Alkylphenolic compounds and risk of breast and prostate cancer in the MCC-Spain study.
Alkylphenolic compounds are chemicals with endocrine disrupting properties that have been widely used in industry with important changes in their usage over time. Few epidemiologic studies have evaluated the effect of alkylphenolic compounds on human health. We investigated whether occupational exposure to alkylphenolic compounds is associated with breast and prostate cancer. We carried out a population-based case-control study including 1513 incident cases of breast cancer, 1095 of prostate cancer, and 3055 controls, frequency matched by sex, age and region. Occupational exposure to alkylphenolic compounds was estimated using a recently developed job-exposure matrix, which considered different scenarios of exposure and different subtypes of alkylphenolic compounds. History of occupational exposure to alkylphenolic compounds was modestly associated with breast cancer (OR = 1.23; 95% CI = 1.01-1.48). Within the different scenarios, the occupational use of domestic tensioactives was positively associated with breast cancer (OR = 1.28; 95% CI = 1.02-1.60), while occupational exposure in other scenarios showed mostly a suggestion of a similar positive associations. Exposure to nonylphenol ethoxylates was positively associated with breast cancer (OR = 1.21; 95% CI = 1.00-1.47), while exposure to other compounds was uncommon. In general, we did not observe associations between alkylphenolic compounds and prostate cancer, except for a positive association among men occupationally exposed to cosmetic, hair and personal hygiene products. Our findings suggest a modest association between breast cancer risk and occupational exposure to alkylphenolic compounds, and no associations between these compounds and prostate cancer risk. These findings warrant further corroboration in other studies.


[Use of an aerosol generator (Guard) to control injurious insects in forestry, agriculture, and medical disinsection].
The Guard aerosol generator is a universal multioperational device without a field-of-use restriction in the application of permitted chemical and biological substances, by combining the function of a controlled dispersion aerosol generator and a remote small- and large-drop sprayer in one mechanism and can use aerosol pesticides. The drop fractionation range is as follows: 3-50, 50-100, 100-300, and 200-400 microm for aerosol, dead water, small-drop, and large-drop spraying, respectively, with smooth and step control of working liquid drops. Treatment using the Guard generator has been shown to be highly effective against agricultural and forestry pests. This paper describes the advantages of the Guard sprayer over those of the conventional air and ground ones. The long-term use of the Guard generator to control mosquitoes and ticks in the Tyumen region could substantially improve the epidemiological situation of tick-borne infections and protect children's recreation centers from attacks of bloodsuckers.


The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic.
The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike protein raised concerns that the virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.


Streptococcal necrotising fasciitis: comparison between histological and clinical features.
Nineteen acute and 17 subacute cases of necrotising fasciitis due to beta haemolytic streptococci are described. Excised tissue from seven and four cases, respectively, was available for histological examination. The two clinical types showed remarkable similarities, with inflammation and necrosis from epidermis to subcutaneous fat. Haemorrhage was present in variable amounts in both types. Gram positive cocci were not always identified in tissue, nor cultured, when serological tests were required to confirm the diagnosis. The only apparent difference between the acute and subacute type was the higher incidence of thrombi in some blood vessels of acute cases, whereas patent vessels or recanalized thrombus were usually found in subacute cases. This quantitative difference in the degree of thrombosis may alone be responsible for the varying clinical features and response to antibiotics.


Prevalence of unsuspected pancreatic cysts on MDCT.
Current generation MDCT technology facilitates identification of small, nonenhancing lesions in the pancreas. The objective of this study was to determine the prevalence of findings of unsuspected pancreatic cysts on 16-MDCT in a population of adult outpatients imaged for disease unrelated to the pancreas. Contrast-enhanced MDCT scans of the abdomen were reviewed from 2,832 consecutive examinations to identify pancreatic cysts. Patients with a history of pancreatic lesions or predisposing factors for pancreatic disease or who were referred for pancreatic CT were excluded. A total of 73 patients had pancreatic cysts, representing a prevalence of 2.6 per 100 patients (95% CI, 2.0-3.2). Cysts ranged in size from 2 to 38 mm (mean, 8.9 mm) and were solitary in 85% of cases. Analysis of demographic information showed a strong correlation between pancreatic cysts and age, with no cysts identified among patients under 40 years and a prevalence of 8.7 per 100 (95% CI, 4.6-12.9) in individuals from 80 to 89 years. After controlling for age, cysts were more common in individuals of the Asian race than all other race categories, with an odds ratio of 3.57 (95% CI, 1.05-12.13). There was no difference by sex in the prevalence of cysts (p = 0.527); however, cysts were on average 3.6 mm larger (p = 0.014) in men than women. In this outpatient population, the prevalence of unsuspected pancreatic cysts identified on 16-MDCT was 2.6%. Cyst presence strongly correlated with increasing age and the Asian race.


Reappraisal of the Subtropical Guidelines on Palivizumab Prophylaxis in Congenital Heart Disease.
Objective: To define the impact of associated abnormalities on the efficacy of the novel subtropical guidelines for palivizumab prophylaxis on respiratory syncytial virus (RSV)-related hospitalizations in patients with hemodynamically significant congenital heart disease (hsCHD). Method: This prospective study enrolled every patient seen at a tertiary care center for hsCHD, who was born between 2014 and 2018 and received at least 1 dose of palivizumab, according to the subtropical guidelines. The patients were followed until the age of 2 years. Results: A total of 772 patients (49% male) were enrolled. Cyanotic CHD was seen in 46% of patients, of whom 23% had associated abnormalities. Lung/airway abnormalities (14%) were the most common followed by the genetic syndromes associated with CHD (7.3%). Among the 772 patients, RSV-related hospitalizations occurred in 3.2 and 2.2% children aged ≤ 12 and 13-24 months, respectively. Most of the RSV infections occurred in patients no longer satisfying the criteria for palivizumab prophylaxis. The patients with associated abnormalities but not the type of CHD, patient age, and patient sex were risk factors for RSV-related hospitalizations. The rates of RSV-related hospitalizations, admission to the intensive care unit, and endotracheal intubation were higher for patients with associated anomalies than for other patients before 24 months of age (10.2 vs. 4.0%, 67 vs. 33%, and 39 vs. 4.2%, p = 0.004, 0.06, 0.013, respectively). Conclusion: Children with abnormalities, especially genetic syndromes and lung/airway problems associated with CHD, are at high risk for RSV-related hospitalization. Our current subtropical guidelines for palivizumab prophylaxis in patients with hsCHD, should be revised to include the results of this study.


IFN-gamma enhances endothelial activation induced by tumor necrosis factor but not IL-1.
Previous studies have established that different cytokines induce distinct patterns of activation in cultured endothelial cells (EC). Treatment of EC with either TNF or IL-1 causes transient induction of endothelial leukocyte adhesion molecule-1 (ELAM-1) and a sustained increase in intercellular adhesion molecule-1 (ICAM-1) expression. TNF but not IL-1 also increases class I MHC Ag expression. IFN-gamma, which by itself increases EC class I MHC and ICAM-1 but does not induce ELAM-1 expression, has been found to act synergistically with TNF to increase class I expression. In our study, we have further examined IFN-gamma effects on both TNF and IL-1 beta responses. In contrast to IFN-gamma plus TNF cotreatment, IFN-gamma up-regulation of class I MHC molecules is not augmented by cotreatment with IL-1 beta. IFN-gamma plus TNF cotreatment synergistically increases ICAM-1 expression by 24 h of cotreatment, whereas IFN-gamma plus IL-1 beta cotreated EC show at most additive increases. IFN-gamma increases TNF-induced ELAM-1 expression such that a greater number of EC express ELAM-1 at both 4 and 24 h in the presence of IFN-gamma plus TNF compared to cultures treated with TNF alone, although the maximal level of surface expression on individual cells is not increased. Inasmuch as these times represent pre- and post-peak expression time (6 h), respectively, IFN-gamma appears both to accelerate and to prolong transient ELAM-1 expression. Although similar interactions are seen with IL-1 beta, IFN-gamma has a consistently greater effect on TNF-induced compared to IL-1-induced ELAM-1 expression. We next explored the possible mechanism(s) of the synergy between IFN-gamma and TNF. IFN-gamma and TNF do not cooperatively enhance total protein synthesis. Unexpectedly, IFN-gamma and IL-1 beta combine to depress protein synthesis, which may contribute to the failure of these cytokines to positively interact. IFN-gamma and TNF cooperatively increase ELAM-1 mRNA at 6 h and ICAM-1 mRNA at both 6 and 24 h, whereas IFN-gamma and IL-1 show markedly less cooperative augmentation of these transcripts. We conclude that IFN-gamma enhances TNF-induced EC activation by selectively and synergistically increasing synthesis of specific surface molecules, whereas IL-1-induced EC activation is largely unaffected by IFN-gamma.


Meta-Analysis of the Efficacy of Virtual Reality-Based Interventions in Cancer-Related Symptom Management.
Background. This meta-analysis summarizes the results from recent studies that examined the use of virtual reality (VR)-based interventions on health-related outcomes in patients with cancer, and quantitatively evaluates the efficacy of VR-based interventions. Findings of this meta-analysis can provide direction for future symptom management research. Methods. The search terms included a combination of "virtual reality" OR "virtual environment" OR "head-mounted display" with "oncology" OR "cancer." Three databases (Medline, PubMed, and CAJ Full-text Database), one search engine (Google Scholar), and the website of ResearchGate, covering the period from December 2013 to May 15, 2019, and including articles published in both English and Chinese, were searched. Data synthesis used the RevMan 5.3 to generate pooled estimates of effect size. Results. A total of 6 empirical studies met the eligibility criteria. VR-based interventions had statistically significant effects on reducing symptoms of anxiety, depression, pain, and cognitive function, whereas statistically significant benefit was observed for fatigue (Z = 2.76, P = .006). Conclusion. Most recent studies have primarily examined VR-based interventions for symptom management in the acute stages of cancer care. However, the management of late and long-term side effects is central to cancer survivorship care. There is burgeoning empirical support for further research to evaluate the efficacy of VR-based interventions in cancer rehabilitation.


