bluuebunny/crossref_metadata_2025 huggingface dataset:
New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection
Authors: Wang Huaqing , Kim Janice J. , Denou Emmanuel , Gallagher Amanda , Thornton David J. , Shajib M. Sharif , Xia Lijun , Schertzer Jonathan D. , Grencis Richard K. , Philpott Dana J. , Khan Waliul I.
Published: November 2015

Mucins secreted by intestinal goblet cells are considered an important component of innate defense in a number of enteric infections, including many parasitic infections, but also likely provide protection against the gut microbiota. Nod proteins are intracellular receptors that play key roles in innate immune response and inflammation. Here, we investigated the role of Nod proteins in regulation of intestinal goblet cell response in naive mice and mice infected with the enteric parasite
Trichuris muris
. We observed significantly fewer periodic acid-Schiff (PAS)-stained intestinal goblet cells and less mucin (Muc2) in Nod1 and Nod2 double-knockout (Nod DKO) mice after
T. muris
infection than in wild-type (WT) mice. Expulsion of parasites from the intestine was significantly delayed in Nod DKO mice. Treatment of naive WT mice with Nod1 and Nod2 agonists simultaneously increased numbers of PAS-stained goblet cells and Muc2-expressing cells, whereas treatment with Nod1 or Nod2 separately had no significant effect. Stimulation of mucin-secreting LS174T cells with Nod1 and Nod2 agonists upregulated core 3 β1,3-
N
-acetylglucosaminyltransferase (C3GnT; an important enzyme in mucin synthesis) and MUC2. We also observed lower numbers of PAS-stained goblet cells and less Muc2 in germfree mice. Treatment with Nod1 and Nod2 agonists enhanced the production of PAS-stained goblet cells and Muc2 in germfree mice. These data provide novel information on the role of Nod proteins in goblet cell response and Muc2 production in relation to intestinal innate defense.
A DinB Ortholog Enables Mycobacterial Growth under dTTP-Limiting Conditions Induced by the Expression of a Mycobacteriophage-Derived Ribonucleotide Reductase Gene
Authors: Ghosh Shreya , Samaddar Sourabh , Kirtania Prithwiraj , Das Gupta Sujoy K.
Published: November 2015

Mycobacterium
species such as
M. smegmatis
and
M. tuberculosis
encode at least two translesion synthesis (TLS) polymerases, DinB1 and DinB2, respectively. Although predicted to be linked to DNA repair, their role
in vivo
remains enigmatic.
M. smegmatis
mc
2
155, a strain commonly used to investigate mycobacterial genetics, has two copies of
dinB2
, the gene that codes for DinB2, by virtue of a 56-kb chromosomal duplication. Expression of a mycobacteriophage D29 gene (gene 50) encoding a class II ribonucleotide reductase in
M. smegmatis
ΔDRKIN, a strain derived from mc
2
155 in which one copy of the duplication is lost, resulted in DNA replication defects and growth inhibition. The inhibitory effect could be linked to the deficiency of dTTP that resulted under these circumstances. The selective inhibition observed in the ΔDRKIN strain was found to be due solely to a reduced dosage of
dinB2
in this strain.
Mycobacterium bovis
, which is closely related to
M. tuberculosis
, the tuberculosis pathogen, was found to be highly susceptible to gene 50 overexpression. Incidentally, these slow-growing pathogens harbor one copy of
dinB2
. The results indicate that the induction of a dTTP-limiting state can lead to growth inhibition in mycobacteria, with the effect being maximum in cells deficient in DinB2.

IMPORTANCE
Mycobacterium
species, such as
M. tuberculosis
, the tuberculosis pathogen, are known to encode several Y family DNA polymerases, one of which is DinB2, an ortholog of the DNA repair-related protein DinP of
Escherichia coli
. Although this protein has been biochemically characterized previously and found to be capable of translesion synthesis
in vitro
, its
in vivo
function remains unknown. Using a novel method to induce dTTP deficiency in mycobacteria, we demonstrate that DinB2 can aid mycobacterial survival under such conditions. Apart from unraveling a specific role for the mycobacterial Y family DNA polymerase DinB2 for the first time, this study also paves the way for the development of drugs that can kill mycobacteria by inducing a dTTP-deficient state.
Phenotypes Associated with the Essential Diadenylate Cyclase CdaA and Its Potential Regulator CdaR in the Human Pathogen Listeria monocytogenes
Authors: Rismondo Jeanine , Gibhardt Johannes , Rosenberg Jonathan , Kaever Volkhard , Halbedel Sven , Commichau Fabian M.
Published: November 2015

Cyclic diadenylate monophosphate (c-di-AMP) is a second messenger utilized by diverse bacteria. In many species, including the Gram-positive human pathogenListeria monocytogenes, c-di-AMP is essential for growth. Here we show that the single diadenylate cyclase ofL. monocytogenes, CdaA, is an integral membrane protein that interacts with its potential regulatory protein, CdaR, via the transmembrane protein domain. The presence of the CdaR protein is not required for the membrane localization and abundance of CdaA. We have also found that CdaR negatively influences CdaA activity inL. monocytogenesand that the role of CdaR is most evident at a high growth temperature. Interestingly, acdaRmutant strain is less susceptible to lysozyme. Moreover, CdaA contributes to cell division, and cells depleted of CdaA are prone to lysis. The observation that the growth defect of a CdaA depletion strain can be partially restored by increasing the osmolarity of the growth medium suggests that c-di-AMP is important for maintaining the integrity of the protective cell envelope. Overall, this work provides new insights into the relationship between CdaA and CdaR.

