. Allergen sensitization is an important risk factor in asthma development. To evaluate sensitivity to allergens by using the skin prick test in patients with a diagnosis of bronchial asthma. Patients with a diagnosis of bronchial asthma followed-up at the Ministry of Health, Diskapi Children's Diseases Training and Research Hospital in Ankara (Turkey) between January 1995 and March 2000 were included. Sensitivity to allergens, as determined by the skin prick test, was evaluated retrospectively. The files of a total of 3025 children (63.3 % boys) with bronchial asthma, aged 3 months to 16 years were evaluated. Of the total, 1667 patients with a diagnosis of bronchial asthma and 1358 with bronchial asthma plus allergic rhinitis were under follow-up. Of the 3025 asthmatic patients, 1902 had undergone the skin prick test and 60.3 % of these patients were atopic. The most common allergens were house dust mite [726 patients (63.3 %)], followed by pollens [565 patients (49.3 %)]. The most common allergen within this group was grass pollens [348 patients (30.3 %)]. Atopy was an important risk factor in our patients and the most common allergens were aeroallegens. The development of sensitization could be delayed by early precautions.


[Coronary bypass surgery in May-Hegglin anomaly].
Twelve years prior to hospitalization because of a severe bleeding, a 70 year old patient was diagnosed with a May-Hegglin anomaly, which is a rare autosomal dominant inherited form of thrombocytopenia. The blood smear contained signs of the May-Hegglin anomaly: Döhle's inclusion bodies and giant platelets. Platelet counts were around 30 G/l. Coronary angiography revealed a highly severe left main stenosis. Even using maximum drug therapy, angina pectoris could not be stabilized. Therefore emergency coronary artery bypass grafting had to be performed. Before skin incision 3 micrograms/kg DDAVP (Desmopressin) were administered and after extracorporeal circulation 8 units of platelets were transfused. In addition, perioperative coagulation management was performed according to usual standards. There were no bleeding complications. The patient could leave the clinic after 11 days in stable condition. Patients showing May-Hegglin anomaly, even with serious thrombocytopenia, can be operated using extracorporal circulation without a high risk of bleeding.


Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study.
Stavudine is widely used in developing countries. Lipoatrophy and mitochondrial toxicity have been linked to stavudine use, but it is unclear whether switching to a lower dose can reduce these toxicities while maintaining human immunodeficiency virus (HIV) suppression. HIV-infected subjects receiving standard-dose stavudine with undetectable HIV type 1 RNA for > or =6 months were randomized (ratio, 3:2) to receive one-half of the stavudine dose (switch arm) or to maintain the dose (continuation arm) while continuing to receive all other prescribed antiretrovirals. The following measurements were obtained at baseline and week 48: fasting lactate, pyruvate, and lipid levels; results of whole-body dual-energy x-ray absorptiometry; and mitochondrial DNA (mtDNA) measurements in fat and peripheral blood mononuclear cells. Change from baseline to week 48 was compared within and between groups. Twenty-four patients (79% of whom were men and 79% of whom were African American; median age, 45 years) were enrolled in the study, 15 were enrolled in the switch arm, and 9 were enrolled in the continuation arm. The median duration of stavudine treatment was 55 months (range, 21-126 months). The median CD4 cell count was 558 cells/mm(3) (range, 207-1698 cells/mm(3)). At baseline, the study arms had similar demographic characteristics and laboratory indices, except for body mass index, total lean body mass, and triglyceride levels (all of which were higher in the switch arm). Three patients (2 in the switch arm) discontinued the study because of study-unrelated reasons. CD4 cell counts remained unchanged. At 48 weeks, 6 patients (4 [27%] in the switch arm and 2 [22%] in the continuation arm) had detectable HIV RNA levels (median, 972 copies/mL; range, 60-49,400 copies/mL). All patients with detectable HIV RNA levels reported significant lapses in treatment adherence; none exhibited mutations in HIV genotype. After the treatment switch, significant changes from study entry to week 48 were noted only for lactate level (median change, -0.27 mmol/L; range, -1.2 to 0.25 mmol/L; P = .02) and fat mtDNA (median change, 40 copies/cell; range, -49 to 261 copies/cell; P = .02). In the continuation arm, a significant loss of bone mineral density was seen at week 48 (median change, -1.7%; range, -6.3% to 0.8%; P = .02). The only significant between-group difference was the change in bone mineral density from baseline (P = .003). Reducing stavudine dose by one-half increased fat mtDNA and decreased lactate levels, suggesting improvement in mitochondrial indices while preserving HIV suppression in subjects who maintained adherence. A significant loss of bone mineral density was seen in patients receiving standard-dose stavudine but not in those receiving low-dose stavudine. These results suggest that switching to low-dose stavudine may improve mitochondrial indices while maintaining virological suppression.


Triple-negative breast cancer: current state of the art.
Triple-negative breast cancer, defined by a lack of expression of estrogen, progesterone and HER-2 receptors, accounts for 15% of all types of breast cancer. The subtype mainly includes a molecularly distinct subgroup, the basal-like subtype (accounting for 75% of all cases). We attempt to define triple-negative breast cancer and compare it with basal-like disease, review the molecular, pathologic and clinical features of triple-negative disease, provide an overview of a retrospective subset analysis of clinical trials, and outline ongoing therapeutic trials and possible paths for future research. We collected data regarding classification, molecular and clinical features and treatment, drawn from the existing literature, including abstracts and verbal accounts. By the term "basal-like", we defined all cases where gene expression array or more sophisticated immunophenotypes are used for identification. When the analysis is restricted to clinical assay (immunohistochemistry), we refer to "triple-negative". Basal-like breast cancer expresses genes characteristic of basal epithelial cells, which include high-molecular weight basal cytokeratins (CK5/6, CK14, CK17), vimentin, p-cadherin, alpha B crystalline, caveolins 1 and 2 and EGFR. The expression of basal markers (basal cytokeratins and EGFR) is related to a worse prognosis and identifies a clinically distinct subgroup within the triple-negative breast cancer. BRCA1 mutations are present in 11% of triple-negative tumors and even more rare is BRCA2 deficiency. BR-CA1-associated breast cancers types are typically characterized by a high rate of DNA aberrations and defective DNA repair pathways (the so-called "BRCAness"). The use of regimens based on DNA-damaging agents, such as anthracyclines, platinum derivatives and cyclophosphamide seems a sensible option for this breast cancer subtypes. Clinical data support a strong sensitivity to primary chemotherapy with pathologic response rates ranging from 27-45% (with anthracyclines and taxanes) to more than 60% with platinum-based triplets. However, based on retrospective data, major response to chemotherapy does not carry better survival ("triple-negative paradox"). There is no specific targeted therapy in the armamentarium: ongoing trials include anti-angiogenic agents, anti-EGFR and EGFR-TK inhibitors, epothilones and PARP inhibitors. A specific systemic regimen cannot yet be recommended. Moreover, only a few data are available on which treatment selection can be based. Use of the existing cytotoxic agents can be optimized for this patient subgroup by investigating the proliferative signals and the suitability of these signals as therapeutic targets, besides assessing the BRCA1-pathway in this subgroup as regards treatment. A greater understanding of the pathologic and molecular characteristics of this phenotype may lead to customized treatment for these patients.


Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia.
Community-acquired pneumonia (CAP) is the most frequent infection-related cause of death. The reference standard to diagnose CAP is a new infiltrate on chest radiograph in the presence of recently acquired respiratory signs and symptoms. This study aims to evaluate the diagnostic and prognostic accuracy of clinical signs and symptoms and laboratory biomarkers for CAP. 545 patients with suspected lower respiratory tract infection, admitted to the emergency department of a university hospital were included in a pre-planned post-hoc analysis of two controlled intervention trials. Baseline assessment included history, clinical examination, radiography and measurements of procalcitonin (PCT), highly sensitive C-reactive protein (hsCRP) and leukocyte count. Of the 545 patients, 373 had CAP, 132 other respiratory tract infections, and 40 other final diagnoses. The AUC of a clinical model including standard clinical signs and symptoms (i.e. fever, cough, sputum production, abnormal chest auscultation and dyspnea) to diagnose CAP was 0.79 [95% CI, 0.75-0.83]. This AUC was significantly improved by including PCT and hsCRP (0.92 [0.89-0.94]; p < 0.001). PCT had a higher diagnostic accuracy (AUC, 0.88 [0.84-0.93]) in differentiating CAP from other diagnoses, as compared to hsCRP (AUC, 0.76 [0.69-0.83]; p < 0.001) and total leukocyte count (AUC, 0.69 [0.62-0.77]; p < 0.001). To predict bacteremia, PCT had a higher AUC (0.85 [0.80-0.91]) as compared to hsCRP (p = 0.01), leukocyte count (p = 0.002) and elevated body temperature (p < 0.001). PCT, in contrast to hsCRP and leukocyte count, increased with increasing severity of CAP, as assessed by the pneumonia severity index (p < 0.001). PCT, and to a lesser degree hsCRP, improve the accuracy of currently recommended approaches for the diagnosis of CAP, thereby complementing clinical signs and symptoms. PCT is useful in the severity assessment of CAP.


MRI-based polymer gel dosimetry for validating plans with multiple matrices in Gamma Knife stereotactic radiosurgery.
One of treatment planning techniques with Leksell GammaPlan (LGP) for Gamma Knife stereotactic radiosurgery (GKSRS) uses multiple matrices with multiple dose prescriptions. Computational complexity increases when shots are placed in multiple matrices with different grid sizes. Hence, the experimental validation of LGP calculated dose distributions is needed for those cases. For the current study, we used BANG3 polymer gel contained in a head-sized glass bottle to simulate the entire treatment process of GKSRS. A treatment plan with three 18 mm shots and one 8 mm shot in separate matrices was created with LGP. The prescribed maximum dose was 8 Gy to three shots and 16 Gy to one of the 18 mm shots. The 3D dose distribution recorded in the gel dosimeter was read using a Siemens 3T MRI scanner. The scanning parameters of a CPMG pulse sequence with 32 equidistant echoes were as follows: TR = 7 s, echo step = 13.6 ms, field-of-view = 256 mm × 256 mm, and pixel size = 1 mm × 1 mm. Interleaved acquisition mode was used to obtain 15 to 45 2-mm-thick slices. Using a calibration relationship between absorbed dose and the spin-spin relaxation rate (R2), we converted R2 images to dose images. MATLAB-based in-house programs were used for R2 estimation and dose comparison. Gamma-index analysis for the 3D data showed gamma values less than unity for 86% of the voxels. Through this study we accomplished the first application of polymer gel dosimetry for a true comparison between measured 3D dose distributions and LGP calculations for plans using multiple matrices for multiple targets.