Access as a policy-relevant concept in low- and middle-income countries.
Although access to health care is frequently identified as a goal for health care policy, the precise meaning of access to health care often remains unclear. We present a conceptual framework that defines access to health care as the empowerment of an individual to use health care and as a multidimensional concept based on the interaction (or degree of fit) between health care systems and individuals, households, and communities. Three dimensions of access are identified: availability, affordability, and acceptability, through which access can be evaluated directly instead of focusing on utilisation of care as a proxy for access. We present the case for the comprehensive evaluation of health care systems as well as the dimensions of access, and the factors underlying each dimension. Such systemic analyses can inform policy-makers about the 'fit' between needs for health care and receipt of care, and provide the basis for developing policies that promote improvements in the empowerment to use care.


Identifying adolescents at highly elevated risk for suicidal behavior in the emergency department.
The feasibility and concurrent validity of adolescent suicide risk screening in medical emergency departments (EDs) has been documented. The objectives of this short-term prospective study of adolescents who screened positive for suicide risk in the ED were: 1) to examine adolescents' rate of suicidal behavior during the 2 months following their ED visits and compare it with reported rates for psychiatric samples; and 2) to identify possible predictors of acute risk for suicidal behavior in this at-risk sample. Participants were 81 adolescents, ages 14-19 years, seeking services for psychiatric and nonpsychiatric chief complaints, who screened positive for suicide risk because of recent suicidal ideation, a suicide attempt, and/or depression plus alcohol or substance misuse. A comprehensive assessment of suicidal behavior, using the Columbia-Suicide Severity Rating Scale, was conducted at baseline and 2 month follow-up. Six adolescents (7.4%) reported a suicide attempt and 15 (18.5%) engaged in some type of suicidal behavior (actual, aborted, or interrupted suicide attempt; preparatory behavior) during the 2 months following their ED visit. These rates suggest that this screen identified a high-risk sample. Furthermore, adolescents who screened positive for suicidal ideation and/or attempt plus depression and alcohol/substance misuse were most likely to engage in future suicidal behavior (38.9%). In this study, use of a higher screen threshold (multiple suicide risk factors) showed promise for identifying highly elevated acute risk for suicidal behavior.


Cell Cycle Regulator p27 Mediates Body Mass Index Effects in Ovarian Cancer in FIGO-stages I-II.
The aim of the present study was to evaluate the association between body mass index (BMI), the biomarker p27, and the clinical factors in FIGO-stages I-II ovarian cancer. A total of 128 patients with ovarian cancer were included in the study. For testing differences in univariate analyzes we used the Pearson's Chi-square test and the log-rank test. For multivariate analyses the logistic regression and Cox regression models were used with recurrent disease and disease-free survival as endpoints, respectively. Patients with BMI ≤25 kg/m2 had a significantly better 5-year disease-free survival compared with patients with BMI >25 kg/m2 in the total series of patients (p=0.008), and in the series of patients (n=77) with non-serous tumors (p=0.047). Patients with p27-positive non-serous tumors had higher survival compared to patients with p27-negative non-serous tumors (p=0.020). The cell cycle regulator p27 mediates BMI effects in ovarian cancer in FIGO-stages I-II.


Room acoustics modelling in the time-domain with the nodal discontinuous Galerkin method.
To solve the linear acoustic equations for room acoustic purposes, the performance of the time-domain nodal discontinuous Galerkin (DG) method is evaluated. A nodal DG method is used for the evaluation of the spatial derivatives, and for the time-integration an explicit multi-stage Runge-Kutta method is adopted. The scheme supports a high order approximation on unstructured meshes. To model frequency-independent real-valued impedance boundary conditions, a formulation based on the plane wave reflection coefficient is proposed. Semi-discrete stability of the scheme is analyzed using the energy method. The performance of the DG method is evaluated for four three-dimensional configurations. The first two cases concern sound propagations in free field and over a flat impedance ground surface. Results show that the solution converges with increasing DG polynomial order and the accuracy of the impedance boundary condition is independent on the incidence angle. The third configuration is a cuboid room with rigid boundaries, for which an analytical solution serves as the reference solution. Finally, DG results for a real room scenario are compared with experimental results. For both room scenarios, results show good agreements.


Stable Graphene-Two-Dimensional Multiphase Perovskite Heterostructure Phototransistors with High Gain.
Recently, two-dimensional (2D) organic-inorganic perovskites emerged as an alternative material for their three-dimensional (3D) counterparts in photovoltaic applications with improved moisture resistance. Here, we report a stable, high-gain phototransistor consisting of a monolayer graphene on hexagonal boron nitride (hBN) covered by a 2D multiphase perovskite heterostructure, which was realized using a newly developed two-step ligand exchange method. In this phototransistor, the multiple phases with varying bandgap in 2D perovskite thin films are aligned for the efficient electron-hole pair separation, leading to a high responsivity of ∼105 A W-1 at 532 nm. Moreover, the designed phase alignment method aggregates more hydrophobic butylammonium cations close to the upper surface of the 2D perovskite thin film, preventing the permeation of moisture and enhancing the device stability dramatically. In addition, faster photoresponse and smaller 1/f noise observed in the 2D perovskite phototransistors indicate a smaller density of deep hole traps in the 2D perovskite thin film compared with their 3D counterparts. These desirable properties not only improve the performance of the phototransistor, but also provide a new direction for the future enhancement of the efficiency of 2D perovskite photovoltaics.


Clinical efficacy of cardiac resynchronization therapy with an implantable defibrillator in a Japanese population: results of the MIRACLE-ICD outcome measured in Japanese indication (MOMIJI) study.
Cardiac resynchronization therapy (CRT) is effective in reducing morbidity and mortality in systolic heart failure patients with cardiac dyssynchrony as demonstrated in studies with primarily Western populations. Although CRT devices with a defibrillator (CRT-D) became available in Japan since 2006, their efficacy remains uncertain in Japanese patients. In this prospective, multicenter study, the efficacy of CRT-D therapy in an all-Japanese population was compared with the study conducted in the US, Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE-ICD). Ninety-three patients were evaluated according to the subject selection criteria of the MIRACLE-ICD study, and 80 patients were enrolled. Results at baseline and 6-month post-CRT-D implantation were compared in terms of composite clinical response (CCR) and other secondary endpoints. Quality of life (QOL) was assessed with a validated Japanese version of the Minnesota Living with Heart Failure questionnaire. CCR was improved in 55 patients (68.8%), unchanged in 14 (17.5%), and worsened in 11 patients (13.7%) (MIRACLE-ICD general phase: 62.0%, 13.4% and 24.6%, respectively). Non-inferiority was verified by 1-sided test with 10% equivalence margin. QOL score improved significantly (50.0±26.2 vs. 23.6±20.2, P<0.01). The MOMIJI study demonstrated that CRT-D effectiveness as assessed with CCR was non-inferior to the trials conducted outside Japan, thus suggesting that the benefits of CRT-D are similar between Japanese and non-Japanese patients.


Type I and II Interferon Signatures Can Predict the Response to Anti-TNF Agents in Inflammatory Bowel Disease Patients: Involvement of the Microbiota.
Anti-TNF agents have been a cornerstone of IBD therapy; however, response to treatment has been variable, and clinically applicable biomarkers are urgently needed. We hypothesized that the type I and type II interferon (IFN) signatures may be a confounding factor for response to antitumor necrosis factor (TNF) treatment via interactions with the host and its gut microbiota. Peripheral blood from 30 IBD patients and 10 healthy controls was subjected to real-time quantitative real-time polymerase chain reaction for type I and type II IFN genes (IFNGs), both at baseline and after treatment with anti-TNF. Correlation between IFN signatures and microbiota composition was also determined for a subgroup of patients and controls. At baseline, type I IFN score was significantly higher in IBD patients (P = 0.04 vs controls). Responders to subsequent anti-TNF treatment had significantly lower baseline scores for both type I and II IFN signatures (P < 0.005 vs nonresponders for both comparisons). During treatment with anti-TNF, the expression of type I and II IFNGs was significantly elevated in responders and decreased in nonresponders. In addition, changes in IFN signatures correlated to specific alterations in the abundance of several microbial taxa of the gut microbiome. Baseline expression of type I and II IFN signatures and their kinetics during anti-TNF administration significantly correlate to treatment responses in IBD patients. Peripheral blood IFN signatures may serve as clinically meaningful biomarkers for the identification of subgroups of patients with favorable response to anti-TNF treatment. Additionally, the distinct synergies between different IFN types and microbiota might help drive therapeutic intervention.


Mitigating Fracture of the Acromion and Scapular Spine After Reverse Shoulder Arthroplasty: A Critical Analysis Review of Patient and Surgical Risk Factors.
Level V. Narrative Review. See Instructions for Authors for a complete description of levels of evidence.


Impact of Nonmodal Phonation on Estimates of Subglottal Pressure From Neck-Surface Acceleration in Healthy Speakers.
Purpose The purpose of this study was to evaluate the effects of nonmodal phonation on estimates of subglottal pressure (Ps) derived from the magnitude of a neck-surface accelerometer (ACC) signal and to confirm previous findings regarding the impact of vowel contexts and pitch levels in a larger cohort of participants. Method Twenty-six vocally healthy participants (18 women, 8 men) were asked to produce a series of p-vowel syllables with descending loudness in 3 vowel contexts (/a/, /i/, and /u/), 3 pitch levels (comfortable, high, and low), and 4 elicited phonatory conditions (modal, breathy, strained, and rough). Estimates of Ps for each vowel segment were obtained by averaging the intraoral air pressure plateau before and after each segment. The root-mean-square magnitude of the neck-surface ACC signal was computed for each vowel segment. Three linear mixed-effects models were used to statistically assess the effects of vowel, pitch, and phonatory condition on the linear relationship (slope and intercept) between Ps and ACC signal magnitude. Results Results demonstrated statistically significant linear relationships between ACC signal magnitude and Ps within participants but with increased intercepts for the nonmodal phonatory conditions; slopes were affected to a lesser extent. Vowel and pitch contexts did not significantly affect the linear relationship between ACC signal magnitude and Ps. Conclusion The classic linear relationship between ACC signal magnitude and Ps is significantly affected when nonmodal phonation is produced by a speaker. Future work is warranted to further characterize nonmodal phonatory characteristics to improve the ACC-based prediction of Ps during naturalistic speech production.


