Prevalence and treatment of opioid use disorders among primary care patients in six health systems.
The U.S. experienced nearly 48,000 opioid overdose deaths in 2017. Treatment of opioid use disorder (OUD) with buprenorphine is a recommended part of primary care, yet little is known about current U.S. practices in this setting. This observational study reports the prevalence of documented OUD and OUD treatment with buprenorphine among primary care patients in six large health systems. Adults with ≥2 primary care visits during a three-year period (10/1/2013-9/30/2016) in six health systems were included. Data were obtained from electronic health record and claims data, with measures, assessed over the three-year period, including indicators for documented OUD from ICD 9 and 10 codes and OUD treatment with buprenorphine. The prevalence of OUD treatment was adjusted for age, gender, race/ethnicity, and health system. Among 1,368,604 primary care patients, 13,942 (1.0 %) had documented OUD, and among these, 21.0 % had OUD treatment with buprenorphine. For those with documented OUD, the adjusted prevalence of OUD treatment with buprenorphine varied across demographic and clinical subgroups. OUD treatment was lower among patients who were older, women, Black/African American and Hispanic (compared to white), non-commercially insured, and those with non-cancer pain, mental health disorders, greater comorbidity, and more opioid prescriptions, emergency department visits or hospitalizations. Among primary care patients in six health systems, one in five with an OUD were treated with buprenorphine, with disparities across demographic and clinical characteristics. Less buprenorphine treatment among those with greater acute care utilization highlights an opportunity for systems-level changes to increase OUD treatment.


Comprehensive analysis of syndromic hearing loss patients in Japan.
More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.


Chemical and radioactive carcinogens in cigarettes: associated health impacts and responses of the tobacco industry, U.S. Congress, and federal regulatory agencies.
²¹⁰Po and ²¹⁰Pb were discovered in tobacco in 1964. This was followed by detailed assessments of the nature of their deposition, and accompanying dose rates to the lungs of cigarette smokers. Subsequent studies revealed: (1) the sources and pathways through which they gain access to tobacco; (2) the mechanisms through which they preferentially deposit in key segments of the bronchial epithelium; and (3) the fact that the accompanying alpha radiation plays a synergistic role in combination with the chemical carcinogens, to increase the fatal cancer risk coefficient in cigarette smokers by a factor of 8 to 25. Nonetheless, it was not until 2009 that Congress mandated that the Food and Drug Administration require that the cigarette industry reveal the presence of these carcinogens. In the meantime, cigarette smoking has become not only the number one source of cancer deaths in the United States, but also a major contributor to heart disease and other health impacts. If the latter effects are included, smoking is estimated to have caused an average of 443,000 deaths and 5.1 million years of potential life lost among the U.S. population each year from 2000 through 2004. The estimated associated collective dose is more than 36 times that to the workers at all the U.S. nuclear power plants, U.S. Department of Energy nuclear weapons facilities, and crews of all the vessels in the U.S. Nuclear Navy. This unnecessary source of lung cancer deaths demands the utmost attention of the radiation protection and public health professions.


TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus.
Sensitization of esophageal sensory afferents by inflammatory mediators plays an important role in esophageal nociception. We have shown esophageal mast cell activation induces long-lasting mechanical hypersensitivity in vagal nodose C-fibers. However, the roles of mast cell mediators and downstream ion channels in this process are unclear. Mast cell tryptase via protease-activated receptor 2 (PAR2)-mediated pathways sensitizes sensory nerves and induces hyperalgesia. Transient receptor potential A1 (TRPA1) plays an important role in mechanosensory transduction and nociception. Here we tested the hypothesis that mast cell activation via a PAR2-dependent mechanism sensitizes TRPA1 to induce mechanical hypersensitivity in esophageal vagal C-fibers. The expression profiles of PAR2 and TRPA1 in vagal nodose ganglia were determined by immunostaining, Western blot, and RT-PCR. Extracellular recordings from esophageal nodose neurons were performed in ex vivo guinea pig esophageal-vagal preparations. Action potentials evoked by esophageal distention and chemical perfusion were compared. Both PAR2 and TRPA1 expressions were identified in vagal nodose neurons by immunostaining, Western blot, and RT-PCR. Ninety-one percent of TRPA1-positive neurons were of small and medium diameters, and 80% coexpressed PAR2. Esophageal mast cell activation significantly enhanced the response of nodose C-fibers to esophageal distension (mechanical hypersensitivity). This was mimicked by PAR2-activating peptide, which sustained for 90 min after wash, but not by PAR2 reverse peptide. TRPA1 inhibitor HC-030031 pretreatment significantly inhibited mechanical hypersensitivity induced by either mast cell activation or PAR2 agonist. Collectively, our data provide new evidence that sensitizing TRPA1 via a PAR2-dependent mechanism plays an important role in mast cell activation-induced mechanical hypersensitivity of vagal nodose C-fibers in guinea pig esophagus.


Urinary kallikrein excretion and plasma renin activity in patients with essential hypertension and primary aldosteronism.
1. The 24 h urinary excretion of kallikrein has been studied in 40 normotensive control subjects and in 74 age-matched patients with essential hypertension under similar conditions. By use of the renin-sodium index, hypertensive patients were divided into two subgroup: low-renin hypertension and normal-renin hypertension patients. Urinary kallikrein determinations were also obtained from six hypertensive patients with primary aldosteronism. 2. Urinary kallikrein was significantly lower both in patients with normal-renin and low-renin essential hypertension. Urinary kallikrein excretion was very high in the patients with primary aldosteronism. 3. In nine hypertensive patients beta-adreno-receptor-blocking therapy caused a significant decrease of plasma renin activity, but had no significant effect on urinary kallikrein excretion. 4. The results support the concept that low urinary kallikrein is likely to be a marker of essential hypertension. Under certain conditions its excretion is positively related to mineralocorticoid hormone concentrations but it is not primarily related to the renin-angiotensin system.


A blended intervention to promote physical activity, health and work productivity among office employees using intervention mapping: a study protocol for a cluster-randomized controlled trial.
Regular participation in moderate-to-vigorous physical activity (MVPA) is related to decreased risk of morbidity and mortality. Among working populations, lack of MVPA may also be a risk factor for absenteeism and presenteeism. Both traditional workplace-based and web-based interventions have been suggested as being effective in promoting participation MVPA, health-related outcomes, and work-related productivity. However, several challenges limit their application in real world contexts. A 'blended' intervention approach combining the two intervention strategies is proposed to overcome these limitations. The proposed intervention aims to utilize the blended approach to increase participation in MVPA, health-related outcomes, and work productivity among inactive workers. The study will comprise of a three-group cluster randomized controlled trial (cluster-RCT), comprising a three-month actual intervention and a nine-month behavioral follow-up period. The three groups will be: a web-based intervention group, a blended intervention group combining the web-based components with face-to-face workshops and posters, and a control group. Physically inactive office employees (N = 495) from 33 companies (i.e., clusters) will be recruited and randomly assigned to the three groups by cluster randomization. The intervention mapping (IM) framework will be used for selecting and applying effective health behavioral theories and behavioral change techniques (BCTs) to the development, implementation and assessment of the intervention, which will be personally tailored. The primary outcome variable will be objectively-measured MVPA using an accelerometer. Secondary outcomes will consist of indices of health including adiposity, blood pressure, blood sugar, blood lipids, self-reported depression, anxiety, stress, health-related quality of life and work-related variables including absenteeism and presenteeism. The proposed study adopts a robust blended intervention approach that is expected to overcome challenges in applying workplace-based and web-based interventions separately and yield larger effects in promoting MVPA participation, health-related outcomes and work productivity. Improvements in work productivity outcomes will be of particular interest to employers. If more effective, the new blended intervention has the potential to be implemented on a larger scale to benefit workplace populations. The trial is prospectively registered at the ClinicalTrials.gov PRS (Trial ID: NCT04391270; Date of First Posted: May 18, 2020).


Effects of intra-articular administration of lidocaine, mepivacaine, and the preservative methyl parahydroxybenzoate on synovial fluid biomarkers of horses.
To compare the extent of inflammation and catabolic collagen response in the middle carpal joints (MCJs) of healthy horses following intra-articular injection of 2% lidocaine, 2% mepivacaine, lactated Ringer solution (LRS), or 0.1% methyl parahydroxybenzoate. 17 adult horses. In the first of 2 experiments, the left middle carpal joint (MCJ) of each of 12 horses was injected with 10 mL of 2% lidocaine (n = 3), 2% mepivacaine (3), or LRS (control; 6). After a 4-week washout period, the right MCJ of the horses that received lidocaine or mepivacaine was injected with 10 mL of LRS, and the right MCJ of horses that received LRS was injected with 10 mL of 2% lidocaine (n = 3) or 2% mepivacaine (3). In experiment 2, the left MCJ of each of 5 horses was injected with 10 mL of 0.1% methyl parahydroxybenzoate. After a 48-hour washout period, the right MCJ of each horse was injected with 10 mL of LRS. Synovial fluid (SF) samples were aseptically collected before and at predetermined times after each injection. Synovial fluid WBC count, neutrophil percentage, and total protein, neutrophil myeloperoxidase, neutrophil elastase, and Coll2-1 concentrations were compared among treatments. Both lidocaine and mepivacaine induced SF changes indicative of inflammation and a catabolic collagen response, but the magnitude of those changes was more pronounced for lidocaine. Methyl parahydroxybenzoate did not cause any SF changes indicative of inflammation. Results suggested that mepivacaine was safer than lidocaine for intra-articular injection in horses.