Filarial susceptibility and effects of Wolbachia in Aedes pseudoscutellaris mosquitoes.
The mosquito Aedes pseudoscutellaris (Theobald), a member of the Aedes (Stegomyia) scutellaris complex (Diptera: Culicidae), is an important vector of subperiodic Wuchereria bancrofti (Cobbold) (Spirurida: Onchocercidae), causing human lymphatic filariasis, on South Pacific islands. Maternal inheritance of filarial susceptibility in the complex has previously been asserted, and larval tetracycline treatment reduced susceptibility; the maternally inherited Wolbachia in these mosquitoes were suggested to be responsible. To investigate the relationship of these two factors, we eliminated Wolbachia from a strain of Ae. pseudoscutellaris by tetracycline treatment, and tested filarial susceptibility of the adult female mosquitoes using Brugia pahangi (Edeson & Buckley). Filarial susceptibility was not significantly different in Wolbachia-free and infected lines of Ae. pseudoscutellaris, suggesting that the Wolbachia in these mosquitoes do not influence vector competence. Crosses between Wolbachia-infected males and uninfected females of Ae. pseudoscutellaris showed cytoplasmic incompatibility (CI), i.e. no eggs hatched, unaffected by larval crowding or restricted nutrient availability, whereas these factors are known to affect CI in Drosophila simulans. Reciprocal crosses between Ae. pseudoscutellaris and Ae. katherinensis Woodhill produced no progeny, even when both parents were Wolbachia-free, suggesting that nuclear factors are responsible for this interspecific sterility.


Wolff-Parkinson-White syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
The management of Wolff-Parkinson-White is based on the distinction between asymptomatic and symptomatic presentations, but evidence is limited in the asymptomatic population. The Wolff-Parkinson-White registry was an 8-year prospective study of either symptomatic or asymptomatic Wolff-Parkinson-White patients referred to our Arrhythmology Department for evaluation or ablation. Inclusion criteria were a baseline electrophysiological testing with or without radiofrequency catheter ablation (RFA). Primary end points were the percentage of patients who experienced ventricular fibrillation (VF) or potentially malignant arrhythmias and risk factors. Among 2169 enrolled patients, 1001 (550 asymptomatic) did not undergo RFA (no-RFA group) and 1168 (206 asymptomatic) underwent ablation (RFA group). There were no differences in clinical and electrophysiological characteristics between the 2 groups except for symptoms. In the no-RFA group, VF occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period (P<0.001) and atrioventricular reentrant tachycardia initiating atrial fibrillation (P<0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank P<0.001). Time-dependent receiver-operating characteristic curves for predicting VF identified an optimal anterograde effective refractory period of the accessory pathway cutoff of 240 milliseconds. The prognosis of the Wolff-Parkinson-White syndrome essentially depends on intrinsic electrophysiological properties of AP rather than on symptoms. RFA performed during the same procedure after electrophysiological testing is of benefit in improving the long-term outcomes.


Pomeron Eigenvalue at Three Loops in N=4 Supersymmetric Yang-Mills Theory.
We obtain an analytical expression for the next-to-next-to-leading order of the Balitsky-Fadin-Kuraev-Lipatov (BFKL) Pomeron eigenvalue in planar N=4 SYM using quantum spectral curve (QSC) integrability-based method. The result is verified with more than 60-digit precision using the numerical method developed by us in a previous paper [N. Gromov, F. Levkovich-Maslyuk, and G. Sizov, arXiv:1504.06640]. As a by-product, we developed a general analytic method of solving the QSC perturbatively.


Molecular mechanism for agonist-promoted alpha(2A)-adrenoceptor activation by norepinephrine and epinephrine.
We present a mechanism for agonist-promoted alpha(2A)-adrenergic receptor (alpha(2A)-AR) activation based on structural, pharmacological, and theoretical evidence of the interactions between phenethylamine ligands and alpha(2A)-AR. In this study, we have: 1) isolated enantiomerically pure phenethylamines that differ both in their chirality about the beta-carbon, and in the presence/absence of one or more hydroxyl groups: the beta-OH and the catecholic meta- and para-OH groups; 2) used [(3)H]UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; agonist] and [(3)H]RX821002 [2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline; antagonist] competition binding assays to determine binding affinities of these ligands to the high- and low-affinity forms of alpha(2A)-AR; 3) tested the ability of the ligands to promote receptor activation by measuring agonist-induced stimulation of [(35)S]GTPgammaS binding in isolated cell membranes; and 4) used automated docking methods and our alpha(2A)-AR model to predict the binding modes of the ligands inside the alpha(2A)-AR binding site. The ligand molecules are sequentially missing different functional groups, and we have correlated the structural features of the ligands and ligand-receptor interactions with experimental ligand binding and receptor activation data. Based on the analysis, we show that structural rearrangements in transmembrane helix (TM) 5 could take place upon binding and subsequent activation of alpha(2A)-AR by phenethylamine agonists. We suggest that the following residues are important in phenethylamine interactions with alpha(2A)-AR: Asp113 (D(3.32)), Val114 (V(3.33)), and Thr118 (T(3.37)) in TM3; Ser200 (S(5.42)), Cys201 (C(5.43)), and Ser204 (S(5.46)) in TM5; Phe391 (F(6.52)) and Tyr394 (Y(6.55)) in TM6; and Phe411 (F(7.38)) and Phe412 (F(7.39)) in TM7.


Characterization of bacterial biofilm communities in tertiary treatment processes for wastewater reclamation and reuse.
The concern with wastewater reuse as a sustainable water resource in urban areas has been growing. For the reclamation and distribution of wastewater, biofilm development deserves careful attention from the point of view of its promotion (e.g. biofiltration) and inhibition (e.g. clogging and hygiene problems). As the first step to control biofilm development, bacterial biofilm communities in tertiary treatment processes were characterized by using molecular biological methods. The result of clone library analysis showed that Nitrospirae-related (nitrite-oxydizing bacteria) and Acidobacteria-related (probably oligotrophic bacteria) groups were dominant. The ratio of the Nitrospirae-related group to the Acidobacteria-related group was associated with ammonia load, whereas other operational conditions (process, media, temperature, salt) did not clearly affect the phylum-level community or the dominant sequence of nitrifying bacteria. The result of real-time PCR also indicated that high ammonia load promotes the proliferation of nitrite- and ammonia-oxidizing bacteria. Regarding water supply systems, some researchers also have suggested the dominance of Nitrospirae- and Acidobacteria-related groups in biofilm formed on water distribution pipes. In tertiary wastewater treatment, therefore, it is concluded that oligotrophic and autotrophic bacteria are the dominant groups in biofilm samples because assimilable organic carbon is too poor to proliferate various heterotrophic bacteria.


Genotype and phenotype data standardization, utilization and integration in the big data era for agricultural sciences.
Large-scale genotype and phenotype data have been increasingly generated to identify genetic markers, understand gene function and evolution and facilitate genomic selection. These datasets hold immense value for both current and future studies, as they are vital for crop breeding, yield improvement and overall agricultural sustainability. However, integrating these datasets from heterogeneous sources presents significant challenges and hinders their effective utilization. We established the Genotype-Phenotype Working Group in November 2021 as a part of the AgBioData Consortium (https://www.agbiodata.org) to review current data types and resources that support archiving, analysis and visualization of genotype and phenotype data to understand the needs and challenges of the plant genomic research community. For 2021-22, we identified different types of datasets and examined metadata annotations related to experimental design/methods/sample collection, etc. Furthermore, we thoroughly reviewed publicly funded repositories for raw and processed data as well as secondary databases and knowledgebases that enable the integration of heterogeneous data in the context of the genome browser, pathway networks and tissue-specific gene expression. Based on our survey, we recommend a need for (i) additional infrastructural support for archiving many new data types, (ii) development of community standards for data annotation and formatting, (iii) resources for biocuration and (iv) analysis and visualization tools to connect genotype data with phenotype data to enhance knowledge synthesis and to foster translational research. Although this paper only covers the data and resources relevant to the plant research community, we expect that similar issues and needs are shared by researchers working on animals. Database URL: https://www.agbiodata.org.


Public health implications regarding the epidemiology and microbiology of public whirlpools.
High temperature bathing in hot tubs, spas and whirlpools poses four potential public health concerns: injury/death, disease transmission, possible teratogenic effects, and congestive heart failure or dysrhythmias for individuals with cardiac problems. Health departments need criteria before initiating environmental and epidemiologic investigations. These criteria must include severity of the disease and number of individuals possibly exposed. In addition, public health officials are obligated to define the magnitude of the problem, inform affected individuals and institute appropriate control measures. Optional information should be collected during an environmental and epidemiologic investigation to clarify the mechanisms of disease transmission and design control measures. The public health response to improving hot water bathing safety and sanitation should be directed at primary prevention. Educational efforts would be directed toward whirlpool operators, users and the medical community. Included should be a review of regulations addressing the construction and operation of public spas and whirlpools.


