The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1).
Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells, and the effect of NPS 2143 on their intracellular calcium responses was determined by flow cytometry. NPS 2143 was also administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder.


Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis.
In animals, liver and white adipose are the main sites for the de novo fatty acid synthesis. Deletion of fatty acid synthase or acetyl-CoA carboxylase (ACC) 1 in mice resulted in embryonic lethality, indicating that the de novo fatty acid synthesis is essential for embryonic development. To understand the importance of de novo fatty acid synthesis and the role of ACC1-produced malonyl-CoA in adult mouse tissues, we generated liver-specific ACC1 knockout (LACC1KO) mice. LACC1KO mice have no obvious health problem under normal feeding conditions. Total ACC activity and malonyl-CoA levels were approximately 70-75% lower in liver of LACC1KO mice compared with that of the WT mice. In addition, the livers of LACC1KO mice accumulated 40-70% less triglycerides. Unexpectedly, when fed fat-free diet for 10 days, there was significant up-regulation of PPARgamma and several enzymes in the lipogenic pathway in the liver of LACC1KO mice compared with the WT mice. Despite the significant up-regulation of the lipogenic enzymes, including a >2-fold increase in fatty acid synthase mRNA, protein, and activity, there was significant decrease in the de novo fatty acid synthesis and triglyceride accumulation in the liver. However, there were no significant changes in blood glucose and fasting ketone body levels. Hence, reducing cytosolic malonyl-CoA and, therefore, the de novo fatty acid synthesis in the liver, does not affect fatty acid oxidation and glucose homeostasis under lipogenic conditions.


An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.
While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .


Impact of implementing developmental screening at 12 and 24 months in a pediatric practice.
The purpose of this study was to investigate the effectiveness and costs of incorporating a parent-completed developmental screening tool, the Ages and Stages Questionnaire, into the 12- and 24-month well-child visits under "real-world" conditions, using a combined in-office and mail-back data collection protocol. A convenience sample of 1428 caregivers and children presenting for their 12- or 24-month well-child visit between April 2005 and March 2006 participated. Children with identified delays or disorders were excluded. Board-certified pediatricians (n = 18) and nurse practitioners (n = 2) acted as secondary participants. Pediatricians were blinded to Ages and Stages Questionnaire results when completing the Pediatric Developmental Impression. Patients with delayed Ages and Stages Questionnaire or Pediatric Developmental Impression results were referred for additional evaluation. Referral rates increased by 224%. Pediatrician referral on the basis of the Pediatric Developmental Impression was predicted significantly by suspected communication delay and gross motor delay. The Ages and Stages Questionnaire and Pediatric Developmental Impression results differed significantly, with overall agreement of 81.8%. Of Ages and Stages Questionnaire-delayed cases, 67.5% were not detected by pediatricians. Of the 78 patients referred on the basis of combined Ages and Stages Questionnaire and Pediatric Developmental Impression results, 53 would not have been referred on the basis of Pediatric Developmental Impression results alone; 37 patients qualified for special services, and 44 were scheduled for additional developmental monitoring. The rate of Ages and Stages Questionnaire return by caregivers/parents was 54%. Referral rates increased dramatically, with the greatest increase at 12 months. Although patients with pediatrician referrals were likely to qualify for services (96%), physician referrals accounted for only 42% of total referrals, which highlights the need for pediatric developmental screening. The 54% Ages and Stages Questionnaire return rate, although acceptable under study conditions, calls for alternative implementation strategies.


Joint Imaging Platform for Federated Clinical Data Analytics.
Image analysis is one of the most promising applications of artificial intelligence (AI) in health care, potentially improving prediction, diagnosis, and treatment of diseases. Although scientific advances in this area critically depend on the accessibility of large-volume and high-quality data, sharing data between institutions faces various ethical and legal constraints as well as organizational and technical obstacles. The Joint Imaging Platform (JIP) of the German Cancer Consortium (DKTK) addresses these issues by providing federated data analysis technology in a secure and compliant way. Using the JIP, medical image data remain in the originator institutions, but analysis and AI algorithms are shared and jointly used. Common standards and interfaces to local systems ensure permanent data sovereignty of participating institutions. The JIP is established in the radiology and nuclear medicine departments of 10 university hospitals in Germany (DKTK partner sites). In multiple complementary use cases, we show that the platform fulfills all relevant requirements to serve as a foundation for multicenter medical imaging trials and research on large cohorts, including the harmonization and integration of data, interactive analysis, automatic analysis, federated machine learning, and extensibility and maintenance processes, which are elementary for the sustainability of such a platform. The results demonstrate the feasibility of using the JIP as a federated data analytics platform in heterogeneous clinical information technology and software landscapes, solving an important bottleneck for the application of AI to large-scale clinical imaging data.


Organic causes of mania.
Manic syndromes have many neurologic, toxic, and metabolic causes. It is important for clinicians to be able to distinguish these organic disorders from primary idiopathic mania (bipolar disorder). The cardinal symptom of organic mania is an abnormally and persistently elevated or irritable mood. Organic mania usually develops in patients who are older than 35 years of age, whereas bipolar disorder generally has its onset between late adolescence and age 25 years. In patients with the first episode of mania, the clinician should thoroughly elicit information about current symptoms, recent infections, use of drugs, and past or family history of psychiatric disorders. In addition, a complete medical examination, computed tomography of the head, electroencephalography, and screening for drugs and toxins should be done. Treatment of organic mania includes correcting the underlying disorder when possible.


Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver.
Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light-dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors.


Adolescent substance use and abuse: current issues.
Substance use and abuse among American adolescents account for significant morbidity and mortality in this age group. A good history is the mainstay in the evaluation, along with the identification of clinical clues of drug use or abuse. Issues of consent and confidentiality should be considered in the assessment, particularly when deciding whether to use drug testing in diagnosis and management. Establishing the patient's stage of substance use can help define the option of either management by the primary care physician or referral to a professional who is experienced in treating chemical dependency. Important research-based principles for prevention programs for children and adolescents include the need for programs to target all forms of drug abuse and to be age-specific, developmentally appropriate, culturally sensitive, and cost-effective.


MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment.
The management of cardiovascular risk through lifestyle modification and pharmacotherapy is paramount to the prevention of cardiovascular disease. Epidemiological studies have identified obesity, dyslipidemia, diabetes, and hypertension as interrelated factors that negatively affect cardiovascular health. Recently, genetic and pharmacological evidence in model systems has implicated microRNAs as dynamic modifiers of disease pathogenesis. An expanded understanding of the function of microRNAs in gene regulatory networks associated with cardiovascular risk will enable identification of novel genetic mechanisms of disease and inform the development of innovative therapeutic strategies.


Mammographic x-ray unit kilovoltage test tool based on k-edge absorption effect.
A simple tool to determine the peak kilovoltage (kVp) of a mammographic x-ray unit has been designed. Tool design is based on comparing the effect of k-edge discontinuity of the attenuation coefficient for a series of element filters. Compatibility with the mammography accreditation phantom (MAP) to obtain a single quality control film is a second design objective. When the attenuation of a series of sequential elements is studied simultaneously, differences in the absorption characteristics due to the k-edge discontinuities are more evident. Specifically, when the incident photon energy is higher than the k-edge energy of a number of the elements and lower than the remainder, an inflection may be seen in the resulting attenuation data. The maximum energy of the incident photon spectra may be determined based on this inflection point for a series of element filters. Monte Carlo photon transport analysis was used to estimate the photon transmission probabilities for each of the sequential k-edge filter elements. The photon transmission corresponds directly to optical density recorded on mammographic x-ray film. To observe the inflection, the element filters chosen must have k-edge energies that span a range greater than the expected range of the end point energies to be determined. For the design, incident x-ray spectra ranging from 25 to 40 kVp were assumed to be from a molybdenum target. Over this range, the k-edge energy changes by approximately 1.5 keV between sequential elements. For this design 21 elements spanning an energy range from 20 to 50 keV were chosen. Optimum filter element thicknesses were calculated to maximize attenuation differences at the k-edge while maintaining optical densities between 0.10 and 3.00. Calculated relative transmission data show that the kVp could be determined to within +/-1 kV. To obtain experimental data, a phantom was constructed containing 21 different elements placed in an acrylic holder. MAP images were used to determine appropriate exposure techniques for a series of end point energies from 25 to 35 kVp. The average difference between the kVp determination and the calibrated dial setting was 0.8 and 1.0 kV for a Senographe 600 T and a Senographe DMR, respectively. Since the k-edge absorption energies of the filter materials are well known, independent calibration or a series of calibration curves is not required.


Smoked marijuana as a cause of lung injury.
In many societies, marijuana is the second most commonly smoked substance after tobacco. While delta9-tetrahydrocannabinol (THC) is unique to marijuana and nicotine to tobacco, the smoke of marijuana, like that of tobacco, consists of a toxic mixture of gases and particulates, many of which are known to be harmful to the lung. Although far fewer marijuana than tobacco cigarettes are generally smoked on a daily basis, the pulmonary consequences of marijuana smoking may be magnified by the greater deposition of smoke particulates in the lung due to the differing manner in which marijuana is smoked. Whereas THC causes modest short-term bronchodilation, regular marijuana smoking produces a number of long-term pulmonary consequences, including chronic cough and sputum, histopathologic evidence of widespread airway inflammation and injury and immunohistochemical evidence of dysregulated growth of respiratory epithelial cells, that may be precursors to lung cancer. The THC in marijuana could contribute to some of these injurious changes through its ability to augment oxidative stress, cause mitochondrial dysfunction, and inhibit apoptosis. On the other hand, physiologic, clinical or epidemiologic evidence that marijuana smoking may lead to chronic obstructive pulmonary disease or respiratory cancer is limited and inconsistent. Habitual use of marijuana is also associated with abnormalities in the structure and function of alveolar macrophages, including impairment in microbial phagocytosis and killing that is associated with defective production of immunostimulatory cytokines and nitric oxide, thereby potentially predisposing to pulmonary infection. In view of the growing interest in medicinal marijuana, further epidemiologic studies are needed to clarify the true risks of regular marijuana smoking on respiratory health.


Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations.
Normocalcemic primary hyperparathyroidism is typically identified after referral to a specialty clinic. At diagnosis, patients demonstrate features seen in hypercalcemic primary hyperparathyroidism. Normocalcemic hypoparathyroidism has been discovered after hypocalcemia unmasked after bisphosphonate administration. We hypothesized that screening unselected, nonreferral populations, such as The Osteoporotic Fractures in Men (MrOS) study and Dallas Heart Study (DHS), would identify asymptomatic subjects with normocalcemic hyperparathyroidism and hypoparathyroidism. Normocalcemic hyperparathyroidism was defined as serum PTH greater than the upper reference range with normal albumin-adjusted serum calcium, excluding common secondary causes (renal failure [estimated glomerular filtration rate <60 mL/min], 25-hydroxyvitamin D <20 ng/mL, and thiazide use), and normocalcemic hypoparathyroidism as PTH below the reference range with normocalcemia. Cross-sectional data were obtained from MrOS, and longitudinal data (baseline and 8 years) from DHS. In 2364 men from MrOS, we identified 9 with normocalcemic hyperparathyroidism (prevalence 0.4%) and 26 with normocalcemic hypoparathyroidism (1.1%). In 3450 men and women from DHS, we identified 108 with normocalcemic hyperparathyroidism (3.1%) and 68 with normocalcemic hypoparathyroidism (1.9%). Of the 108 normocalcemic hyperparathyroid subjects, 64 had follow-up data. Hypercalcemic primary hyperparathyroidism developed in 1 subject whereas 13 (0.6% of the follow-up cohort) showed persistently elevated PTH levels with normocalcemia. Of the 26 normocalcemic hypoparathyroid subjects with follow-up data, none developed overt hypoparathyroidism and 2 (0.09%) had persistent evidence of normocalcemic hypoparathyroidism. This study documents normocalcemic primary hyperparathyroidism and hypoparathyroidism identified among community-dwelling individuals. Larger studies are needed to determine the true prevalence and natural history of these parathyroid disorders.


Technologic organization of malaria control in São Paulo, Brazil, 1930-1990.
Since the 1970s, when the world seemed on the threshold of malaria eradication, the incidence of the disease has increased in several countries. The upturn in cases raised a series of questions, and for some time malariologists and public health authorities scarcely understood what was happening. In an attempt to better comprehend the process, this article reviews the frequency of malaria cases in São Paulo, Brazil, between 1930 and 1990, examining the following factors in each of three 20-year time periods: the importance of malaria in the society, the conditions under which the disease occurred, the epidemiologic knowledge of the time, the technical instruments available to fight it, and the control strategies that were used. Through the construction of technological models based on these factors, it became clear that the occurrence of the disease, knowledge about it, and, consequently, the ways it was dealt with changed over time. In light of this research, the article discusses current options for the control of malaria.


RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships.
RNA:DNA hybrids represent a non-canonical nucleic acid structure that has been associated with a range of human diseases and potential transcriptional regulatory functions. Mapping of RNA:DNA hybrids in human cells reveals them to have a number of characteristics that give insights into their functions. We find RNA:DNA hybrids to occupy millions of base pairs in the human genome. A directional sequencing approach shows the RNA component of the RNA:DNA hybrid to be purine-rich, indicating a thermodynamic contribution to their in vivo stability. The RNA:DNA hybrids are enriched at loci with decreased DNA methylation and increased DNase hypersensitivity, and within larger domains with characteristics of heterochromatin formation, indicating potential transcriptional regulatory properties. Mass spectrometry studies of chromatin at RNA:DNA hybrids shows the presence of the ILF2 and ILF3 transcription factors, supporting a model of certain transcription factors binding preferentially to the RNA:DNA conformation. Overall, there is little to indicate a dependence for RNA:DNA hybrids forming co-transcriptionally, with results from the ribosomal DNA repeat unit instead supporting the intriguing model of RNA generating these structures in trans. The results of the study indicate heterogeneous functions of these genomic elements and new insights into their formation and stability in vivo.


A Novel, non-invasive Test Enabling Bladder Cancer Detection in Urine Sediment of Patients Presenting with Haematuria-A Prospective Multicentre Performance Evaluation of ADXBLADDER.
Bladder cancer is the sixth most commonly diagnosed cancer in the European Union. Here, we evaluate the performance of a novel, commercially available enzyme-linked immunosorbent assay utilising MCM5 antibodies (ADXBLADDER; Arquer Diagnostics Ltd, Sunderland, UK) for the detection of bladder cancer, in a blinded, prospective study of 856 patients, across seven centres, presenting with haematuria. The results were compared with the patients' clinical data and final diagnosis as defined by the results of the imaging and cystoscopy, with a prevalence of bladder cancer of 8.6%. ADXBLADDER detected bladder tumours in 54/74 cancers, giving overall sensitivity of 73.0% and an overall negative predictive value (NPV) of 96.4%. Sensitivity and NPV of ADXBLADDER were highest in muscle-invasive bladder cancer, both at 100%, and on analysis of non-pTa (pT1 and above) tumours, the sensitivity for detection was 97% with an NPV of 99.8%. A subset of 173 patients had matching cytology data; of these patients, 18 were positive for bladder cancer. ADXBLADDER detected 16/18 of these cancers, whilst cytology was positive in only four of 18, providing evidence that ADXBLADDER may be a more sensitive test for bladder cancer than standard urine cytology. PATIENT SUMMARY: We conducted a large clinical study of a novel, simple urine test (ADXBLADDER), which measures a protein (MCM5) in urine and can be used to detect bladder cancer in patients. We recruited 856 patients and demonstrated that the new urine test can detect bladder cancer with a high degree of accuracy, performing better than the most commonly used urine test-urine cytology. In conclusion, this novel ADXBLADDER urine test can be used to help detect bladder cancers and it can replace the current, standard urine test.


The S2 Cu(i) site in CupA from Streptococcus pneumoniae is required for cellular copper resistance.
Pathogenic bacteria have evolved copper homeostasis and resistance systems for fighting copper toxicity imposed by the human immune system. Streptococcus pneumoniae is a respiratory pathogen that encodes an obligatorily membrane-anchored Cu(i) binding protein, CupA, and a P1B-type ATPase efflux transporter, CopA. The soluble, cytoplasmic domain of CupA (sCupA) contains a binuclear Cu(i) cluster consisting of S1 and S2 Cu(i) ions. The NMR solution structure of apo-sCupA reveals the same cupredoxin fold of Cu2-sCupA, except that the Cu(i) binding loop (residues 112-116, harboring S2 Cu ligands M113 and M115) is highly dynamic as documented by both backbone and side chain methionine methyl order parameters. In contrast to the more solvent exposed, lower affinity S2 Cu site, the high affinity S1 Cu-coordinating cysteines (C74, C111) are pre-organized in the apo-sCupA structure. Biological experiments reveal that the S1 site is largely dispensable for cellular Cu resistance and may be involved in buffering low cytoplasmic Cu(i). In contrast, the S2 site is essential for Cu resistance. Expression of a chimeric CopZ chaperone fused to the CupA transmembrane helix does not protect S. pneumoniae from copper toxicity and substitution of a predicted cytoplasm-facing Cu(i) entry metal-binding site (MBS) on CopA also gives rise to a Cu-sensitivity phenotype. These findings suggest that CupA and CopA may interact and filling of the CupA S2 site with Cu(i) results in stimulation of cellular copper efflux by CopA.


Patients With Borderline Hip Dysplasia Achieve Clinically Significant Improvement After Arthroscopic Femoroacetabular Impingement Surgery: A Case-Control Study With a Minimum 5-Year Follow-up.
Hip arthroscopy for the treatment of femoroacetabular impingement syndrome (FAIS) in patients with borderline hip dysplasia (BHD) is becoming a more common practice. However, the literature on achieving meaningful outcomes at midterm follow-up, as well as predictors of these outcomes, is limited. To (1) compare the rates of achieving meaningful clinical outcomes between patients with and without BHD and (2) identify the predictors for achieving clinical success among patients with BHD 5 years after undergoing hip arthroscopic surgery for FAIS. Cohort study; Level of evidence, 3. Data from consecutive patients who underwent primary hip arthroscopic surgery with routine capsular closure for the treatment of FAIS between January 2012 and August 2014 were collected and retrospectively analyzed. Patients with BHD (lateral center-edge angle [LCEA] 20°-25°) were matched 1:2 by age (±1 year) and body mass index (BMI; ±5 kg/m2) to control patients with normal acetabular coverage (LCEA 25°-40°). Data collected included baseline and 5-year postoperative patient-reported outcomes. The minimal clinically important difference (MCID) and patient acceptable symptom state (PASS) were calculated for each patient-reported outcome measure and compared between the 2 groups. A binary logistic regression analysis was used to identify significant predictors of achieving the MCID and PASS in the BHD group. The MCID in the BHD group was defined as 9.6, 14.1, and 9.5 for the Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sports Subscale, and modified Harris Hip Score, respectively. Threshold scores for achieving the PASS in both groups were 90.9, 76.6, and 81.9, respectively. A total of 88 patients were identified with having BHD and were matched to 176 controls. No statistical differences were identified for age, BMI, or sex. Both the BHD and the non-BHD groups had statistically significant increases in patient-reported outcome scores over the 5-year period, but the difference in both groups was not statistically significant (P > .05 for all). There was no statistical difference in the frequency of patients in the BHD and non-BHD groups achieving the MCID (86.6% vs 85.2%, respectively; P = .804) or PASS (76.0% vs 73.7%, respectively; P = .675) on at least 1 outcome measure. The logistic regression model demonstrated that being physically active (odds ratio [OR], 27.59; P = .005) and being female (OR, 14.64; P = .025) were independent predictors of achieving the MCID, while running (OR, 11.1; P = .002), being female (OR, 7.6; P = .011), and a larger preoperative LCEA (OR, 2.3; P = .001) were independent preoperative predictors of achieving the PASS. The rates of achieving clinical success 5 years after undergoing arthroscopic treatment with capsular closure for FAIS were not significantly different between patients with BHD and those with normal acetabular coverage. Being physically active, running for exercise, female sex, and a larger LCEA were preoperative predictors of achieving clinical success at 5 years in patients with BHD.