Global priorities for marine biodiversity conservation.
In recent decades, many marine populations have experienced major declines in abundance, but we still know little about where management interventions may help protect the highest levels of marine biodiversity. We used modeled spatial distribution data for nearly 12,500 species to quantify global patterns of species richness and two measures of endemism. By combining these data with spatial information on cumulative human impacts, we identified priority areas where marine biodiversity is most and least impacted by human activities, both within Exclusive Economic Zones (EEZs) and Areas Beyond National Jurisdiction (ABNJ). Our analyses highlighted places that are both accepted priorities for marine conservation like the Coral Triangle, as well as less well-known locations in the southwest Indian Ocean, western Pacific Ocean, Arctic and Antarctic Oceans, and within semi-enclosed seas like the Mediterranean and Baltic Seas. Within highly impacted priority areas, climate and fishing were the biggest stressors. Although new priorities may arise as we continue to improve marine species range datasets, results from this work are an essential first step in guiding limited resources to regions where investment could best sustain marine biodiversity.


Application of a polymerase chain reaction-ELISA to detect Wuchereria bancrofti in pools of wild-caught Anopheles punctulatus in a filariasis control area in Papua New Guinea.
Chemotherapy-based eradication programs are aimed at stopping transmission of Wuchereria bancrofti by its obligatory mosquito vector. This study compares one year post-treatment W. bancrofti infection rates of Anopheles punctulatus, the main vector of lymphatic filariasis in Papua New Guinea, using traditional dissection techniques and a polymerase chain reaction (PCR)-based ELISA of a parasite-specific Ssp I repeat. A total of 633 mosquitoes in 35 batches were dissected. Six batches contained W. bancrofti-infected mosquitoes, giving a minimum infection rate of 0.9%. This value was not different than the actual infection rate, which was 9 (1.4%) of 633 mosquitoes (P = 0.48). The DNA was extracted from 47 pools containing a mean of 13.2 mosquitoes per pool. A total of 621 mosquitoes were processed for the PCR-ELISA, including 486 caught by human bait and 135 by light trap, which included both dead and live mosquitoes. Of 23 pools of alcohol-preserved human-bait mosquitoes, seven were positive by the PCR-ELISA, giving an infection rate identical to that obtained by dissection of individual mosquitoes (1.4%). The minimum infection rates for pools of light-trap mosquitoes found dead and alive were 2.7% (2 of 74) and 4.9% (3 of 61), respectively. These values did not differ from each other (P = 0.84), but the overall infection rate of light-trap mosquitoes was greater than that of mosquitoes captured by human bait (3.7% versus 1.4%; P = 0.09). These data indicate that the PCR-ELISA of a W. bancrofti Ssp I repeat using pools of mosquitoes is comparable to traditional dissection techniques for monitoring transmission intensity following introduction of mass chemotherapy. This approach may also be useful for rapid and cost-effective assessment of transmission in endemic areas where the frequency of overt lymphatic pathology is low.


Characterization of mcr-1-Harboring Plasmids from Pan Drug-Resistant Escherichia coli Strains Isolated from Retail Raw Chicken in South Korea.
A number of studies from different countries have characterized mcr-1-harboring plasmids isolated from food; however, nothing has been reported about it in South Korea. In this study, we report the characterization of mcr-1 plasmids from pan drug-resistant (PDR) Escherichia coli strains isolated from retail food in the country. Colistin-resistant E. coli strains were isolated from retail raw chicken, and PCR was carried out to detect the mcr-1 gene. Whole genome sequencing of the mcr-1-positive strains was performed for further characterization. The results of whole genome sequencing revealed that all mcr-1 plasmids belonged to the IncI2 type. In addition to the mcr-1 plasmids, all of the isolates also carried additional plasmids possessing multiple antibiotic resistance genes, and the PDR was mediated by resistant plasmids except for fluoroquinolone resistance resulting from mutations in gyrA and parC. Interestingly, the mcr-1 plasmids were transferred by conjugation to other pathogenic strains including enterohemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), Salmonella, and Klebsiella at the frequencies of 10-3-10-6, 10-2-10-5, 10-4-10-5, 10-4-10-6, and 10-5-10-6, respectively. The results showed that mcr-1 plasmids can be easily transmitted to pathogenic bacteria by conjugation.


A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer.
Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.


Absolute Quantification of Human Milk Caseins and the Whey/Casein Ratio during the First Year of Lactation.
Whey proteins and caseins in breast milk provide bioactivities and also have different amino acid composition. Accurate determination of these two major protein classes provides a better understanding of human milk composition and function, and further aids in developing improved infant formulas based on bovine whey proteins and caseins. In this study, we implemented a LC-MS/MS quantitative analysis based on iBAQ label-free quantitation, to estimate absolute concentrations of α-casein, β-casein, and κ-casein in human milk samples (n = 88) collected between day 1 and day 360 postpartum. Total protein concentration ranged from 2.03 to 17.52 with a mean of 9.37 ± 3.65 g/L. Casein subunits ranged from 0.04 to 1.68 g/L (α-), 0.04 to 4.42 g/L (β-), and 0.10 to 1.72 g/L (α-), with β-casein having the highest average concentration among the three subunits. Calculated whey/casein ratio ranged from 45:55 to 97:3. Linear regression analyses show significant decreases in total protein, β-casein, κ-casein, total casein, and a significant increase of whey/casein ratio during the course of lactation. Our study presents a novel and accurate quantitative analysis of human milk casein content, demonstrating a lower casein content than earlier believed, which has implications for improved infants formulas.


Importance of Multifaceted Approaches in Infection Control: A Practical Experience from an Outbreak Investigation.
This study presents the results of a multidisciplinary, nosocomial MRSA outbreak investigation in an 8-bed medical intensive care unit (ICU). The identification of seven MRSA positive patients in the beginning of 2014 led to the closure of the ward for several weeks. A multidisciplinary, retrospective investigation was initiated in order to identify the reason and the source for the outbreak, describe MRSA transmission in the department and identify limitations in infection control. The investigation comprised an epidemiological description of MRSA cases from 2012 to 2014 and a characterization of MRSA isolates, including phage-, spa- and PFGE-typing. Additionally, MRSA screening was performed from the hospital staff and the environment. To identify the reason for the outbreak, work-related, psychological and behavioral factors were investigated by impartial audits and staff interviews. Thirty-one MRSA cases were registered during the study period, and 36 isolates were investigated. Molecular typing determined the outbreak strain (phage type 54/812, PFGE type A4, spa type t003) and identified the probable index case. Nasal carriage in one employee and a high environmental contamination with the outbreak strain was documented. Important gaps in nursing procedures and general management were identified. Elevated stress levels and communication problems preceded the outbreak. Compliance with hand hygiene and isolation procedures was evaluated as appropriate. This study demonstrates the complexity of controlling hospital-associated infections. The combined use of different typing methods is beneficial for outbreak investigations. Psychological, behavioral and other work-related factors have an important impact on the spread of nosocomial pathogens. These factors should be addressed and integrated in routine infection control practice.


The staging value of sentinel lymph node biopsy for breast cancer: translating pathologic findings to clinical practice.
Axillary nodal status is an important prognostic factor in guiding locoregional and systemic treatment for breast cancer. Sentinel lymph node biopsy (SNB) has revolutionized axillary staging by replacing axillary lymph node dissection (ALND) in node-negative women. Even in select patients whose sentinel lymph nodes (SLNs) contain metastases, SNB alone has become an accepted method of managing the axilla. Identification of micrometastases through immunohistochemical analysis of SLNs that are tumorfree on hematoxylin and eosin staining (H&E) does not confer additional clinical benefit. The use of SNB after neoadjuvant chemotherapy (NAC) remains controversial. In addition to axillary nodal status, tumor biology plays an increasingly important role in guiding therapeutic decisions.


