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1.  Adenosine A1 receptor activation mediates the developmental shift at layer 5 pyramidal cell synapses and is a determinant of mature synaptic strength 
The Journal of Physiology  2013;591(Pt 13):3371-3380.
During the first postnatal month glutamatergic synapses between layer 5 pyramidal cells in the rodent neocortex switch from an immature state exhibiting a high probability of neurotransmitter release, large unitary amplitude and synaptic depression to a mature state with decreased probability of release, smaller unitary amplitude and synaptic facilitation. Using paired recordings, we demonstrate that the developmental shift in release probability at synapses between rat somatosensory layer 5 thick-tufted pyramidal cells is mediated by a higher and more heterogeneous activation of presynaptic adenosine A1 receptors. Immature synapses under control conditions exhibited distributions of coefficient of variation, failure rate and release probability that were almost coincident with the A1 receptor blocked condition; however, mature synapses under control conditions exhibited much broader distributions that spanned those of both the A1 receptor agonized and antagonized conditions. Immature and mature synapses expressed A1 receptors with no observable difference in functional efficacy and therefore the heterogeneous A1 receptor activation seen in the mature neocortex appears due to increased adenosine concentrations that vary between synapses. Given the central role demonstrated for A1 receptor activation in determining synaptic amplitude and the statistics of transmission between mature layer 5 pyramidal cells, the emplacement of adenosine sources and sinks near the synaptic terminal could constitute a novel form of long-term synaptic plasticity.
PMCID: PMC3717233  PMID: 23613526
2.  mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome 
Science (New York, N.Y.)  2013;342(6165):1524-1528.
Mitochondrial dysfunction contributes to numerous health problems, including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies. We found that rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, robustly enhances survival and attenuates disease progression in a mouse model of Leigh syndrome. Administration of rapamycin to these mice, which are deficient in the mitochondrial respiratory chain subunit Ndufs4 [NADH dehydrogenase (ubiquinone) Fe-S protein 4], delays onset of neurological symptoms, reduces neuroinflammation, and prevents brain lesions. Although the precise mechanism of rescue remains to be determined, rapamycin induces a metabolic shift toward amino acid catabolism and away from glycolysis, alleviating the buildup of glycolytic intermediates. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.
PMCID: PMC4055856  PMID: 24231806
3.  FlgN Is Required for Flagellum-Based Motility by Bacillus subtilis 
Journal of Bacteriology  2014;196(12):2216-2226.
The assembly of the bacterial flagellum is exquisitely controlled. Flagellar biosynthesis is underpinned by a specialized type III secretion system that allows export of proteins from the cytoplasm to the nascent structure. Bacillus subtilis regulates flagellar assembly using both conserved and species-specific mechanisms. Here, we show that YvyG is essential for flagellar filament assembly. We define YvyG as an orthologue of the Salmonella enterica serovar Typhimurium type III secretion system chaperone, FlgN, which is required for the export of the hook-filament junction proteins, FlgK and FlgL. Deletion of flgN (yvyG) results in a nonmotile phenotype that is attributable to a decrease in hag translation and a complete lack of filament polymerization. Analyses indicate that a flgK-flgL double mutant strain phenocopies deletion of flgN and that overexpression of flgK-flgL cannot complement the motility defect of a ΔflgN strain. Furthermore, in contrast to previous work suggesting that phosphorylation of FlgN alters its subcellular localization, we show that mutation of the identified tyrosine and arginine FlgN phosphorylation sites has no effect on motility. These data emphasize that flagellar biosynthesis is differentially regulated in B. subtilis from classically studied Gram-negative flagellar systems and questions the biological relevance of some posttranslational modifications identified by global proteomic approaches.
PMCID: PMC4054197  PMID: 24706744
4.  A germline mutation in the BRCA1 3’UTR predicts Stage IV breast cancer 
BMC Cancer  2014;14:421.
A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer.
The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont.
Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort.
A variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.