IMPORTANCECyclic diadenylate monophosphate (c-di-AMP) is a recently identified second messenger that is utilized by the Gram-positive human pathogenListeria monocytogenes. Here we show that the single diadenylate cyclase ofL. monocytogenes, CdaA, is an integral membrane protein that interacts with CdaR, its potential regulatory protein. We show that CdaR is not required for membrane localization or abundance of the diadenylate cyclase, but modulates its activity. Moreover, CdaA seems to contribute to cell division. Overall, this work provides new insights into the relationship between CdaA and CdaR and their involvement in cell growth.
How do Systematic Reviews of Acupuncture for Pain Relief Incorporate Risk of Bias Assessments into the Synthesis? A Methodological Study
Authors: Li Xiao-qian , Tao Kun-ming , Yang Ge-liang , Zhou Qing-hui , Ling Chang-quan
Published: November 2015

Objective

By reviewing the assessment of internal validity in relevant systematic reviews (SRs), the aim of this study was to identify how critical appraisals of risk of bias (RoB) inform the synthesis of evidence in SRs of acupuncture for pain relief.

Methods

SRs were searched in Medline, EMBASE, and the Cochrane Database of SRs from their inception to 30 December 2014. Only SRs of acupuncture for pain relief were included. Basic information, types of RoB appraisal tool, whether or not there was domain-level assessment of RoB, whether or not the reviews ranked studies by RoB, plus whether or not (and, if so, how) RoB appraisal was incorporated into the synthesis were determined.

Results

A total of 91 SRs met the inclusion criteria and were included in the final analysis. Over half of the SRs (85, 64.8%) used standard tools, such as the Jadad quality score and the Cochrane RoB tool, followed by adapted tools (n=23, 25.3%). Of the 85 SRs that assessed RoB, 29 (34.1%) presented domain-level assessment and 71 SRs (83.5%) included ranking of the studies based on RoB assessment. Of these 71, 35 (49.4%) used a cut-off threshold score and 26 (36.6%) required all criteria sum-up. Of the 85 SRs that assessed RoB, 48 (56.5%) incorporated RoB appraisal into the data synthesis.

Conclusions

Although most SRs of acupuncture for pain relief conducted some form of RoB assessment, nearly half of them failed to incorporate the RoB assessment into the synthesis.
Poor oral health including active caries in 187 UK professional male football players: clinical dental examination performed by dentists
Authors: Needleman Ian , Ashley Paul , Meehan Lyndon , Petrie Aviva , Weiler Richard , McNally Steve , Ayer Chris , Hanna Rob , Hunt Ian , Kell Steven , Ridgewell Paul , Taylor Russell
Published: November 2015

Background

The few studies that have assessed oral health in professional/elite football suggest poor oral health with minimal data on impact on performance. The aim of this research was to determine oral health in a representative sample of professional footballers in the UK and investigate possible determinants of oral health and self-reported impact on well-being, training and performance.

Methods

Clinical oral health examination of senior squad players using standard methods and outcomes carried out at club training facilities. Questionnaire data were also collected. 8 teams were included, 5 Premier League, 2 Championship and 1 League One.

Results

6 dentists examined 187 players who represented >90% of each senior squad. Oral health was poor: 37% players had active dental caries, 53% dental erosion and 5% moderate-severe irreversible periodontal disease. 45% were bothered by their oral health, 20% reported an impact on their quality of life and 7% on training or performance. Despite attendance for dental check-ups, oral health deteriorated with age.

Conclusions

This is the first large, representative sample study in professional football. Oral health of professional footballers is poor, and this impacts on well-being and performance. Successful strategies to promote oral health within professional football are urgently needed, and research should investigate models based on best evidence for behaviour change and implementation science. Furthermore, this study provides strong evidence to support oral health screening within professional football.
Treatment ofClostridium difficileinfection in mice with vancomycin alone is as effective as treatment with vancomycin and metronidazole in combination
Authors: Erikstrup Lise Tornvig , Aarup Mie , Hagemann-Madsen Rikke , Dagnaes-Hansen Frederik , Kristensen Brian , Olsen Katharina Elisabeth Pribil , Fuursted Kurt
Published: November 2015

Objective

Clostridium difficileis a major cause of nosocomial infectious diarrhoea. Treatment ofC. difficileinfection (CDI) depends on disease severity. A combination of vancomycin and metronidazole is often recommended in severe cases. The aim of this study was to examine, in a murine model of CDI, if mice treated with a combination of vancomycin and metronidazole had a better clinical outcome than mice treated with vancomycin or metronidazole alone.

Design

C57BL/6J mice pretreated with an antimicrobial mixture were challenged withC. difficileVPI 10463 or phosphate-buffered saline by oral gavage. After the challenge, the mice were treated with placebo, vancomycin, metronidazole or a combination of vancomycin and metronidazole for 10 days. The mice were monitored for 20 days with weight and a clinical score. Stool samples were examined forC. difficilespore load and presence ofC. difficiletoxins.