Effect of gastric bypass surgery on the absorption and bioavailability of metformin.
Use of gastric bypass surgery is common and increasing. Over 40% of patients in diabetes remission after gastric bypass surgery may redevelop diabetes within 5 years. Metformin, the first-line drug for diabetes, has low bioavailability and slow, incomplete gastrointestinal absorption. We hypothesized that gastric bypass would further reduce the absorption and bioavailability of metformin. In a nonblinded, single-dose pharmacokinetic study, 16 nondiabetic post-gastric bypass patients and 16 sex- and BMI-matched control subjects (mean age 40 years and BMI 39.2 kg/m(2)) were administered two 500-mg metformin tablets. Plasma metformin levels were sampled at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h. Metformin absorption, estimated by the area under the curve (AUC) of the plasma drug concentrations from time 0 to infinity (AUC(0-∞)), was the primary outcome, and metformin bioavailability, assessed by measuring 24-h urine metformin levels, was a secondary outcome. Compared with control subjects, metformin AUC(0-∞) was increased in gastric bypass subjects by 21% (13.7 vs. 11.4 μg/mL/h; mean difference 2.3 [95% CI -1.3 to 5.9]) and bioavailability was increased by 50% (41.8 vs. 27.8%; 14.0 [4.1-23.9]). Gastric bypass patients had significantly lower AUC glucose levels over 8 h compared with control subjects (35.8 vs. 41.7 μg/mL/h; 5.9 [3.1-8.8]), but this was likely a result of differences in baseline fasting glucose and not metformin absorption. Metformin absorption and bioavailability seem to be higher after gastric bypass, and this may have implications on dosing and toxicity risk. Studies are needed to confirm these findings and delineate potential mechanisms.


Effect of Metformin and Statin Use on Survival in Pancreatic Cancer Patients: a Systematic Literature Review and Meta-analysis.
Current epidemiological studies report conflicting results for the effect of statin or metformin on pancreatic cancer overall survival. This literature review and meta-analysis summarize the studies reporting an association between statin or metformin use and overall survival of pancreatic cancer patients. We systematically searched for studies about the association between statin or metformin use and pancreatic cancer overall survival in electronic databases (PubMed, ISI Web of Science, MEDLINE, Cochrane, Scopus, Google Scholar). A meta-analysis based on hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using random effect models. Heterogeneity between the studies was examined using I2 statistics, and sensitivity analyses were conducted to assess the robustness of the findings. Of 116 statin-related articles identified, 6 retrospective cohort studies representing 12,057 patients were included. There was significant heterogeneity between studies. Statin use was associated with improved survival among pancreatic cancer patients (meta-HR = 0.75; 95% CI: 0.59, 0.90; P < 0.001). Of 311 metformin-related articles, 8 retrospective cohort studies and 2 randomized clinical trials, representing 3,042 patients were identified. Metformin use was associated with better overall survival among pancreatic cancer patients (meta-HR = 0.79; 95% CI: 0.70, 0.92, P < 0.001), and significant heterogeneity was observed between studies. Our findings suggest that the improved survival time of pancreatic cancer patients are associated with statin or metformin use. Due to the multiple sources of heterogeneity of the original studies, these findings should be considered cautiously, and confirmed with larger prospective individual-level studies.


Vessel wall MR imaging for the detection of intracranial inflammatory vasculopathies.
Intracranial vasculopathies are routinely investigated by lumen-based modalities such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), and digital subtraction angiography (DSA). These techniques are useful to analyze the vessel lumen, allowing to detect vessel stenosis or occlusion. However, the primum movins of the disease, i.e., an abnormal thickening of the vessel wall, remains within the arterial wall. The vasculopathy can moreover be present without always narrowing the lumen or modifying its regularity. Hence, there is a need to detect directly and analyze vessel wall abnormalities. Development of 3D high-resolution black blood sequences for intracranial vessel wall MR imaging (VW-MRI) enabled routine clinical applications not only vasculitis, but also of intracranial atherosclerotic disease (ICAD), intracranial dissections, reversible intracranial dissections, reversible cerebral vasoconstriction syndrome (RCVS), Moyamoya disease, and intracranial aneurysms. This high-resolution intracranial VW- MRI approach is increasingly used on a clinical basis at many centers to solve diagnostic problems, especially in patients with ischemic stroke or intracranial hemorrhage. An expert consensus Guideline from the American Society of Neuroradiology provides recommendations for clinical implementation of intracranial vessel wall MRI. There are several technical aspects needed to be considered when implementing VW-MRI in intracranial vessels, including flow suppression, both in blood and cerebrospinal fluid (CSF), spatial resolution and signal-to-noise ratio (SNR). In this article, we review the technical aspects of VW-MRI, and recommend applications for vascular diseases including non-occlusive intracranial vasculopathies, Moyamoya disease, and identifying culprit plaques. We also give a focus on the utility of VW-MRI for determining stroke etiology in adults and in children and young adults.


Inhibitory Effect of Thymoquinone on Testosterone-Induced Benign Prostatic Hyperplasia in Wistar Rats.
This study addresses the possible protective effects of thymoquinone (TQ) against the development of experimentally-induced benign prostatic hyperplasia (BPH) in Wistar rats. Eighteen adult male rats were divided into three groups; the negative control group (n = 6) received vehicle, and two groups received subcutaneous testosterone injection (3 mg/kg). Animals receiving testosterone were randomized to untreated BPH group (n = 6) and BPH + TQ treated group (n = 6, 50 mg/kg orally for 14 days). Histological changes and the mRNA levels of transforming growth factor-β1 (TGF-β1 ) and vascular endothelial growth factor-A (VEGF-A) were analyzed. Additionally, dihydrotestosterone and interleukin-6 (IL-6) serum levels were determined. The presented research shows significant increases in prostate weight/body weight ratio, prostate epithelial thickness, serum IL-6 and dihydrotestosterone levels, and the prostatic expressions of TGF-β1 and VEGF-A in the untreated BPH rats. Histological examination of the prostate tissues in the BPH rats showed an elevated level of proliferation in the stromal area and glandular epithelia with abundant intraluminal papillary folds. However, a reduction in prostate weight/body weight ratio, epithelial hyperplasia, serum IL-6 levels, and the expressions of TGF-β1 and VEGF-A were observed in the BPH + TQ treated rats compared with the untreated BPH rats. The findings support TQ as a useful natural treatment for animal BPH model. Copyright © 2017 John Wiley & Sons, Ltd.


Sequentially acting Sox transcription factors in neural lineage development.
Pluripotent embryonic stem (ES) cells can generate all cell types, but how cell lineages are initially specified and maintained during development remains largely unknown. Different classes of Sox transcription factors are expressed during neurogenesis and have been assigned important roles from early lineage specification to neuronal differentiation. Here we characterize the genome-wide binding for Sox2, Sox3, and Sox11, which have vital functions in ES cells, neural precursor cells (NPCs), and maturing neurons, respectively. The data demonstrate that Sox factor binding depends on developmental stage-specific constraints and reveal a remarkable sequential binding of Sox proteins to a common set of neural genes. Interestingly, in ES cells, Sox2 preselects for neural lineage-specific genes destined to be bound and activated by Sox3 in NPCs. In NPCs, Sox3 binds genes that are later bound and activated by Sox11 in differentiating neurons. Genes prebound by Sox proteins are associated with a bivalent chromatin signature, which is resolved into a permissive monovalent state upon binding of activating Sox factors. These data indicate that a single key transcription factor family acts sequentially to coordinate neural gene expression from the early lineage specification in pluripotent cells to later stages of neuronal development.


Is pulmonary vein isolation still the cornerstone in atrial fibrillation ablation?
Radiofrequency catheter ablation for atrial fibrillation (AF) has become a frequently used therapy after failure of at least one antiarrhythmic drug. The cornerstone of AF ablation has been durable pulmonary vein isolation. However, understanding the positive and negative outcomes of catheter ablation of AF is severely limited by diverse ablation methodologies that do not seem to result in durable pulmonary vein isolation. Without durable pulmonary isolation ablation, it is unclear if ablation strategies need to be modified to include extrapulmonary vein ablation targets in combination with pulmonary vein isolation or alone to improve long-term procedural success rates. The marked discrepancy between AF ablation procedure success rates and actual long-term pulmonary vein isolation rates does suggest that targeting other mechanisms can be considered to achieve similar or better results when compared to pulmonary vein isolation alone.


Child Influenza Vaccination and Adult Work Loss: Reduced Sick Leave Use Only in Adults With Paid Sick Leave.
Children are a population of interest for influenza. They are at increased risk for severe influenza, comprise a substantial portion of influenza morbidity, and significantly contribute to its transmission in the household and subsequent parental work loss. The association between influenza vaccination and work loss prevention, however, has rarely been studied, and the sparse existing literature has very limited generalizability to U.S. adults, thus requiring better characterization. Using pooled National Health Interview Survey data (2013-2015, analyses conducted in 2018) nationally representative of working U.S. adults with household children (n=23,014), zero-inflated negative binomial regression examined the association of child influenza vaccination (exposure) with sick days (outcome) stratified by paid sick leave (no: n=10,741, yes: n=12,273). Child influenza vaccination was associated with significantly lower sick day usage, but only among adults with paid sick leave (prevalence rate ratio=0.79, 95% CI=0.67, 0.93), equating to average annual sick days of 4.07 vs 3.29 in adults with unvaccinated versus vaccinated household children (difference=0.78 fewer days annually). Influenza vaccination of children is associated with reduced sick leave in household adults, helping to keep the workforce healthy and reduce influenza's costly annual economic burden. This only occurred among adults with paid sick leave, however, which is distributed inequitably by income, education, gender, occupation, and race/ethnicity. Health in All Policies considers downstream health effects of social and economic policy; the failure of federal policy to ensure paid sick leave likely contributes to propagating influenza and health inequities.