Effects of modifying the tRNA(3Lys) anticodon on the initiation of human immunodeficiency virus type 1 reverse transcription.
tRNA(3Lys) is a primer for reverse transcription in human immunodeficiency virus type 1 (HIV-1), and the anticodon of tRNA(3Lys) has been implicated in playing a role in both its placement onto the HIV-1 genome and its interaction with HIV-1 reverse transcriptase (RT). In this work, the anticodon in a tRNA(3Lys) gene was changed from UUU to CUA (tRNA(3Lys)Su+) or, in addition, G-73 was altered to A (tRNA(3Lys)Su+G73A). COS-7 cells were transfected with either wild-type or mutant tRNA(3Lys) genes, and both the wild-type and mutant tRNA(3Lys) produced were purified by using immobilized tRNA-specific hybridization probes. Each mutant tRNA(3Lys) was tested for its ability to prime reverse transcription in vitro, either alone or in competition with wild-type tRNA(3Lys). Short RT extensions of wild-type and mutant tRNALys could be distinguished from each other by their different mobilities in one-dimensional single-stranded conformation polymorphism polyacrylamide gel electrophoresis. These reverse transcription products show that heat-annealed tRNA(3Lys)Su+ has the same ability as heat-annealed wild-type tRNA(3Lys) to prime RT and competes equally well with wild-type tRNA(3Lys) for priming RT. tRNA(3Lys)Su+G73A has 60% of the wild-type ability to prime RT but competes poorly with wild-type tRNA(3Lys) for priming RT. However, the priming abilities of wild-type and mutant tRNA(3) are quite different when in vivo-placed tRNA is examined. HIV-1 produced in COS cells transfected with a plasmid containing both the HIV-1 proviral DNA and DNA coding for tRNA(3Lys)Su+ contains both endogenous, cellular wild-type tRNA(3Lys) and mutant tRNA(3Lys). When total viral RNA is used as the source of primer tRNA placed onto the genomic RNA in vivo, only wild-type tRNA(3Lys) is used as a primer. If the total viral RNA is first heated and exposed to hybridizing conditions, then both the wild-type and mutant tRNA(3Lys) act as primers for RT. These results indicate that the tRNA(3Lys)Su+ packaged into the virions is unable to act as a primer for RT, and a model is proposed to explain the disparate results between heat-annealed and in vivo-placed primer tRNA.


Smith-Lemli-Opitz syndrome.
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital malformation and intellectual disability syndrome, with clinical characteristics that encompass a wide spectrum and great variability. Elucidation of the biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol deficiency syndrome caused by mutation in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models, especially models of brain cells, would be useful, and in vivo human studies are also essential. Biomarker development will be crucial in facilitating clinical trials in this rare condition, because the clinical phenotype can change over many years. Additional research in these and other areas is critical if we are to make headway towards ameliorating the effects of this devastating condition.


Population rates of cardiac catheterization and yield of high-risk coronary artery disease.
The optimal population rate of cardiac catheterization is unknown. One potential way to determine it would be to examine whether there is a population rate beyond which the yield of high-risk coronary artery disease (CAD) does not rise. Using a detailed clinical registry that captures all patients undergoing cardiac catheterization in Alberta, we determined annual population rates of cardiac catheterization and the corresponding yield of cases of high-risk CAD in each of Alberta's 17 health regions from 1995 to 2002. Least squares linear regression analysis and hierarchical modelling methods were then used to assess the linear relation between catheterization rates and rates of high-risk CAD. The age-adjusted average rate of cardiac catheterization among men ranged from 404.9 to 638.1 per 100,000 population aged over 20 years. Among women, the average rate ranged from 171.8 to 314.0 per 100,000. For both sexes, increased regional rates of catheterization were associated with a linearly increasing yield of high-risk CAD, with no evidence of a plateau in yield when more procedures were performed. One additional case of high-risk CAD was identified for every 2.5 additional cardiac catheterization procedures performed among men, and for every 3.7 additional procedures performed among women. The increasing yield of patients with high-risk CAD associated with increased regional population rates of cardiac catheterization, together with the absence of a plateau in yield, suggests that Alberta's population rates of cardiac catheterization are suboptimal to detect people with high-risk CAD.


Electromyographic Profile of the Shoulder During Stability Exercises With Kettlebells.
Shoulder rehabilitation can be a difficult task due to the dynamic nature of the joint complex. Various weight training implements, including kettlebells (KB), have been utilized for therapeutic exercise in the rehabilitation setting to improve shoulder girdle strength and motor control. The KBs are unique in that they provide an unstable load and have been purported to promote greater muscle activation versus standard dumbbells. Recent literature has examined the efficacy of KB exercises for global strengthening and aerobic capacity; however, electromyographic data for shoulder-specific activities are lacking. To examine muscle activation patterns about the rotator cuff and scapular musculature during 5 commonly-utilized KB exercises. Cross-sectional analysis of a single group. Clinical biomechanics laboratory. Ten participants performed all exercises in a randomized order. Mean electromyographic values for each subject were compared between exercises for each target muscle. Significant differences (P < .05) between exercises were observed for all target muscles except for the infraspinatus. The data in this study indicates that certain KB exercises may elicit activation of the shoulder girdle at different capacities. Physical therapy practitioners, athletic trainers, and other clinical professionals who intend to optimize localized strengthening responses may elect to prescribe certain exercises over others due to the inherent difference in muscular utilization. Ultimately, this data may serve to guide or prioritize exercise selection to achieve higher levels of efficacy for shoulder strength and stability gains.


Risk of metabolic syndrome, cardiovascular disease, and diabetes in androgen deprivation therapy.
Men with prostate cancer may be at increased risk for metabolic syndrome, cardiovascular disease, and diabetes from androgen deprivation therapy (ADT). This article reviews current literature related to potential adverse effects of using ADT for localized prostate cancer. The use of gonadotropin-releasing hormone agonist therapy for prostate cancer in the early 1990s compared to the late 1990s is addressed. Oncology nurses play an important role in educating men about strategies for preventing and reducing side effects of cancer treatment. Therefore, having knowledge regarding the impact of hormone therapy on men's health will be important to prostate cancer survivors.


The use of cannabinoids for sleep: A critical review on clinical trials.
Cannabis and its pharmacologically active constituents, phytocannabinoids, have long been reported to have multiple medicinal benefits. One association often reported by users is sedation and subjective improvements in sleep. To further examine this association, we conducted a critical review of clinical studies examining the effects of cannabinoids on subjective and objective measures of sleep. PubMED, Web of Science, and Google Scholar were searched using terms and synonyms related to cannabinoids and sleep. Articles chosen included randomized controlled trials and open label studies. The Cochrane risk of bias tool was used to assess the quality of trials that compared cannabinoids with control interventions. The current literature focuses mostly on the use of tetrahydrocannabinol (THC) and/or cannabidiol (CBD) in the treatment of chronic health conditions such as multiple sclerosis, posttraumatic stress disorder (PTSD), and chronic pain. Sleep is often a secondary, rather than primary outcome in these studies. Many of the reviewed studies suggested that cannabinoids could improve sleep quality, decrease sleep disturbances, and decrease sleep onset latency. While many of the studies did show a positive effect on sleep, there are many limiting factors such as small sample sizes, examining sleep as a secondary outcome in the context of another illness, and relatively few studies using validated subjective or objective measurements. This review also identified several questions that should be addressed in future research. These questions include further elucidation of the dichotomy between the effects of THC and CBD, as well as identifying any long-term adverse effects of medicinal cannabinoid use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes.
In this work, the interaction of six natural benzo[c]phenanthridine alkaloids (macarpine, sanguilutine, sanguirubine, chelerythrine, sanguinarine and chelirubine) with parallel and antiparallel G-quadruplex DNA structures was studied. HT22 corresponding to the end of human telomeres and the modified promoter oncogene c-kit21 and Pu22 sequences have been used. Spectroscopically-monitored melting experiments and fluorescence titrations, competitive dialysis and nuclear magnetic resonance spectroscopy were used for this purpose. The results showed that these alkaloids stabilized G-quadruplex structures in terms of increments of Tm values (from 15 to 25 °C) with high selectivity over duplexes and unfolded DNA. The mode of binding was mainly by stacking on the terminal G-tetrads with stoichiometries of 1 : 2 (DNA : ligand). The presence of non-specific electrostatic interactions was also observed. Overall, the results pointed to a strong stabilization of G-quadruplex structures by these alkaloids.


Review of extensive workups of 34 patients overexposed to radiofrequency radiation.
The medical records of 34 patients seen at the Aerospace Medicine Directorate, U.S. Air Force Research Laboratory for confirmed exposure to radiofrequency radiation (RFR) exceeding the permitted exposure limits were reviewed to see if RFR overexposure created any detectable clinical or laboratory alterations that could be correlated with power density or the product of power density and time exposed. The goal of this study was to determine which physiological and laboratory parameters required closest attention on work up of future patients with RFR exposure. All 34 patients received an extensive history and physical examination, and a large battery of laboratory studies. Clinical findings were also compared with laboratory results. A sensation of warmth was positively associated with power density. A negative correlation was observed between an abnormal tissue destruction screen and power density. Sophisticated neurological tests in 23 patients and extensive psychometric and psychological exams in 30 patients revealed no neurological or ophthalmologic findings attributable to RFR. A few patients reported burning pain that resolved over several weeks; neurological findings were minimal or absent. Patients with suspected RFR overexposures need to be seen promptly at the nearest medical facility. Based on this study, an extensive evaluation of persons overexposed to non-ionizing radiation should not be routinely performed. However, a careful history and physical examination with laboratory studies as indicated should be performed and the patient's concerns about RFR effects addressed fully.