Efficient and quick inactivation of SARS coronavirus and other microbes exposed to the surfaces of some metal catalysts.
To study the two metal catalysts Ag/Al2O3 and Cu/Al2O3 that interdict the transmission pathway for SARS and other respiratory infectious diseases. Two metal catalysts Ag/Al2O3 and Cu/Al2O3 were pressed into wafers. One hundred microL 10(6) TCID50/mL SARS-CoV, 100 microL 10(6) PFU/mL recombinant baculovirus expressing hamster's prion protein (haPrP) protein and roughly 10(6) E. coli were slowly dropped onto the surfaces of the catalyst wafers and exposed for 5 and 20 min, respectively. After eluted from the surfaces of wafers, the infectivity of viruses and propagation of bacteria were measured. The expression of PrP protein was determined by Western blot. The morphological changes of bacteria were observed by electronic microscopy. After exposure to the catalysts surfaces for 5 and 20 min, the infectivity of SARS-CoV in Vero cells and baculovirus in Sf9 cells dropped down to a very low and undetectable level, and no colony was detected using bacteria culture method. The expression of haPrP protein reduced to 21.8% in the preparation of Sf9 cells infected with recombinant baculovirus exposed for 5 min and was undetectable exposed for 20 min. Bacterial membranes seemed to be cracked and the cytoplasm seemed to be effluent from cell bodies. Exposures to the surfaces of Ag/Al2O3 and Cu/Al2O3 destroy the replication and propagation abilities of SARS-CoV, baculovirus and E. coli. Inactivation ability of metal catalysts needs to interact with air, utilizing oxygen molecules in air. Efficiently killing viruses and bacteria on the surfaces of the two metal catalysts has a promising potential for air-disinfection in hospitals, communities, and households.


Factors associated with perceived control and the relationship to quality of life in patients with heart failure.
Health-related quality of life (HRQOL) is as important as survival to patients with heart failure (HF). Perceptions of loss of control are common in HF and negatively affect HRQOL. Knowledge of modifiable factors associated with perceived control could guide the development of interventions to improve perceived control and thus HRQOL. Accordingly, this study examined factors related to perceived control and the relationship between perceived control and HRQOL. Patients (N=232, mean age 61 ± 12, 67% male, 78% Caucasian) provided data on HRQOL (Minnesota Living with Heart Failure questionnaire), perceived control (Control Attitudes Scale-Revised), and factors possibly associated with perceived control (knowledge and barriers (Heart Failure Knowledge and Barriers to Adherence Scale), attitudes (Dietary Sodium Restriction Questionnaire), and social support (Multidimensional Scale of Perceived Social Support)). Patients also provided data on depressive symptoms, which were a covariate of HRQOL. Hierarchical multiple regression analysis was used to analyze the data. Fewer barriers to following a low sodium diet, more positive attitudes toward following a low sodium diet, and better social support were related to higher perceived control (F=7.54, R(2)=0.17, p<0.001). Perceived control was independently associated with HRQOL, controlling for depressive symptoms, New York Heart Association functional class, age, gender, and all variables possibly associated with perceived control (F=29.67, R(2)=0.55, p<0.001). Interventions targeting attitudes and barriers to a low sodium diet and social support may improve perceived control and, in turn, HRQOL.


APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice.
Approximately 15-20% of all human breast cancers are classified as triple-negative because they lack estrogen and progesterone receptors and Her-2-neu, which are commonly targeted by chemotherapeutic drugs. New treatment strategies are therefore urgently needed to combat triple-negative breast cancers (TNBCs). Almost 80% of the triple-negative tumors express mutant p53 (mtp5), a functionally defective tumor suppressor protein. Whereas wild-type p53 (wtp53) promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, mtp53 fails to regulate these functions, resulting in tumor vascularization, growth, resistance to chemotherapy, and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for suppressing TNBC metastasis. APR-246 is a small-molecule drug that reactivates mtp53, thereby restoring p53 function. In this study, we sought to determine whether administration of APR-246, either alone or in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits stem cell-like characteristics of tumor cells and migration in vitro, and metastasis of human mtp53-expressing TNBC cells to the lungs in mouse models. APR-246 reduced both the stem cell-like properties and migration of TNBC cells in vitro. In mouse models, administration of either APR-246 or 2aG4 reduced metastasis of TNBC cells to the lungs; a combination of the two diminished lung metastasis to the same extent as either agent alone. Combination treatment significantly reduced the incidence of lung metastasis compared either single agent alone. Metastasis of human mtp53-expressing TNBC cells to the lungs of nude mice is inhibited by the treatment that combines activation of mtp53 with targeting of phosphatidylserine residues on tumor blood vessels. We contend therefore that our findings strongly support the use of combination treatment involving mtp53 activation and immunotherapy in patients with TNBC.


Protocol for diagnosis of urinary tract infection: reconsidering the criterion for significant bacteriuria.
The traditional criterion of 10(5) colony-forming units (CFU) per milliliter of urine to diagnose urinary tract infection was based on studies of pregnant and nonpregnant women with asymptomatic bacteriuria or acute pyelonephritis. Recent studies of symptomatic women revealed that urine cultures in approximately one third of those with confirmed urinary tract infections grew only 10(2) to 10(4) CFU/mL. The major causes of acute dysuria among such women are urinary tract infection, sexually transmitted disease, and vaginitis. In most instances, it is possible to make the diagnosis based on clinical features. The major features of urinary tract infection are internal dysuria; frequency, urgency, and voiding of small volumes; abrupt onset; suprapubic pain; presence of pyuria. Presence of hematuria which occurs in about 50 percent of patients strongly suggests bacterial cystitis. Three to seven days of empiric antimicrobial therapy is indicated for these patients, with selection of a first-line antimicrobial agent that offers efficacy against Escherichia coli or Staphylococcus saprophyticus; reasonable cost; few side effects. Ampicillin is not recommended. Indications for culture include uncertain clinical features; history of previous infection within the past three weeks; duration of symptoms of more than seven days; recent hospitalization or catheterization; pregnancy; diabetes. To maximize the sensitivity and specificity of the urine culture in acutely symptomatic women, it is necessary to request the laboratory to report 10(2) to 10(4) CFU/mL.


NNC-Scorpionate Zirconium-Based Bicomponent Systems for the Efficient CO2 Fixation into a Variety of Cyclic Carbonates.
Two new derivatives of the bis(3,5-dimethylpyrazol-1-yl)methane modified by introduction of organosilyl groups on the central carbon atom, one of which bearing a chiral fragment, have been easily prepared. We verified the potential utility of these compounds through the reaction with [Zr(NMe2)4] for the preparation of novel zirconium complexes in which an ancillary bis(pyrazol-1-yl)methanide acts as a robust monoanionic tridentate scorpionate in a κ3-NNC chelating mode, forming strained four-membered heterometallacycles. These κ3-NNC-scorpionate zirconium amides were investigated as catalysts in combination with tetra-n-butylammonium bromide as cocatalyst for CO2 fixation into five-membered cyclic carbonate products. The study has led to the development of an efficient zirconium-based bicomponent system for the selective cycloaddition reaction of CO2 with epoxides. Kinetics investigations confirmed apparent first-order dependence on the catalyst and cocatalyst concentrations. In addition, this system displays very broad substrate scope, including mono- and disubstituted substrates, as well as the challenging biorenewable terpene derived limonene oxide, under mild and solvent-free conditions.


Physiology of sweat gland function: The roles of sweating and sweat composition in human health.
The purpose of this comprehensive review is to: 1) review the physiology of sweat gland function and mechanisms determining the amount and composition of sweat excreted onto the skin surface; 2) provide an overview of the well-established thermoregulatory functions and adaptive responses of the sweat gland; and 3) discuss the state of evidence for potential non-thermoregulatory roles of sweat in the maintenance and/or perturbation of human health. The role of sweating to eliminate waste products and toxicants seems to be minor compared with other avenues of excretion via the kidneys and gastrointestinal tract; as eccrine glands do not adapt to increase excretion rates either via concentrating sweat or increasing overall sweating rate. Studies suggesting a larger role of sweat glands in clearing waste products or toxicants from the body may be an artifact of methodological issues rather than evidence for selective transport. Furthermore, unlike the renal system, it seems that sweat glands do not conserve water loss or concentrate sweat fluid through vasopressin-mediated water reabsorption. Individuals with high NaCl concentrations in sweat (e.g. cystic fibrosis) have an increased risk of NaCl imbalances during prolonged periods of heavy sweating; however, sweat-induced deficiencies appear to be of minimal risk for trace minerals and vitamins. Additional research is needed to elucidate the potential role of eccrine sweating in skin hydration and microbial defense. Finally, the utility of sweat composition as a biomarker for human physiology is currently limited; as more research is needed to determine potential relations between sweat and blood solute concentrations.


Diffusion of macromolecule through retina after experimental branch retinal vein occlusion and estimate of intraretinal barrier.
The disposition and diffusion knowledge of intravitreally injected macromolecule drugs through retina in pathological condition is crucial but the related studies are absent. Retinal edema is a common pathological change of fundus diseases and retinal vein occlusion (RVO) pig model were established to emulate it. FITC-dextrans of various molecular weights were dissolved in RPMI-1640 solutions and the rate of transretinal diffusion was determined with a spectrophotometer. Theoretical maximum size of molecule (MSM) was calculated by extrapolating the trend-linear relationship with the diffusion rate. In separate experiments to determine the sites of barrier to diffusion, FITC-dextrans were applied to either the inner or outer retinal surface, processed as frozen sections, and viewed with a fluorescence microscope. Paired-Samples T test was used to compared the diffusion rate of dextrans of the both eyes of one pig. The MSM in RVO tissues and normal tissue was 6.5+/-0.39 nm and 6.18+/-0.54 nm respectively (t=4.143, P=0.0001). FITC-dextrans applying to inner retinal surface, 4.4 kDa dextran were largely arrested at inner nuclear layer (INL). The INL of the 19.6-71.2 kDa dextran diffusion retina section became dark and the nerve fiber layer (NFL) and inner plexiform layer got brighter. As for 150 kDa dextran, the NFL was bright and the other layers were dark. FITC-dextrans applying to outer retinal surface, most dextrans were blocked before outer nuclear layer (ONL). In summary, ONL and INL may act as bottle-neck barriers to diffusion of macromolecules. Compared with normal neuroretina, the MSM of fresh edema retina after RVO increased limitedly.