Superficial CD34 positive fibroblastic tumor: report of three cases and review of the literature.
Superficial CD34 positive fibroblastic tumor (SCPFT) is a recently recognized, unique neoplasm with distinctive histomorphological features such as high pleomorphism, low mitotic rate, and diffuse CD34 reactivity. Hereby we present three cases of our experience with clinicopathological, morphological, and immunohistochemical characteristics. The patients were a 31-year-old female, 53-year-old female, and 33-year-old male. The tumors were all superficially located; left forearm, medial aspect of the left ankle, and left thigh, respectively. Histomorphologically they had expansile and focal infiltrative growth pattern consisting of highly pleomorphic spindle cells with intranuclear inclusions, yet low mitotic rate. Tumoral cells showed strong and diffuse reactivity for CD34. One of our cases showed focal and weak reactivity for pancytokeratin. Unlike the other two tumors, one case was positive for desmin. During the clinical follow-up, one case showed local recurrence four times. SCPFT is a newly recognized, borderline mesenchymal neoplasm of soft tissues that can show local recurrence or even rarely metastasize. To the best of our knowledge, this three case series is the first to be reported from Turkey. Our aim to report these three cases was to make contribution to the literature about this rare entity and increase awareness.


[Mixoploidy in wild and cultivated Cruciferae species able to hybridize with Brassica napus].
Chromosome numbers in root meristem cells of the seedlings of wild and cultivated Cruciferae species able to hybridize with Brassica napus have been studied. The seedlings of Brassica junceae, Diplotaxis tenuifolia and Raphanum raphanistrum showed exclusively diploid metaphases. Up to 5% of B. napus and B. cretica seedlings were mixoploids. Diploid cells prevailed among the mixoploids, but hypo- and hyperdiploid ones were observed as well. Nearly 20 % of B. campestris and R. sativum seedlings were mixoploid, and di-tetraploid chimeras constituted considerable proportion of them. Less than a half of B. nigra seedlings were diploid, while the rest of plants were mixoploid. Among them the seedlings bearing preferentially tetra- and triploid cells dominated. Biological implications and presumable reasons underlying the discovered mixoploidy are discussed.


The time-course of feature-based attention effects dissociated from temporal expectation and target-related processes.
Selective attention prioritises relevant information amongst competing sensory input. Time-resolved electrophysiological studies have shown stronger representation of attended compared to unattended stimuli, which has been interpreted as an effect of attention on information coding. However, because attention is often manipulated by making only the attended stimulus a target to be remembered and/or responded to, many reported attention effects have been confounded with target-related processes such as visual short-term memory or decision-making. In addition, attention effects could be influenced by temporal expectation about when something is likely to happen. The aim of this study was to investigate the dynamic effect of attention on visual processing using multivariate pattern analysis of electroencephalography (EEG) data, while (1) controlling for target-related confounds, and (2) directly investigating the influence of temporal expectation. Participants viewed rapid sequences of overlaid oriented grating pairs while detecting a "target" grating of a particular orientation. We manipulated attention, one grating was attended and the other ignored (cued by colour), and temporal expectation, with stimulus onset timing either predictable or not. We controlled for target-related processing confounds by only analysing non-target trials. Both attended and ignored gratings were initially coded equally in the pattern of responses across EEG sensors. An effect of attention, with preferential coding of the attended stimulus, emerged approximately 230 ms after stimulus onset. This attention effect occurred even when controlling for target-related processing confounds, and regardless of stimulus onset expectation. These results provide insight into the effect of feature-based attention on the dynamic processing of competing visual information.


Beatwise ECG Classification for the Detection of Atrial Fibrillation with Deep Learning.
Atrial fibrillation (AF) is the most common, sustained cardiac arrhythmia. Early intervention and treatment could have a much higher chance of reversing AF. An electrocardiogram (ECG) is widely used to check the heart's rhythm and electrical activity in clinics. The current manual processing of ECGs and clinical classification of AF types (paroxysmal, persistent and permanent AF) is ill-founded and does not truly reflect the seriousness of the disease. In this paper, we proposed a new machine learning method for beat-wise classification of ECGs to estimate AF burden, which was defined by the percentage of AF beats found in the total recording time. Both morphological and temporal features for categorizing AF were extracted via two combined classifiers: a 1D U-Net that evaluates fiducial points and segmentation to locate each heartbeat; and the other Recurrent Neural Network (RNN) to enhance the temporal classification of an individual heartbeat. The output of the classifiers had four target classes: Normal Sinus Rhythm (SN), AF, Noises (NO), and Others (OT). The approach was trained and validated on the Icentia11k dataset, with 1001 and 250 patients' ECGs, respectively. The testing accuracy for the four classes was found to be 0.86, 0.81, 0.79, and 0.75, respectively. Our study demonstrated the feasibility and superior performance of combing U-net and RNN to conduct a beat-wise classification of ECGs for AF burden. However, further investigation is warranted to validate this deep learning approach.Clinical relevance- This paper proposes a novel machine learning network for ECG beatwise classification, specifically for aiding AF burden determination.


Understanding Shoulder and Elbow Injuries in the Windmill Softball Pitcher.
Although pitching-related injuries in the overhead athlete have been studied extensively, injuries associated with windmill pitching are not as clearly elucidated. Windmill pitching produces high forces and torques in the upper extremity, and studies have shown it creates similar shoulder and elbow joint loads to those reported in baseball pitchers. Studies have shown that the windmill pitching motion generates high levels of biceps activation with an eccentric load, placing the biceps at increased risk for overuse injuries. Although the American Orthopaedic Society for Sports Medicine published prevention guidelines including recommendations for maximum pitch counts in softball, these recommendations have not been adopted by most United States softball governing bodies. The repetitive windmill motion in conjunction with high pitch count demands in competitive softball creates notable challenges for the sports medicine physician. As with overhead throwing athletes, identifying and preventing overuse is crucial in preventing injuries in the windmill pitcher, and prevention and rehabilitation should focus on optimizing mechanics and kinematics, core, hip, and lower body strength, and recognition of muscle fatigue. With more than two million fastpitch softball participants in the United States, it is essential to better understand the etiology, evaluation, and prevention of injuries in the windmill pitching athlete.


Structure model of a complex between the factor for inversion stimulation (FIS) and DNA: modeling protein-DNA complexes with dyad symmetry and known protein structures.
A method is presented to predict overall conformations of protein-DNA complexes on the basis of the known three-dimensional structures of the proteins. The method is restricted to proteins with a common twofold symmetry axis, which show only minor conformational changes upon binding to DNA. The method uses a numerical finite difference solution of the linearized Poisson-Boltzmann equation and subsequent energy minimization cycles. Structural parameters-the rotation angle of the DNA relative to the protein around the common symmetry axis, the protein-DNA distance, and intermolecular hydrogen-bonding contacts-are presented for two test cases, DNA bound to CAP (catabolite gene activator protein) and to the Cro-repressor of bacteriophage 434. The DNA curvature in the starting model of the docking procedure was chosen as a smoothed approximation of the conformation found in the X-ray structures of these complexes. The method is further used to predict the unknown structure of the complex between the factor for inversion stimulation (FIS) and DNA, which is bent upon binding to FIS. In contrast to the test cases, the unknown curvature of the starting model is derived from a calibration of electrostatic precalculations for different proteins according to crystallographically observed DNA bending. The results of the modeling are in good accordance with the experimentally observed overall structure of protein-DNA complexes for the two test cases; for FIS, they correspond to several of the experimentally proposed protein-DNA contacts.


Unilateral vortex keratopathy of unknown etiology.
A 54-year-old man with noncontributory medical history presented to an ophthalmologist in January 2022 after 10 days of irritation in his right eye. The patient recounts having felt something get into his eye and under his contact lens (CL) while he was climbing into his car, but he was unsure what the foreign body may have been. Initial examination by the clinician found uncorrected distance visual acuity of 20/100-2 with a corneal abrasion, 4+ corneal edema, and 3+ conjunctival injection, for which he was placed on topical antibiotics (ocuflox and tobradex) with a bandage CL. 1 week later, visual acuity was 20/80, corneal edema had improved, and he was noted to have corneal scarring and an epithelial defect. Tobradex was continued while prednisolone drops and preservative-free artificial tears were started. 1 week later, the patient had worsening visual acuity to 20/250 and was referred to our tertiary center. On initial consultation, the patient had an uncorrected distance visual acuity of 20/500 and an uncorrected near visual acuity of >J10 in the right eye. Slitlamp examination of the right eye was significant for vortex keratopathy and mild corneal pannus with 360-degree subtle conjunctivalization of the limbus ( Figure 1JOURNAL/jcrs/04.03/02158034-202210000-00022/figure1/v/2022-10-03T121249Z/r/image-tiff ). The corneal topograph was obtained showing significant surface irregularity on the Placido image ( Figure 2JOURNAL/jcrs/04.03/02158034-202210000-00022/figure2/v/2022-10-03T121249Z/r/image-tiff ). Examination of the left eye was unremarkable. The ocular history is significant for myopia of -4.0 diopters and CL use for 20 years. The patient admits to regularly wearing soft CLs for several days straight and only removing them for a few hours. Antibiotics were discontinued, corticosteroid drops were reduced in frequency, and the patient was continued on preservative-free artificial tears. What imaging might you consider? What is your differential diagnosis at this point? What would be the most appropriate surgical and/or medical interventions? What would you counsel in prognosis for this patient?


Structural differences between human proteins and aero- and microbial allergens define allergenicity.
The current paradigm suggests that structural homology of allergenic proteins to microbial (particularly helminths) or human proteins underlie their allergenic nature. To examine systematically the structural relationships among allergens and proteins of pathogens (helminths, protozoans, fungi and bacteria) as they relate to allergenicity, we compared the amino acid sequence of 499 molecularly-defined allergens with the predicted proteomes of fifteen known pathogens, including Th2 inducing helminths and Th1-inducing protozoans, and humans using a variety of bioinformatic tools. Allergenicity was assessed based on IgE prevalences using publicly accessible databases and the literature. We found multiple homologues of common allergens among proteins of helminths, protozoans, fungi and humans, but not of bacteria. In contrast, 187 allergens showed no homology with any of the microbial genera studied. Interestingly, allergens without homologues or those with limited levels of sequence conservation were the most allergenic displaying high IgE prevalences in the allergic population. There was an inverse relationship between allergenicity and amino acid conservation levels with either parasite, including helminth, or human proteins. Our results suggest that allergenicity may be associated with the relative "uniqueness" of an antigen, i.e. immunogenicity, while similarity would lead to immunological tolerance.