PMCID: PMC4059881  PMID: 24915755
BRCA1-3’UTR-variant; Mutation; Breast cancer; Stage IV breast cancer; Metastatic breast cancer; Biomarker; Diagnostic marker
5.  Responses evoked by a vestibular implant providing chronic stimulation 
Patients with bilateral vestibular loss experience dehabilitating visual, perceptual, and postural difficulties, and an implantable vestibular prosthesis that could improve these symptoms would be of great benefit to these patients. In previous work, we have shown that a one-dimensional, unilateral canal prosthesis can improve the vestibulooccular reflex (VOR) in canal-plugged squirrel monkeys. In addition to the VOR, the potential effects of a vestibular prosthesis on more complex, highly integrative behaviors, such as the perception of head orientation and posture have remained unclear. We tested a one-dimensional, unilateral prosthesis in a rhesus monkey with bilateral vestibular loss and found that chronic electrical stimulation partially restored the compensatory VOR and also that percepts of head orientation relative to gravity were improved. However, the one-dimensional prosthetic stimulation had no clear effect on postural stability during quiet stance, but sway evoked by head-turns was modestly reduced. These results suggest that not only can the implementation of a vestibular prosthesis provide partial restitution of VOR but may also improve perception and posture in the presence of bilateral vestibular hypofunction (BVH). In this review, we provide an overview of our previous and current work directed towards the eventual clinical implementation of an implantable vestibular prosthesis.
PMCID: PMC4041130  PMID: 22699148
vestibular; vestibular prosthesis; implant; vestibulooccular reflex; psychophysics; balance; posture
6.  Nursing the tropics: nurses as agents of imperial hygiene 
Mrs Francis Piggott proposed the Colonial Nursing Association in 1895 as a means of supplying Britain's colonies and dominions with trained professional nurses, who would support the health of white colonists abroad. Over 8400 nurses were placed between 1896 and the Association's end in 1966. Despite the burgeoning of scholarship on gender and empire over the last few decades, there is still more research to be done examining nurses as professional, working women, who present a fascinating variation on the figure of the woman traveler.
This essay focuses on 1896–1927, exploring how nurses were prepared for their labor abroad and how these skills were challenged and adapted within a foreign environment. We contextualize this discussion with examples from literary tales of exploration and adventure and discourses of empire.
Though the sources of disease against which nurses fought changed during this period, we assert that the underlying role of the nurse continued the same: she was meant to use the tools of personal as well as public ‘hygiene’ to create both physical and cultural boundaries around her white patients and herself, setting colonists apart from their colonial setting.
PMCID: PMC3669591  PMID: 23729785
history of empire; hygiene; nurses; travel; West Africa
7.  Rapid Transposon Liquid Enrichment Sequencing (TnLE-seq) for Gene Fitness Evaluation in Underdeveloped Bacterial Systems 
Applied and Environmental Microbiology  2013;79(23):7510-7517.
Whole-genome fitness analysis in microbes that uses saturating transposon mutagenesis combined with massively parallel sequencing (Tn-seq) is providing a measure of the contribution of each gene to a given growth condition. With this technique, gene fitness profiles and essential genes are discovered by simultaneous analyses of whether the absence of each gene product alters the growth kinetics of the bacterium. Here we modify the standard Tn-seq procedure to simplify and shorten the process by including delivery of the transposon through conjugation and liquid culture enrichment of the mutant pool, creating transposon liquid enrichment sequencing (TnLE-seq). To illustrate the success of these modifications and the robustness of the procedure, analyses of gene fitness of two cultures of the strictly anaerobic bacterium Desulfovibrio vulgaris Hildenborough were performed, with growth on lactate as the electron donor and sulfate as the electron acceptor. These data demonstrate reproducibility and provide a base condition for analysis of fitness changes in deletion mutants and in various growth conditions. The procedural modifications will facilitate the application of this powerful genetic analysis to microbes lacking a facile genetic system. Pilot studies produced 2.5 × 105 and 3.4 × 105 unique insertion mutants in the anaerobe Desulfovibrio vulgaris Hildenborough grown under typical laboratory conditions in rich medium. These analyses provided two similar high-resolution maps of gene fitness across the genome, and the method was also applied to growth in minimal medium. These results were also compared to the coverage obtained with a ca. 13,000-member cataloged transposon library constructed by sequencing transposon insertion sites in individual mutants.