ECG and XML: an instance of a possible XML schema for the ECG telemonitoring.
Management of many types of chronic diseases relies heavily on patients' self-monitoring of their disease conditions. In recent years, Internet-based home telemonitoring systems allowing transmission of patient data to a central database and offering immediate access to the data by the care providers have become available. The adoption of Extensible Mark-up Language (XML) as a W3C standard has generated considerable interest in the potential value of this language in health informatics. However, the telemonitoring systems often work with only one or a few types of medical devices. This is because different medical devices produce different types of data, and the existing telemonitoring systems are generally built around a proprietary data schema. In this paper, we describe a generic data schema for a telemonitoring system that is applicable to different types of medical devices and different diseases, and then we present an architecture for the exchange of clinical information as data, signals of telemonitoring and clinical reports in the XML standard, up-to-date information in each electronic patient record and integration in real time with the information collected during the telemonitoring activities in the XML schema, between all the structures involved in the healthcare process of the patient.


Vertical integration of general practices with acute hospitals in England: rapid impact evaluation.
Vertical integration means merging organisations that operate at different stages along the patient pathway. We focus on acute hospitals running primary care medical practices. Evidence is scarce concerning the impact on use of health-care services and patient experience. To assess the impact of vertical integration on use of hospital services, service delivery and patient experience and whether patients with multiple long-term conditions are affected differently from others. Rapid, mixed methods evaluation with four work packages: (1) review of NHS trust annual reports and other sources to understand the scale of vertical integration across England; (2) development of the statistical analysis; (3) analysis of national survey data on patient experience, and national data on use of hospital services over the 2 years preceding and following vertical integration, comparing vertically integrated practices with a variety of control practices; and (4) focus groups and interviews with staff and patients across three case study sites to explore the impact of vertical integration on patient experience of care. At 31 March 2021, 26 NHS trusts were in vertically integrated organisations, running 85 general practices across 116 practice sites. The earliest vertical integration between trusts and general practices was in 2015; a mean of 3.3 practices run by each trust (range 1-12). On average, integrated practices have fewer patients, are slightly more likely to be in the most deprived decile of areas, are more likely to hold an alternative provider medical services contract and have worse Quality and Outcomes Framework scores compared with non-integrated practices. Vertical integration is associated with statistically significant, modest reductions in rates of accident and emergency department attendances: 2% reduction (incidence rate ratio 0.98, 95% confidence interval 0.96 to 0.99; p < 0.0001); outpatient attendances: 1% reduction (incidence rate ratio 0.99, 95% confidence interval 0.99 to 1.00; p = 0.0061), emergency inpatient admissions: 3% reduction (incidence rate ratio 0.97, 95% confidence interval 0.95 to 0.99; p = 0.0062) and emergency readmissions: 5% reduction (incidence rate ratio 0.95, 95% confidence interval 0.91 to 1.00; p = 0.039), with no impact on length of stay, overall inpatient admissions or inpatient admissions for ambulatory care sensitive conditions. The falls in accident and emergency department and outpatient attendance rates are temporary. Focus groups and interviews with staff (N = 22) and interviews with patients (N = 14) showed that with vertical integration, health service improvements are introduced following a period of cultural interchange. Patients with multiple long-term conditions continue to encounter 'navigation work' choosing and accessing health-care provision, with diminishing continuity of care. In the quantitative analysis, we could not replicate the counterfactual of what would have happened in those specific locations had practices not merged with trusts. There was imbalance across three case study sites with regard to staff and patients recruited for interview, and the latter were drawn from patient participation groups who may not be representative of local populations. Vertical integration can lead to modest reductions in use of hospital services and has minor or no impact on patient experience of care. Our analysis does not reveal a case for widespread roll-out of the approach. Further quantitative follow-up of the longer-term impact of vertical integration on hospital usage and more extensive interviewing of patients and their carers about patient experiences of navigating care. This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (BRACE Project no. 16/138/31) and will be published in full in Health and Social Care Delivery Research; Vol. 11, No. 17. See the NIHR Journals Library website for further project information.


Sleep patterns in preschool-age children with autism, developmental delay, and typical development.
A prominent noncore symptom of autistic disorder is disturbed sleep, but relatively few studies have investigated this symptom. A multimethod approach assessed the quantity and quality of sleep in 194 children (68 with autism [AUT], 57 with developmental delay without autism [DD], 69 with typical development) recorded over 1 week. Parent perceptions, structured questionnaires, and actigraphy were compared. In addition, problem sleep as defined by parents was compared with research diagnostic criteria for behavioral insomnia obtained from actigraph recordings. On actigraphy, children in the DD group, after sleep onset, exhibited more and longer awakenings than the other two groups. In contrast, children in the AUT group exhibited less total sleep time in 24 hours than the other two groups. Parent reports of sleep problems were higher in the AUT and DD groups than the typical development group, but parent reports did not concur with more objective RDC for behavioral insomnia. Parent reports of sleep problems in all of the groups were significantly associated with increased self-reports of stress. Total 24-hour sleep durations for all of the groups were shorter than recommended for preschool-age children. Our study provides objective evidence that sleep patterns are different in preschool children across the categories of AUT, DD, or typical development.


Inventory of the benthic eukaryotic diversity in the oldest European lake.
We have profound knowledge on biodiversity on Earth including plants and animals. In the recent decade, we have also increased our understanding on microorganisms in different hosts and the environment. However, biodiversity is not equally well studied among different biodiversity groups and Earth's systems with eukaryotes in freshwater sediments being among the least known. In this study, we used high-throughput sequencing of the 18S rRNA gene to investigate the entire diversity of benthic eukaryotes in three distinct habitats (littoral sediment and hard substrate, profundal sediment) of Lake Ohrid, the oldest European lake. Eukaryotic sequences were dominated by annelid and arthropod animals (54% of all eukaryotic reads) and protists (Ochrophyta and Ciliophora; together 40% of all reads). Eukaryotic diversity was 15% higher in the deep profundal than on either near-surface hard substrates or littoral sediments. The three habitats differed in their taxonomic and functional community composition. Specifically, heterotrophic organisms accounted for 92% of the reads in the profundal, whereas phototrophs accounted for 43% on the littoral hard substrate. The profundal community was the most homogeneous, and its network was the most complex, suggesting its highest stability among the sampled habitats.


Regeneration and proliferation of cardiomyocytes and its microRNA regulatory mechanisms.
Myocardial regeneration is identified as a concept at histological level. The core content is to increase the number of cardiomyocytes (CMs), so as to maintain the steady state of CMs under pathological or physiological conditions and ensure the normal cardiac function. In this review, we discussed the relevant factors involved in the regeneration of CMs, generalized in mice, large mammals and human. During different development stages of mammalian hearts, CMs showed several controlling and growth modes on the physiological or pathological state: mitosis, hypertrophy, nuclear polyploidy and multinucleation, amitosis and etc. We also discussed the mechanisms of specific microRNAs implicated in the cardiac development, as well as disease-induced apoptosis in CMs and the process of re-entering cell cycle after injury. It is hoped that this review will contribute to a deeper understanding of therapeutic approaches for myocardial regeneration after injury.


Roles of causation and meaning for interpreting correlations.
The essays by Tougas and Willeford address, among other things, a number of ways to understand causation, which play crucial roles in the framework of thinking proposed by Pauli and Jung. The intention of my following reply is to say a few words about how these options are related to one another within our reconstruction of the Pauli-Jung conjecture. In the tradition of the sciences, looking for causation has become a virtually innate reflex to interpret empirically observed correlations. The concept of synchronicity suggests looking for meaningful coincidences as an alternative, complementary interpretation, particularly appropriate for psychophysical correlations.


Vitamin A and Retinoic Acid in Cognition and Cognitive Disease.
The history of vitamin A goes back over one hundred years, but our realization of its importance for the brain and cognition is much more recent. The brain is more efficient than other target tissues at converting vitamin A to retinoic acid (RA), which activates retinoic acid receptors (RARs). RARs regulate transcription, but their function in the cytoplasm to control nongenomic actions is also crucial. Controlled synthesis of RA is essential for regulating synaptic plasticity in regions of the brain involved in learning and memory, such as the hippocampus. Vitamin A deficiency results in a deterioration of these functions, and failure of RA signaling is perhaps associated with normal cognitive decline with age as well as with Alzheimer's disease. Further, several psychiatric and developmental disorders that disrupt cognition are also linked with vitamin A and point to their possible treatment with vitamin A or RA.


Relationship between germination of Candida albicans and increased adherence to human buccal epithelial cells.
A strong correlation was shown between germination and increased adherence of Candida albicans to human buccal epithelial cells, indicating that germination or other changes in the fungi accompanying germination were responsible for enhanced adherence. Partial inhibition of germination by cysteine resulted in a comparably lower adherence. Preferential adherence of germinated fungi occurred in competition assays with nongerminated and germinated fungi. The enhanced adherence to human mucosal cells of germinated C albicans could represent one mechanism contributing to the pathogenicity of the organism.