Results

None of the mice in the vancomycin-treated group died during the treatment phase compared to a mortality of 17%, 33% and 55% in the combination, metronidazole and infected control group, respectively. Mice treated with vancomycin alone or in combination with metronidazole recovered from CDI faster than mice treated with metronidazole alone. However, after discontinuation of treatment, vancomycin-treated and combination-treated mice succumbed to clinical and bacteriological relapse.

Conclusions

Mice treated with vancomycin alone had a better clinical outcome in the treatment phase of CDI than mice treated with metronidazole alone. A combination of vancomycin and metronidazole did not improve the clinical outcome when compared to treatment with vancomycin alone.

Trial registration number

The trial registration number from the Danish Experimental Animal Inspectorate is J number 2012-15-2934-00422.
How different terminology for ductal carcinoma in situ impacts women's concern and treatment preferences: a randomised comparison within a national community survey
Authors: McCaffery Kirsten , Nickel Brooke , Moynihan Ray , Hersch Jolyn , Teixeira-Pinto Armando , Irwig Les , Barratt Alexandra
Published: November 2015

Objective

There have been calls to remove ‘carcinoma’ from terminology for in situ cancers such as ductal carcinoma in situ (DCIS), to reduce overdiagnosis and overtreatment. We investigated the effect of describing DCIS as ‘abnormal cells’ versus ‘pre-invasive breast cancer cells’ on women's concern and treatment preferences.

Setting and participants

Community sample of Australian women (n=269) who spoke English as their main language at home.

Design

Randomised comparison within a community survey. Women considered a hypothetical scenario involving a diagnosis of DCIS described as either ‘abnormal cells’ (arm A) or ‘pre-invasive breast cancer cells’ (arm B). Within each arm, the initial description was followed by the alternative term and outcomes reassessed.

Results

Women in both arms indicated high concern, but still indicated strong initial preferences for watchful waiting (64%). There were no differences in initial concern or preferences by trial arm. However, more women in arm A (‘abnormal cells’ first term) indicated they would feel more concerned if given the alternative term (‘pre-invasive breast cancer cells’) compared to women in arm B who received the terms in the opposite order (67% arm A vs 52% arm B would feel more concerned, p=0.001). More women in arm A also changed their preference towards treatment when the terminology was switched from ‘abnormal cells’ to ‘pre-invasive breast cancer cells’ compared to arm B. In arm A, 18% of women changed their preference to treatment while only 6% changed to watchful waiting (p=0.008). In contrast, there were no significant changes in treatment preference in arm B when the terminology was switched (9% vs 8% changed their stated preference).

Conclusions

In a hypothetical scenario, interest in watchful waiting for DCIS was high, and changing terminology impacted women's concern and treatment preferences. Removal of the cancer term from DCIS may assist in efforts towards reducing overtreatment.
Disability pension and symptoms of anxiety and depression: a prospective comparison of farmers and other occupational groups. The HUNT Study, Norway
Authors: Torske Magnhild Oust , Hilt Bjørn , Bjørngaard Johan Håkon , Glasscock David , Krokstad Steinar
Published: November 2015

Objectives

Agriculture has undergone major changes, and farmers have been found to have a high prevalence of depression symptoms. We investigated the risk of work disability in Norwegian farmers compared with other occupational groups, as well as the associations between symptoms of anxiety and depression and future disability pension.

Methods

We linked working participants of the HUNT2 Survey (1995–97) aged 20–61.9 years, of whom 3495 were farmers and 25 521 had other occupations, to national registry data on disability pension, with follow-up until 31 December 2010. We used Cox proportional hazards regression to estimate hazard ratios (HRs) of disability pension, and to investigate the associations between symptoms of anxiety and depression caseness at baseline (score on the anxiety or depression subscales of the Hospital Anxiety and Depression Scale (HADS) ≥8) and disability pension.

Results

Farmers had a twofold increased risk of disability pension (age-adjusted and sex-adjusted HR 2.07, 95% CI 1.80 to 2.38) compared with higher grade professionals. Farmers with symptoms of depression caseness had a 53% increased risk of disability pension (HR 1.53, 95% CI 1.25 to 1.87) compared with farmers below the cut-off point of depression caseness symptoms, whereas farmers with symptoms of anxiety caseness had a 51% increased risk (HR 1.51, 95% CI 1.23 to 1.86).

Conclusions

Farmers have an increased risk of disability pension compared with higher grade professionals, but the risk is lower than in most other manual occupational groups. Farmers who report high levels of depression or anxiety symptoms are at substantially increased risk of future work disability, and the risk increase appears to be fairly similar across most occupational groups.
Sedentary behaviour among elite professional footballers: health and performance implications
Authors: Weiler Richard , Aggio Daniel , Hamer Mark , Taylor Tom , Kumar Bhavesh
Published: November 2015

Background

Elite athletes should have little concern about meeting recommended guidelines on physical activity. However, sedentary behaviour is considered a health risk independent of physical activity, and is recognised in public health guidelines advising against prolonged sedentary time. There has been very little research on athletes’ physical activity behaviour outside elite sport.