PMCID: PMC3837734  PMID: 24077707
8.  Youth Versus Adult “Weightlifting” Injuries Presenting to United States Emergency Rooms: Accidental Versus Nonaccidental Injury Mechanisms 
Myer, GD, Quatman, CE, Khoury, J, Wall, EJ, and Hewett, TE. Youth versus adult “weightlifting” injuries presenting to united states emergency rooms: accidental versus nonaccidental injury mechanisms. J Strength Cond Res 23(7): 2054–2060, 2009—Resistance training has previously been purported to be unsafe and ineffective in children. The purpose of this investigation was to evaluate resistance training-related injuries presenting to U.S. emergency rooms by age, type, and mechanism of injury. We hypothesized that older athletes would sustain greater percentages of joint sprains and muscle strains, whereas younger athletes would sustain a greater percentage of accidental injuries that would result in an increased percentage of fractures in youths. The U.S. Consumer Product Safety Commission (CPSC) National Electronic Injury Surveillance System was queried from 2002 to 2005 using the CPSC code for “Weightlifting.” Subjects between the ages of 8 and 30 were grouped by age categories 8 to 13 (elementary/middle school age), 14 to 18 (high school), 19 to 22 (college), and 23 to 30 (adult). Injuries were classified as “accidental” if caused by dropped weight or improper equipment use. Multiple logistic regression was used to compare accidental injuries between age groups. The sample consisted of 4, 111 patients. Accidental injuries decreased (p < 0.05) with age: 8 to 13 > 14 to 18 > 19 to 22 years = 23 to 30 years. Conversely, sprain/strain injuries increased in each successive age group (p < 0.05). Evaluation of only the nonaccidental injuries (n = 2, 565) showed that the oldest categories (19–22 and 23–30 yr) demonstrated a greater percentage of sprains and strains relative to younger age categories (p < 0.001). Two thirds of the injuries sustained in the 8 to 13 group were to the hand and foot and were most often related to “dropping” and “pinching” in the injury descriptions, and there was an increased percentage of fractures in the 8 to 13 group relative to all other groups (p < 0.001). The study findings indicate that children have lower risk of resistance training-related joint sprains and muscle strains than adults. The majority of youth resistance training injuries are the result of accidents that are potentially preventable with increased supervision and stricter safety guidelines.
PMCID: PMC4034275  PMID: 19855330
pediatric resistance training; weight room injuries; resistance training injuries; weight room safety guidelines; resistance training safety
9.  The development and experience of epidemiological transition theory over four decades: a systematic review 
Global Health Action  2014;7:10.3402/gha.v7.23574.
Epidemiological transition (ET) theory, first postulated in 1971, has developed alongside changes in population structures over time. However, understandings of mortality transitions and associated epidemiological changes remain poorly defined for public health practitioners. Here, we review the concept and development of ET theory, contextualising this in empirical evidence, which variously supports and contradicts the original theoretical propositions.
A Medline literature search covering publications over four decades, from 1971 to 2013, was conducted. Studies were included if they assessed human populations, were original articles, focused on mortality and health or demographic or ET and were in English. The reference lists of the selected articles were checked for additional sources.
We found that there were changes in emphasis in the research field over the four decades. There was an increasing tendency to study wide-ranging aspects of the determinants of mortality, including risk factors, lifestyle changes, socio-economics, and macro factors such as climate change. Research on ET has focused increasingly on low- and middle-income countries rather than industrialised countries, despite its origins in industrialised countries. Countries have experienced different levels of progress in ET in terms of time, pace, and underlying mechanisms. Elements of ET are described for many countries, but observed transitions have not always followed pathways described in the original theory.
The classic ET theory largely neglected the critical role of social determinants, being largely a theoretical generalisation of mortality experience in some countries. This review shows increasing interest in ET all over the world but only partial concordance between established theory and empirical evidence. Empirical evidence suggests that some unconsidered aspects of social determinants contributed to deviations from classic theoretical pathways. A better-constructed, revised ET theory, with a stronger basis in evidence, is needed.
PMCID: PMC4038769  PMID: 24848657
epidemiological transition; demographic transition; mortality; social determinants
10.  Mannitol and other osmotic diuretics as adjuncts for treating cerebral malaria 
Cerebral oedema occurs with cerebral malaria, and some clinicians think osmotic diuretics, such as mannitol or urea, may improve outcomes.
To compare mannitol or urea to placebo or no diuretic for treating children or adults with cerebral malaria.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register (Issue 4, 2010), CENTRAL (The Cochrane Library Issue 12, 2010), MEDLINE (1966 to November 2010), EMBASE (1974 to November 2010), LILACS (1982 to November 2010), and the reference lists of articles. We contacted relevant organizations and researchers.
Selection criteria
Randomized or quasi-randomized controlled trials comparing mannitol or urea to placebo or no treatment in children and adults with cerebral malaria. Primary outcomes were death, life-threatenining sequelae and major neurological sequelae at six months.
Data collection and analysis
Two authors applied the inclusion criteria, assessed risk of bias, and extracted data independently.