Grasp cueing shows obligatory attention to action goals.
To understand the grounding of cognitive mechanisms in perception and action, we used a simple detection task to determine how long it takes to predict an action goal from the perception of grasp postures and whether this prediction is under strategic control. Healthy observers detected visual probes over small or large objects after seeing either a precision grip or a power grip posture. Although the posture was uninformative it induced attention shifts to the grasp-congruent object within 350 ms. When the posture predicted target appearance over the grasp-incongruent object, observers' initial strategic allocation of attention was overruled by the congruency between grasp and object. These results might help to characterize the human mirror neuron system and reveal how joint attention tunes early perceptual processes toward action prediction.


Anaplasma phagocytophilum infection in dogs: 34 cases (2000-2007).
OBJECTIVE- To determine demographic characteristics of dogs from the upper Midwest infected with Anaplasma phagocytophilum and identify clinical and clinicopathologic abnormalities and response to treatment. DESIGN- Retrospective case series and owner telephone survey. ANIMALS- 34 dogs with granulocytic anaplasmosis. PROCEDURES- Records were reviewed for information on signalment, history, physical examination findings, clinicopathologic and serologic findings, and treatment. Owners were contacted by telephone within 4 months after dogs were discharged. RESULTS- Median age was 8 years. Distribution of month of diagnosis was bimodal, with 15 dogs examined during May or June and 11 others examined during October or November. Camping and hiking were the most frequently reported tick exposure activities. Lethargy (25/34) and anorexia (21/34) were the most common initial complaints, fever was the most common clinical sign (27/32), and thrombocytopenia was the most common clinicopathologic abnormality (21/22). Fifteen of 20 dogs were seropositive for antibodies against A phagocytophilum. Doxycycline was prescribed for 31 dogs, and clinical signs and fever resolved within 3 to 5 days. Median time for platelet count to return to reference limits was 7 days. No owners reported clinical sequelae when contacted after dogs were discharged. CONCLUSIONS AND CLINICAL RELEVANCE- Results suggested that granulocytic anaplasmosis should be suspected in dogs in endemic areas examined because of fever, lethargy, or thrombocytopenia, especially in dogs examined during the late spring or early fall. Treatment with doxycycline was successful in resolving clinical signs and thrombocytopenia.


Taxonomic and functional characterization of a microbial community from a volcanic englacial ecosystem in Deception Island, Antarctica.
Glaciers are populated by a large number of microorganisms including bacteria, archaea and microeukaryotes. Several factors such as solar radiation, nutrient availability and water content greatly determine the diversity and abundance of these microbial populations, the type of metabolism and the biogeochemical cycles. Three ecosystems can be differentiated in glaciers: supraglacial, subglacial and englacial ecosystems. Firstly, the supraglacial ecosystem, sunlit and oxygenated, is predominantly populated by photoautotrophic microorganisms. Secondly, the subglacial ecosystem contains a majority of chemoautotrophs that are fed on the mineral salts of the rocks and basal soil. Lastly, the englacial ecosystem is the least studied and the one that contains the smallest number of microorganisms. However, these unknown englacial microorganisms establish a food web and appear to have an active metabolism. In order to study their metabolic potentials, samples of englacial ice were taken from an Antarctic glacier. Microorganisms were analyzed by a polyphasic approach that combines a set of -omic techniques: 16S rRNA sequencing, culturomics and metaproteomics. This combination provides key information about diversity and functions of microbial populations, especially in rare habitats. Several whole essential proteins and enzymes related to metabolism and energy production, recombination and translation were found that demonstrate the existence of cellular activity at subzero temperatures. In this way it is shown that the englacial microorganisms are not quiescent, but that they maintain an active metabolism and play an important role in the glacial microbial community.


Sequential treatments with TRK inhibitors in a patient with NTRK fusion-positive sarcoma: A case report.
Precision medicine and tumor-agnostic treatment strategies have recently been promoted for clinical use. One of the most successful treatments in patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors is targeting the tropomyosin receptor kinase (TRK) with an inhibitor. The TRK inhibitors, larotrectinib, and entrectinib, have been approved in many countries. Nevertheless, the most effective administration regimen for these TRK inhibitors is uncertain. To date, no reports have shown the efficacy of sequential treatment with larotrectinib and entrectinib in patients with NTRK fusion-positive tumors. In this report, we present a patient with NTRK fusion-positive sarcoma arising from the anterior mediastinum, with tumor progression after 4 months of entrectinib use. The patient took larotrectinib subsequently and maintained disease control for more than 21 months. A 48-year-old female visited a physician because she experienced difficulty in breathing and chest and back pain with no obvious cause 2 months ago. Computed tomography (CT)-guided biopsy was performed at a district general hospital, and histopathological examination revealed a small round cell tumor. She was referred to our hospital, and a second CT-guided biopsy was performed to confirm the pathological diagnosis. Considering the results of the histopathological examination, Ewing sarcoma was suspected, but a specific fusion gene was not detected due to poor quality specimens. After 3 regimens of cytotoxic chemotherapy, biopsy was repeated, and specimens were analyzed using next-generation sequencing. The PHF20-NTRK1 fusion gene was detected, and the tumor was finally diagnosed as an NTRK fusion-positive sarcoma. She was administered the TRK inhibitor entrectinib, but the tumor started to grow after 4 months of medication, and she stopped taking entrectinib. After 1 cycle of cytotoxic chemotherapy, another TRK inhibitor, larotrectinib, was administered. Her stable disease was maintained for more than 21 months. Here, we have shown that sequential administration of both drugs can be effective. In the treatment of NTRK fusion-positive tumors, there are cases in which 2 approved first-generation TRK inhibitors can be used sequentially.


Bone formation and calcification by isolated osteoblastlike cells.
Two cell populations were isolated from calvaria of chick embryos: PF cells were liberated by collagenase treatment from the periosteum, OB cells from the periosteum-free calvarium. Both populations were cultured in plastic culture dishes. After 6 d of culture, monolayers of each cell type either were scraped off the culture dishes, transplanted on the chorio-allantoic membrane of 7-d-old quail eggs, and cultured there for 6 d, or were used for biochemical experiments. OB transplants proved capable of producing calcified bone matrix, whereas PF transplants formed only fibrous tissue. Biochemically, OB cells showed high cAMP production in the presence of parathyroid hormone (PTH), whereas cAMP production was not stimulated in PF cultures. Lactate production was stimulated by PTH in both populations although somewhat differently. Citrate decarboxylation was high in OB cells and was inhibited by PTH but was low in PF cells, where it was stimulated by the same hormone. The differences in hormonal response between the two cell types made it possible to conclude that PF cultures are relatively free of OB cells. The PF contamination in OB cultures was more difficult to assess. The experiments described in this report show that the OB population contains osteoblasts or osteoblastlike cells which are, under favorable circumstances, capable of bone formation.


Vitamin D improves pulmonary function in a rat model for congenital diaphragmatic hernia.
A congenital diaphragmatic hernia (CDH) is an anomaly caused by defects in the diaphragm; the resulting limited thorax cavity in turn restricts lung growth (pulmonary hypoplasia). This condition is related to pulmonary hypertension. Despite advances in neonatal CDH therapy, the mortality for severe pulmonary hypoplasia remains high. Therefore, it is essential to establish prenatal therapeutic interventions. Vitamin D was reported to have beneficial effects on adult pulmonary hypertension. This study aims to evaluate the efficacy of prenatal vitamin D administration for CDH. First, serum 25-hydroxyvitamin D [25(OH)D] levels in umbilical cord blood were evaluated among CDH newborns. Second, Sprague Dawley rat CDH models were exposed to nitrofen on embryo day 9 (E9). Randomly selected rats in the nitrofen-treated group were infused with calcitriol from E9 to E21. Samples from CDH pups diagnosed after birth were used for lung weight measurements, blood gas analysis, and immunohistochemical analysis. Third, microarray analysis was performed to examine the effect of vitamin D on gene expression profiles in CDH pulmonary arterial tissues. Serum 25(OH)D levels in the umbilical cord blood of newborns who did not survive were significantly lower than those who were successfully discharged. Prenatal vitamin D showed no significant effect on CDH incidence or lung weight but attenuated alveolarization and pulmonary artery remodeling accompanied the improved blood gas parameters. Vitamin D inhibited several gene expression pathways in the pulmonary arteries of CDH rats. Our results suggest that prenatal vitamin D administration attenuates pulmonary vascular remodeling by influencing several gene pathways in CDH.


Nonlinear channel equalization for QAM signal constellation using artificial neural networks.
Application of artificial neural networks (ANN's) to adaptive channel equalization in a digital communication system with 4-QAM signal constellation is reported in this paper. A novel computationally efficient single layer functional link ANN (FLANN) is proposed for this purpose. This network has a simple structure in which the nonlinearity is introduced by functional expansion of the input pattern by trigonometric polynomials. Because of input pattern enhancement, the FLANN is capable of forming arbitrarily nonlinear decision boundaries and can perform complex pattern classification tasks. Considering channel equalization as a nonlinear classification problem, the FLANN has been utilized for nonlinear channel equalization. The performance of the FLANN is compared with two other ANN structures [a multilayer perceptron (MLP) and a polynomial perceptron network (PPN)] along with a conventional linear LMS-based equalizer for different linear and nonlinear channel models. The effect of eigenvalue ratio (EVR) of input correlation matrix on the equalizer performance has been studied. The comparison of computational complexity involved for the three ANN structures is also provided.