Low glycaemic index or low glycaemic load diets for overweight and obesity.
Obesity is increasingly prevalent, yet the nutritional management remains contentious. It has been suggested that low glycaemic index or load diets may stimulate greater weight loss than higher glycaemic index or load diets or other weight reduction diets. To assess the effects of low glycaemic index or load diets for weight loss in overweight or obese people. Trials were identified through The Cochrane Library, MEDLINE, EMBASE, CINAHL and manual searches of bibliographies. Randomised controlled trials comparing a low glycaemic index or load diet (LGI) with a higher glycaemic index or load diet or other diet (Cdiet) in overweight or obese people. Two authors independently selected trials, assessed quality and extracted data, including any information provided on adverse effects. We identified six eligible randomised controlled trials (total of 202 participants). Interventions ranged from five weeks to six months duration with up to six months follow-up after the intervention ceased. The decrease in body mass (WMD -1.1 kg, 95% confidence interval (CI) -2.0 to -0.2, P < 0.05) (n = 163), total fat mass (WMD -1.1 kg, 95% CI -1.9 to -0.4, P < 0.05) (n =147) and body mass index (WMD -1.3, 95% CI -2.0 to -0.5, P < 0.05) (n = 48) was significantly greater in participants receiving LGI compared to Cdiets. The decrease in total cholesterol was significantly greater with LGI compared to Cdiets (WMD -0.22 mmol/L, 95% CI -0.43 to -0.02, P < 0.05), as was the change in LDL-cholesterol (WMD -0.24 mmol/L, 95% CI -0.44 to -0.05, P < 0.05). No study reported adverse effects, mortality or quality of life data. Overweight or obese people on LGI lost more weight and had more improvement in lipid profiles than those receiving Cdiets. Body mass, total fat mass, body mass index, total cholesterol and LDL-cholesterol all decreased significantly more in the LGI group. In studies comparing ad libitum LGI diets to conventional restricted energy low-fat diets, participants fared as well or better on th LGI diet, even though they could eat as much as desired. Lowering the glycaemic load of the diet appears to be an effective method of promoting weight loss and improving lipid profiles and can be simply incorporated into a person's lifestyle. Further research with longer term follow-up will determine whether improvement continues long-term and improves quality of life.


Oak Ridge Reservation Environmental Protection Rad Neshaps Radionuclide Inventory Web Database and Rad Neshaps Source and Dose Database.
The U.S. Environmental Protection Agency promulgated national emission standards for emissions of radionuclides other than radon from US Department of Energy facilities in Chapter 40 of the Code of Federal Regulations (CFR) 61, Subpart H. This regulatory standard limits the annual effective dose that any member of the public can receive from Department of Energy facilities to 0.1 mSv. As defined in the preamble of the final rule, all of the facilities on the Oak Ridge Reservation, i.e., the Y-12 National Security Complex, Oak Ridge National Laboratory, East Tennessee Technology Park, and any other U.S. Department of Energy operations on Oak Ridge Reservation, combined, must meet the annual dose limit of 0.1 mSv. At Oak Ridge National Laboratory, there are monitored sources and numerous unmonitored sources. To maintain radiological source and inventory information for these unmonitored sources, e.g., laboratory hoods, equipment exhausts, and room exhausts not currently venting to monitored stacks on the Oak Ridge National Laboratory campus, the Environmental Protection Rad NESHAPs Inventory Web Database was developed. This database is updated annually and is used to compile emissions data for the annual Radionuclide National Emission Standards for Hazardous Air Pollutants (Rad NESHAPs) report required by 40 CFR 61.94. It also provides supporting documentation for facility compliance audits. In addition, a Rad NESHAPs source and dose database was developed to import the source and dose summary data from Clean Air Act Assessment Package-1988 computer model files. This database provides Oak Ridge Reservation and facility-specific source inventory; doses associated with each source and facility; and total doses for the Oak Ridge Reservation dose.


Decision-Making, Ethics, and End-of-Life Care in Pediatric Extracorporeal Membrane Oxygenation: A Comprehensive Narrative Review.
Pediatric extracorporeal membrane oxygenation is associated with significant morbidity and mortality. We sought to summarize literature on communication and decision-making, end-of-life care, and ethical issues to identify recommended approaches and highlight knowledge gaps. PubMed, Embase, Web of Science, and Cochrane Library. We reviewed published articles (1972-2020) which examined three pediatric extracorporeal membrane oxygenation domains: 1) decision-making or communication between clinicians and patients/families, 2) ethical issues, or 3) end-of-life care. Two reviewers independently assessed eligibility using Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Of 2,581 publications screened, we identified one systematic review and 35 descriptive studies. No practical guides exist for communication and decision-making in pediatric extracorporeal membrane oxygenation. Conversation principles and parent/clinician perspectives are described. Ethical issues related to consent, initiation, discontinuation, resource allocation, and research. No patient-level synthesis of ethical issues or end-of-life care in pediatric extracorporeal membrane oxygenation was identified. Despite numerous ethical issues reported surrounding pediatric extracorporeal membrane oxygenation, we found limited patient-level research and no practical guides for communicating with families or managing extracorporeal membrane oxygenation discontinuation.


Making psychiatric epidemiology useful: the contribution of epidemiology to government policy.
This paper aims to discuss the contribution of epidemiology to aspects of public policy that have either a direct influence on mental health and mental disorders, or an indirect effect by influencing environmental factors which influence mental health. Both kinds of public policy will need to be considered by governments wishing to protect, promote and improve the mental health of their populations. The paper draws on information from both relatively wealthy and low-income countries. The paper defines epidemiology and mental health policy, sets out the range of government policies which may have an impact on mental health, and explores the ways in which epidemiology may contribute to mental health policy in relation to service inputs, processes and outcomes as well as to wider government policies. The paper also examines the advantages and disadvantages of different sources of data. There are a number of reasons to carry out large-scale surveys of psychiatric morbidity. First, effective policy should address the needs of the population, which can best be assessed by the epidemiology and the social and economic causes and consequences of psychiatric morbidity. Secondly, representative information in a defined geographic area can document the use of existing services and can estimate the extent of unmet needs and the services required meeting those needs. Thirdly, valid information on prevalence and associated risk factors of presumed causal importance allow aetiological hypotheses to be generated and tested and models developed for prevention. Finally, by repeating community surveys, it is possible to monitor the health of the population and trends. Epidemiological findings emphasize the importance of mental health policy addressing the key role of primary care, the social context and social consequences of disorder, the importance of addressing services for children, the need to reduce premature mortality from suicide and from physical illness. Epidemiological findings show that mental health and mental disorders are related to the environment both in its structural physical sense and in the sense of the social processes connected to and influenced by particular settings. Thus epidemiology can contribute to general policies on employment and unemployment, housing and homelessness, education and women's issues. Mental health policy is increasingly recognized as an essential area for countries wishing to enhance their economic, social and human capital. Epidemiological data are a basic prerequisite to informing such policies. Expert professional and epidemiological advice to ministries is essential if policy is to be rooted in the evidence for population needs, risk factors, effective treatments and services, and measurement of outcomes. It is therefore important to develop the capacity for policy work in the psychiatric profession by including public health, epidemiology and policy placements for young psychiatrists.


Image Quality Metric Derived Refractions Predicted to Improve Visual Acuity Beyond Habitual Refraction for Patients With Down Syndrome.
To determine which optimized image quality metric (IQM) refractions provide the best predicted visual acuity (VA). Autorefraction (AR), habitual refraction (spectacles, n = 23; unaided, n = 7), and dilated wavefront error (WFE) were obtained from 30 subjects with Down syndrome (DS; mean age, 30 years; range, 18-50). For each eye, the resultant metric value for 16 IQMs was calculated after >25000 sphero-cylindrical combinations of refraction were added to the measured WFE to generate residual WFE. The single refraction corresponding to each of the 16 optimized IQMs per eye was selected and used to generate acuity charts. Charts also were created for AR, habitual refraction, and a theoretical zeroing of all lower-order aberrations, and grouped into 10 sets with a clear chart in each set. Dilated controls (five observers per set) read each chart until five letters were missed on a high contrast monitor through a unit magnification telescope with a 3 mm pupil aperture. Average letters lost for the five observers for each chart was used to rank the IQMs for each DS eye. Average acuity for the best performing refraction for all DS eyes was within five letters (0.11 ± 0.05 logMAR) of the clear chart acuity. Optimized IQM refractions had ∼3.5 lines mean improvement from the habitual refraction (0.37 ± 0.22 logMAR, P < 0.001). Three metrics (Visual Strehl Ratio [VSX], VSX computed in frequency domain [VSMTF], and standard deviation of intensity values [STD]) identified refractions that were ranked first, or within 0.09 logMAR of first, in >98% of the eyes. Optimized IQM refraction is predicted to improve VA in DS eyes based on control observers reading simulated charts. Refractions identified through optimization of IQM may bypass some of the challenges of current refraction techniques for patients with DS. The optimized refractions are predicted to provide better VA compared to their habitual correction.


Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32.
Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Ten affected individuals (ages 7-58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (theta = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765-106,368,585. No segregating copy number variations were found within the disease interval. We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy-lower extremity, dominant.


Recent trends in publication of basic science and clinical research by United States investigators in anesthesia journals.
United States anesthesia research production declined sharply from 1980-2005. Whether this trend has continued despite recent calls to improve output is unknown. We conducted an observational internet analysis to quantify American basic science and clinical anesthesia research output in 14 anesthesia journals with impact factors greater than one at three-year intervals during the past decade. American investigators published 1,486 (21.7%) of the total of 6,845 research articles identified in anesthesia journals in 2001, 2004, 2007, and 2010. Approximately two-thirds of all US articles were published in Anesthesiology and Anesthesia and Analgesia. There was a significant correlation (r2 = 0.316; P = 0.036) between the number of articles published by American authors in each anesthesia journal and the corresponding journal's impact factor in 2010. Significantly (P < 0.05; Pearson's Chi-square) fewer basic science articles were published in 2007 and 2010 compared with 2001. US clinical research output also declined in 2007 (201; 15.7%) compared with 2001 (266; 19.1%) and 2004, but an increase occurred in 2010 (279; 21.8%, P < 0.05 versus 2007). The results indicate that US anesthesia research output continued to decrease from 2001 to 2007. An increase in clinical but not basic science research was observed in 2010 compared with 2007, suggesting that a modest recovery in clinical research production may have begun.