Unique properties of PTEN-L contribute to neuroprotection in response to ischemic-like stress.
Phosphatase and tensin homolog (PTEN) signalling might influence neuronal survival after brain ischemia. However, the influence of the less studied longer variant termed PTEN-L (or PTENα) has not been studied to date. Therefore, we examined the translational variant PTEN-L in the context of neuronal survival. We identified PTEN-L by proteomics in murine neuronal cultures and brain lysates and established a novel model to analyse PTEN or PTEN-L variants independently in vitro while avoiding overexpression. We found that PTEN-L, unlike PTEN, localises predominantly in the cytosol and translocates to the nucleus 10-20 minutes after glutamate stress. Genomic ablation of PTEN and PTEN-L increased neuronal susceptibility to oxygen-glucose deprivation. This effect was rescued by expression of either PTEN-L indicating that both PTEN isoforms might contribute to a neuroprotective response. However, in direct comparison, PTEN-L replaced neurons were protected against ischemic-like stress compared to neurons expressing PTEN. Neurons expressing strictly nuclear PTEN-L NLS showed increased vulnerability, indicating that nuclear PTEN-L alone is not sufficient in protecting against stress. We identified mutually exclusive binding partners of PTEN-L or PTEN in cytosolic or nuclear fractions, which were regulated after ischemic-like stress. GRB2-associated-binding protein 2, which is known to interact with phosphoinositol-3-kinase, was enriched specifically with PTEN-L in the cytosol in proximity to the plasma membrane and their interaction was lost after glutamate exposure. The present study revealed that PTEN and PTEN-L have distinct functions in response to stress and might be involved in different mechanisms of neuroprotection.


Gene promoter hypermethylation in tumors and serum of head and neck cancer patients.
Promoter hypermethylation is an important pathway for repression of gene transcription in cancer cells. We analyzed aberrant DNA methylation at four genes in primary tumors from 95 head and neck cancer patients and then used the presence of this methylation as a marker for cancer cell detection in serum DNA. These four genes were tested by methylation-specific PCR and included: p16 (CDKN2A), O6-methylguanine-DNA-methyltransferase, glutathione S-transferase P1, and death-associated protein kinase (DAP-kinase). Fifty-five % (52 of 95) of the primary tumors displayed promoter hypermethylation in at least one of the genes studied: 27% (26/95) at p16, 33% (31 of 95) at O6-methylguanine-DNA-methyltransferase; and 18% (17 of 92) at DAP-kinase. No promoter hypermethylation was observed at the glutathione S-transferase P1 gene promoter. We detected a statistically significant correlation between the presence of DAP-kinase gene promoter hypermethylation and lymph node involvement (P = 0.014) and advanced disease stage (P = 0.016). In 50 patients with paired serum available for epigenetic analysis, the same methylation pattern was detected in the corresponding serum DNA of 21 (42%) cases. Among the patients with methylated serum DNA, 5 developed distant metastasis compared with the occurrence of metastasis in only 1 patient negative for serum promoter hypermethylation (P = 0.056). Promoter hypermethylation of key genes in critical pathways is common in head and neck cancer and represents a promising serum marker for monitoring affected patients.


Constrained source space imaging: application to fast, region-based functional MRI.
A new technique called constrained source space imaging is introduced that holds promise for ultrafast acquisition of functional magnetic resonance imaging data. A sparse set of arbitrarily positioned, coarse voxels is first localized using radiofrequency selective excitation, from which magnetization signals are separated using only the spatial sensitivities of multichannel receiver coils, without the need for k-space encoding using imaging gradients. This method permits very fast acquisitions of targeted magnetization without complex or time-consuming image reconstruction techniques. Furthermore, because the data acquisition is performed without imaging gradients, T2* decays can be densely sampled and processed for contrast enhancement to improve functional magnetic resonance imaging data quality. Here, the constrained source space imaging technique is validated in proof-of-concept form, for a simple functional magnetic resonance imaging motor task using a prototype dual-band stimulated echo acquisition mode excitation to image four voxels at TR = 250 ms. Results demonstrate good voxel signal separation and good characterization of hemodynamic responses in primary motor cortices (M1) and supplementary motor areas through T2* fitting of the measured signals. With further refinement, the constrained source space imaging method has potential utility in a priori ROI-based functional magnetic resonance imaging experiments with TR values under 100 ms. Rapid, multivoxel measurements of other sources of MR signal contrast are also possible.


Participation and performance trends of East-African runners in Swiss half-marathons and marathons held between 2000 and 2010.
This study examined the changes in participation, performance and age of East African runners competing in half-marathons and marathons held in Switzerland between 2000 and 2010. Race times, sex, age and origin of East African versus Non-African finishers of half-marathon and marathon finishers were analyzed. Across time, the number of Kenyan and Ethiopian finishers remained stable (P > 0.05) while the number of Non-African finishers increased for both women and men in both half-marathons and marathons (P < 0.05). In half-marathons, the top ten African women (71 ± 1.4 min) and top three (62.3 ± 0.6 min) and top ten (62.8 ± 0.4 min) African men were faster than their Non-African counterparts (P < 0.05). In marathons, however, there was no difference in race times between the top three African men (130.0 ± 0.0 min) and women (151.7 ± 2.5 min) compared to Non-African men (129.0 ± 1.0 min) and women (150.7 ± 1.2 min) (P > 0.05). In half-marathons and marathons was no difference in age between the best Non-African and the best African runners (P > 0.05). During the last decade in Switzerland, the participation of Kenyan and Ethiopian runners in half- and full- marathons remained stable. In marathons there was no difference in age and performance between the top African and the top Non-African runners. Regarding half-marathons, the top African runners were faster but not younger than the top Non-African runners. Future insight should be gained by comparing the present results with participation, performance and age trends for East African runners competing in marathons held in larger countries.


Intramuscular tendon involvement on MRI has limited value for predicting time to return to play following acute hamstring injury.
Hamstring injury with intramuscular tendon involvement is regarded as a serious injury with a delay in return to play (RTP) of more than 50 days and reinjury rates up to 63%. However, this reputation is based on retrospective case series with high risk of bias. Determine whether intramuscular tendon involvement is associated with delayed RTP and elevated rates of reinjury. MRI of male athletes with an acute hamstring injury was obtained within 5 days of injury. Evaluation included standardised MRI scoring and scoring of intramuscular tendon involvement. Time to RTP and reinjury rate were prospectively recorded. Out of 70 included participants, intramuscular tendon disruption was present in 29 (41.4%) injuries. Injuries without intramuscular tendon disruption had a mean time to RTP of 22.2±7.4 days. Injuries with <50%, 50%-99% and 100% disruption of tendon cross-sectional area had a mean time to RTP of 24.0±9.7, 25.3±8.6 and 31.6±10.9 days, respectively. Injuries with full-thickness disruption took longer to RTP compared with injuries without disruption (p=0.025). Longitudinal intramuscular tendon disruption was not significantly associated with time to RTP. Waviness was present in 17 (24.3%) injuries. Mean time to RTP for injuries without and with waviness was 22.6±7.5 and 30.2±10.8 days (p=0.014). There were 11 (15.7%) reinjuries within 12 months, five (17.2%) in the group with intramuscular tendon disruption and six (14.6%) in the group without intramuscular tendon disruption. Time to RTP for injuries with full-thickness disruption of the intramuscular tendon and waviness is significantly longer (by slightly more than 1 week) compared with injuries without intramuscular tendon involvement. However, due to the considerable overlap in time to RTP between groups with and without intramuscular tendon involvement, its clinical significance for the individual athlete is limited.


Glycoprotein Acetyls: A Novel Inflammatory Biomarker of Early Cardiovascular Risk in the Young.
Background Low-grade inflammation in the young may contribute to the early development of cardiovascular disease. We assessed whether circulating levels of glycoprotein acetyls (GlycA) were better able to predict the development of adverse cardiovascular disease risk profiles compared with the more commonly used biomarker high-sensitivity CRP (C-reactive protein). Methods and Results A total of 3306 adolescents and young adults from the Avon Longitudinal Study of Parents and Children (mean age, 15.4±0.3; n=1750) and Cardiovascular Risk in Young Finns Study (mean age, 32.1±5.0; n=1556) were included. Baseline associations between inflammatory biomarkers, body composition, cardiovascular risk factors, and subclinical measures of vascular dysfunction were assessed cross-sectionally in both cohorts. Prospective risk of developing hypertension and metabolic syndrome during 9-to-10-year follow-up were also assessed as surrogate markers for future cardiovascular risk. GlycA showed greater within-subject correlation over 9-to-10-year follow-up in both cohorts compared with CRP, particularly in the younger adolescent group (r=0.36 versus 0.07). In multivariable analyses, GlycA was found to associate with multiple lifestyle-related cardiovascular disease risk factors, cardiometabolic risk factor burden, and vascular dysfunction (eg, mean difference in flow-mediated dilation=-1.2 [-1.8, -0.7]% per z-score increase). In contrast, CRP levels appeared predominantly driven by body mass index and showed little relationship to any measured cardiovascular risk factors or phenotypes. In both cohorts, only GlycA predicted future risk of both hypertension (risk ratio [RR], ≈1.1 per z-score increase for both cohorts) and metabolic syndrome (RR, ≈1.2-1.3 per z-score increase for both cohorts) in 9-to-10-year follow-up. Conclusions Low-grade inflammation captured by the novel biomarker GlycA is associated with adverse cardiovascular risk profiles from as early as adolescence and predicts future risk of hypertension and metabolic syndrome in up to 10-year follow-up. GlycA is a stable inflammatory biomarker which may capture distinct sources of inflammation in the young and may provide a more sensitive measure than CRP for detecting early cardiovascular risk.