A 5.8-kDa component of manuka honey stimulates immune cells via TLR4.
Honey is used as a therapy to aid wound healing. Previous data indicate that honey can stimulate cytokine production from human monocytes. The present study further examines this phenomenon in manuka honey. As inflammatory cytokine production in innate immune cells is classically mediated by pattern recognition receptors in response to microorganisms, bacterial contamination of honey and the effect of blocking TLR2 and -4 on stimulatory activity were assessed. No vegetative bacteria were isolated from honey; however, bacterial spores were cultured from one-third of samples, and low levels of LPS were detected. Blocking TLR4 but not TLR2 inhibited honey-stimulated cytokine production significantly. Cytokine production did not correlate with LPS levels in honey and was not inhibited by polymyxin B. Further, the activity was reduced significantly following heat treatment, indicating that component(s) other than LPS are responsible for the stimulatory activity of manuka honey. To identify the component responsible for inducing cytokine production, honey was separated by molecular weight using microcon centrifugal filtration and fractions assessed for stimulatory activity. The active fraction was analyzed by MALDI-TOF mass spectroscopy, which demonstrated the presence of a number of components of varying molecular weights. Additional fractionation using miniaturized, reverse-phase solid-phase extraction resulted in the isolation of a 5.8-kDa component, which stimulated production of TNF-alpha via TLR4. These findings reveal mechanisms and components involved in honey stimulation of cytokine induction and could potentially lead to the development of novel therapeutics to improve wound healing for patients with acute and chronic wounds.


Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients.
Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency disorder characterised by susceptibility to chronic Candida and fungal dermatophyte infections of the skin, nails and mucous membranes. Molecular epidemiology studies of CMC infection are limited in number and scope and it is not clear whether single or multiple strains inducing CMC persist stably or are exchanged and replaced. We subjected 42 C. albicans individual single colony isolates from 6 unrelated CMC patients to multilocus sequence typing (MLST). Multiple colonies were typed from swabs taken from multiple body sites across multiple time points over a 17-month period. Among isolates from each individual patient, our data show clonal and persistent diploid sequence types (DSTs) that were stable over time, identical between multiple infection sites and exhibit azole resistant phenotypes. No shared origin or common source of infection was identified among isolates from these patients. Additionally, we performed C. albicans MLST SNP genotype frequency analysis to identify signatures of past loss of heterozygosity (LOH) events among persistent and azole resistant isolates retrieved from patients with autoimmune disorders including CMC.


Response of THP-1 monocytes to blue light from dental curing lights.
Blue light curing units (wavelengths of 400-500 nm) are a mainstay of restorative dentistry, and several high-intensity light sources have been developed to polymerize resin composites more rapidly. The biological safety of visible light has been assumed, but some reports of adverse biological effects of blue light in non-dental contexts support further evaluation of the biological safety of high-intensity blue light. The current study tested the hypothesis that blue light provokes cell stress responses resulting in the secretion of cytokines or expression of heat-shock proteins (HSP) in monocytes. Human monocytic cells were irradiated with three light sources (quartz-tungsten-halogen, plasma-arc and laser), then cellular proliferation, secretion of the inflammatory cytokine TNFalpha and induction of HSP72 were measured. Results indicated that although all three light sources significantly inhibited proliferation of monocytes, the secretion of TNFalpha was not induced following exposure to blue light and was not potentiated with administration of the activator lipopolysaccharide. Similarly, treatment with the plasma-arc light, which caused the largest temperature increase in previous studies, did not induce HSP72. The current results do not support activation of monocytes by blue light as an inflammatory risk factor in dental tissues during curing of composites. However, the results of the current study should be further verified in primary monocytes and an animal model before decisions about clinical risks are made.


Determinants of 24-h blood pressure in IDDM patients.
To assess the influence of basic clinical data on ambulatory blood pressure (AMBP) in insulin-dependent diabetes mellitus (IDDM) patients and to evaluate the reproducibility of the method. AMBP was measured in 66 IDDM patients with urinary albumin excretion (UAE) < 20 micrograms/min and in 53 healthy subjects. Determinants of AMBP were identified in a stepwise multiple regression model. In addition, 14 diabetic patients were monitored on two days of the same type, and 14 patients were monitored on one work day and one day off. In healthy subjects, sex was the most important determinant of 24-h blood pressure (BP), whereas UAE and age were the main covariates in diabetes patients. The male-female difference in 24-h diastolic BP (dBP) was 5.6 mmHg lower in diabetic patients than in healthy control subjects (P < 0.05). In patients with long diabetes duration, nighttime dBP (69 +/- 7 mmHg) was higher than in patients with medium diabetes duration (63 +/- 8 mmHg, P < 0.05; after matching for age and sex). Daytime dBP was 5 mmHg higher on a work day than on a day off (P < 0.02). Standard deviation of the difference for repeated measurement of 24-h systolic/diastolic BP in the same subject was 5.7/2.5 mmHg. The male-female difference in 24-h dBP was attenuated in diabetes. The influence of UAE on AMBP was noticed even in normoalbuminuric diabetic patients. Standardized AMBP was highly reproducible.


Bariatric surgery in the super-super morbidly obese: outcome analysis of patients with BMI >70 using the ACS-NSQIP database.
Bariatric surgery offers patients short- and long-term benefits to their health and quality of life. Currently, we see more patients with superior body mass index (BMI) looking for these benefits. Evidence-based medicine is integral in the evaluation of risks versus benefit; however, data are lacking in this high-risk population. To assess the morbidity and mortality of patients with BMI ≥70 undergoing bariatric surgery. University Hospital, Bronx, New York, United States using national database. Using the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) database for years 2005 to 2016, we identified patients who underwent primary laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass. Patients with BMI ≥70 were assigned to the BMI >70 (BMI70+) cohort and less obese patients were assigned to the BMI <70 (U70) cohort. Length of stay and 30-day morbidity and mortality were compared. A total of 163,413 patients underwent non-revisional bariatric surgery. Of those, 2322 had a BMI ≥70. BMI70+ was associated with increased mortality (.4% versus .1%, P = .0001), deep vein thrombosis (.6% versus .3%, P = .007), pulmonary (1.9% versus .5%, P = .0001), renal (.9% versus .2%, P = .0001), and infectious complications (1.1% versus .4%, P = .0001). BMI70+ patients had longer mean length of stay (2.6 versus 2.1 d, P = .0001) and operative time (126.1 versus 114.5 min, P = .0001). There was no statistically significant difference in the number of myocardial infarctions (.1% versus .1%, P = .319), pulmonary embolisms (.3% versus .2%, P = .596), and transfusion requirements (.1% versus .1%, P = .105) between groups. Evaluation of risk and benefit is performed on a case-by-case basis, but evidence-based medicine is critical in empowering surgeons and patients to make informed decisions. The overall rate of morbidity and mortality for BMI70+ patients undergoing bariatric surgery was increased over U70 patients but was still relatively low. Our study will allow surgeons to incorporate objective data into their assessment of risk for super-obese patients pursuing bariatric surgery.


A Sequence-Independent Strategy for Amplification and Characterisation of Episomal Badnavirus Sequences Reveals Three Previously Uncharacterised Yam Badnaviruses.
Yam (Dioscorea spp.) plants are potentially hosts to a diverse range of badnavirus species (genus Badnavirus, family Caulimoviridae), but their detection is complicated by the existence of integrated badnavirus sequences in some yam genomes. To date, only two badnavirus genomes have been characterised, namely, Dioscorea bacilliform AL virus (DBALV) and Dioscorea bacilliform SN virus (DBSNV). A further 10 tentative species in yam have been described based on their partial reverse transcriptase (RT)-ribonuclease H (RNaseH) sequences, generically referred to here as Dioscorea bacilliform viruses (DBVs). Further characterisation of DBV species is necessary to determine which represent episomal viruses and which are only present as integrated badnavirus sequences in some yam genomes. In this study, a sequence-independent multiply-primed rolling circle amplification (RCA) method was evaluated for selective amplification of episomal DBV genomes. This resulted in the identification and characterisation of nine complete genomic sequences (7.4-7.7 kbp) of existing and previously undescribed DBV phylogenetic groups from Dioscorea alata and Dioscorea rotundata accessions. These new yam badnavirus genomes expand our understanding of the diversity and genomic organisation of DBVs, and assist the development of improved diagnostic tools. Our findings also suggest that mixed badnavirus infections occur relatively often in West African yam germplasm.