Methods

Given health and performance links, we investigated in-season post-training activity levels in 28 elite professional footballers during the English Premiership season. Players volunteered to wear a triaxial wrist accelerometer for 1 week, removing it only for training and matches. In total, 25 players met the inclusion criteria for analysis. Players recorded on average 632.6 min wear time p/day during the post-training period (SD±52.9) for a mean of 3.8 days (SD±1.5).

Results

On average, players recorded 76.2 min p/day (SD±28.8) of moderate or vigorous activity post-training. The majority (79%) of post-training time was spent in sedentary activities (500.6 min per day±59.0).

Conclusions

Professional footballers are alarmingly sedentary in their leisure time, and comparatively more so than non-athletic groups of a similar age and older. This raises questions over optimum recovery and performance, as well as long-term health and cardiovascular risk. Worryingly, retirement from elite sport is likely to further imbalance activity and sedentary behaviour. Promoting regular periodic light to moderate leisure time activity could be beneficial. Further research and provision of education and support for players is required in this area.
A ‘novel’ model for integrating Sport and Exercise Medicine (SEM) and Musculoskeletal (MSK) management into primary care in the UK
Authors: Heron Neil
Published: November 2015

Background

Musculoskeletal (MSK) symptoms are common within primary care but some general practitioners (GPs)/family physicians do not feel comfortable managing these symptoms, preferring to refer onwards. We aimed to establish a reproducible GP-staffed MSK and sport and exercise medicine (SEM) clinic within primary care, in keeping with recent policy changes within the UK health system.

Methods

A monthly MSK and SEM clinic was held within a Belfast GP practice, staffed by 1 GP with a specialist interest in MSK/SEM conditions, and its performance was reviewed over two 3-month periods. Parameters audited included diagnoses, patient satisfaction and secondary care referral rates.

Results

83 patients, 36 males and 47 females, were reviewed in the clinic and the main presenting joint was the shoulder. Patient self-reported satisfaction with the service was high. Comparing referral rates between August and October 2013 and the same period in 2014, overall referrals from the practice were reduced by 147, orthopaedic and rheumatology referrals were reduced by 2 and 3, while physiotherapy and X-ray referrals were reduced by 47 and 90, respectively. Comparing the referral rates between January and March 2014 and the same period in 2015, overall outpatient referrals were reduced by 152, orthopaedic and rheumatology referrals were reduced by 9 and 4, while physiotherapy and X-ray referrals were reduced by 41 and 3, respectively.

Discussion

We present a novel, reproducible service model for managing MSK/SEM symptoms in primary care which could be commissioned by local groups. This model can make sound economic sense and deliver high patient satisfaction within primary care, reducing waiting times and the secondary care referral burden.
The Child Sport Concussion Assessment Tool (Child SCAT3): normative values and correspondence between child and parent symptom scores in male child athletes
Authors: Porter Shaun , Smith-Forrester Jenna , Alhajri Najah , Kusch Cody , Sun Jonathan , Barrable Bill , Panenka William J , Virji-Babul Naznin
Published: November 2015

Background

Children and youth are at increased risk of sustaining sport-related concussions. There is a need to develop age-specific tools to evaluate the effects of concussion. The objective of this study was to determine normative values for the Child Sport Concussion Assessment Tool (Child SCAT3) in child athletes and evaluate the symptom scoring agreement between the child and parent.

Methods

Child SCAT3 was administered to ice hockey players enrolled in a regional minor hockey association. Statistical analyses were performed to evaluate the differences between child and parent reporting as well as those based on age.

Results

227 athletes (7–12 years of age) completed the Child SCAT3. 29 players reported a history of concussion. For the objective components, the average total Standard Assessment of Concussion adapted to a child version (SAC-C) score of 24.4 was made up by orientation (3.7), immediate memory (12.9), concentration (3.8) and delayed recall (3.9) sections. Average errors in the modified Balance Error Scoring System (BESS) were 1.6, tandem gait time 14.9 s and coordination score 0.95. For the subjective component, children reported an average of eight symptoms and a severity of 11; parents reported seven symptoms with a severity of 9. Overall, children reported higher symptom severity in comparison with their parents. In addition, parents significantly underestimated both physical and sleep-related symptoms in comparison with the children's scores.

Conclusions

Results provide representative scores for the Child SCAT3 in young male ice hockey players. Clinicians should be aware that parents tend to underestimate their child's symptoms and symptom severity, particularly in the domains of physical symptoms and sleep. Encouraging objective symptom documentation with sleep or pain diaries, for example, may be useful for reliable clinical assessment in this age group.
Exercise as medicine—the use of group medical visits to promote physical activity and treat chronic moderate depression: a preliminary 14-week pre–post study
Authors: Adams David J , Remick Ronald A , Davis Jennifer C , Vazirian Sara , Khan Karim M
Published: November 2015

Objective

The evidence that regular physical activity can treat depressive disorders is increasingly robust. However, motivating patients with depression to engage in physical activity can be challenging. Interdisciplinary group medical visits (GMVs) with an integrated physical activity component may be a novel means to support patients in becoming more active.