HIV-1 infection alters the retinol-binding protein:transthyretin ratio even in the absence of the acute phase response.
The ratio of retinol-binding protein (RBP) to transthyretin (TTR) has been proposed as an indirect method with which to assess vitamin A status in the context of inflammation. Few studies have been conducted among adults, and none examined the effect of HIV-1 infection. Our goal was to assess the RBP:TTR ratio among adults, including the effects of HIV-1 and the acute phase response. We used data from a cross-sectional study of 600 Kenyan women, of whom 400 had HIV-1. The effect of vitamin A supplementation among the HIV-1-infected participants was subsequently assessed in a randomized trial. Among HIV-1-uninfected women without an acute phase response, a RBP:TTR cut-off value of 0.25 had approximately 80% sensitivity and specificity to detect vitamin A deficiency (retinol <0.70 micromol/L). No RBP:TTR cut-off value demonstrated both high sensitivity and specificity among HIV-1 infected women without evidence of inflammation. HIV-1 infection and advanced HIV-1 disease were associated with higher RBP:TTR ratios. The effect of HIV-1 was independent of the acute phase response, which also increased the RBP:TTR ratio. Serum retinol increased with vitamin A supplementation among those with a low RBP:TTR ratio, although the effect was small and was not present among those with concurrent inflammation. Thus, the RBP:TTR ratio has modest ability to predict vitamin A deficiency among healthy adults, but HIV-1 infection alters the ratio, even in the absence of the acute phase response. Our results raise questions about the utility of this measurement given the high prevalence of HIV-1 infection in areas where vitamin A deficiency is common.


The hairpin region of Ndc80 is important for the kinetochore recruitment of Mph1/MPS1 in fission yeast.
The establishment of proper kinetochore-microtubule attachments facilitates faithful chromosome segregation. Incorrect attachments activate the spindle assembly checkpoint (SAC), which blocks anaphase onset via recruitment of a cohort of SAC components (Mph1/MPS1, Mad1, Mad2, Mad3/BubR1, Bub1 and Bub3) to kinetochores. KNL1, a component of the outer kinetochore KMN network (KNL1/Mis12 complex/Ndc80 complex), acts as a platform for Bub1 and Bub3 localization upon its phosphorylation by Mph1/MPS1. The Ndc80 protein, a major microtubule-binding site, is critical for MPS1 localization to the kinetochores in mammalian cells. Here we characterized the newly isolated mutant ndc80-AK01 in fission yeast, which contains a single point mutation within the hairpin region. This hairpin connects the preceding calponin-homology domain with the coiled-coil region. ndc80-AK01 was hypersensitive to microtubule depolymerizing reagents with no apparent growth defects without drugs. Subsequent analyses indicated that ndc80-AK01 is defective in SAC signaling, as mutant cells proceeded into lethal cell division in the absence of microtubules. Under mitotic arrest conditions, all SAC components (Ark1/Aurora B, Mph1, Bub1, Bub3, Mad3, Mad2 and Mad1) did not localize to the kinetochore. Further genetic analyses indicated that the Ndc80 hairpin region might act as a platform for the kinetochore recruitment of Mph1, which is one of the most upstream SAC components in the hierarchy. Intriguingly, artificial tethering of Mph1 to the kinetochore fully restored checkpoint signaling in ndc80-AK01 cells, further substantiating the notion that Ndc80 is a kinetochore platform for Mph1. The hairpin region of Ndc80, therefore, plays a critical role in kinetochore recruitment of Mph1.


Aromatic ring strain in arylselenenyl bromides: role in facile synthesis of selenenate esters via intramolecular cyclization.
The synthesis and reactivity of 2,6-disubstituted arylselenium compounds derived from 2-bromo-5-tert-butylisophthalic acid (43) are described. The syntheses of bis(5-tert-butylisophthalic acid dimethyl ester)diselenide (46) and bis(5-tert-butylisophthalic acid diisopropyl ester)diselenide (47) have been achieved by the reaction of the corresponding ester precursors with disodium diselenide. Reduction of diselenide 46 with lithium aluminum hydride affords 2,2'-bis(5-tert-butylbenzene-1,3-dimethanol)diselenide (53). Diselenides 46 and 47 exhibit intramolecular Se...O interaction. Compound 53 does not show any intramolecular Se...O interaction. The anomalous Se...O nonbonded coordination observed in the single-crystal X-ray structures of compounds 46, 47 and 53 is compared and contrasted. The corresponding selenenyl bromides 54 and 55, derived from the reaction of diselenides 46 and 47 with bromine, are quite stable in the solid state. However, they undergo hydrolysis and subsequent intramolecular cyclization upon heating or after having been kept in solution over a period of time to give the corresponding selenenate esters 56 and 57. The X-ray crystallographic study and density functional theory calculations on 54 at the B3LYP/6-31G(d) level of theory indicate a significant distortion in planarity of the aromatic ring. Glutathione peroxidase-like activities of diselenides 46 and 47 and their selenenate esters 56 and 57 have been studied both by thiophenol and bioassay methods. The very low glutathione peroxidase-like activity of the diselenides (46 and 47) and their selenenate esters (56 and 57) in the thiophenol assay is attributed to the presence of the relatively strong Se...O intramolecular interaction in the selenenyl sulfide intermediates. The interaction retards the catalytic activity through both thiol exchange and an intramolecular cyclization reaction.


Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats.
Osteonecrosis (ON) of the femoral head in childhood can lead to loss of femoral head architecture and subsequent deformity. When femoral head ON was surgically induced in 24 rats, zoledronic acid treatment and prophylaxis improved sphericity and maintenance of architecture at 6 weeks. This preliminary experiment supports the use of bisphosphonates in childhood ON. We hypothesized that the bisphosphonate zoledronic acid could preserve femoral head structure while allowing bone repair. Osteonecrosis (ON) was surgically induced in the right femoral head of 24 female Wistar rats. The rats were randomized into three treatment groups and dosed subcutaneously with saline, zoledronic acid (0.1 mg/kg) at 1 and 4 weeks postoperation (ZA post), or zoledronic acid (0.1 mg/kg) given 2 weeks preoperation and at 1 and 4 weeks postoperation (ZA pre-post). After death at 6 weeks postoperation, undecalcified specimens were analyzed by DXA and standardized histomorphometric analysis. Seventy-one percent of saline-operated femoral heads were aspherical (Mose score > 1), whereas only 13% and 0% of operated heads in the ZA-treated groups were aspherical (p < 0.05). DXA-measured bone mineral density in saline-treated femoral heads was reduced by 34% and 43% compared with the ZA-treated groups (p < 0.01). Histomorphometry showed decreases of 12% and 17% in bone volume (BV/TV) in saline groups compared with ZA post and ZA pre-post (p < 0.05), and a decrease in trabecular number (Tb.N) of 18% and 14% (p < 0.05), respectively. Bone formation rate (BFR) was increased by 56% in saline-treated operated heads over ZA post and was 4.8 times increased over the ZA pre-post group (p < 0.05). The differences in BV/TV and Tb.N in treated groups must therefore be caused by a reduction in bone turnover. Observational histology confirmed the retention of necrotic architecture in treated groups. Zoledronic acid treatment and prophylaxis preserved femoral head architecture after traumatic ON in this rat model at 6 weeks. These data indicate that, by conserving femoral head architecture, bone repair may occur in conjunction with improved femoral head shape.


The association between the D166E polymorphism of the lipoprotein associated phospholipase A2 and risk of myocardial infarction.
Although numerous studies have evaluated the association between lipoprotein associated phospholipase A2 (Lp-PLA2) gene polymorphisms and coronary heart disease, the conclusions are still inconsistency. Here we detected the correlation between D166E polymorphism of Lp-PLA2 and myocardial infarction (MI). Further, its clinical value as biomarker was assessed. A total of 297 patients were enrolled, all diagnosed as MI at the Hebei General Hospital between May 2017 and May 2018, with 262 healthy subjects recruited as controls. Blood specimens of all participants were collected for testing serum lipid, blood glucose, Lp-PLA2, HsCRP, IL-17 and IL-35. The D166E polymorphism was genotyped. The correlation between D166E polymorphism and MI was explored using multiple logistic regression analysis. We detected higher levels of TC, TG, LDLC, Lp-PLA2, HsCRP and IL-17 but lower levels of HDLC and IL-35 in MI patients, compared with healthy controls (p<0.05). Also, the positive ratio of family history is higher in MI patients than that in control. Indexes were collected after one-week and one-month hospitalization, respectively, and levels of Lp-PLA2, HsCRP, IL-17 and IL-35 decreased to the normal levels (p>0.05). We also observed positive correlations between Lp-PLA2 with HsCRP and IL-17 (r=0.6517, 0.2689), and negative correlations between IL-35 with Lp-PLA2, HsCRP and IL-17 (r=-0.3142, -0.3968, -0.2516), respectively. The G allele at D166E accounted for a higher percentage in MI patients than in controls, and so as the GG and GC genotypes (p<0.05). Logistic regression analysis showed close associations between MI with Lp-PLA2 and GG genotype at D166E, with odds ratios of 1.239 (1.023-2.017) and 9.863 (4.107-21.331), which suggested they were independent risk factors for the development of coronary heart disease. The D166E (C/G) mutation of Lp-PLA2 was a potential risk factor of MI.