In vitro effect of temperature on the conformational structure and collagen binding of SdrF, a Staphylococcus epidermidis adhesin.
Staphylococcus epidermidis is the leading etiologic agent of device-related infections. S. epidermidis is able to bind, by means of the adhesins of its cell wall, the host matrix proteins filming the artificial surfaces. Thence, bacteria cling to biomaterials and infection develops. The effect of temperature on integrity, structure, and biological activity of the collagen-binding adhesin (SdrF) of S. epidermidis has been here investigated. By cloning in E. coli XL1-Blue, a recombinant of the SdrF binding domain B (rSdrFB), carrying an N-terminal polyhistidine, was obtained. Purification was by HiTrap(TM) Chelating HP columns. Assessment of purity, molecular weight, and integrity was by SDS-PAGE. The rSdrFB-collagen binding was investigated by ELISA. A full three-dimensional reconstruction of rSdrFB was achieved by small-angle X-ray scattering (SAXS). At 25 °C, rSdrFB bound to type I collagen in a dose-dependent, saturable manner, with a Kd of 2.48 × 10(-7) M. When temperature increased from 25 to 37 °C, a strong conformational change occurred, together with the abolition of the rSdrFB-collagen binding. The rSdrFB integrity was not affected by temperature variation. SdrFB-collagen binding is switched on/off depending on the temperature. Implications with the infection pathogenesis are enlightened.


Fungal biotransformation products of dehydroabietic acid.
Dehydroabietic acid (DHA) (1) is one of the main compounds in Scots pine wood responsible for aquatic and microbial toxicity. The degradation of 1 by Trametes versicolor and Phlebiopsis gigantea in liquid stationary cultures was followed by HPLC-DAD-ELSD. Both fungi rapidly degraded DHA relative to a control. More breakdown products were observed for T. versicolor than for P. gigantea. After 13 days, four compounds were identified by means of spectroscopic methods in P. gigantea cultures: 1beta-hydroxy-DHA (2), 1beta,7alpha-dihydroxy-DHA (3), 1beta,16-dihydroxy-DHA (5), and tentatively 1beta-hydroxy-7-oxo-DHA (4). In T. versicolor cultures, 1beta,16-dihydroxy-DHA (5), 7beta,16-dihydroxy-DHA (6), 1beta,7beta,16-trihydroxy-DHA (7), 1beta,16-dihydroxy-7-oxo-DHA (8), 1beta,15-dihydroxy-DHA (9), and 1beta,7alpha,16-trihydroxy-DHA (10) were identified after 9 days of incubation. Thus the biotransformation of 1 by the two fungi was different, with only 5 being produced by both strains. Compounds 3, 7, 8, and 10 are reported for the first time as natural products.


A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica.
Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3(+) and CD8(+) T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.


High-field, high-current superconductors.
This article deals with superconducting materials which have zero electrical resistance while carrying high electrical current densities (around 10(6) amperes per square centimeter) in high magnetic fields (up to 50 teslas). The technological importance of these materials is due to their use in the windings of loss-free electromagnets which generate high magnetic fields. Such magnets are the foundation for superconducting electrotechnology, a rapidly growing field whose applications include advanced electrical machines and fusion reactors. The article focuses primarily on the materials aspects of this new techology. A brief overview is given of the physical principles which underlie this special type of superconducting behavior, and some of the important basic parameters are examined. The technology required to adapt the materials to electromagnets is also discussed. A few concluding remarks concern future possibilities for materials that can be used in generating very high magnetic fields.


Mechanistic Insights into the Capsule-Targeting Depolymerase from a Klebsiella pneumoniae Bacteriophage.
The production of capsular polysaccharides by Klebsiella pneumoniae protects the bacterial cell from harmful environmental factors such as antimicrobial compounds and infection by bacteriophages (phages). To bypass this protective barrier, some phages encode polysaccharide-degrading enzymes referred to as depolymerases to provide access to cell surface receptors. Here, we characterized the phage RAD2, which infects K. pneumoniae strains that produce the widespread, hypervirulence-associated K2-type capsular polysaccharide. Using transposon-directed insertion sequencing, we have shown that the production of capsule is an absolute requirement for efficient RAD2 infection by serving as a first-stage receptor. We have identified the depolymerase responsible for recognition and degradation of the capsule, determined that the depolymerase forms globular appendages on the phage virion tail tip, and present the cryo-electron microscopy structure of the RAD2 capsule depolymerase at 2.7-Å resolution. A putative active site for the enzyme was identified, comprising clustered negatively charged residues that could facilitate the hydrolysis of target polysaccharides. Enzymatic assays coupled with mass spectrometric analyses of digested oligosaccharide products provided further mechanistic insight into the hydrolase activity of the enzyme, which, when incubated with K. pneumoniae, removes the capsule and sensitizes the cells to serum-induced killing. Overall, these findings expand our understanding of how phages target the Klebsiella capsule for infection, providing a framework for the use of depolymerases as antivirulence agents against this medically important pathogen. IMPORTANCE Klebsiella pneumoniae is a medically important pathogen that produces a thick protective capsule that is essential for pathogenicity. Phages are natural predators of bacteria, and many encode diverse "capsule depolymerases" which specifically degrade the capsule of their hosts, an exploitable trait for potential therapies. We have determined the first structure of a depolymerase that targets the clinically relevant K2 capsule and have identified its putative active site, providing hints to its mechanism of action. We also show that Klebsiella cells treated with a recombinant form of the depolymerase are stripped of capsule, inhibiting their ability to grow in the presence of serum, demonstrating the anti-infective potential of these robust and readily producible enzymes against encapsulated bacterial pathogens such as K. pneumoniae.


[Hormonal function of the ovaries in women with breast hyperplasia].
In females showing fibrous-cystic mastopathy and fibroadenomatosis of mammary glands a specific form of progesterone insufficiency- relative one, was revealed, a high persistantly maintained level of urine pregnandiol and blood progesterone in a luteal phase (indicating a high hormonal activity of the corpus luteum) being observed. But luteal transformations were insignificant both in endometrium and vaginal epithelium, a moderate hypoestrogenemia being noted in the first phase and increased estrogen excretion- in the second phase of the cycle.


Adenosine A(1) receptor induced delayed preconditioning in rabbits: induction of p38 mitogen-activated protein kinase activation and Hsp27 phosphorylation via a tyrosine kinase- and protein kinase C-dependent mechanism.
Transient adenosine A(1) receptor (A(1)R) activation in rabbits induces delayed preconditioning against myocardial infarction 24 to 72 hours later. The cellular mechanisms downstream of A(1)R mediating this delayed cardioprotection have not been elucidated. This study examined the role of protein kinase C (PKC) and tyrosine kinases (TKs) in the signaling cascade mediating A(1)R-induced late preconditioning in rabbits. The small heat shock protein Hsp27 has been shown to confer cytoskeletal protection when in the phosphorylated state. We therefore also evaluated the potential role of the p38 mitogen-activated protein kinase (p38 MAPK) and Hsp27 as distal mediators of A(1)R-induced delayed preconditioning. Pharmacological preconditioning of rabbits with the selective A(1) agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 100 microgram/kg) significantly reduced myocardial infarct size compared with control animals, after 30-minute regional ischemia/2-hour reperfusion in vivo 24 hours later (23.7+/-3.1 versus 43.0+/-4.1%; P<0.05). This delayed protection was abrogated by prior inhibition of either PKC with chelerythrine chloride (5 mg/kg) or of TKs with lavendustin A (1.3 mg/kg), suggesting that both PKC and TK are crucial for the development of delayed preconditioning after A(1) receptor activation in the rabbit. Myocardial tissue extracts obtained 24 hours after CCPA treatment were analyzed for p38 MAPK catalytic activity using an in vitro kinase assay. This showed an almost 7-fold increase in p38 MAPK activity in myocardial samples pretreated with CCPA compared with control hearts. Two-dimensional gel electrophoresis revealed an increase in the phosphorylated isoforms of Hsp27 in hearts pretreated with CCPA compared with control hearts. Prior inhibition of either PKC or TK prevented the CCPA-induced increase in p38 MAPK activity and phosphorylation of Hsp27. This study identifies new components of the signaling mechanism of A(1)R-induced delayed preconditioning. Our results suggest an important role for both PKC and TK as mediators of late preconditioning against infarction after A(1)R activation and, although correlative, point to the p38 MAPK/Hsp27 pathway as a potential distal effector of this protection.


Feasibility and Research Insights From a Randomized Controlled Trial for Recurrent Urinary Tract Infection Prevention in Postmenopausal Women Using Vaginal Estrogen Therapy.
The aim of the study was to inform feasibility parameters (eligibility, enrollment, and retention) for a recurrent urinary tract infection (rUTI) prevention randomized controlled trial (RCT). We assessed feasibility parameters of an RCT of postmenopausal women with uncomplicated rUTIs using vaginal estrogen. Participants were randomized to either d-mannose or a control arm. All participants were required to be using vaginal estrogen and to have a negative urine culture before 90-day trial participation. An RCT exit survey and separate survey for UTI patients (N = 196) were added to inform feasibility parameters and patient preferences for rUTI prevention and study participation after slower enrollment than anticipated. At the time of interim and subsequent futility analyses, 545 patients had been evaluated for frequent/recurrent UTIs from March 1, 2018, to January 18, 2020. Of these, 213 (39.1%) had culture-proven rUTIs and 71 (33.3% of those with culture-proven rUTIs) were eligible for the RCT. Reasons for ineligibility included complicated UTIs, premenopausal/perimenopausal status, or existing UTI prevention regimen. Of the 71 eligible participants, 57 (80.3%) enrolled, and 44 began their planned 90-day study period (77.2%; 80.0% after excluding 2 participants awaiting negative urine cultures at the time of analysis). The study was halted before conclusion. Study retention (76.0%-83.7%) was slightly lower than expected. Urinary tract infection survey patients demonstrated significant interest in rUTI research participation. We learned several important lessons that can benefit future research. Many patients with frequent/recurrent UTIs are interested in research, but rigorous eligibility criteria and referral urine culture documentation made recruitment challenging.