Methods

We conducted a ‘pre–post’ pilot study within a primary care setting. Participants were adults (≥18 years) with a chronic major depressive disorder or a bipolar 2 disorder (depression; chronic). A psychiatrist and exercise therapist co-led a series of 14 weekly 2 h GMVs. Each group visit combined specific medical advice, physical activity, patient discussions and a targeted educational component. Participants also attended 11 weekly hatha yoga classes. Primary outcome was ‘steps’ as measured by accelerometer (SenseWear) as well as depression (Patient Health Questionnaire, PHQ-9) and anxiety (Generalised Anxiety Disorder, GAD-7) ratings.

Results

14 of 15 participants (93.3%) completed the 14-week programme. After 3 months postintervention, median depression scales (PHQ-9) decreased 38% from 16 to 10 (p<0.01; IQR pre/post 8/12); and median anxiety scales (GAD-7) decreased 50% from 13 to 6.5 (p<0.05; IQR 8.5/9). Median daily ‘steps’ increased 71% from 3366 to 5746 (IQR 2610/6237), though this was not significant (p>0.10).

Conclusions

While other studies have examined the efficacy of GMVs in addressing chronic illnesses and the promotion of lifestyle changes, none to our knowledge have embedded physical activity within the actual patient visits. Interdisciplinary GMVs (eg, psychiatrist/exercise professional) may be a means to decrease depression and anxiety ratings within clinical care while improving physical activity.
Rethinking the role of fat oxidation: substrate utilisation during high-intensity interval training in well-trained and recreationally trained runners
Authors: Hetlelid Ken J , Plews Daniel J , Herold Eva , Laursen Paul B , Seiler Stephen
Published: November 2015

Background

Although carbohydrate is the predominant fuel source supporting high-intensity exercise workloads, the role of fat oxidation, and the degree to which it may be altered by training status, is less certain.

Methods

We compared substrate oxidation rates, using indirect calorimetry, during a high-intensity interval training (HIT) session in well-trained (WT) and recreationally trained (RT) runners. Following preliminary testing, 9 WT (VO2max71±5 mL/min/kg) and 9 RT (VO2max55±5 mL/min/kg) male runners performed a self-paced HIT sequence consisting of six, 4 min work bouts separated by 2 min recovery periods on a motorised treadmill set at a 5% gradient.

Results

WT and RT runners performed the HIT session with the same perceived effort (rating of perceived exertion (RPE) =18.3±0.7 vs 18.2±1.1, respectively), blood lactate (6.4±2.1 vs 6.2±2.5 mmol/L) and estimated carbohydrate oxidation rates (4.2±0.29 vs 4.4±0.45 g/min; effect size (ES) 90% confidence limits (CL)=−0.19±0.85). Fat oxidation (0.64±0.13 vs 0.22±0.16 g/min for WT and RT, respectively) accounted for 33±6% of the total energy expenditure in WT vs 16±6% in RT most likely very large difference in fat oxidation (ES 90% CL=1.74±0.83) runners. Higher rates of fat oxidation had a very large correlation with VO2max(r=0.86; 90% CI (0.7 to 0.94).

Conclusions

Despite similar RPE, blood lactate and carbohydrate oxidation rates, the better performance by the WT group was explained by their nearly threefold higher rates of fat oxidation at high intensity.
The impact of 12 weeks walking football on health and fitness in males over 50 years of age
Authors: Arnold Josh Timothy , Bruce-Low Stewart , Sammut Luke
Published: November 2015

Aim

To describe and characterise anthropometrical and fitness changes following a 12-week walking football programme in individuals over the age of 50 years.

Methods

Following ethical approval, 10 male participants (mean (SD): age 66 (7) years) with a range of comorbidities completed a 12-week walking football programme, consisting of a single 2 h training session each week. Body mass, fat mass, fat free mass, maximal oxygen consumption, maximal heart rate, exercise time to exhaustion and isometric hand-grip strength, were assessed at baseline and immediately following the intervention. Week-0–12 intervention differences were determined using means (95% CIs) and t tests; effect sizes were calculated using Cohen's d (0.2 small, 0.5 medium, 0.8 large).

Results

12 weeks walking football significantly reduced body fat mass (week 0, 27.4 (9.0) kg versus week 12, 24.4 (8.9) kg, p=<0.05, d=1.0) and reduced percentage body fat (week 0, 30.3 (8.2) % versus week 12, 27.5 (8.5) %, p=<0.05, d=1.0). A significant increase in time to volitional exhaustion during increamental exercise (week 0, 545 (102) s versus week 12, 603 (102) s, p=<0.05, d=0.7) was observed without any change in peak blood lactate. Non-significant differences with medium effect sizes were seen for a reduction whole body mass, increase in lean body mass and a reduction in body mass index.