Detecting gait abnormalities after concussion or mild traumatic brain injury: A systematic review of single-task, dual-task, and complex gait.
While a growing number of studies have investigated the effects of concussion or mild traumatic brain injury (mTBI) on gait, many studies use different experimental paradigms and outcome measures. The path for translating experimental studies for objective clinical assessments of gait is unclear. This review asked 2 questions: 1) is gait abnormal after concussion/mTBI, and 2) what gait paradigms (single-task, dual-task, complex gait) detect abnormalities after concussion. Data sources included MEDLINE/PubMed, Scopus, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) accessed on March 14, 2017. Original research articles reporting gait outcomes in people with concussion or mTBI were included. Studies of moderate, severe, or unspecified TBI, and studies without a comparator were excluded. After screening 233 articles, 38 studies were included and assigned to one or more sections based on the protocol and reported outcomes. Twenty-six articles reported single-task simple gait outcomes, 24 reported dual-task simple gait outcomes, 21 reported single-task complex gait outcomes, and 10 reported dual-task complex gait outcomes. Overall, this review provides evidence for two conclusions: 1) gait is abnormal acutely after concussion/mTBI but generally resolves over time; and 2) the inconsistency of findings, small sample sizes, and small number of studies examining homogenous measures at the same time-period post-concussion highlight the need for replication across independent populations and investigators. Future research should concentrate on dual-task and complex gait tasks, as they showed promise for detecting abnormal locomotor function outside of the acute timeframe. Additionally, studies should provide detailed demographic and clinical characteristics to enable more refined comparisons across studies.


Meticillin-resistant Staphylococcus aureus (MRSA) acquisition risk in an endemic neonatal intensive care unit with an active surveillance culture and decolonization programme.
Meticillin-resistant Staphylococcus aureus (MRSA) is a leading cause of healthcare-associated infection in the neonatal intensive care unit (NICU). Decolonization may eliminate bacterial reservoirs that drive MRSA transmission. To measure the association between colonization pressure from decolonized and non-decolonized neonates and MRSA acquisition to inform use of this strategy for control of endemic MRSA. An eight-year retrospective cohort study was conducted in a level-4 NICU that used active surveillance cultures and decolonization for MRSA control. Weekly colonization pressure exposures were defined as the number of patient-days of concurrent admission with treated (decolonized) and untreated (non-decolonized) MRSA carriers in the preceding seven days. Poisson regression was used to estimate risk of incident MRSA colonization associated with colonization pressure exposures. The population-attributable fraction was calculated to assess the proportion of overall unit MRSA incidence attributable to treated or untreated patients in this setting. Every person-day increase in exposure to an untreated MRSA carrier was associated with a 6% increase in MRSA acquisition risk [relative risk (RR): 1.06; 95% confidence interval (CI): 1.01-1.11]. Risk of acquisition was not influenced by exposure to treated, isolated MRSA carriers (RR: 1.01; 95% CI: 0.98-1.04). In the context of this MRSA control programme, 22% (95% CI: 4.0-37) of MRSA acquisition could be attributed to exposures to untreated MRSA carriers. Untreated MRSA carriers were an important reservoir for transmission. Decolonized patients on contact isolation posed no detectable transmission threat, supporting the hypothesis that decolonization may reduce patient-to-patient transmission. Non-patient reservoirs may contribute to unit MRSA acquisition and require further investigation.


Jones phase microscopy of transparent and anisotropic samples.
We developed an interferometric microscopy technique, referred to as Jones phase microscopy, capable of extracting the spatially resolved Jones polarization matrix associated with transparent and anisotropic samples. This is a generalization of quantitative phase imaging, which is recovered from one diagonal element of the measured matrix. The principle of the technique is demonstrated with measurements of a liquid crystal spatial light modulator and the potential for live cell imaging with experiments on live neurons in culture.


Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score.
Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using factor prophylaxis. The HJHS has been shown to be highly reliable. We compared its validity and sensitivity to the WFH scale. We studied 226 boys with mild, moderate, and severe hemophilia at 5 centers. The HJHS was scored by trained physiotherapists. Study physicians at each site blindly determined individual and total joint scores using a series of visual analog scales. The mean age was 10.8 years. Sixty-eight percent were severe (93% of whom were treated with prophylaxis), 15% were moderate (24% treated with prophylaxis), and 17% were mild (3% treated with prophylaxis). The HJHS correlated moderately with the physician total joint score (rs=0.42, P<0.0001) and with overall arthropathy impact (rs=0.42, P<0.0001). The HJHS was 97% more efficient than the WFH at differentiating severe from mild and moderate hemophilia. The HJHS was 74% more efficient than the WFH at differentiating subjects treated with prophylaxis from those treated on demand. We identified items on the HJHS that may be redundant or rarely endorsed and could be removed from future versions. Both the HJHS and WFH showed evidence of strong construct validity. The HJHS is somewhat more sensitive for mild arthropathy; its use should be considered for studies of children receiving prophylaxis.


Impact of different sequences of mechanical and thermal processing on the rheological properties of Porphyridium cruentum and Chlorella vulgaris as functional food ingredients.
Microalgae are a promising and sustainable source for enhancing the nutritional value of food products. Moreover, incorporation of the total biomass might contribute to the structural properties of the enriched food product. Our previous study demonstrated the potential of Porphyridium cruentum and Chlorella vulgaris as multifunctional food ingredients, as they displayed interesting rheological properties after applying a specific combination of mechanical and thermal processing. The aim of the current study was to investigate the impact of a different sequence of high pressure homogenization (HPH) and thermal processing on the thickening and gelling potential of these microalgal biomasses in aqueous suspensions. Thermal processing largely increased the gel strength and viscosity of both microalgae, which was ascribed to larger and stronger aggregates as a result of partial solubilization of polymers, while subsequent HPH generally reduced the rheological properties. Interestingly, large amounts of intact cells were still observed for both microalgae when HPH was performed after a thermal treatment, irrespective of the applied homogenization pressure, implying that cell disruption was hindered by the preceding thermal treatment. Although thermal processing was regarded as the most effective processing technique to obtain increased rheological properties, the combination with a preceding HPH treatment should still be considered when cell disruption is desired, for instance to increase the bioavailability of intracellular components. Finally, biomass of P. cruentum showed the largest potential for use as a structuring agent, as the gel strength and viscosity in thermally treated suspensions of this microalga were about 10 times higher than for C. vulgaris.


[Clinical effect of abdominal acupuncture for diarrhea irritable bowel syndrome].
To compare the efficacy differences between abdominal acupuncture and western medication for diarrhea irritable bowel syndrome (IBS-D). Sixty-one patients with IBS-D were randomly assigned into an acupuncture group (30 cases after 1 dropping) and a western medication group (28 cases after 2 dropping). Acupuncture was used at Yinqiguiyuan points [Zhongwan (CV 12), Xiawan (CV 10), Qihai (CV 6), Guanyuan (CV 4)], Fusiguan points [bilateral Huaroumen (ST 24), Wailing (ST 26)], Tiaopiqi point [bilateral Daheng (SP 15)], once every other day, 3 times a week. Pinaverium bromide tablet was used orally in the western medication group, 50 mg a time, 3 times a day. All the treatment was given for 4 weeks in the two groups. IBS symptom severity score (IBS-SSS) and clinical symptom scores for abdominal pain and distension, diarrhea, poor stool output, defecation urgency and stool abnormality were observed before and after the treatment as well as 3 months after treatment. Adverse reactions were recorded and the effects were evaluated. ①After treatment and at follow-up, the IBS-SSS scores of the two groups were lower than those before treatment (all P<0.01). Compared with the western medication group, the scores and the improvements between the two time points and before treatment were better in the acupuncture group (P<0.05, P<0.01). ②The symptom scores in the two groups after treatment were lower than those before treatment including abdominal pain, abdominal distension, diarrhea, poor stool output, defecation urgency and stool abnormality (P<0.05, P<0.01), and the scores of abdominal pain, abdominal distension, diarrhea, poor stool output and stool abnormality in the acupuncture group were lower than those in the western medication group (P<0.05, P<0.01). ③The total effective rate and the cured and remarkable effective rate of the acupuncture group were higher than those of the western medication group [(86.7% (26/30) vs 64.3% (18/28), P<0.05; 70.0% (21/30) vs 35.7% (10/28), P<0.01)], and the therapeutic efficacy of the acupuncture group was better than that of the western medication group (P<0.05). There was no adverse reaction. Abdominal acupuncture is more effective for IBS-D than western medication and can relieve abdominal pain, abdominal distension, diarrhea, poor stool output, stool abnormality, with long-term effect.


Evaluation of selective human MAO inhibitory activities of some novel pyrazoline derivatives.
A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses, IR, (1)H NMR and ESI-MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined, compounds 5ae, 5af and 5ag were more selective than moclobemide, with respect to the K i values experimentally found. In addition, the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae-5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking.