Electrophysiological monitoring and identification of neural roots during somatic-autonomic reflex pathway procedure for neurogenic bladder.
To identify and separate the ventral root from dorsal root, which is the key for success of the artificial somatic-autonomic reflex pathway procedure for neurogenic bladder after spinal cord injury (SCI). Here we report the results of intra-operating room monitoring with 10 paralyzed patients. Ten male volunteers with complete suprasacral SCI underwent the artificial somatic-autonomic procedure under general anesthesia. Vastus medialis, tibialis anticus and gastrocnemius medialis of the left lower limb were monitored for electromyogram (EMG) activities resulted from L4, L5, and S1 stimulation respectively to differentiate the ventral root from dorsal root. A Laborie Urodynamics system was connected with a three channel urodynamic catheter inserted into the bladder. The L2 and L3 roots were stimulated separately while the intravesical pressure was monitored to evaluate the function of each root. The thresholds of stimulation on ventral root were 0.02 ms duration, 0.2-0.4 mA, (mean 0.3 mA+/-0.07 mA), compared with 0.2-0.4 ms duration, 1.5-3 mA (mean 2.3 mA+/-0.5 mA) for dorsal root (P<0.01) to cause revoked potentials and EMG. Electrical stimulation on L4 roots resulted in the EMG being recorded mainly on vastus medialis, while stimulation on L5 or S1 roots caused electrical activities of tibialis anticus or gastrocnemius medialis respectively. The continuous stimulation for about 3-5 seconds on S2 or S3 ventral root (0.02 ms, 20 Hz, and 0.4 mA) could resulted in bladder detrusor contraction, but the strongest bladder contraction over 50 cm H2O was usually caused by stimulation on S3 ventral root in 7 of the 10 patients. Intra-operating room electrophysiological monitoring is of great help to identify and separate ventral root from dorsal root, and to select the appropriate sacral ventral root for best bladder reinnervation. Different parameters and thresholds on different roots are the most important factors to keep in mind to avoid damaging the roots and to assure the best results.


[The use of national public health surveys in the general population for the surveillance of occupational risks].
The primary mission of the Department of Occupational Health of the French Institute for Public Health Surveillance (InVS) is to monitor health in relationship to occupational activities. Data produced in other fields can contribute to its mission in particular data from public health surveys carried out among the general population in France. A study on occupational and mental health using data from the 2002-2003 Insee Decennial Health Survey serves as an exemplary case to illustrate this process. The data analysis according to job type shows important differences and variations in the prevalence of depressive symptoms within social groups and sectors of professional activity. Despite some limitations, the use of major public health surveys provides interesting assets and benefits to complement surveillance tools for occupational risks.


Primary closure of the perineal wound after abdomino-perineal amputation for adenocarcinoma.
This is a prospective study of primary closure of the perineum in 35 successive cases of abdomino-perineal amputation of the rectum for adenocarcinoma (January 1972 - December 1978). All operations are performed by the same surgeon in a one-team approach. In 33 patients the perineum is closed, and 32 patients are available for evaluation. In 66% of them the wound heals per primam. Very extensive and exenterative procedures do not lower the chances for success. In women the results are better than in men. They are even better after posterior vaginal wall resection and posterior exeneration (no failures). Early postoperative failures are usually due to bleeding; the late ones are caused by infection. The procedure is complicated by one death (81 years), one ureteral fistula (47 years) and one late perineal hernia which may be imputed to the method. Primary closure of the perineum appears to be a very feasible (33/35), usefull and rather safe procedure from which the patient has a lot to win and quite nothing to loose.


Titin isoforms are increasingly protected against oxidative modifications in developing rat cardiomyocytes.
During the perinatal adaptation process N2BA titin isoforms are switched for N2B titin isoforms leading to an increase in cardiomyocyte passive tension (Fpassive). Here we attempted to reveal how titin isoform composition and oxidative insults (i.e. sulfhydryl (SH)-group oxidation or carbonylation) influence Fpassive of left ventricular (LV) cardiomyocytes during rat heart development. Moreover, we also examined a hypothetical protective role for titin associated small heat shock proteins (sHSPs), Hsp27 and αB-crystallin in the above processes. Single, permeabilized LV cardiomyocytes of the rat (at various ages following birth) were exposed either to 2,2'-dithiodipyridine (DTDP) to provoke SH-oxidation or Fenton reaction reagents (iron(II), hydrogen peroxide (H2O2), ascorbic acid) to induce protein carbonylation of cardiomyocytes in vitro. Thereafter, cardiomyocyte force measurements for Fpassive determinations and Western immunoblot assays were carried out for the semiquantitative determination of oxidized SH-groups or carbonyl-groups of titin isoforms and to monitor sHSPs' expressions. DTDP or Fenton reagents increased Fpassive in 0- and 7-day-old rats to relatively higher extents than in 21-day-old and adult animals. The degrees of SH-group oxidation or carbonylation declined with cardiomyocyte age to similar extents for both titin isoforms. Moreover, the above characteristics were mirrored by increasing levels of HSP27 and αB-crystallin expressions during cardiomyocyte development. Our data implicate a gradual build-up of a protective mechanism against titin oxidation through the upregulation of HSP27 and αB-crystallin expressions during postnatal cardiomyocyte development.


Group B streptococcal septicemia and delayed-onset congenital right-sided diaphragmatic hernia.
A case is reported of fulminant early-onset group B streptococcal septicemia and delayed-onset congenital right-sided diaphragmatic hernia in a neonate. The latter condition should be considered when early-onset group B streptococcal disease is followed by increasing respiratory distress, right-sided pleural effusion and partial or complete opacification of the right side of the thorax.


Computers and audit.
A computerized information system was installed in a large group practice. This paper describes how the computer system was used for the systematic auditing of clinical activities, and also demonstrates how it acted as a catalyst for the review and changes of administrative and management procedures. An analysis of the issues that arose in an audit group is used to identify how the objectives and activities of the group evolved with experience. It is demonstrated that a computer system and audit can complement and enhance each other to the benefit of clinical and managerial decision making.


A bacterial view of the periodic table: genes and proteins for toxic inorganic ions.
Essentially all bacteria have genes for toxic metal ion resistances and these include those for Ag+, AsO2-, AsO4(3-), Cd2+ Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, TeO3(2-), Tl+ and Zn2+. The largest group of resistance systems functions by energy-dependent efflux of toxic ions. Fewer involve enzymatic transformations (oxidation, reduction, methylation, and demethylation) or metal-binding proteins (for example, metallothionein SmtA, chaperone CopZ and periplasmic silver binding protein SilE). Some of the efflux resistance systems are ATPases and others are chemiosmotic ion/proton exchangers. For example, Cd2+-efflux pumps of bacteria are either inner membrane P-type ATPases or three polypeptide RND chemiosmotic complexes consisting of an inner membrane pump, a periplasmic-bridging protein and an outer membrane channel. In addition to the best studied three-polypeptide chemiosmotic system, Czc (Cd2+, Zn2+, and Co2), others are known that efflux Ag+, Cu+, Ni2+, and Zn2+. Resistance to inorganic mercury, Hg2+ (and to organomercurials, such as CH3Hg+ and phenylmercury) involve a series of metal-binding and membrane transport proteins as well as the enzymes mercuric reductase and organomercurial lyase, which overall convert more toxic to less toxic forms. Arsenic resistance and metabolizing systems occur in three patterns, the widely-found ars operon that is present in most bacterial genomes and many plasmids, the more recently recognized arr genes for the periplasmic arsenate reductase that functions in anaerobic respiration as a terminal electron acceptor, and the aso genes for the periplasmic arsenite oxidase that functions as an initial electron donor in aerobic resistance to arsenite.


Structure of human thymidylate synthase under low-salt conditions.
Human thymidylate synthase, a target in cancer chemotherapy, was crystallized from PEG 3350 with 30 mM ammonium sulfate (AS) in the crystallization medium. The crystals are isomorphous with the high-salt crystals ( approximately 2.0 M AS) and the structure has been solved and refined (R = 22.6%, R(free) = 24.3%) at 1.8 A resolution. The high- and low-AS-concentration structures are quite similar, with loop 181-197 is in the inactive conformation. Also, residues 95-106 and 129-135 (eukaryotic inserts region) show high mobility as assessed by poor electron density and high values of crystallographic temperature factors (residues 1-25 and 108-129 are disordered in both structures). The high mobility of this region may reflect the situation at physiological ionic strength. Of the four sulfate ions observed bound at 2.0 M AS, only two are present at 30 mM AS. The inactive conformation appears to be stabilized by the side chain of Val3 or a leucine residue from the disordered regions. The low-salt conditions of these crystals should be much more suitable for the study of thymidylate synthase inhibitors, especially those that utilize sulfate-binding sites to stabilize the inactive conformation of loop 181-197.


Implications for kinetochore-microtubule attachment from the structure of an engineered Ndc80 complex.
Kinetochores are proteinaceous assemblies that mediate the interaction of chromosomes with the mitotic spindle. The 180 kDa Ndc80 complex is a direct point of contact between kinetochores and microtubules. Its four subunits contain coiled coils and form an elongated rod structure with functional globular domains at either end. We crystallized an engineered "bonsai" Ndc80 complex containing a shortened rod domain but retaining the globular domains required for kinetochore localization and microtubule binding. The structure reveals a microtubule-binding interface containing a pair of tightly interacting calponin-homology (CH) domains with a previously unknown arrangement. The interaction with microtubules is cooperative and predominantly electrostatic. It involves positive charges in the CH domains and in the N-terminal tail of the Ndc80 subunit and negative charges in tubulin C-terminal tails and is regulated by the Aurora B kinase. We discuss our results with reference to current models of kinetochore-microtubule attachment and centromere organization.


Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice.
Asthenozoospermia accounts for over 80% of primary male infertility cases. Reduced sperm motility in asthenozoospermic patients are often accompanied by teratozoospermia, or defective sperm morphology, with varying severity. Multiple morphological abnormalities of the flagella (MMAF) is one of the most severe forms of asthenoteratozoospermia, characterized by heterogeneous flagellar abnormalities. Among various genetic factors known to cause MMAF, multiple variants in the DNAH2 gene are reported to underlie MMAF in humans. However, the pathogenicity by DNAH2 mutations remains largely unknown. In this study, we identified a novel recessive variant (NM_020877:c.12720G > T;p.W4240C) in DNAH2 by whole-exome sequencing, which fully co-segregated with the infertile male members in a consanguineous Pakistani family diagnosed with asthenozoospermia. 80-90% of the sperm from the patients are morphologically abnormal, and in silico analysis models reveal that the non-synonymous variant substitutes a residue in dynein heavy chain domain and destabilizes DNAH2. To better understand the pathogenicity of various DNAH2 variants underlying MMAF in general, we functionally characterized Dnah2-mutant mice generated by CRISPR/Cas9 genome editing. Dnah2-null males, but not females, are infertile. Dnah2-null sperm cells display absent, short, bent, coiled, and/or irregular flagella consistent with the MMAF phenotype. We found misexpression of centriolar proteins and delocalization of annulus proteins in Dnah2-null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis. Scanning and transmission electron microscopy analyses revealed that flagella ultrastructure is severely disorganized in Dnah2-null sperm. Absence of DNAH2 compromises the expression of other axonemal components such as DNAH1 and RSPH3. Our results demonstrate that DNAH2 is essential for multiple steps in sperm flagella formation and provide insights into molecular and cellular mechanisms of MMAF pathogenesis.