Glycosaminoglycan synthesis by cultured human retinal pigmented epithelium from normal postmortem donors and a postmortem donor with retinitis pigmentosa.
Cultured human retinal pigmented epithelium (RPE) synthesized and secreted glycosaminoglycans (GAGs) with the characteristics of chondroitin sulfate, dermatan sulfate, and hyaluronic acid from radioactive precursors. Cells subcultured for up to 18 passages from normal RPE and from the RPE of a patient with X-linked retinitis pigmentosa synthesized and secreted the same types and proportions of GAGs as primary cultures of normal RPE. Extracts of native human interphotoreceptor matrix contained hyaluronic acid and chondroitin sulfate but little or no dermatan sulfate, and the chondroitin sulfate differed in electrophoretic mobility and enzyme susceptibility from the chondroitin sulfates secreted by cultured RPE. Cultured human choroidal cells and cultured human skin fibroblasts secreted a much higher proportion of hyaluronic acid than cultured RPE. This study demonstrates that the profile of GAGs synthesized from radioactive precursors and secreted by cultured human RPE is a specific and stable characteristic of these cells that is retained even after extensive proliferation in vitro.


Factors leading to dyspepsia in renal transplant recipients.
Renal transplantation is the definitive treatment for end stage renal disease. Patients subjected to transplantation require lifelong immunosuppression and are prone to several gastrointestinal disorders. Dyspepsia is a common disorder in these patients. The objective of this study was to determine factors leading to dyspepsia in renal (kidney) transplant recipients. It was a cross sectional study conducted at department of hepatogastroenterology and transplant sciences, SIUT Karachi, from 1-6-15 to 1-12-15 for six months. All renal transplanted patients having dyspeptic symptoms for more than 6 weeks. EGD was performed, biopsy specimens obtained from antrum and duodenum, these were sent for histopathological examination. Frequency and percentages were obtained for categorical variables, mean ± SD was calculated for continuous variables. Chi square test was used for categorical variable and student t-test for continuous variables. Ninety patients were included in the study out of which 64 (71.1%) were males, mean age was 35.82 ± 10.04 years (range: 18-65 years). Gastritis (non H.pylori associated) in 78 (78.6%), duodenitis in 35 (38.9%) and H. pylori infection in 29 (32.2%), renal transplant recipients. Most of the patients belonged to Sindhi ethnicity, 27 (30%), followed by Punjabi. Hypertension was the most common co-morbid condition in our patients found in 29 (32.2%), while most of them don't have any co morbid condition. Duodenitis was found to be associated with tacrolimus use (p = 0.037). Gastritis is the most common factor accountable for this symptoms, followed by duodenitis and H. Pylori. Patients taking tacrolimus as immunosuppressant are more prone to develop duodenitis.


Swedish metacarpophalangeal standards compared with previously published norms.
Metacarpophalangeal lengths are used to create pattern profiles that are useful for assessment of skeletal dysplasias and malformation syndromes. The purpose of this study was to establish Swedish standards and compare them with previously published norms. A group of healthy Swedish children was followed longitudinally from the age of 1 month to 18 years. The length of the tubular bones of the hand was measured on radiographs. In addition to the conventional measurements including epiphyses, diaphyseal lengths alone were recorded. Means and standard deviations of the metacarpophalangeal lengths are presented by gender and age. In spite of reasonably good correlation to previously published norms, demonstrated deviations encourage us to recommend the use of local standards whenever available.


Induction of Nrf2-mediated cellular defenses and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in the liver.
Coffee consumption has been associated with a significant decrease in the risk of developing chronic diseases such as Parkinson disease, diabetes type-2 and several types of cancers (e.g. colon, liver). In the present study, a coffee-dependent induction of enzymes involved in xenobiotic detoxification processes was observed in rat liver and primary hepatocytes. In addition, coffee was found to induce the mRNA and protein expression of enzymes involved in cellular antioxidant defenses. These inductions were correlated with the activation of the Nrf2 transcription factor as shown using an ARE-reporter luciferase assay. The induction of detoxifying enzymes GSTs and AKR is compatible with a protection against both genotoxicity and cytotoxicity of aflatoxin B1 (AFB1). This hypothesis was confirmed in in vitro and ex vivo test systems, where coffee reduced both AFB1-DNA and protein adducts. Interestingly, coffee was also found to inhibit cytochrome CYP1A1/2, indicating that other mechanisms different from a stimulation of detoxification may also play a significant role in the chemoprotective effects of coffee. Further investigations in either human liver cell line and primary hepatocytes indicated that the chemoprotective effects of coffee against AFB1 genotoxicity are likely to be of relevance for humans. These data strongly suggest that coffee may protect against the adverse effects of AFB1. In addition, the coffee-mediated stimulation of the Nrf2-ARE pathway resulting in increased endogenous defense mechanisms against electrophilic but also oxidative insults further support that coffee may be associated with a protection against various types of chemical stresses.


Lithium Sulfide (Li2S)/Graphene Oxide Nanospheres with Conformal Carbon Coating as a High-Rate, Long-Life Cathode for Li/S Cells.
In recent years, lithium/sulfur (Li/S) cells have attracted great attention as a candidate for the next generation of rechargeable batteries due to their high theoretical specific energy of 2600 W·h kg(-1), which is much higher than that of Li ion cells (400-600 W·h kg(-1)). However, problems of the S cathode such as highly soluble intermediate species (polysulfides Li2Sn, n = 4-8) and the insulating nature of S cause poor cycle life and low utilization of S, which prevents the practical use of Li/S cells. Here, a high-rate and long-life Li/S cell is proposed, which has a cathode material with a core-shell nanostructure comprising Li2S nanospheres with an embedded graphene oxide (GO) sheet as a core material and a conformal carbon layer as a shell. The conformal carbon coating is easily obtained by a unique CVD coating process using a lab-designed rotating furnace without any repetitive steps. The Li2S/GO@C cathode exhibits a high initial discharge capacity of 650 mA·h g(-1) of Li2S (corresponding to the 942 mA·h g(-1) of S) and very low capacity decay rate of only 0.046% per cycle with a high Coulombic efficiency of up to 99.7% for 1500 cycles when cycled at the 2 C discharge rate.


Differential role of PKC isoforms in GnRH and phorbol 12-myristate 13-acetate activation of extracellular signal-regulated kinase and Jun N-terminal kinase.
GnRH is the first key hormone of reproduction. The role of protein kinase C (PKC) isoforms in GnRH-stimulated MAPK [ERK and Jun N-terminal kinase (JNK)] was examined in the αT3-1 and LβT2 gonadotrope cells. Incubation of the cells with GnRH resulted in a protracted activation of ERK1/2 and a slower and more transient activation of JNK1/2. Gonadotropes express conventional PKCα and conventional PKCβII, novel PKCδ, novel PKCε, and novel PKCθ, and atypical PKC-ι/λ. The use of green fluorescent protein-PKC constructs revealed that GnRH induced rapid translocation of PKCα and PKCβII to the plasma membrane, followed by their redistribution to the cytosol. PKCδ and PKCε localized to the cytoplasm and Golgi, followed by the rapid redistribution by GnRH of PKCδ to the perinuclear zone and of PKCε to the plasma membrane. Interestingly, PKCα, PKCβII, and PKCε translocation to the plasma membrane was more pronounced and more prolonged in phorbol-12-myristate-13-acetate (PMA) than in GnRH-treated cells. The use of selective inhibitors and dominant-negative plasmids for the various PKCs has revealed that PKCβII, PKCδ, and PKCε mediate ERK2 activation by GnRH, whereas PKCα, PKCβII, PKCδ, and PKCε mediate ERK2 activation by PMA. Also, PKCα, PKCβII, PKCδ, and PKCε are involved in GnRH and PMA stimulation of JNK1 in a cell-context-dependent manner. We present preliminary evidence that persistent vs. transient redistribution of selected PKCs or redistribution of a given PKC to the perinuclear zone vs. the plasma membrane may dictate its selective role in ERK or JNK activation. Thus, we have described the contribution of selective PKCs to ERK and JNK activation by GnRH.


Atypical fibromuscular hyperplasia. Report of two cases.
Two cases of atypical fibromuscular hyperplasia of the internal carotid artery (ICA) are reported. These cases are unique because the changes involve the intima of the vessels without involvement of medial structures as seen in the more common form of fibromuscular hyperplasia. Case 1 is only the fourth report of a symptomatic fibromuscular stenosis at the origin of the ICA. Case 2 is the first report of fibromuscular hyperplasia involving the common carotid artery. Changes similar to those in Case 2 (an elongated area of tubular fibromuscular stenosis) have been reported in the ICA. These atypical or intimal forms of fibromuscular hyperplasia appear to be more common in males and blacks, and may be more often unilateral as well.