A picture tells a thousand…exposures: Opportunities and challenges of deep learning image analyses in exposure science and environmental epidemiology.
Artificial intelligence (AI) is revolutionizing our world, with applications ranging from medicine to engineering. Here we discuss the promise, challenges, and probable data sources needed to apply AI in the fields of exposure science and environmental health. In particular, we focus on the use of deep convolutional neural networks to estimate environmental exposures using images and other complementary data sources such as cell phone mobility and social media information. Characterizing the health impacts of multiple spatially-correlated exposures remains a challenge in environmental epidemiology. A shift toward integrated measures that simultaneously capture multiple aspects of the urban built environment could improve efficiency and provide important insights into how our collective environments influence population health. The widespread adoption of AI in exposure science is on the frontier. This will likely result in new ways of understanding environmental impacts on health and may allow for analyses to be efficiently scaled for broad coverage. Image-based convolutional neural networks may also offer a cost-effective means of estimating local environmental exposures in low and middle-income countries where monitoring and surveillance infrastructure is limited. However, suitable databases must first be assembled to train and evaluate these models and these novel approaches should be complemented with traditional exposure metrics. The promise of deep learning in environmental health is great and will complement existing measurements for data-rich settings and could enhance the resolution and accuracy of estimates in data poor scenarios. Interdisciplinary partnerships will be needed to fully realize this potential.


Type 2 ryanodine receptor domain A contains a unique and dynamic α-helix that transitions to a β-strand in a mutant linked with a heritable cardiomyopathy.
Ryanodine receptors (RyRs) are large tetrameric calcium (Ca(2+)) release channels found on the sarcoplasmic reticulum that respond to dihydropyridine receptor activity through a direct conformational interaction and/or indirect Ca(2+) sensitivity, propagating sarcoplasmic reticulum luminal Ca(2+) release in the process of excitation-contraction coupling. There are three human RyR subtypes, and several debilitating diseases are linked to heritable mutations in RyR1 and RyR2 including malignant hypothermia, central core disease, catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Despite the recent appreciation that many disease-associated mutations within the N-terminal RyRABC domains (i.e., residues 1-559) are located in the putative interfaces mediating tetrameric channel assembly, the precise structural and dynamical consequences of the mutations are not well understood. We used solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to examine the effect of ARVD2-associated (i.e., R176Q) and CPVT-associated [i.e., P164S, R169Q and delta exon 3 (Δ3)] mutations on the structure and dynamics of RyR2A. Our solution NMR data exposed a mobile α-helix, unique to type 2; further, this α2 helix rescues the β-strand lost in RyR2A Δ3 but remains dynamic in the hot-spot loop (HS-loop) P164S, R169Q and R176Q mutant proteins. Docking of our X-ray crystal/NMR hybrid structure into the RyR1 cryo-electron microscopy map revealed that this RyR2A α2 helix is in close proximity to dense "columns" projecting toward the channel pore. This is in contrast to the HS-loop mutations that cause structural changes largely localized to the intersubunit interface between adjacent ABC domains. Taken together, our data suggest that ARVD2 and CPVT mutations have at least two distinct structural consequences linked to channel dysfunction: perturbation of the HS-loop (i.e., domain A):domain B intersubunit interface and disruption of the communication between the N-terminal region and the channel domain.


Understanding users' perspectives of barriers to maternal health care use in Maharashtra, India.
This paper uses data collected using in-depth, semi-structured interviews to examine utilization of maternal health care services among two rural and urban populations of Pune and Mumbai in Maharashtra, India. The study aims to identify key social, economic and cultural factors influencing women's decisions to use maternal health care and the places used for child delivery, whilst considering the accessibility of facilities available in the local area. Socioeconomic status was not found to be a barrier to service use when women perceived the benefits of the service to outweigh the cost, and when the service was within reasonable distance of the respondent's place of residence. A large number of women perceived private services to be superior to those provided by the government, although cost often meant they were unable to use them. The provision of services did not ensure that women used them; they had to first perceive them to be beneficial to their health and that of their unborn child. Respondents identified the poor quality of services offered at government institutions to be a motivating factor for delivering at home. Thus further investigation is needed into the quality of services provided by government facilities in the area. A number of respondents who had received antenatal care went on to deliver in the home environment without a trained birth attendant. Further research is needed to establish the types of care provided during an antenatal consultation to establish the feasibility of using these visits to encourage women, particularly those with high-risk pregnancies, to be linked to a trained attendant for delivery.


Development of a rat model by 3,4-benzopyrene intra-pulmonary injection and evaluation of the effect of green tea drinking on p53 and bcl-2 expression in lung carcinoma.
A convenient animal model of primary lung cancer is compelling for investigation into the disease mechanisms and for development of therapeutic strategies. This study aims to develop a reproducible rat model for lung carcinoma by intra-pulmonary injection of 3,4-benzopyrene, and to evaluate the preventive effect of green tea on the formation of lung carcinoma. Sprague-Dawley rats of the same ages were randomly assigned into three groups treated differently. Rats in group one were given green tea in drinking water (tea concentration: 1.2%; tea polyphenols in the tea solution: 0.3%); rats in the groups two and three were given blank drinking water. Rats in the groups one and two were injected intra-pulmonarily with 3,4-benzopyrene dissolved in corn oil (2 mg/0.2 mL/injection, fortnightly, 4 times in all); rats in the group three were injected with the vehicle corn oil as the control for injection. All the rats were sacrificed one year after the first intra-pulmonary injection. Tumors developed in rats and lung tissues were collected for carcinoma diagnosis and for p53 and bcl-2 expression. Intra-pulmonary injection of 3,4-benzopyrene steady induced lung carcinoma at a success rate of 75%. Administration with green tea drinking significantly reduced the incidence of lung carcinoma to 30%. Green tea up-regulated p53 expression in lung carcinoma, but significantly down-regulated bcl-2 expression. Intra-pulmonary injection of 3,4-benzopyrene can steady induce lung carcinoma in rats, and green tea has preventive effect against lung cancer possibly by regulating expression of some critical genes such as p53 and bcl-2.


Partitioning of bacterial communities between seawater and healthy, black band diseased, and dead coral surfaces.
Distinct partitioning has been observed in the composition and diversity of bacterial communities inhabiting the surface and overlying seawater of three coral species infected with black band disease (BBD) on the southern Caribbean island of Curaçao, Netherlands Antilles. PCR amplification and sequencing of bacterial 16S rRNA genes (rDNA) with universally conserved primers have identified over 524 unique bacterial sequences affiliated with 12 bacterial divisions. The molecular sequences exhibited less than 5% similarity in bacterial community composition between seawater and the healthy, black band diseased, and dead coral surfaces. The BBD bacterial mat rapidly migrates across and kills the coral tissue. Clone libraries constructed from the BBD mat were comprised of eight bacterial divisions and 13% unknowns. Several sequences representing bacteria previously found in other marine and terrestrial organisms (including humans) were isolated from the infected coral surfaces, including Clostridium spp., Arcobacter spp., Campylobacter spp., Cytophaga fermentans, Cytophaga columnaris, and Trichodesmium tenue.


Ventilation rate in adults with a tracheal tube during cardiopulmonary resuscitation: A systematic review.
The optimal ventilation rate during cardiopulmonary resuscitation (CPR) with a tracheal tube is unknown. We evaluated whether in adults with cardiac arrest and a secure airway (tracheal tube), a ventilation rate of 10min-1, compared to any other rate during CPR, improves outcomes. A systematic review up to 14 July 2016. We included both adult human and animal studies. A GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to evaluate the quality of evidence for each outcome. We identified one human observational study with 67 patients and ten animal studies (234 pigs and 30 dogs). All studies carried a high risk of bias. All studies evaluated for return of spontaneous circulation (ROSC). Studies showed no improvement in ROSC with a ventilation rate of 10 min-1 compared to any other rate. The evidence for longer-term outcomes such as survival to discharge and survival with favourable neurological outcome was very limited. A ventilation rate recommendation of 10 min-1 during adult CPR with a tracheal tube and no pauses for chest compression is a very weak recommendation based on very low quality evidence.


The role of lifestyle factors on comorbidity of chronic liver disease and cardiometabolic disease in Chinese population: A prospective cohort study.
Lifestyle factors are associated with chronic liver disease (CLD) and death after CLD diagnosis. However, their associations with pathways of CLD progression have been unclear, particularly transition to cardiometabolic disease (CMD), a major comorbid condition with CLD. We assessed the associations of lifestyle factors with CLD progression. The study population involved 486,828 participants of the prospective China Kadoorie Biobank (CKB) aged 30-79 years without a history of cardiovascular disease, diabetes, CLD, or cancer at baseline. Liver-cardiometabolic comorbidity (LCC) was defined as developing CMD subsequently after first CLD (FCLD) in an individual. A multi-state model was used to estimate the associations of high-risk lifestyle factors (smoking, alcohol, physical inactivity, and central adiposity) with CLD progression from healthy to FCLD, subsequently to LCC, and further to death. During a median follow-up of 11 years, 5046 participants developed FCLD, 519 developed LCC, and 157 died afterwards. There were positive associations between the number of high-risk lifestyle factors and risks of all transitions. The hazard ratios (95% CIs) per 1-factor increase were 1.30 (1.25-1.35) for transitions from baseline to FCLD, 1.21 (1.09-1.34) for FCLD to LCC, 1.20 (1.17-1.23) for baseline to death, 1.15 (1.09-1.22) for FCLD to death, and 1.17 (1.06-1.31) for LCC to death. For CLD subtypes, lifestyle factors showed different associations with disease-specific transitions even within the same transition stage. High-risk lifestyle factors played a key role in all disease transition stages from healthy to FCLD, subsequently to LCC, and then to death, with different magnitude of associations. Kadoorie Charitable Foundation, Chinese MoST and NSFC.