Conclusions

This investigation suggests the potential efficacy of walking football as a public health intervention, even in populations presenting a range of comorbidities, with future research investigating its move to scale.
Incidence of nonresponse and individual patterns of response following sprint interval training
Authors: Gurd Brendon J. , Giles Matthew D. , Bonafiglia Jacob T. , Raleigh James P. , Boyd John C. , Ma Jasmin K. , Zelt Jason G.E. , Scribbans Trisha D.
Published: November 2015

The current study sought to explore the incidence of nonresponders for maximal or submaximal performance following a variety of sprint interval training (SIT) protocols. Data from 63 young adults from 5 previously published studies were utilized in the current analysis. Nonresponders were identified using 2 times the typical error (TE) of measurement for peak oxygen uptake (2 × TE = 1.74 mL/(kg·min)), lactate threshold (2 × TE = 15.7 W), or 500 kcal time-to-completion (TTC; 2 × TE = 306 s) trial. TE was determined on separate groups of participants by calculating the test–retest variance for each outcome. The overall rate of nonresponders for peak oxygen uptake across all participants studied was 22% (14/63) with 4 adverse responders observed. No nonresponders for peak oxygen uptake were observed in studies where participants trained 4 times per week (n = 18), while higher rates were observed in most studies requiring training 3 times per week (30%–50%; n = 45). A nonresponse rate of 44% (8/18) and 50% (11/22) was observed for the TTC test and lactate threshold, respectively. No significant correlations were observed between the changes in peak oxygen uptake and TTC (r = 0.014; p = 0.96) or lactate threshold (r = 0.17; p = 0.44). The current analysis demonstrates a significant incidence of nonresponders for peak oxygen uptake and heterogeneity in the individual patterns of response following SIT. Additionally, these data support the importance of training dose and suggest that the incidence of nonresponse may be mitigated by utilizing the optimal dose of SIT.
Historical occurrence of alien arthropods and pathogens on trees in Canada
Authors: Nealis V.G. , DeMerchant I. , Langor D. , Noseworthy M.K. , Pohl G. , Porter K. , Shanks E. , Turnquist R. , Waring V.
Published: November 2015

The Canadian Forest Invasive Alien Species (CanFIAS) database provides point records of alien arthropod (insects and mites) and pathogen (fungi) species found on trees in Canada extracted from more than 100 years of national surveys. Each record includes a species identification, location, year of observation, and host association and is linked electronically to its original source. More than 175 000 records of 329 alien arthropod species and 11 plant pathogens are available. Historical rates of detection, as indicated by first records, were greatest in the decades following the two world wars. The overall rate has been approximately three species per year since 1900. Richness of alien species is greatest in the Coastal and Great Lakes–St. Lawrence forest ecozones and lowest in the Subalpine and Tundra ecozones. The alien species most significant in terms of extent of invasion and damage to trees are tree-host specialists, feeding on or infecting mostly one or two genera in a single plant family. Important commercial trees including pine, spruce, poplar, and birch and amenity genera including willow, cherry, and maple host the greatest diversity of alien species. Sap-feeding insects are the most speciose feeding group, but foliage-feeding and wood-boring insects and plant pathogens cause the most damage.
Milk Production and Fertility in Cattle
Authors: Berry D.P. , Friggens N.C. , Lucy M. , Roche J.R.
Published: November 2015

Evolutionary biology provides reasons for why the intensive selection for milk production reduces reproductive success rates. There is considerable exploitable genetic variation in reproductive performance in both dairy and beef cattle, and examination of national genetic trends demonstrates that genetic gain for both reproductive performance and milk production is possible in a well-structured breeding program. Reproductive failure is often postulated to be a consequence of the greater negative energy balance associated with the genetic selection for increased milk production. However, experimental results indicate that the majority of the decline in reproductive performance cannot be attributed to early lactation energy balance, per se; reproductive success will, therefore, not be greatly improved by nutritional interventions aimed at reducing the extent of negative energy balance. Modeling can aid in better pinpointing the key physiological components governing reproductive success and, also, the impact of individual improvements on overall fertility, helping to prioritize variables for inclusion in breeding programs.
Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity
Authors: Barrat Franck J. , Elkon Keith B. , Fitzgerald Katherine A.
Published: November 2015

An important concept in immunology is the classification of immune responses as either innate or adaptive, based on whether the antigen receptors are encoded in the germline or generated somatically by gene rearrangement. The innate immune system is an ancient mode of immunity, and by being a first layer in our defense against infectious agents, it is essential for our ability to develop rapid and sustained responses to pathogens. We discuss the importance of nucleic acid recognition by the innate immune system to mounting an appropriate immune response to pathogens and also how inflammation driven by uncontrolled recognition of self-nucleic acids can lead to autoimmune diseases. We also summarize current efforts to either harness the immune system using agonists of nucleic acid–specific innate sensors or, on the contrary, by using inhibitors in autoimmune situations.
Drugging Undruggable Molecular Cancer Targets
Authors: Lazo John S. , Sharlow Elizabeth R.
Published: November 2015

Cancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. In this article, we outline the basis for the undruggable moniker, propose a reclassification of these targets as undrugged, and highlight three general classes of this imposing group as exemplars with some attendant strategies currently being explored to reclassify them. Expanding the spectrum of disease-relevant targets to pharmacological manipulation is central to reducing cancer morbidity and mortality.
Sleep Pharmacogenetics: Personalized Sleep-Wake Therapy
Authors: Holst Sebastian C. , Valomon Amandine , Landolt Hans-Peter
Published: November 2015

Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordered patients has identified the neurotransmitters and neuromodulators dopamine, serotonin, norepinephrine, histamine, hypocretin, melatonin, glutamate, acetylcholine, γ-amino-butyric acid, and adenosine as important players in the regulation and maintenance of sleep-wake-dependent changes in neuronal activity and the sleep-wake continuum. Dysregulation of these neurochemical systems leads to sleep-wake disorders. Most currently available pharmacological treatments are symptomatic rather than causal, and their beneficial and adverse effects are often variable and in part genetically determined. To evaluate opportunities for evidence-based personalized medicine with present and future sleep-wake therapeutics, we review here the impact of known genetic variants affecting exposure of and sensitivity to drugs targeting the neurochemistry of sleep-wake regulation and the pathophysiology of sleep-wake disturbances. Many functional polymorphisms modify drug response phenotypes relevant for sleep. To corroborate the importance of these and newly identified variants for personalized sleep-wake therapy, human sleep pharmacogenetics should be complemented with pharmacogenomic investigations, research about sleep-wake-dependent pharmacological actions, and studies in mice lacking specific genes. These strategies, together with future knowledge about epigenetic mechanisms affecting sleep-wake physiology and treatment outcomes, may lead to potent and safe novel therapies for the increasing number of sleep-disordered patients (e.g., in aged populations).
The Microbiome and the Respiratory Tract
Authors: Dickson Robert P. , Erb-Downward John R. , Martinez Fernando J. , Huffnagle Gary B.
Published: November 2015

Although the notion that “the normal lung is free from bacteria” remains common in textbooks, it is virtually always stated without citation or argument. The lungs are constantly exposed to diverse communities of microbes from the oropharynx and other sources, and over the past decade, novel culture-independent techniques of microbial identification have revealed that the lungs, previously considered sterile in health, harbor diverse communities of microbes. In this review, we describe the topography and population dynamics of the respiratory tract, both in health and as altered by acute and chronic lung disease. We provide a survey of current techniques of sampling, sequencing, and analysis of respiratory microbiota and review technical challenges and controversies in the field. We review and synthesize what is known about lung microbiota in various diseases and identify key lessons learned across disease states.
Systemic Nutrient and Stress Signaling via Myokines and Myometabolites
Authors: Rai Mamta , Demontis Fabio
Published: November 2015

Homeostatic systems mount adaptive responses to meet the energy demands of the cell and to compensate for dysfunction in cellular compartments. Such surveillance systems are also active at the organismal level: Nutrient and stress sensing in one tissue can lead to changes in other tissues. Here, we review the emerging understanding of the role of skeletal muscle in regulating physiological homeostasis and disease progression in other tissues. Muscle-specific genetic interventions can induce systemic effects indirectly, via changes in the mass and metabolic demand of muscle, and directly, via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) in response to nutrients and stress. In turn, myokines and myometabolites signal to various target tissues in an autocrine, paracrine, and endocrine manner, thereby determining organismal resilience to aging, disease, and environmental challenges. We propose that tailoring muscle systemic signaling by modulating myokine and myometabolite levels may combat many degenerative diseases and delay aging.
Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction
Authors: Hu Chunyan , Lu Ko-Ting , Mukohda Masashi , Davis Deborah R. , Faraci Frank M. , Sigmund Curt D.
Published: November 2015

The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARγ would exacerbate ANG II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng·kg−1·min−1) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against ANG II-induced endothelial dysfunction.
Polymorphisms Associated with Age at Onset in Patients with Moderate-to-Severe Plaque Psoriasis
Authors: Prieto-Pérez Rocío , Solano-López Guillermo , Cabaleiro Teresa , Román Manuel , Ochoa Dolores , Talegón María , Baniandrés Ofelia , López-Estebaranz José Luis , de la Cueva Pablo , Daudén Esteban , Abad-Santos Francisco
Published: November 2015

Psoriasis is a chronic skin disease in which genetics play a major role. Although many genome-wide association studies have been performed in psoriasis, knowledge of the age at onset remains limited. Therefore, we analyzed 173 single-nucleotide polymorphisms in genes associated with psoriasis and other autoimmune diseases in patients with moderate-to-severe plaque psoriasis type I (early-onset, <40 years) or type II (late-onset, ≥40 years) and healthy controls. Moreover, we performed a comparison between patients with type I psoriasis and patients with type II psoriasis. Our comparison of a stratified population with type I psoriasisn=155and healthy controlsN=197is the first to reveal a relationship between theCLMN,FBXL19,CCL4L,C17orf51,TYK2,IL13,SLC22A4,CDKAL1, andHLA-B/MICAgenes. When we compared type I psoriasis with type II psoriasisN=36, we found a significant association between age at onset and the genesPSORS6,TNF-α,FCGR2A,TNFR1,CD226,HLA-C,TNFAIP3, andCCHCR1. Moreover, we replicated the association between rs12191877 (HLA-C) and type I psoriasis and between type I and type II psoriasis. Our findings highlight the role of genetics in age of onset of psoriasis.
Thyroid Peroxidase Antibodies in Non-Interferon Treated Hepatitis C Patients in Pakistan
Authors: Shafiq Muhammad Imtiaz , Gauhar Amna , Akram Muhammad , Elahi Shan
Published: November 2015