Prospective analysis of the medicine possession ratio of antidepressants in the private health sector of South Africa, 2006 - 2011.
Major depressive disorder (MDD) is a disabling mental illness with high morbidity and mortality rates. Inadequate treatment efficacy, unfavourable side-effect profiles and consequent shortfalls in compliance are major stumbling blocks in its treatment. Non-compliance data in low- to middle-income countries are lacking. To investigate the prevalence of antidepressant (AD) non-compliance in the private healthcare sector of South Africa (SA). We conducted a prospective cohort study analysing AD medicine claims (N=35 175) for 14 135 patients, obtained from a nationally representative pharmaceutical benefit management company, over a 6-year study period (1 January 2006 - 31 December 2011). The medicine possession ratio (MPR) was used as a proxy to determine compliance with AD medication. Only patients >18 years of age whose treatment had been initiated by a psychiatrist following an appropriate International Classification of Diseases (10th edition) (ICD-10) diagnosis of a mood disorder were included. A patient was considered compliant if the MPR was between ≥80% and ≤110% over a >4-month treatment period. After the first 4 months, only 34% of patients were compliant. A statistically significant association was found between active ingredient consumed and compliance (p<0.0001). Only 26.2% of patients who received amitriptyline-containing products were compliant, compared with 38.8% and 38.7% for venlafaxine and duloxetine, respectively. Compliance data collected from pharmacy claims provide a workable estimate of the broader clinical scenario they represent. Although differences between classes of AD were evident, non-compliance was found to be high in the private healthcare environment of SA, comparable with global trends.


Methylmercury inhibits cysteine uptake in cultured primary astrocytes, but not in neurons.
The maintenance of adequate intracellular glutathione (GSH) concentrations is dependent on the availability and transport of the rate-limiting substrate, cysteine. A suggested mechanism of methylmercury (MeHg) neurotoxicity in brain involves the formation of oxygen radicals, and a decrease in intracellular levels of GSH. Recently, we have characterized various cysteine transport systems (both Na(+)-dependent and -independent) in cerebrocortical astrocytes and hippocampal neurons. The present study was carried out to investigate the effect of MeHg on cysteine uptake in both astrocytes and neurons, and to determine whether cysteine transport is differentially affected in the two cell types by MeHg treatment. Sixty-minute pretreatment with MeHg caused significant concentration-dependent inhibition in cysteine uptake in astrocytes, but not in neurons. As most of the cysteine transport is Na(+)-dependent (80-90% of total), additional studies focused on MeHg's effect on the Na(+)-dependent cysteine transporters X(AG(-)) and ASC. An additive inhibitory effect on cysteine uptake was observed in astrocytes treated with MeHg (5 microM) plus sub-maximal inhibitory concentrations (0.1 and 0.5 mM) of threo-beta-hydroxy-aspartate (THA), a specific inhibitor of the Na(+)-dependent transporter, X(AG(-)), compared to astrocytes treated with MeHg (P<0.001) or THA alone (P<0.05). There was no additive effect of MeHg and maximal inhibitory concentrations of THA (1.0 and 5.0 mM) on astrocytic cysteine uptake inhibition. Additional studies examined the sensitivity of the Na(+)-dependent ASC transport system to MeHg treatment. Maximal inhibitory concentration of L-serine (10 mM) alone had a rather modest inhibitory effect on cysteine uptake, and when applied in the presence of MeHg there was no additive effect. These results suggest that the inhibition of cysteine uptake by MeHg in astrocytes occurs through specific inhibition of both the X(AG(-)) as well as the ASC transport system.


Lithium neutron producing target for BINP accelerator-based neutron source.
Pilot innovative accelerator-based neutron source for neutron capture therapy is under construction now at the Budker Institute of Nuclear Physics, Novosibirsk, Russia. One of the main elements of the facility is lithium target, that produces neutrons via threshold (7)Li(p,n)(7)Be reaction at 25 kW proton beam with energies 1.915 or 2.5 MeV. In the present report, the results of experiments on neutron producing target prototype are presented, the results of calculations of hydraulic resistance for heat carrier flow and lithium layer temperature are shown. Calculation showed that the lithium target could run up to 10 mA proton beam before melting. Choice of target variant is substantiated. Program of immediate necessary experiments is described. Target design for neutron source constructed at BINP is presented. Manufacturing the neutron producing target up to the end of 2004 and obtaining a neutron beam on BINP accelerator-based neutron source are planned during 2005.


Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments.
Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes.


A timer-actuated immunoassay cassette for detecting molecular markers in oral fluids.
An inexpensive, hand-held, point-of-care, disposable, self-contained immunoassay cassette comprised of air pouches for pumping, a metering chamber, reagents storage chambers, a mixer, and a lateral flow strip was designed, constructed, and tested. The assay was carried out in a consecutive flow format. The detection was facilitated with up-converting phosphor (UCP) reporter particles. The automated, timely pumping of the various reagents was driven by a spring-loaded timer. The utility of the cassette was demonstrated by detecting antibodies to HIV in saliva samples and further evaluated with a non-contagious, haptenized DNA assay. The cassette has several advantages over dip sticks such as sample preprocessing, integrated storage of reagents, and automated operation that reduces operator errors and training. The cassette and actuator described herein can readily be extended to detect biomarkers of other diseases in body fluids and other fluids at the point of care. The system is particularly suitable for resource-poor countries, where funds and trained personnel are in short supply.


Synaptotagmin 13 is neuroprotective across motor neuron diseases.
In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.


A case study of cytokine profiles in acute human babesiosis.
The immune response in a patient with acute babesiosis was determined by measurements of lymphocyte subpopulations, serum levels of cytokines, and adhesion molecules. The ratio of CD4+:CD8+ lymphocytes was reduced early in the infection, but returned to a normal value after treatment with azithromycin and quinine. Natural killer (NK) cells markedly increased in the acute phase but progressively decreased and to the normal range in the convalescent phase. Serum levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-2 (IL-2), IL-6, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 were highly elevated in the acute phase while normal levels of these mediators were observed one month after treatment. These results suggest that CD8+ T cells and NK cells may be involved in the host defense mechanisms against acute babesiosis.


Non-medical approved clinicians: Results of a first national survey in England and Wales.
The 2007 amendments to the Mental Health Act, 1983 in England and Wales enabled non-medics to take on the role of legally 'responsible clinician' for the overall care and treatment of service users detained under the Act, where previously this was the sole domain of the psychiatrist as Responsible Medical Officer. Following state sanction as an 'Approved Clinician', certain psychologists, nurses, social workers or occupational therapists may be allocated as a Responsible Clinician for specific service users. Between 2007 and 2017 only 56 non-medics had become Approved Clinicians. This study reports on a first national survey of 39 non-medical Approved Clinicians. Descriptive statistics and thematic analysis of free text answers are presented here. The survey results show the limited uptake of the role, save for in the North Eastern region of England. Non-medical Approved Clinicians were motivated by a combination of altruistic intents (namely a belief that they could offer more psychologically-informed, recovery-oriented care) and desire for professional development in a role fitting their expertise and experience. Barriers and facilitators to wider uptake of the role appear to be: organisational support, attitudes of psychiatrist colleagues and a potentially lengthy and laborious approvals application process. The survey is a starting point to further research on the interpretation and implementation of the range of statutory roles and responsibilities under English and Welsh mental health law.


Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors.
MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT(1) and 5-HT(2) receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT(2) receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT(1) receptors do not appear to be involved in MDMA effects on mood and impulse control. Nederlands Trial Register NTR2352.


COVID-19: A Vaccine Priority Index Mapping Tool for Rapidly Assessing Priority Populations in North Carolina.
The initial limited supply of COVID-19 vaccine in the U.S. presented significant allocation, distribution, and delivery challenges. Information that can assist health officials, hospital administrators and other decision makers with readily identifying who and where to target vaccine resources and efforts can improve public health response. The objective of this project was to develop a publicly available geographical information system (GIS) web mapping tool that would assist North Carolina health officials readily identify high-risk, high priority population groups and facilities in the immunization decision making process. Publicly available data were used to identify 14 key health and socio-demographic variables and 5 differing themes (social and economic status; minority status and language; housing situation; at risk population; and health status). Vaccine priority population index (VPI) scores were created by calculating a percentile rank for each variable over each N.C. Census tract. All Census tracts (N = 2,195) values were ranked from lowest to highest (0.0 to 1.0) with a non-zero population and mapped using ArcGIS. The VPI tool was made publicly available (https://enchealth.org/) during the pandemic to readily assist with identifying high risk population priority areas in N.C. for the planning, distribution, and delivery of COVID-19 vaccine. While health officials may have benefitted by using the VPI tool during the pandemic, a more formal evaluation process is needed to fully assess its usefulness, functionality, and limitations. When considering COVID-19 immunization efforts, the VPI tool can serve as an added component in the decision-making process.


Failure of stimulated skeletal muscle mainly contributed by passive force: an in vivo rabbit model.
OBJECTIVE: To evaluate the role of active and passive muscle forces in the failure mechanism of stimulated muscle. DESIGN: An in vivo rabbit model. BACKGROUND: Eccentric contractions can result in a greater incidence of muscle injury. However, the relative role of the active and passive muscle force in the failure mechanism of the activated muscle is not well elucidated. METHODS: After anaesthesia, New Zealand white rabbits were fixed in a frame on a materials testing machine. The triceps surae muscle-tendon units were passively stretched to rupture with our without continuous nerve stimulation. The force and muscle length were simultaneously recorded. Active muscle force, passive muscle force, and ratio of the active to passive muscle were calculated and depicted against strain. RESULTS: The results showed that the mean maximal passive force of triceps surae muscle was 293.1 N at a strain of 38%. The mean peak active muscle force was 21.5 N at a strain of 21%. The ratio of active to passive muscle force reached its peak first, followed by the active muscle force, and then the passive muscle force. The ratio of active to passive muscle force at the peak total force was only 3.3%. CONCLUSIONS: The stimulated muscle can exert its maximal response at extreme physiological extension. Injury of the stimulated muscle is caused mainly by passive muscle force.