[Can we predict the premature labor in patients with placenta previa?; a retrospective study on maternal symptoms during pregnancy].
This study aimed to predict the gestational weeks by characterizing maternal genital bleeding and uterine contraction during pregnancy in patients with placenta previa. Included in this study were 87 patients with placenta previa, diagnosed at the time of delivery at our institution. Genital bleeding and uterine contraction characteristics and clinical data from mothers who delivered at < 37 weeks were compared to that of mothers who delivered at > or = 37 weeks. There were 37 deliveries (42.5%) at < 37 gestational weeks and 50 deliveries (57.4%) at > or = 37 gestational weeks. In 69 of 87 cases (79.3%), genital bleeding was recognized during pregnancy, and in 63 cases (72.4%) genital bleeding was the first symptom to occur during pregnancy. Uterine contraction during pregnancy was recognized in 48 cases (55.2%), including 36 (41.4%) that occurred as the first symptom of pregnancy. Logistic regression analysis revealed that when genital bleeding occurred at < 29 and < 31 weeks, patients were at high risk for delivery at < 34 and < 37 weeks, respectively, and when first uterine contraction occurred at < 29 weeks, they were at high risk for delivery at < 34 weeks. In patients with placenta previa, the number of gestational weeks to the occurrence of the first genital bleeding can be used as a predictor of the number of weeks to term.


Use of colistin and sorbitol for better isolation of Serratia marcescens in clinical samples.
A comparison was made of different culture media and procedures for detection of Serratia marcescens from faecal, pharyngeal and ocular swabs collected from 213 neonates. MacConkey agar and MacConkey agar with sorbitol (1%) and/or colistin (200 i.u./ml) were used both for primary isolation and after enrichment using Mossel Enterobacteriaceae broth with colistin (200 i.u./ml). The use of MacConkey agar supplemented with colistin for primary isolation improved considerably the isolation rate of S. marcescens from faecal swabs but not from pharyngeal swabs; the number of ocular isolations were insufficient to demonstrate differences between procedures. Moreover the enrichment procedures consistently increased the number of S. marcescens isolates especially from pharyngeal and ocular swabs. Use of sorbitol made detection of S. marcescens from clinical specimens easier and time- and cost-efficient.


The expression of proliferating cell nuclear antigen (PCNA) and p 53 protein correlate with prognosis of patients with oral squamous cell carcinoma.
Few Data are available regarding expression of proliferating cell nuclear antigen (PCNA) versus overexpression of p 53 protein and prognosis for oral squamous cell carcinoma (O-SCC). This study evaluated the relationship between expression of PCNA and p 53 protein and certain clinical and pathologic parameters to prognosis in O-SCC. Scattered PCNA immunoreactive cells were found in 50 of 51 (98.0%) tumors. The mean PCNA-labelling index (PCNA-LI) of O-SCC was 34.7 +/- 12.0% (n = 50). The PCNA-LI was significantly high in O-SCC when compared to normal squamous epithelium (3.9 +/- 2.1%, n = 10). Altogether, 28 of 51 (54.9%) tumors showed nuclear immunoreactive for the p 53 protein. p 53-positive nuclei were clearly stained as granular or reticular in O-SCC. Microscopically, it appeared that the staining patterns of PCNA- and p 53-positive cells were quite similar. The mean value of PCNA-LI for the p 53-positive cases was 37.9 +/- 11.9% (n = 28), which was significantly higher than the 30.8 +/- 11.1% of the 23 negative cases. The survival rates at 3-year and 5-year for patients with p 53-negative O-SCC were 78.3% and 73.4%, respectively, while those for patients with p 53-positive O-SCC were 51.9% and 43.2%, respectively. No significant correlation could be found between PCNA-LI and T classification, N classification and Stage classification. The expression of p 53 was detected in 48.5% (16/33) of cases without regional lymph node metastasis, and 66.7% (12/18) with regional lymph node metastasis. There was a significant difference between PCNA-LI and p 53-positive cases, and prognosis. In PCNA-LI, the Grade 4 by mode of invasion was significantly higher than Grade 1, 2 and 3. The PCNA-LI and p 53-positive cases were significantly correlated with histological grading of malignancy. The present study shows a relationship between PCNA and p 53 protein. It also suggests that both PCNA and p 53 positive rates are the malignant potential of the O-SCC.


Using standardized encounters to understand reported racial/ethnic disparities in patient experiences with care.
To assess the extent to which racial/ethnic differences in ratings of patient experiences with health care represent true differences versus differences in expectations, how scales are used, or how identical physician-patient interactions are perceived by members of different groups. Primary data collection from a nationally representative online panel (n=567), including white, African American, and Latino respondents. We administered questions on expectations of care, a series of written vignettes, a video-depicted doctor-patient interaction, and modified CAHPS Clinician and Group Doctor Communication items. Different groups reported generally similar expectations regarding physicians' behaviors and provided similar mean responses to CAHPS communication items in response to standardized encounters. Preliminary evidence suggests that unlike more subjective global ratings, reported disparities in more specific and objective CAHPS composites may primarily reflect differences in experiences, rather than differences in expectations and scale use, adding to our confidence in using the latter to assess disparities.


Association analysis of self-reported outcomes with a validated subset.
In health-science research, outcomes ascertained through surveys and interviews are subject to potential bias with respect to the true outcome status, which is only ascertainable with clinical and laboratory assessment. This measurement error may lead to biased inference when evaluating associations between exposures and outcomes of interest. Here, we consider a cohort study in which the outcome of interest is ascertained via questionnaire, subject to imperfect ascertainment, but where a subset of participants also have a clinically assessed, validated outcome available. This presents a methodological opportunity to address potential bias. Specifically, we constructed the likelihood in two parts, one using the validated subset and the other using a subset without validation. This work expands on that proposed by Pepe and enables inference with standard statistical software. Weighted generalized linear model estimates for our method and maximum likelihood estimates (MLE) for Pepe's method were computed, and the statistical inference was based on the standard large-sample likelihood theory. We compare the finite sample performance of two approaches through Monte Carlo simulations. This methodological work was motivated by a large cohort study of long-term childhood cancer survivors, allowing us to provide a relevant application example where we examined the association between clinical factors and chronic health conditions.


Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis.
Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock. This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1 + 2 (PF1 + 2), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and D-dimers. Base deficit was used as a measure of tissue hypoperfusion. Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + 2 levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and D-Dimers, associated with the observed reduction in PAI-1 and not alterations in TAFI. Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.


X-ray magnetic circular dichroism (XMCD) study of a methoxide-bridged Dy(III)-Cr(III) cluster obtained by fluoride abstraction from cis-[Cr(III)F2(phen)2](+).
An isostructural series of dinuclear chromium(III)-lanthanide(III) clusters is formed by fluoride abstraction of cis-[CrF2(phen)2](+) by Ln(3+) resulting in LnF3 and methoxide-bridged Cr-Ln clusters (Ln = Nd (1), Tb (2), Dy (3)) of formula [Cr(III)(phen)2(μ-MeO)2Ln(NO3)4]·xMeOH (x = 2-2.73). In contrast to fluoride, methoxide bridges in a nonlinear fashion, which facilitates chelation. For 3, X-ray magnetic circular dichroism (XMCD) provides element-specific magnetization curves that are compared to cluster magnetization and susceptibility data acquired by SQUID magnetometry. The combination of XMCD and SQUID is able to resolve very small magnetic coupling values and reveals a weak Cr(III)-Dy(III) coupling of j = -0.04(3) cm(-1). The Dy(III) ion has a ground-state Kramers doublet of mJ = ±13/2, and the first excited doublet is found to be mJ = ±11/2 at an energy of δ = 57(21) cm(-1). The Cr(III) ion exhibits a uniaxial anisotropy of DCr = -1.7(1.0) cm(-1). Further, we observe that a weak anisotropic coupling of dipolar origin is sufficient to model the data, suggesting that methoxide bridges do not play a significant role in the magnetic coupling for the present systems.


Risk of Developing Parkinson Disease in Bipolar Disorder: A Systematic Review and Meta-analysis.
Parkinson disease (PD) manifests by motor and nonmotor symptoms, which may be preceded by mood disorders by more than a decade. Bipolar disorder (BD) is characterized by cyclic episodes of depression and mania. It is also suggested that dopamine might be relevant in the pathophysiology of BD. To assess the association of BD with a later diagnosis of idiopathic PD. An electronic literature search was performed of Cochrane Controlled Register of Trials, MEDLINE, Embase, and PsycINFO from database inception to May 2019 using the terms Parkinson disease, bipolar disorder, and mania, with no constraints applied. Studies that reported data on the likelihood of developing PD in BD vs non-BD populations were included. Two review authors independently conducted the study selection. Two review authors independently extracted study data. Data were pooled using a random-effects model, results were abstracted as odds ratios and 95% CIs, and heterogeneity was reported as I2. Odds ratios of PD. Seven studies were eligible for inclusion and included 4 374 211 participants overall. A previous diagnosis of BD increased the likelihood of a subsequent diagnosis of idiopathic PD (odds ratio, 3.35; 95% CI, 2.00-5.60; I2 = 92%). A sensitivity analysis was performed by removing the studies that had a high risk of bias and also showed an increased risk of PD in people with BD (odds ratio, 3.21; 95% CI, 1.89-5.45; I2 = 94%). Preplanned subgroup analyses according to study design and diagnostic certainty failed to show a significant effect. This review suggests that patients with BD have a significantly increased risk of developing PD compared with the general population. Subgroup analyses suggested a possible overestimation in the magnitude of the associations. These findings highlight the probability that BD may be associated with a later development of PD and the importance of the differential diagnosis of parkinsonism features in people with BD.


Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2.
Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signaling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa module, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa module, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa module, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors.


Testing the reliability of forecasting systems.
The problem of statistically evaluating forecasting systems is revisited. The forecaster claims the forecasts to exhibit a certain nominal statistical behaviour; for instance, the forecasts provide the expected value (or certain quantiles) of the verification, conditional on the information available at forecast time. Forecasting systems that indeed exhibit the nominal behaviour are referred to as reliable. Statistical tests for reliability are presented (based on an archive of verification-forecast pairs). As noted previously, devising such tests is encumbered by the fact that the dependence structure of the verification-forecast pairs is not known in general. Ignoring this dependence though might lead to incorrect tests and too-frequent rejection of forecasting systems that are actually reliable. On the other hand, reliability typically implies that the forecast provides information about the dependence structure, and using this in conjunction with judicious choices of the test statistic, rigorous results on the asymptotic distribution of the test statistic are obtained. These results are used to test for reliability under minimal additional assumptions on the statistical properties of the verification-forecast pairs. Applications to environmental forecasts are discussed. A python implementation of the discussed methods is available online.


MIWI2 targets RNAs transcribed from piRNA-dependent regions to drive DNA methylation in mouse prospermatogonia.
Argonaute/Piwi proteins can regulate gene expression via RNA degradation and translational regulation using small RNAs as guides. They also promote the establishment of suppressive epigenetic marks on repeat sequences in diverse organisms. In mice, the nuclear Piwi protein MIWI2 and Piwi-interacting RNAs (piRNAs) are required for DNA methylation of retrotransposon sequences and some other sequences. However, its underlying molecular mechanisms remain unclear. Here, we show that piRNA-dependent regions are transcribed at the stage when piRNA-mediated DNA methylation takes place. MIWI2 specifically interacts with RNAs from these regions. In addition, we generated mice with deletion of a retrotransposon sequence either in a representative piRNA-dependent region or in a piRNA cluster. Both deleted regions were required for the establishment of DNA methylation of the piRNA-dependent region, indicating that piRNAs determine the target specificity of MIWI2-mediated DNA methylation. Our results indicate that MIWI2 affects the chromatin state through base-pairing between piRNAs and nascent RNAs, as observed in other organisms possessing small RNA-mediated epigenetic regulation.


["Sens et motions": a supportive media therapy in oncology].
Art therapy is overused in oncology support care, to the point of appearing as an improved form of animation. In the absence of a clearly defined system, there are few guidelines for practice. Here we propose and describe "Sens et motions", an original, reproducible and assessable approach to cancer care.


Isolation and growth of a cytopathic agent from multiple sclerosis brain tissue.
Although many studies support a role for viruses in multiple sclerosis (MS) etiopathology, no specific agent has been consistently associated with significant numbers of MS patients without concomitant detection in non-MS controls. Previous studies have shown the presence of viral-like structures in MS plaques, although the specificity of these structures for MS has been questioned. The present study describes the use of polyclonal antisera against feline and human brain-derived cytopathic agents and immunoaffinity chromatography to purify and partially characterize possible virus-like structures from MS brain tissue. Chromatography eluates from 4 MS brains contained pleomorphic particles up to 350 nm in diameter and tubular/filamentous-like structures approximately 10-18 nm in thickness. Inoculation of primary rat glial cell cultures with chromatography eluates from MS brain tissue resulted in a reproducible pattern of cytopathic effects in the form of multinucleation in cells identified immunocytochemically as oligodendrocytes. Antisera raised against the feline and MS-derived cytopathic agents were used to successfully immunolabel infected oligodendrocyte-like cells and syncytia and to detect a 66,000 M(r) protein on Western blots of inoculated cultures or concentrated MS brain eluates. Similar structures, cytopathic effects (CPE) and protein expression were not observed in eluates from 5 control brains or in cultures inoculated with control brain eluates. These studies demonstrate that cytopathic, virus-like structures can be isolated from MS brain tissue using antisera raised against a cytopathic agent rescued from demyelinating brain lesions in cats. The identity of this agent and its possible role in MS aetio-pathology remains unknown.


Phylogeny of some mycoplasmas from ruminants based on 16S rRNA sequences and definition of a new cluster within the hominis group.
Almost complete (> 96%) 16S rRNA sequences from nine ruminant mycoplasmas have been determined by solid-phase DNA sequencing. Polymorphisms were found in four of the 16S rRNA sequences, which indicated the existence of two different rRNA operons. Seven polymorphisms were found in Mycoplasma agalatiae, three were found in Mycoplasma bovis, one was found in Mycoplasma alkalescens, and one was found in Mycoplasma bovirhinis. The sequence data were used for construction of phylogenetic trees. All but one of the ruminant mycoplasmas sequenced in this work clustered in the hominis group. A close relationship was found between M. agalactiae and M. bovis, with a 99% nucleotide similarity between their 16S rRNA sequences. They were also found to be members of the Mycoplasma lipophilum cluster of the hominis group. Furthermore, the 16S rRNA comparisons showed that Mycoplasma alkalescens and Mycoplasma canadense are closely related (> 98.5%), and these species were found to cluster in the Mycoplasma hominis cluster of the hominis group. Interestingly, M. bovirhinis grouped in a new phylogenetic cluster of the hominis group. The new cluster, which was supported by bootstrap percentage values, signature nucleotide analysis, and higher-order structural elements, was named the Mycoplasma synoviae cluster. Mycoplasma bovoculi, Mycoplasma conjunctivae, and Mycoplasma ovipneumoniae clustered in the Mycoplasma neurolyticum cluster of the hominis group. Mycoplasma alvi clustered with Mycoplasma pirum in the M. pneumoniae cluster of the pneumoniae group.


Outcomes of prolotherapy for intra-tendinous Achilles tears: a case series.
The intra-tendinous tear is a new pathology that is defined as a discontinuity of fibres situated entirely within the tendon. Prolotherapy involves injecting an irritant, such as hyperosmolar dextrose, to stimulate a tissue healing response and ultimately reduce pain. 43 consecutive patients diagnosed with an intra-tendinous tear were included (27 males: 16 females, mean (SD) age 41 (11.3). Patients were injected with 0.4ml-1.5ml (mean 0.8ml) of 50% dextrose and 0.5% marcaine mixed in a 1:1 ratio. A 4-6 week period of walking boot immobilisation was followed by progressive rehabilitation (6-8 weeks). Outcomes were assessed with a VISA-A questionnaire at baseline, 3 months and a mean 12.6 (7.0) months post-treatment. Ultrasound scans were conducted before treatment and 5.2 (2.3) weeks later to assess sonographic changes. 30 patients (70%) responded with VISA-A scores increasing by 31 (30.5) points after 3 months (f=0.62, p<0.05) and by 40 (29.3) points after 12.60 (7.0) months (f=0.87, p<0.05). After 5.2 (2.3) weeks, echogenicity was significantly reduced (p<0.05) and 27% of tears were no longer detectable. No significant differences were observed in remaining tears with respect to tear size, tendon thickness or neovascularisation. Treatment resulted in clinically significant improvements and controlled trials are warranted. IV.


Causal relationship between Helicobacter pylori antibodies and gastroesophageal reflux disease (GERD): A mendelian study.
Observational studies have indicated that both Helicobacter pylori infection and the presence of Helicobacter pylori antibodies may increase the risk of gastroesophageal reflux disease (GERD). However, the exact association between Helicobacter pylori antibodies and the occurrence of GERD remains largely unresolved. Therefore, this two-sample Mendelian randomization (MR) study aims to investigate the causal relationship between Helicobacter pylori infection and GERD. This study encompassed seven different specific protein antibodies targeting Helicobacter pylori and utilized a genome-wide association study (GWAS) on GERD. MR analysis was conducted to assess the causal relationship between Helicobacter pylori antibodies and the development of GERD. Genetically predicted serum levels of Helicobacter pylori IgG antibodies were positively associated with an increased risk of GERD (odds ratio [OR] = 1.001, 95% CI 1.000-1.003, P = 0.043). No causal relationship was found between other Helicobacter pylori antibodies and gastroesophageal reflux disease. The outcomes derived from our two-sample Mendelian randomization analysis demonstrate a discernible link between the levels of Helicobacter pylori IgG antibodies and an augmented susceptibility to GERD. However, it is imperative to expand the sample size further in order to corroborate the correlation between Helicobacter pylori infection and GERD.


Increased BOLD variability in the parietal cortex and enhanced parieto-occipital connectivity during tactile perception in congenitally blind individuals.
Previous studies in early blind individuals posited a possible role of parieto-occipital connections in conveying nonvisual information to the visual occipital cortex. As a consequence of blindness, parietal areas would thus become able to integrate a greater amount of multimodal information than in sighted individuals. To verify this hypothesis, we compared fMRI-measured BOLD signal temporal variability, an index of efficiency in functional information integration, in congenitally blind and sighted individuals during tactile spatial discrimination and motion perception tasks. In both tasks, the BOLD variability analysis revealed many cortical regions with a significantly greater variability in the blind as compared to sighted individuals, with an overlapping cluster located in the left inferior parietal/anterior intraparietal cortex. A functional connectivity analysis using this region as seed showed stronger correlations in both tasks with occipital areas in the blind as compared to sighted individuals. As BOLD variability reflects neural integration and processing efficiency, these cross-modal plastic changes in the parietal cortex, even if described in a limited sample, reinforce the hypothesis that this region may play an important role in processing nonvisual information in blind subjects and act as a hub in the cortico-cortical pathway from somatosensory cortex to the reorganized occipital areas.


[Is Age a Comorbidity?]
Aging is normal process, only somehow questioned by the "anti-aging wave". Normal and pathological aging are therefore separate developments. Older adults often suffer from the frailty syndrome, partly due to diminished resilience. Aging per se is not a comorbidity.