Objective. Interferon therapy of HCV infected patients is associated with development of thyroid dysfunctions. Patients with pretreatment presence of antithyroid peroxidase (TPO-Ab) are at greater risk. This study, probably the first in Pakistan, was planned to determine TPO-Ab in sera of treatment-naive local HCV patients.Setting. Centre for Nuclear Medicine (CENUM), Mayo Hospital, Lahore.Patients and Methods. During July to December 2012, 190 patients (140 females, 50 males) newly diagnosed for HCV infection were selected for this study. Their age range was 15–55 years (mean: 35.3 ± 9.1 years). 262 age matched healthy subjects (211 females and 50 males) were recruited as control. Serum-free thyroxin (FT4) and thyroid stimulating hormone (TSH) were detected by radioimmunoassay techniques. Serum TPO-Ab titer was determined by ELISA method using commercial kits.Results. Serum FT4and TSH levels in HCV patients and controls were within normal range. Between two groups there was no significant difference in mean value of FT4(16.0 ± 3.0 versus 16.2 ± 3.9;P=0.619) but mean TSH value was significantly lower in HCV patients (1.5 ± 0.8 versus 1.8 ± 0.9;P=0.003). Among HCV patients 51 (26.8%) were TPO-Ab positive and among control subjects 18 (6.9%) were TPO-Ab positive. The difference was statistically significant(P<0.001). Further analysis showed that among HCV patients 39 (27.8%) females and 12 (24.0%) males were TPO-Ab positive, respectively, and difference was not statistically significant(P=0.873). Moreover, TPO-Ab positive patients were older and had significantly higher serum TSH as compared to TPO-Ab negative HCV patients.Conclusion. Independent of patient’s gender and increasing with advancing age, about one-fourth of local untreated HCV patients are TPO-Ab positive and are at greater risk of developing thyroid disorders during and after interferon treatment.
Improved Cat Swarm Optimization for Simultaneous Allocation of DSTATCOM and DGs in Distribution Systems
Authors: Kanwar Neeraj , Gupta Nikhil , Niazi K. R. , Swarnkar Anil
Published: November 2015

This paper addresses a new methodology for the simultaneous optimal allocation of DSTATCOM and DG in radial distribution systems to maximize power loss reduction while maintaining better node voltage profiles under multilevel load profile. Cat Swarm Optimization (CSO) is one of the recently developed powerful swarm intelligence-based optimization techniques that mimics the natural behavior of cats but usually suffers from poor convergence and accuracy while subjected to large dimension problem. Therefore, an Improved CSO (ICSO) technique is proposed to efficiently solve the problem where the seeking mode of CSO is modified to enhance its exploitation potential. In addition, the problem search space is virtually squeezed by suggesting an intelligent search approach which smartly scans the problem search space. Further, the effect of network reconfiguration has also been investigated after optimally placing DSTATCOMs and DGs in the distribution network. The suggested measures enhance the convergence and accuracy of the algorithm without loss of diversity. The proposed method is investigated on 69-bus test distribution system and the application results are very promising for the operation of smart distribution systems.
Prostate Cancer-Associated Disseminated Intravascular Coagulation with Excessive Fibrinolysis Treated with Degarelix
Authors: Ong Shawn Y. , Taverna Josephine , Jokerst Clint , Enzler Thomas , Hammode Emad , Rogowitz Elisa , Green Myke R. , Babiker Hani M.
Published: November 2015

Disseminated intravascular coagulation (DIC) with excessive fibrinolysis (XFL) is a rare and acute life-threatening variant of DIC in patients with prostate cancer. Patients present with coagulopathy, hypofibrinogenemia, and systemic bleeding. We describe a case of DIC XFL caused by prostate cancer (PC) successfully treated with a single injection of degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist. This led to prompt control of the patient’s coagulopathy within ten days of treatment. Our case highlights features of this rare and devastating hemorrhagic complication of PC along with a fast-acting and effective therapeutic drug option.
Acupuncture Attenuated Inflammation and Inhibited Th17 and Treg Activity in Experimental Asthma
Authors: Wei Ying , Dong Ming , Zhang Hongying , Lv Yubao , Liu Jiaqi , Wei Kai , Luo Qingli , Sun Jing , Liu Feng , Xu Fei , Dong Jingcheng
Published: November 2015

Acupuncture is an effective therapeutic method in asthma treatment in traditional Chinese medicine. Here, we evaluated the effect of acupuncture on airway hyperresponsiveness (AHR) and the associated inflammatory changes as well as Th17 and Treg activity in ovalbumin- (OVA-) induced experimental asthma. Our results revealed that acupuncture treatment significantly inhibited AHR, lung inflammation, and mucus secretion of experimental asthma mice. Furthermore, a decrease in lymphocytes and eosinophils as well as neutrophils was observed in bronchoalveolar lavage fluid (BALF) of mice treated with acupuncture. Acupuncture reduced the OVA specific IgE level as well as the Th17 cytokine levels including IL-17A, IL-17F, and IL-22 in the serum of the experimental asthma mice. Acupuncture treatment group also had reduced CD4+IL-17A+ cell numbers and increased CD4+Foxp3+ cell numbers in BALF. In addition, acupuncture could inhibit IL-17R, RORγt, p65, and the inhibitor of NF-κB kinase-α(IKKα) protein expression. Our results indicated that acupuncture was effective in inhibiting AHR and inflammation in OVA-induced experimental asthma, which may be associated with the regulation of Th17 and Treg activity and NF-κB pathway.