Risk factors for liver abscess formation in patients with blunt hepatic injury after non-operative management.
To identify risk factors for liver abscess formation in patients with blunt hepatic injury who underwent non-operative management (NOM). From January 2004 to October 2008, retrospective data were collected from a single level I trauma center. Clinical data, hospital course, and outcome were all extracted from patient medical records for further analysis. A total of 358 patients were enrolled for analysis. There were 13 patients with liver abscess after blunt hepatic injury. Patients with abscess had a significant increase in glutamic oxaloacetic transaminase (GOT, p = 0.006) and glutamic pyruvic transaminase (GPT, p < 0.0001), and a decrease in arterial blood pH (p = 0.023) compared to patients without abscess in the univariate analyses. In addition, high-grade hepatic injury and transarterial embolization (TAE, p < 0.001) were also risk factors for liver abscess formation. Five factors (GOT, GPT, pH level in the arterial blood sample, TAE, and high-grade hepatic injury) were included in the multivariate analysis. TAE, high-grade hepatic injury, and GPT level were statistically significant. The odds ratios of TAE and high-grade hepatic injury were 15.41 and 16.08, respectively. A receiver operating characteristic (ROC) analysis was used for GPT, and it suggested cutoff values of 372.5 U/L. A prediction model based on the ROC analysis had 100 % sensitivity and 86.7 % specificity to predict liver abscess formation in patients with two of the three independent risk factors. TAE, high-grade hepatic injury, and a high GPT level are independent risk factors for liver abscess formation.


A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland.
We evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid NRX194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (ER)-negative breast cancer in vivo. In cell culture studies, we measured the ability of 4204 to block the effects of lipopolysaccharide and induce apoptosis. For the lung cancer prevention studies, A/J mice were injected with the carcinogen vinyl carbamate and then fed 4204 (30-60 mg/kg diet) for 15 weeks, beginning 1 week after the administration of the carcinogen. For breast cancer prevention studies, mouse mammary tumor virus-neu mice were fed control diet or 4204 (20 mg/kg diet) for 50 weeks; for treatment, tumors at least 32 mm3 in size were allowed to form, and then mice were fed control diet or 4204 (60 mg/kg diet) for 4 weeks. Low nanomolar concentrations of 4204 blocked the ability of lipopolysaccharide and tumor necrosis factor-alpha to induce the release of nitric oxide and interleukin 6 and the degradation of IKBalpha in RAW264.7 macrophage-like cells. In the A/J mouse model of lung cancer, 4204 significantly (P < 0.05) reduced the number and size of tumors on the surface of the lungs and reduced the total tumor volume per slide by 64% to 81% compared with the control group. In mouse mammary tumor virus-neu mice, 4204 not only delayed the development of ER-negative mammary tumors in the prevention studies but also caused marked tumor regression (92%) or growth arrest (8%) in all of the mammary tumors when used therapeutically. The combined anti-inflammatory and anticarcinogenic actions of 4204 suggest that it is a promising new rexinoid that should be considered for future clinical trials.


3-D discrete shearlet transform and video processing.
In this paper, we introduce a digital implementation of the 3-D shearlet transform and illustrate its application to problems of video denoising and enhancement. The shearlet representation is a multiscale pyramid of well-localized waveforms defined at various locations and orientations, which was introduced to overcome the limitations of traditional multiscale systems in dealing with multidimensional data. While the shearlet approach shares the general philosophy of curvelets and surfacelets, it is based on a very different mathematical framework, which is derived from the theory of affine systems and uses shearing matrices rather than rotations. This allows a natural transition from the continuous setting to the digital setting and a more flexible mathematical structure. The 3-D digital shearlet transform algorithm presented in this paper consists in a cascade of a multiscale decomposition and a directional filtering stage. The filters employed in this decomposition are implemented as finite-length filters, and this ensures that the transform is local and numerically efficient. To illustrate its performance, the 3-D discrete shearlet transform is applied to problems of video denoising and enhancement, and compared against other state-of-the-art multiscale techniques, including curvelets and surfacelets.


The pyramidal cell and its local-circuit interneurons: a hypothetical unit of the Mammalian cerebral cortex.
A pyramidal cell with five of its local-circuit interneurons (Cajal-Retzius, Martinotti, Cajal double-bouquet, basket, and chandelier cells), constitutes a distinct structural/functional assemblage of the mammalian neocortex. This pyramidal/local-circuit neuronal assemblage is proposed herein as a basic neocortical unit. This unit is shared by all mammals, embodies both specific structural as well as functional elements, and constitutes an essential developmental building block of the neocortex. In the model, the pyramidal cell represents a distinct, stable, projective, excitatory neuron that has remained essentially unchanged in the course of mammalian phylogeny. On the other hand, its local-circuit interneurons are more likely to be inhibitory and less stable, designed perhaps to adapt, and modify in response to environmental needs. The proposed model infers that the number of pyramidal cells contacted by each local-circuit interneuron as well as the number of synaptic contacts established with each one are elements acquired post-natally in response to individual needs. Thereby, the overall three-dimensional distribution and extent of these pyramidal/local-circuit neuronal assemblages should be species-specific, variable among individual of the same species, and able to adapt in response to environmental needs. The model introduces a different approach, perhaps a new vantage point, for the study of the basic structural organization of the mammalian cerebral cortex. Relationships of the proposed model to cortical function in general and to learning behavior in particular are discussed.


Anopheles Imd pathway factors and effectors in infection intensity-dependent anti-Plasmodium action.
The Anopheles gambiae immune response against Plasmodium falciparum, an etiological agent of human malaria, has been identified as a source of potential anti-Plasmodium genes and mechanisms to be exploited in efforts to control the malaria transmission cycle. One such mechanism is the Imd pathway, a conserved immune signaling pathway that has potent anti-P. falciparum activity. Silencing the expression of caspar, a negative regulator of the Imd pathway, or over-expressing rel2, an Imd pathway-controlled NFkappaB transcription factor, confers a resistant phenotype on A. gambiae mosquitoes that involves an array of immune effector genes. However, unexplored features of this powerful mechanism that may be essential for the implementation of a malaria control strategy still remain. Using RNA interference to singly or dually silence caspar and other components of the Imd pathway, we have identified genes participating in the anti-Plasmodium signaling module regulated by Caspar, each of which represents a potential target to achieve over-activation of the pathway. We also determined that the Imd pathway is most potent against the parasite's ookinete stage, yet also has reasonable activity against early oocysts and lesser activity against late oocysts. We further demonstrated that caspar silencing alone is sufficient to induce a robust anti-P. falciparum response even in the relative absence of resident gut microbiota. Finally, we established the relevance of the Imd pathway components and regulated effectors TEP1, APL1, and LRIM1 in parasite infection intensity-dependent defense, thereby shedding light on the relevance of laboratory versus natural infection intensity models. Our results highlight the physiological considerations that are integral to a thoughtful implementation of Imd pathway manipulation in A. gambiae as part of an effort to limit the malaria transmission cycle, and they reveal a variety of previously unrecognized nuances in the Imd-directed immune response against P. falciparum.


Surveillance for central-line-associated bloodstream infections: Accuracy of different sampling strategies.
Active daily surveillance of central-line days (CLDs) in the assessment of rates of central-line-associated bloodstream infections (CLABSIs) is time-consuming and burdensome for healthcare workers. Sampling of denominator data is a method that could reduce the time necessary to conduct active surveillance. To evaluate the accuracy of various sampling strategies in the estimation of CLABSI rates in adult and pediatric units in Greece. Daily denominator data were collected across Greece for 6 consecutive months in 33 units: 11 adult units, 4 pediatric intensive care units (PICUs), 12 neonatal intensive care units (NICUs), and 6 pediatric oncology units. Overall, 32 samples were evaluated using the following strategies: (1) 1 fixed day per week, (2) 2 fixed days per week, and (3) 1 fixed week per month. The CLDs for each month were estimated as follows: (number of sample CLDs/number of sampled days) × 30. The estimated CLDs were used to calculate CLABSI rates. The accuracy of the estimated CLABSI rates was assessed by calculating the percentage error (PE): [(observed CLABSI rates - estimated CLABSI rates)/observed CLABSI rates]. Compared to other strategies, sampling over 2 fixed days per week provided the most accurate estimates of CLABSI rates for all types of units. Percentage of estimated CLABSI rates with PE ≤±5% using the strategy of 2 fixed days per week ranged between 74.6% and 88.7% in NICUs. This range was 79.4%-94.1% in pediatric onology units, 62.5%-91.7% in PICUs, and 80.3%-92.4% in adult units. Further evaluation with intraclass correlation coefficients and Bland-Altman plots indicated that the estimated CLABSI rates were reliable. Sampling over 2 fixed days per week provides a valid alternative to daily collection of CLABSI denominator data. Adoption of such a monitoring method could be an important step toward better and less burdensome infection control and prevention.