Liver transplantation for haemophiliacs with hepatitis C cirrhosis.
Experience of liver transplantation in haemophiliacs with end stage hepatitis C liver disease is limited and particularly difficult questions are raised when there is also HIV infection. This is the first report in Great Britain to describe the operative replacement therapy and initial outcome in four haemophiliacs with end stage HCV cirrhosis. Two patients had factor VIII, one had factor IX, and one had factor X deficiency. One patient had also contracted HIV infection from factor replacement but had no AIDS defining illnesses. Intraoperatively patients were given either factor VIII infusions, factor IX bolus, or fresh frozen plasma, according to formulae devised to calculate exact clotting factor requirements. Baseline preoperative coagulation studies included prothrombin time, activated partial thromboplastin time, fibrinogen concentrations, and factor VIII, IX, and X concentrations. Factor concentrations were then assayed at 12, 24, 48, and 72 hours postoperatively. Postoperatively all patients had coagulation factor concentrations sustained within the normal ranges by 72 hours unsupported (137, 125, 95, 104 IU/dl), representing de novo synthesis by the graft. Transfusion requirements during the operative and immediate post-transplant period were no greater than those of patients without clotting disorders. Two patients had episodes of bleeding postoperatively, one of which was fatal, occurring at the site of a previous untreated subdural bleed. In both instances the bleeding occurred in the presence of normal concentrations of clotting factor. The remaining three patients are at 6, 6, and 12 months post-transplant and remarkably improved clinically with sustained factor concentrations. One patient has evidence of graft dysfunction from HCV recurrence and all have evidence of recurrent viraemia with HCV on polymerase chain reaction studies. Orthotopic liver transplantation should be considered in haemophiliac patients with end stage liver disease from hepatitis C infection with or without concomitant HIV infection. Their clinical condition is likely to be greatly improved by orthotopic liver transplantation and the haemophilia cured with only a small risk of severe graft dysfunction from recurrent HCV infection.


Antiglomerular Basement Membrane Disease.
Antiglomerular basement membrane (anti-GBM) disease is a rare but life-threatening autoimmune vasculitis that is characterized by the development of pathogenic autoantibodies to type IV collagen antigens expressed in the glomerular and alveolar basement membranes. Once deposited in tissue, these autoantibodies incite a local capillaritis which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90% of patients, and with concurrent alveolar hemorrhage in ∼50%. A small proportion of cases may present with pulmonary disease in isolation. Serological testing for anti-GBM antibodies may facilitate rapid diagnosis, though renal biopsy is often required to confirm the presence of necrotizing or crescentic GN and linear deposition of autoantibody on the glomerular basement membrane. Alveolar hemorrhage may be evident clinically, or detected on imaging, pulmonary function testing, or bronchoscopy. Prompt treatment with plasmapheresis, cyclophosphamide, and steroids is usually indicated to remove pathogenic autoantibodies, to prevent their ongoing production, and to ameliorate end-organ inflammation. Alveolar hemorrhage is usually responsive to this treatment, and long-term respiratory sequelae are uncommon. Renal prognosis is more variable, though with aggressive treatment, independent renal function is maintained at 1 year in more than 80% of patients not requiring renal replacement therapy at presentation. Relapse in uncommon in anti-GBM disease, unless there is a concomitant antineutrophil cytoplasm antibody (present in 30-40%), in which case maintenance immunosuppression is recommended.


Clinical Presentation, Management and Outcome of Japanese Patients With Acute Myocardial Infarction in the Troponin Era - Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) - .
New criteria for diagnosis of acute myocardial infarction (AMI) were proposed in 2000 as a universal definition, in which cardiac troponin (cTn) was the preferred biomarker. A large number of patients formerly classified by creatine kinase (CK) as unstable angina are now ruled-in by cTn as non-ST-elevation myocardial infarction (NSTEMI). The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective and multicenter registry conducted in 28 institutions. We enrolled 3,283 consecutive patients with AMI diagnosed by cTn-based criteria who were admitted to participating institutions within 48 h of symptom onset. There were 2,262 patients (68.9%) with STEMI and 1,021 (31.1%) with NSTEMI. CK was not elevated more than twice the upper limit of normal in 458 patients (44.9%) with NSTEMI (NSTEMI-CK). Although there was no significant difference in the in-hospital mortality of STEMI and NSTEMI with CK elevation (NSTEMI+CK) patients (7.1% vs. 7.8%, P=0.57), it was significantly lower in patients with NSTEMI-CK than in those with STEMI or NSTEMI+CK (1.7%, P<0.001 for each). J-MINUET revealed the clinical presentation, management and outcomes of Japanese patients with AMI in the current cTn era. We should be aware of the difference between AMI diagnosed by CK-based criteria and AMI diagnosed by cTn-based criteria when using universal definitions for the diagnosis of AMI.


Atypical case of Smith-Lemli-Opitz syndrome: implications for diagnosis.
Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder comprised of recognizable facial abnormalities, growth retardation, and multiple congenital anomalies, commonly involving genitalia, second and third toe syndactyly, and cleft palate. The condition is associated with hypocholesterolemia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from deficient activity of the enzyme 7-dehydrocholesterol reductase. The clinical spectrum of SLO ranges from individuals with mental retardation and minor anomalies to those with major structural defects and early or even prenatal lethality. Low maternal serum unconjugated estriol (uE3) levels and a variety of fetal ultrasound anomalies have been identified in affected pregnancies, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal antenatal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype. The infant died at birth. At autopsy the infant had hydrops, unusual face, cleft palate, genital abnormalities, Dandy-Walker malformation, and absence of toe syndactyly. Tests performed on cultured skin fibroblasts showed elevated levels of 7DHC and abnormalities of cholesterol biosynthesis characteristic of the metabolic defect that causes SLO. The atypical findings of hydrops, uncharacteristic facial appearance, and absence of toe syndactyly in this case additionally illustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal fetal ultrasound findings in the presence of a normal karyotype lends additional support for consideration of prenatal biochemical testing for SLO in pregnancies with these findings, including pregnancies not previously known to be at risk.


Are Asians at greater mortality risks for being overweight than Caucasians? Redefining obesity for Asians.
To assess whether overweight Asians, assessed on the basis of WHO criteria, are at greater mortality risk than overweight Caucasians, and to determine whether alternative cut-off points (BMI = 23.0-24.9 kg/m2 for overweight and BMI >or= 25.0 kg/m2 for obesity) suggested by the WHO Western Pacific Regional Office are appropriate. The cohort was followed prospectively until the end of 2001. All-cause and CVD mortality risks of the overweight and obese group, relative to the reference group (BMI = 18.5-24.9 or 18.5-22.9 kg/m2), were assessed using Cox regression analysis, adjusting for age, smoking and gender. Excess deaths were estimated with a method proposed by the US Centers for Disease Control and Prevention. National Health Interview Survey (NHIS 2001) and a middle-aged perspective cohort in Taiwan. Subjects comprised 36 386 civil servants and school teachers, aged 40 years and older, who underwent a medical examination during 1989-1992. In the WHO-defined overweight group, Asians showed a significant increase in all-cause mortality risk compared with Caucasians. Asians showed risks equivalent to Caucasians' at lower BMI (around 5 units). Every unit of BMI increase, at 25.0 kg/m2 or above, was associated with a 9 % increase in relative mortality risk from all causes. Applying a cut-off point of 25.0 kg/m2 for obesity would result a prevalence of 27.1 %, while the traditional WHO cut-off point of 30.0 kg/m2 yielded obesity prevalence of 4.1 %. Excess deaths due to obesity accounted for 8.6 % of all deaths and 21.1 % of CVD deaths, based on the alternative cut-offs. In this Asian population, significant mortality risks started at BMI >or= 25.0 kg/m2, rather than at BMI >or= 30.0 kg/m2. The study supports the use of BMI >or= 25.0 kg/m2 as a new cut-off point for obesity and BMI = 23.0-24.9 kg/m2 for overweight. The magnitude of obesity-attributable deaths has been hitherto under-appreciated among Asians.


Intramural gastric hematoma in a hemophiliac with an inhibitor.
A rare complication of an intramural gastric hematoma developed in a hemophiliac with an inhibitor. Ultrasonography assisted in making the correct diagnosis.


Low competitive status elicits aggression in healthy young men: behavioural and neural evidence.
Winners are commonly assumed to compete more aggressively than losers. Here, we find overwhelming evidence for the opposite. We first demonstrate that low-ranking teams commit more fouls than they receive in top-tier soccer, ice hockey and basketball men's leagues. We replicate this effect in the laboratory, showing that male participants deliver louder sound blasts to a rival when placed in a low-status position. Using neuroimaging, we characterize brain activity patterns that encode competitive status as well as those that facilitate status-dependent aggression in healthy young men. These analyses reveal three key findings. First, anterior hippocampus and striatum contain multivariate representations of competitive status. Second, interindividual differences in status-dependent aggression are linked with a sharper status differentiation in the striatum and with greater reactivity to status-enhancing victories in the dorsal anterior cingulate cortex. Third, activity in ventromedial, ventrolateral and dorsolateral prefrontal cortex is associated with trial-wise increases in status-dependent aggressive behaviour. Taken together, our results run counter to narratives glorifying aggression in competitive situations. Rather, we show that those in the lower ranks of skill-based hierarchies are more likely to behave aggressively and identify the potential neural basis of this phenomenon.


Systematic Review of Management of Moderate Wasting in Children over 6 Months of Age.
The effective management of the 33 million children with moderate acute malnutrition (MAM) is key to reducing childhood morbidity and mortality. In this review, we aim to evaluate the effectiveness of specially formulated foods (SFFs) compared to non-food-based approaches to manage MAM in children >6 months old. We conducted a search on ten databases until 23 August 2021 and included five studies, covering 3387 participants. Meta-analysis of four studies comparing SFFs to counselling or standard of care showed that SFFs likely increase recovery rate, reduce non-response, and may improve weight-for-height z-score, weight-for-age z-score and time to recovery, but have little or no effect on MUAC gain. One study on a multicomponent intervention (SFFs, antibiotics and counselling provided to high-risk MAM) compared to counselling only was reported narratively. The intervention may increase weight gain after 24 weeks but may have little or no effect on weight gain after 12 weeks and on non-response and mortality after 12 and 24 weeks of enrollment. The effect of this intervention on recovery was uncertain. In conclusion, SFFs may be beneficial for children with moderate wasting in humanitarian contexts. Programmatic recommendations should consider context and cost-effectiveness.