The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance.
Telomeres are linear guanine-rich DNA structures at the ends of chromosomes. The length of telomeric DNA is actively regulated by a number of mechanisms in highly proliferative cells such as germ cells, cancer cells, and pluripotent stem cells. Telomeric DNA is synthesized by way of the ribonucleoprotein called telomerase containing a reverse transcriptase (TERT) subunit and RNA component (TERC). TERT is highly conserved across species and ubiquitously present in their respective pluripotent cells. Recent studies have uncovered intricate associations between telomeres and the self-renewal and differentiation properties of pluripotent stem cells. Interestingly, the past decade's work indicates that the TERT subunit also has the capacity to modulate mitochondrial function, to remodel chromatin structure, and to participate in key signaling pathways such as the Wnt/β-catenin pathway. Many of these non-canonical functions do not require TERT's catalytic activity, which hints at possible functions for the extensive number of alternatively spliced TERT isoforms that are highly expressed in pluripotent stem cells. In this review, some of the established and potential routes of pluripotency induction and maintenance are highlighted from the perspectives of telomere maintenance, known TERT isoform functions and their complex regulation.


Novel regulatory roles of cAMP receptor proteins in fast-growing environmental mycobacteria.
Mycobacterium smegmatis is a fast-growing, saprophytic, mycobacterial species that contains two cAMP-receptor protein (CRP) homologues designated herein as Crp1 and Crp2. Phylogenetic analysis suggests that Crp1 (Msmeg_0539) is uniquely present in fast-growing environmental mycobacteria, whereas Crp2 (Msmeg_6189) occurs in both fast- and slow-growing species. A crp1 mutant of M. smegmatis was readily obtained, but crp2 could not be deleted, suggesting it was essential for growth. A total of 239 genes were differentially regulated in response to crp1 deletion (loss of function), including genes coding for mycobacterial energy generation, solute transport and catabolism of carbon sources. To assess the role of Crp2 in M. smegmatis, the crp2 gene was overexpressed (gain of function) and transcriptional profiling studies revealed that 58 genes were differentially regulated. Identification of the CRP promoter consensus in M. smegmatis showed that both Crp1 and Crp2 recognized the same consensus sequence (TGTGN8CACA). Comparison of the Crp1- and Crp2-regulated genes revealed distinct but overlapping regulons with 11 genes in common, including those of the succinate dehydrogenase operon (MSMEG_0417-0420, sdh1). Expression of the sdh1 operon was negatively regulated by Crp1 and positively regulated by Crp2. Electrophoretic mobility shift assays with purified Crp1 and Crp2 demonstrated that Crp1 binding to the sdh1 promoter was cAMP-independent whereas Crp2 binding was cAMP-dependent. These data suggest that Crp1 and Crp2 respond to distinct signalling pathways in M. smegmatis to coordinate gene expression in response to carbon and energy supply.


Differential effects of frozen storage on the molecular detection of bacterial taxa that inhabit the nasopharynx.
Frozen storage often precedes metagenomic analysis of biological samples; however, the freezing process can have adverse effects on microbial composition. The effect of freezing on the detection of bacteria inhabiting the infant nasopharynx, a major reservoir of bacterial pathogens, was investigated. 16S ribosomal RNA (rRNA) gene-based terminal restriction fragment length polymorphism (T-RFLP) analysis of nasopharyngeal (NP) swabs from twelve Gambian infants was employed. NP swabs were analysed within hours of collection and then after 30 days of storage at -70°C. There was substantial heterogeneity among subjects with respect to the effect of freezing on the number of operational taxonomic units (OTUs) detected. Nevertheless, the mean number of OTUs decreased after frozen storage and the relative abundance for 72% of the OTUs changed by less than 0.5% after deep frozen storage. There were differences in the odds of detection and relative abundance of OTUs matched with Moraxella sp., Haemophilus sp./Burkholderia sp., and Pseudomonas sp. A strong interaction between sex and the effect of freezing was found, whereby there was no significant change observed for males while the mean number of OTUs significantly declined among female infants following frozen storage. Although frozen storage of biological samples is often necessary for archiving and logistic purposes, the potential effects on the number of taxa (composition) detected in microbial community studies are significant and should not be overlooked. Moreover, genetic factors such as sex may influence the integrity of nucleic acids during the freezing process.


Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative.
The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.


Update on the acute treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a genetic autosomal dominant condition caused by C1-esterase inhibitor protein (C1INH) deficiency that results in episodic tissue angioedema. Recently, new therapies have been developed to more effectively manage this rare but serious condition. This review will provide a concise summary of HAE acute treatment options for the practicing allergist/immunologist. Clinical study data for emerging HAE therapies were reviewed and summarized. Based on efficacy and safety data from completed clinical studies, three new HAE treatments have recently been approved by the Food and Drug Administration: nanofiltered plasma-derived C1INH for prophylactic therapy, pasteurized plasma-derived C1INH for acute therapy, and ecallantide for acute therapy. Two other promising therapies, recombinant C1INH and icatibant, are in various stages of the U.S. regulatory process. The medical management of HAE is entering a new era with the availability of safe, effective condition-specific treatments. Clinicians should consider a number of patient- and medication-specific factors when designing individualized treatment plans for HAE patients.


Perceptions and perceived impact of graphic cigarette health warning labels on smoking behavior among U.S. young adults.
In 2011, the Food and Drug Administration published a final rule requiring cigarette packages and advertisements to include graphic health warning labels (HWLs) with new warning statements. Implementation of this rule has been stalled by legal challenge. This study assessed correlates of smoking-related intentions related to graphic HWLs among current cigarette smokers and nonsmokers in a national sample of U.S. young adults aged 18-34. Data were collected from 4,236 participants aged 18-34 using an online panel in January 2012 for the Legacy Young Adult Cohort Study. Analyses were weighted to provide nationally representative estimates. Our main outcome was assessed with a single item: "Do you think that new warning labels with graphic pictures would make you think about not smoking?" Twenty-two percent of the young adults were current cigarette smokers. Fifty-three percent endorsed that new graphic HWLs would make them think about not smoking (40% among current smokers compared with 56% among nonsmokers). Among nonsmokers, those aged 18-24, females, Hispanics, and those who were aware of graphic cigarette HWLs were more likely to report intention to not smoke related to graphic HWLs. Among current smokers, intending to quit within the next 6 months was correlated with intention resulting from graphic HWLs. Hispanic ethnicity and intention to quit within 30 days were strong correlates of intention in light, nondaily, and self-identified social/occasional smokers. This study supports previous findings that graphic HWLs play an important role in preventing smoking, in addition to encouraging cessation in young adults.


Low doses of ionizing radiation and circulatory diseases: a systematic review of the published epidemiological evidence.
Recent analyses of mortality among atomic bomb survivors have suggested a linear dose-response relationship between ionizing radiation and diseases of the circulatory system for exposures in the range 0-4 Sv. If confirmed, this has substantial implications. We have therefore reviewed the published literature to see if other epidemiological data support this finding. Other studies allowing a comparison of the rates of circulatory disease in individuals drawn from the same population but exposed to ionizing radiation at different levels within the range 0-5 Gy or 0-5 Sv were identified through systematic literature searches. Twenty-six studies were identified. In some, disease rates among those exposed at different levels may have differed for reasons unrelated to radiation exposure, while many had low power to detect effects of the relevant magnitude. Among the remainder, one study found appreciable evidence that exposure to low-dose radiation was associated with circulatory diseases, but five others, all with appreciable power, did not. We conclude that the other epidemiological data do not at present provide clear evidence of a risk of circulatory diseases at doses of ionizing radiation in the range 0-4 Sv, as suggested by the atomic bomb survivors. Further evidence is needed to characterize the possible risk.


The effect of warmer winters on the demography of an outbreak insect is hidden by intraspecific competition.
Warmer climates are predicted to increase bark beetle outbreak frequency, severity, and range. Even in favorable climates, however, outbreaks can decelerate due to resource limitation, which necessitates the inclusion of competition for limited resources in analyses of climatic effects on populations. We evaluated several hypotheses of how climate impacts mountain pine beetle reproduction using an extensive 9-year dataset, in which nearly 10,000 trees were sampled across a region of approximately 90,000 km2 , that was recently invaded by the mountain pine beetle in Alberta, Canada. Our analysis supports the hypothesis of a positive effect of warmer winter temperatures on mountain pine beetle overwinter survival and provides evidence that the increasing trend in minimum winter temperatures over time in North America is an important driver of increased mountain pine beetle reproduction across the region. Although we demonstrate a consistent effect of warmer minimum winter temperatures on mountain pine beetle reproductive rates that is evident at the landscape and regional scales, this effect is overwhelmed by the effect of competition for resources within trees at the site level. Our results suggest that detection of the effects of a warming climate on bark beetle populations at small spatial scales may be difficult without accounting for negative density dependence due to competition for resources.