An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice.
Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects ∼10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in ∼65% of patients, and may be associated with endocrine and metabolic disorders including: primary hyperparathyroidism, hypercalciuria, renal tubular acidosis, cystinuria, and hyperoxaluria. Investigations of families with nephrolithiasis and nephrocalcinosis have identified some causative genes, but further progress is limited as large families are unavailable for genetic studies. We therefore embarked on establishing mouse models for hereditary nephrolithiasis and nephrocalcinosis by performing abdominal X-rays to identify renal opacities in N-ethyl-N-nitrosourea (ENU)-mutagenized mice. This identified a mouse with RCALC inherited as an autosomal dominant trait, designated RCALC type 2 (RCALC2). Genomewide mapping located the Rcalc2 locus to a ∼16-Mbp region on chromosome 11D-E2 and whole-exome sequence analysis identified a heterozygous mutation in the DNA polymerase gamma-2, accessory subunit (Polg2) resulting in a nonsense mutation, Tyr265Stop (Y265X), which co-segregated with RCALC2. Kidneys of mutant mice (Polg2+/Y265X ) had lower POLG2 mRNA and protein expression, compared to wild-type littermates (Polg2+/+ ). The Polg2+/Y265X and Polg2+/+ mice had similar plasma concentrations of sodium, potassium, calcium, phosphate, chloride, urea, creatinine, glucose, and alkaline phosphatase activity; and similar urinary fractional excretion of calcium, phosphate, oxalate, and protein. Polg2 encodes the minor subunit of the mitochondrial DNA (mtDNA) polymerase and the mtDNA content in Polg2+/Y265X kidneys was reduced compared to Polg2+/+ mice, and cDNA expression profiling revealed differential expression of 26 genes involved in several biological processes including mitochondrial DNA function, apoptosis, and ubiquitination, the complement pathway, and inflammatory pathways. In addition, plasma of Polg2+/Y265X mice, compared to Polg2+/+ littermates had higher levels of reactive oxygen species. Thus, our studies have identified a mutant mouse model for inherited renal calcification associated with a Polg2 nonsense mutation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.


Bed occupancy, turnover intervals and MRSA rates in English hospitals.
This article (a follow on from an article concentrating on Northern Ireland) examines the relationship between percentage bed occupancy (PO), turnover interval (TI) and methicillin-resistant Staphylococcus aureus (MRSA) rates in the acute beds of specialist English hospital trusts and describes the TI and levels of bed occupancy. The data were collected from publicly available data: MRSA rates of blood-borne infection per 1000 bed days from the Department of Health; average length of stay from Hospital Episode Statistics; and percentage occupancy from the Department of Health Hospital Activity statistics were used. Pearson's Correlation coefficients were used as basis for inferential analysis. The mean TI for all trusts was as 0.94 days, median 0.95 days. Twenty percent of trusts had TIs, on average, of less than 0.58 days (13.9 hours) and 10% had a TI less than 0.32 days (7.6 hours). The mean PO was 84.98% and the median was 84.76%. Seventy percent of the trusts exceeded the recommended 82% bed occupancy. The inference from this study is that there is a relationship between TI and PO and rate of MRSA infection in specialist English hospitals and that PO rates are at a level which may interfere with good infection control procedures.


Comparative evaluation of the influence of television advertisements on children and caries prevalence.
Children watch television during most of their free time. They are exposed to advertisers' messages and are vulnerable to sophisticated advertisements of foods often detrimental to oral and general health. To evaluate the influence of television advertisements on children, the relationship with oral health and to analyze the content of those advertisements. A questionnaire-based study was performed among 600 schoolchildren of Mangalore, Karnataka, followed by oral examination. Based on the survey, favorite and non-favorite channels and viewing times were analyzed. Advertisements on children's favorite and non-favorite channels were then viewed, analyzed, and compared. Higher caries prevalence was found among children who watched television and asked for more food and soft drinks. Cariogenic food advertisements were popular on children's favorite channels. Television advertisements may strongly influence children's food preferences and eating habits, resulting in higher caries prevalence. Advertisements regarding healthy food, oral hygiene maintenance, prevention of diseases such as caries should be given priority for the benefit of the health of children.


Microscopic polyarteritis: presentation, pathology and prognosis.
We have described 34 patients with microscopic polyarteritis, all of whom had clinical evidence of a systemic small vessel vasculitis predominantly affecting the skin and musculoskeletal systems accompanied by a focal necrotising glomerulonephritis with renal impairment. Thirty three patients received immunosuppressive treatment, comprising prednisolone, azathioprine, cyclophosphamide and plasma exchange in various combinations. The five-year actuarial patient and kidney survival rates were 65 and 55 per cent respectively, suggesting that aggressive immunosuppressive therapy in these patients is beneficial.


Toxicological and chemical assessment of ordinance compounds in marine sediments and porewaters.
Toxicological and chemical studies were performed with a silty and a sandy marine sediment spiked with 2,6-dinitrotoluene (2,6-DNT), 2,4,6-trinitrophenylmethylnitramine (tetryl), or 2,4,6-trinitrophenol (picric acid). Whole sediment toxicity was analyzed by the 10-day survival test with the amphipod Ampelisca abdita, and porewater toxicity tests assessed macro-algae (Ulva fasciata) zoospore germination and germling growth, sea urchin (Arbacia punctulata) embryological development, and polychaete (Dinophilus gyrociliatus) survival and reproduction. Whole sediments spiked with 2,6-DNT were not toxic to amphipods. The fine-grained sediment spiked with tetryl was also not acutely toxic. The tetryl and picric acid LC50 values in the sandy sediment were 3.24 and 144 mg/kg dry weight, respectively. The fine-grained sediment spiked with picric acid generated a U-shaped concentration-response curve in the amphipod test, with increased survival both in the lowest and highest concentration. Grain-size distribution and organic carbon content strongly influenced the behavior of ordnance compounds in spiked sediments. Very low concentrations were measured in some of the treatments and irreversible binding and biodegradation are suggested as the processes responsible for the low measurements. Porewater toxicity varied with its sedimentary origin and with ordnance compound. The sea urchin embryological development test tended to be the least sensitive. Tetryl was the most toxic chemical in all porewater tests, and picric acid the least toxic. Samples spiked with 2,6-DNT contained a degradation product identified as 2-methyl-3-nitroaniline (also known as 2-amino-6-nitrotoluene), and unidentified peaks, possibly degradation products, were also seen in some of the picric acid- and tetryl-spiked samples. Degradation products may have played a role in observed toxicity.


In vitro expansion of the mammary stem/progenitor cell population by xanthosine treatment.
Mammary stem cells are critical for growth and maintenance of the mammary gland and therefore are of considerable interest for improving productivity and efficiency of dairy animals. Xanthosine treatment has been demonstrated to promote expansion of putative mammary stem cells in vivo, and hepatic and hair follicle stem cells in vitro. In the latter, xanthosine promoted the symmetrical division of hepatic and hair follicle stem cells. The objective of this study was to determine if treating primary cultures of bovine mammary epithelial cells (MEC) with xanthosine increases the stem/progenitor cell population by promoting symmetrical division of mammary stem cells. In vitro treatment with xanthosine increased the population of MEC during the exponential phase of cell growth, reducing the doubling time from 86 h in control cultures to 60 h in xanthosine-treated cultures. The bromodeoxyuridine (BrdU) labeling index and the proportion of MEC in S-phase both were increased by xanthosine treatment, indicating that increased cell accretion was due to increased cell proliferation. Analysis of daughter-pairs indicated that xanthosine promoted a shift from asymmetric to symmetric cell division. Moreover, the 30 % increase in symmetric cell division was concomitant with an increase in the proportion of MEC that were positive for a putative stem cell marker (FNDC3B) and a trend toward increased telomerase activity. These results suggest that xanthosine treatment in vitro can increase cell proliferation, promote symmetric cell division and enhance stem/progenitor cell activity. Xanthosine treatment increased the proliferation rate of bovine MEC in vitro. This was likely to be mediated by an increase in the proportion of stem/progenitor cells in the MEC population due to promotion of symmetrical stem cell division by xanthosine.


CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity.
We have shown in a murine model system for acute, lethal cytomegalovirus (CMV) disease in the immunocompromised natural host that control of virus multiplication in tissues, protection from virus-caused tissue destruction, and survival are mediated by virus-specific CD8+ CD4-T lymphocytes. Protection from a lethal course of disease did not result in a rapid establishment of virus latency, but led to a long-lasting, persistent state of infection. The CD8- CD4+ subset of T lymphocytes was not effective by itself in controlling murine CMV (MCMV) multiplication in tissue or essential for the protective function of the CD8+ CD4- effector cells. The antiviral efficacy of the purified CD8+ CD4- subset was not impaired by preincubation with fibroblasts that presented viral structural antigens, but was significantly reduced after depletion of effector cells specific for the nonstructural immediate-early antigens of MCMV, which are specified by the first among a multitude of viral genes expressed during MCMV replication in permissive cells. Thus, MCMV disease provides the first example of a role for nonstructural herpesvirus immediate-early antigens in protective immunity.


Linear geometric ICA: fundamentals and algorithms.
Geometric algorithms for linear independent component analysis (ICA) have recently received some attention due to their pictorial description and their relative ease of implementation. The geometric approach to ICA was proposed first by Puntonet and Prieto (1995). We will reconsider geometric ICA in a theoretic framework showing that fixed points of geometric ICA fulfill a geometric convergence condition (GCC), which the mixed images of the unit vectors satisfy too. This leads to a conjecture claiming that in the nongaussian unimodal symmetric case, there is only one stable fixed point, implying the uniqueness of geometric ICA after convergence. Guided by the principles of ordinary geometric ICA, we then present a new approach to linear geometric ICA based on histograms observing a considerable improvement in separation quality of different distributions and a sizable reduction in computational cost, by a factor of 100, compared to the ordinary geometric approach. Furthermore, we explore the accuracy of the algorithm depending on the number of samples and the choice of the mixing matrix, and compare geometric algorithms with classical ICA algorithms, namely, Extended Infomax and FastICA. Finally, we discuss the problem of high-dimensional data sets within the realm of geometrical ICA algorithms.


Household food insecurity associated with stunting and underweight among preschool children in Antioquia, Colombia.
To assess criterion validity of a household food security scale through its associations with child health status in participants of the Colombian Plan for Improving Food and Nutrition in Antioquia (Mejoramiento Alimentario y Nutricional de Antioquia (MANA)). A 12-item household food security survey (Colombian Household Food Security Scale, CHFSS) was applied to a cross-sectional stratified random sample of 2 784 low-income households with preschool children receiving MANA food supplements in Antioquia, Colombia. Anthropometrics and health status of the children were also assessed. Chi-square tests were used to initially compare child health status and household food security status. Logistic regression models were further developed to assess this relationship in bivariate and multiple regression models. Statistically significant associations were found between household food insecurity and diagnoses of children's diarrhea, respiratory infections, and parasitosis (P < 0.0001). The risk for child stunting and underweight increased in a dose-response way as food insecurity became more severe. Our research establishes an important link between household food insecurity and child nutritional status in participants of a food assistance program. The results affirm the criterion validity of the CHFSS, establishing the proposed instrument as a valid measure for food insecurity with high-risk populations.


The novel compound MP407 inhibits platelet aggregation through cyclic AMP-dependent processes.
Platelet hyperactivity plays a critical role for initiating several vascular diseases such as atherothrombosis. Therefore, development of effective antiplatelet agents is necessary for ameliorating platelet-related diseases. In this study, we investigated the effects of the new synthesized compound, MP407 on platelet aggregation and further elucidated the underlying mechanisms. Our results demonstrated that MP407 dose-dependently inhibited collagen-induced platelet aggregation, thromboxane B2 (TXB2) production, intracellular Ca2+ mobilization, platelet membrane GPIIb/IIIa expression, and the phosphorylation of Akt, GSK3β, p38MAPK, and phospho (Ser) PKC substrate (p47). Moreover, MP407 is able to increase the cyclic AMP formation both in resting and activated platelets. However, blocking cyclic AMP formation with 2'5'-ddAdo, an inhibitor of adenylate cyclase, greatly reversed the antiplatelet activity of MP407 and related platelet-activating pathways. MP407 also enhanced VASP phosphorylation at Ser157 in collagen-stimulated platelets, which was attenuated by addition of 2'5'-ddAdo. Therefore, the antiplatelet activity of MP407 may be modulated by cyclic AMP-dependent regulation of Akt, GSK3β, p38MAPK and VASP phosphorylation. Notably, treatment with MP407 markedly reduced the pulmonary thrombosis and the numbers of paralysis and death in mice induced by ADP injection, but did not affect the bleeding time. Taken together, MP407 may be a potential candidate or lead compound for developing novel antiplatelet or antithrombotic agents for platelet hyperactivity-triggered disease therapy.


Characterization of the Distribution of Pyrene Molecules in Confined Geometries with the Model Free Analysis.
Evidence is provided showing that global Model Free Analysis (MFA) of monomer and excimer fluorescence decays of pyrene dissolved in aqueous solutions of sodium dodecyl sulfate (SDS) provides the same structural and dynamic information on SDS micelles as the well-established Micelle Model (MM) does. Both MFA and MM were employed to characterize the quenching kinetics between dyes and quenchers located in surfactant micelles and the aggregation number of surfactant micelles. However, contrary to the MM, which assumes that dyes and quenchers distribute themselves among SDS micelles according to a Poisson distribution and react with a rate constant that is proportional to the number of reactants in a micelle, the MFA accomplishes this task without making any assumption about the process of pyrene excimer formation in SDS micelles. The ability of the MFA to retrieve accurately the molar fraction of pyrene molecules that are isolated in SDS micelles and do not form excimers was taken advantage of to establish that it equaled the Poisson probability of exciting micelles that contained a single pyrene. The molar fraction of isolated pyrenes could then be utilized to determine the aggregation number of the SDS micelles, and the rate constant of excimer formation between one excited- and one ground-state pyrene located inside a same micelle. Within experimental error, both the MFA and MM yielded the same micelle aggregation number and rate constant of excimer formation, with the MFA making no prior assumptions about the physical principles underlying the process of excimer formation contrary to the MM. The ability of the MFA to retrieve quantitative parameters providing structural and dynamic information about macromolecular systems with no prior knowledge about their architecture or labeling scheme implies that it can be applied to characterize a wide range of macromolecular architectures in solution.


Why, and how, mixed methods research is undertaken in health services research in England: a mixed methods study.
Recently, there has been a surge of international interest in combining qualitative and quantitative methods in a single study--often called mixed methods research. It is timely to consider why and how mixed methods research is used in health services research (HSR). Documentary analysis of proposals and reports of 75 mixed methods studies funded by a research commissioner of HSR in England between 1994 and 2004. Face-to-face semi-structured interviews with 20 researchers sampled from these studies. 18% (119/647) of HSR studies were classified as mixed methods research. In the documentation, comprehensiveness was the main driver for using mixed methods research, with researchers wanting to address a wider range of questions than quantitative methods alone would allow. Interviewees elaborated on this, identifying the need for qualitative research to engage with the complexity of health, health care interventions, and the environment in which studies took place. Motivations for adopting a mixed methods approach were not always based on the intrinsic value of mixed methods research for addressing the research question; they could be strategic, for example, to obtain funding. Mixed methods research was used in the context of evaluation, including randomised and non-randomised designs; survey and fieldwork exploratory studies; and instrument development. Studies drew on a limited number of methods--particularly surveys and individual interviews--but used methods in a wide range of roles. Mixed methods research is common in HSR in the UK. Its use is driven by pragmatism rather than principle, motivated by the perceived deficit of quantitative methods alone to address the complexity of research in health care, as well as other more strategic gains. Methods are combined in a range of contexts, yet the emerging methodological contributions from HSR to the field of mixed methods research are currently limited to the single context of combining qualitative methods and randomised controlled trials. Health services researchers could further contribute to the development of mixed methods research in the contexts of instrument development, survey and fieldwork, and non-randomised evaluations.


Evaluation of serologic and viral detection methods for diagnosing feline herpesvirus-1 infection in cats with acute respiratory tract or chronic ocular disease.
To determine the value of virus isolation (VI), immunofluorescent antibody (IFA) assay, serum neutralization (SN), and ELISA for the diagnosis of clinical feline herpesvirus-1 (FHV-1) infection in cats. 46 clinically normal cats, 17 cats with signs of acute respiratory tract disease, and 38 cats with signs of chronic ocular disease. Conjunctival swabs for VI, conjunctival scrapings for IFA testing, and venous blood samples for SN or ELISA testing were obtained from all cats. FHV-1 was detected in 10.9 and 28.3% of clinically normal cats and in 18.2 and 33.3% of cats with FHV-1-associated disease by VI and the IFA assay, respectively. There were no significant differences in the viral detection rate between cats with acute respiratory tract disease and cats with chronic ocular disease or between diseased cats and clinically normal cats; however, FHV-1 was never detected by both methods in clinically normal cats. Overall FHV-1 seroprevalence was 97% when tested by ELISA and 66% when tested by SN. Seroprevalence did not vary significantly among the 3 groups for either serologic test. Magnitude of SN and ELISA titers varied greatly but independently of presence or absence of clinical signs of FHV-1-associated disease. Sensitivity, specificity, and positive and negative predictive values were assessed for VI and the IFA assay--jointly and individually--and for each SN and ELISA titer magnitude. Values never all exceeded 50%. Because FHV-1 can be detected commonly in clinically normal cats by the IFA assay or VI, neither test appears to aid in the clinical diagnosis of FHV-1 infection. Seroprevalence does not appear to vary between affected and clinically normal cats. SN, ELISA, VI, and the IFA assay appear to be of limited value in the diagnosis of FHV-1-associated disease in cats. Concurrent assessment of the IFA assay and VI results may permit exclusion of FHV-1 as an etiologic agent if results of both tests are negative.


Sex-specific sibling interactions and offspring fitness in vertebrates: patterns and implications for maternal sex ratios.
Vertebrate sex ratios are notorious for their lack of fit to theoretical models, both with respect to the direction and the magnitude of the sex ratio adjustment. The reasons for this are likely to be linked to simplifying assumptions regarding vertebrate life histories. More specifically, if the sex ratio adjustment itself influences offspring fitness, due to sex-specific interactions among offspring, this could affect optimal sex ratios. A review of the literature suggests that sex-specific sibling interactions in vertebrates result from three major causes: (i) sex asymmetries in competitive ability, for example due to sexual dimorphism, (ii) sex-specific cooperation or helping, and (iii) sex asymmetries in non-competitive interactions, for example steroid leakage between fetuses. Incorporating sex-specific sibling interactions into a sex ratio model shows that they will affect maternal sex ratio strategies and, under some conditions, can repress other selection pressures for sex ratio adjustment. Furthermore, sex-specific interactions could also explain patterns of within-brood sex ratio (e.g. in relation to laying order). Failure to take sex-specific sibling interactions into account could partly explain the lack of sex ratio adjustment in accordance with theoretical expectations in vertebrates, and differences among taxa in sex-specific sibling interactions generate predictions for comparative and experimental studies.


Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia.
Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development. This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents. The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.


Devario in Bangladesh: Species diversity, sibling species, and introgression within danionin cyprinids (Teleostei: Cyprinidae: Danioninae).
Four species of Devario are recorded from Bangladesh: D. aequipinnatus, D. anomalus, D. coxi, new species, and D. devario. Devario aequipinnatus has a wide distribution in northern India and Bangladesh. Devario coxi, from southeastern Bangladesh near Cox's Bazar, differs from D. aequipinnatus in mtDNA (COI, p-distance 1.8%), colouration, proportional measurements, and meristics. The minor morphological differences and low frequency of overlapping meristics suggest relatively recent separation of D. coxi from other D. aequipinnatus. Devario anomalus occurs only in southeastern Bangladesh and is here reported from localities in addition to the type locality. It differs from the similar D. xyrops in adjacent Myanmar by slender body shape and by 2.3% p-distance in the COI gene. Specimens of D. anomalus from the Sangu River were found to have the mitochondrial genome of D. aequipinnatus from Bangladesh, but agree with other D. anomalus in the nuclear RAG1 gene. Devario devario has a wide distribution on the Indian Peninsula and border regions; in Bangladesh it is restricted in distribution to the Ganga, Brahmaputra, and Meghna drainages. Reports of D. assamensis and D. malabaricus from Bangladesh are misidentifications. Perilampus ostreographus M'Clelland, 1839, is tentatively synonymized with D. aequipinnatus. Phylogenetic analysis of 14 species of striped devarios based on the COI gene results in a polytomy with four unresolved clades. Devario deruptotalea from the Chindwin basin is the sister group of D. aequipinnatus+D. coxi. Devario devario is the sistergroup of D. xyrops+D. anomalus.


Precautions in the use of intensity-modulated radiation therapy.
Intensity-modulated radiation therapy (IMRT) represents a significant technological advancement in the ability to deliver highly conformal radiation therapy. Thanks to increased availability, general clinical implementation has become progressively more common. However, there are several precautions worthy of comment regarding the clinical applications of IMRT. In theory, the increased irradiated volume and leakage radiation that occasionally accompanies IMRT could contribute to unanticipated complications and safety concerns. The protracted delivery time of IMRT with the associated increased linac monitor units can result in photoactivation of elements within the linac collimator, thereby inadvertently increasing radiation exposure to patients and staff when high-energy photons are used. The increased volumes of normal tissue exposed to lower doses of radiation through IMRT theoretically could promote carcinogenesis and complications due to the bystander effect, low-dose hyper-radiosensitivity, and diminished repair of double strand DNA breaks at very low doses. Tumor control may be adversely affected by the lower radiation dose-rates of delivery sometimes associated with IMRT as well the occasionally seen low dose "cold shoulder" on the dose-volume histograms. Unusual clinical reactions can appear as a result of the complex, unfamiliar dose-distributions occasionally generated by IMRT treatment planning. Here we discuss some of the precautions worthy of consideration when using IMRT and how these might be addressed in routine practice.


Segmental Resection versus Total Proctocolectomy for Crohn's Colitis: What is the Best Operation in the Setting of Medically Refractory Disease or Dysplasia?
Crohn's disease (CD) may affect any part of the gastrointestinal tract. When isolated to the colon, and patients become medically refractory, there are several surgical options - segmental resection, subtotal colectomy with ileorectal anastomosis, or a total proctocolectomy and end ileostomy. Unfortunately, surgery does not cure CD, and, regardless of the extent of bowel removed, recurrence may be seen in the small bowel. This may lead to need for further immunosuppression or surgery. Therefore, when appropriate, a segmental colectomy or subtotal colectomy may prevent a permanent ostomy required with a total proctocolectomy. In the setting of dysplasia identified on colonoscopy, low quality evidence guides our treatment paradigms. Even though identification of dysplasia has greatly improved with chromoendoscopy, rates of synchronous or metachronous neoplasm remain high. Thus, a total proctocolectomy and end ileostomy, whereas a larger operation, may be best for the patient to remove all at risk tissue. Further research with prospective or randomized control trials is needed to improve our practice guidelines of both scenarios.


Trends in chronologic age and infant respiratory syncytial virus hospitalization: an 8-year cohort study.
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children and the leading cause of hospitalization in infants aged <1 year. We examined trends in RSV hospitalization (RSVH) among infants from 1998 to 2006, using the United States (US) National Hospital Discharge Survey (NHDS) database. RSVH was defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 079.6 (RSV), 466.11 (acute bronchiolitis due to RSV), and 480.1 (pneumonia due to RSV). Age at the time of hospitalization was determined using NHDS birth records; RSVH rates were analyzed for infants grouped into three age cohorts (<3 months, 3 to 6 months, and >6 to <24 months). Trends in hospitalization rates were evaluated using linear regression. Relative rates (RR) and 95% confidence intervals (CI) were computed to compare average RSVH rates for infants across age-specific groups. The annual proportion of RSVH by age group was also calculated. Approximately 1.1 million (90,000-147,000 per year) RSVHs in predominantly term children aged <24 months were analyzed. Compared with children aged >6 to <24 months, rates for RSVH were significantly higher among infants aged <3 months (RR, 7.38; 95% CI, 7.35-7.41) and infants aged 3 to 6 months (RR, 5.28; 95% CI, 5.26-5.29). The proportion of RSVH in the first year of life was lowest among infants aged <1 month (9%). [corrected] The greatest proportion of RSVH was observed in children aged 3 to 6 months (14%-23% RSVH per year; chi-square P<0.0001). When the definition of RSVH was expanded to include unspecified hospitalizations for acute bronchiolitis, similar results were observed. RRs were highest among the <3- month and 3- to 6-month age groups. The highest proportion of RSVH was among the 3- to 6-month age group. Analysis of the impact of RSV season, clinical practices, and other factors on these trends is warranted.


Serum anti-müllerian hormone levels in patients with epithelial ovarian cancer.
Objectives. The aim of our study was to examine serum anti-Müllerian hormone (AMH) concentration in ovarian cancer patients in relation to clinicopathological features, such as a pathological subtype of the tumor, (FIGO) stage, grading, and overall 5-year survival. Material and Methods. We enrolled 72 epithelial ovarian cancer patients in our study, aged 45-79 years, who underwent optimal cytoreductive surgery. In all patients, serum AMH concentration was measured using a two-step sandwich type enzyme immunoassay before surgery. As a reference value for women over 45 years we accepted anti-Müllerian hormone concentration below 1 ng/mL. Results. In the whole group of patients with ovarian cancer, median serum concentration of AMH was 0.07 (0.0-0.37) ng/mL, whereas in the group of those with positive AMH values (≥0.14 ng/mL) it was 0.31 (0.15-0.73) ng/mL. No significant correlation was found between serum AMH levels and FIGO stage, histological subtype, or grading (P > 0.05). The analysis of five-year survival rate related to AMH levels showed no statistically significant differences. There were no differences in survival rates between patients with positive or negative serum AMH levels. Conclusion. Measurement of serum anti-Müllerian hormone levels was not useful in predicting clinicopathological features and survival in patients with ovarian cancer.


[Predictors of return to work after occupational injury in a locomotive enterprise].
To identify the potential determinants of return to work (RTW) following work-related injury. A historical cohort of workers with occupational injury in a state-owned locomotive vehicle company in central China was followed up for RTW. Demographic, employment and medical information was retrieved from the company archival documents; and post-injury information was interviewed by questionnaires. Univariate analysis and Cox Regression Model were used to examine the associations between potential determinants and outcomes of RTW. Three hundred of the 323 included cases (92.9%) eventually returned to work after the median absence of 43 days (average of 49.2 days). Factors from socio-demographic, clinical, economic and psychological domains were found affecting RTW in the univariate analyses. The multivariate analysis indicated that age, injury severity, injury locus, injury nature, pain in the injury locus, self-reported health status and pre-injury monthly salary were significant determinants of RTW. There are multidimensional factors affecting RTW after occupational injury. Proper clinical treatment and rehabilitation, as well as economic and social support to facilitate workers' RTW would be the priorities for intervention. Future studies should be conducted in a larger representative sample to confirm the findings and to develop a multidisciplinary intervention strategy towards promoting RTW.


A case report of truncus arteriosus communis and genetic counseling.
Truncus arteriosus communis (TAC) is a rare heart disorder with the prevalence of approximately 1%, mostly in male newborns. In this disease, aorta and pulmonary artery have not been separated during fetus development and both originate jointly from left ventricle. In addition, various disorders are reported like ventricular septal defect (VSD), mitral and tricuspid valves defects, aortic septal defect (ASD), reduction of lung and lung vessels' resistance, pulmonary hypertension, increase in heart rate, high perspiration, bad digestion, and tetralogy of Fallot. Parents of deceased patient were referred for genetic counseling after the death of third girl due to severe cardiac disorder. Cardiologist declared the disease in deceased girl as TAC based on findings along with VSD, ASD and hypoplastic aortic arch which resulted to death in the first day of birth. There was no chromosomal disorder in chromosome analysis of patient' skin. Parents were interested to have another child, so they were referred to university's Genetic Counseling Center to become aware of their next child's condition. This disorder is genetically heterogeneous and multifactorial and because all external factors are not recognized, the accurate estimation of risk is not possible and the probability of risk for the next child is about 10% to 20%.