Main results
One trial met the inclusion criteria, comparing mannitol 20% to saline placebo in 156 Ugandan children. Allocation was concealed. No difference in mortality, time to regain consciousness, or neurological sequelae were detected.
Authors’ conclusions
There are insufficient data to know what the effects of osmotic diuretics are in children with cerebral malaria. Larger, multicentre trials are needed.
PMCID: PMC4018680  PMID: 21491391
Antimalarials [therapeutic use]; Diuretics, Osmotic [*therapeutic use]; Malaria, Cerebral [*drug therapy]; Mannitol [*therapeutic use]; Quinine [therapeutic use]; Randomized Controlled Trials as Topic; Uganda; Urea [therapeutic use]; Adult; Child; Humans
11.  Traumeel S in preventing and treating mucositis in young patients undergoing SCT: a report of the Children’s Oncology Group 
Bone marrow transplantation  2012;47(11):1409-1414.
Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children’s Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi-center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3–25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day −1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day −1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area-under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P = 0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT.
PMCID: PMC4008329  PMID: 22504933
Traumeel S; mucositis; SCT
12.  Reproductive costs for everyone: How female loads impact human mobility strategies 
Journal of human evolution  2013;64(5):448-456.
While mobility strategies are considered important in understanding selection pressures on individuals, testing hypotheses of such strategies requires high resolution datasets, particularly at intersections between morphology, ecology and energetics. Here we present data on interactions between morphology and energetics in regards to the cost of walking for reproductive women and place these data into a specific ecological context of time and heat load. Frontal loads (up to 16% of body mass), as during pregnancy and child-carrying, significantly slow the optimal and preferred walking speed of women, significantly increase cost at the optimal speed, and make it significantly more costly for women to walk with other people. We further show for the first time significant changes in the curvature in the Cost of Transport curve for human walking, as driven by frontal loads. The impact of these frontal loads on females, and the populations to which they belong, would have been magnified by time constraints due to seasonal changes in day length at high latitudes and thermoregulatory limitations at low latitudes. However, wider pelves increase both stride length and speed flexibility, providing a morphological offset for load-related costs. Longer lower limbs also increase stride length. Observed differences between preferred and energetically optimal speeds with frontal loading suggest that speed choices of women carrying reproductive loads might be particularly sensitive to changes in heat load. Our findings show that female reproductive costs, particularly those related to locomotion, would have meaningfully shaped the mobility strategies of the hominin lineage, as well as modern foraging populations.
PMCID: PMC3771649  PMID: 23465336
Cost of transport; Speed; Sexual dimorphism; Walking; Pelvis; Energetics
13.  Impact of long-term contraceptive promotion on incident pregnancy: a randomized controlled trial among HIV positive couples in Lusaka, Zambia 
To evaluate the impact of family planning promotion on incident pregnancy in a combined effort to address Prongs 1 and 2 of Prevention of Mother-to-Child Transmission of HIV.
We conducted a factorial randomized controlled trial of two video-based interventions.
“Methods-focused” and “Motivational” messages promoted long-term contraceptive use among 1060 couples with HIV in Lusaka, Zambia.
Among couples not using contraception prior to randomization (N=782), the video interventions had no impact on incident pregnancy. Among baseline contraceptive users, viewing the “Methods” video which focused on the IUD and contraceptive implant was associated with a significantly lower pregnancy incidence (HR=0.38; 95%CI:0.19–0.75) relative to those viewing control and/or motivational videos. The effect was strongest in concordant positive couples (HR=0.22; 95%CI:0.08–0.58) and couples with HIV+ women (HR=0.23; 95%CI:0.09–0.55).
The “Methods video” intervention was previously shown to increase uptake of longer-acting contraception and to prompt a shift from daily oral contraceptives to quarterly injectables and long-acting methods such as the IUD and implant. Follow-up confirms sustained intervention impact on pregnancy incidence among baseline contraceptive users, in particular couples with HIV positive women. Further work is needed to identify effective interventions to promote long-acting contraception among couples who have not yet adopted modern methods.
PMCID: PMC3625483  PMID: 23202814
Couples’ voluntary HIV counseling and testing; family planning; long-term contraception; randomized controlled trial; Zambia
14.  Environmental Public Health Tracking: Success Stories from a Collaborative Surveillance System 
PMCID: PMC4050798
Surveillance; Environmental Health; Tracking
15.  Surgical Technique for Treatment of Recalcitrant Adductor Longus Tendinopathy 
Arthroscopy Techniques  2014;3(2):e293-e297.
Chronic groin pain in the athlete can be a difficult problem to manage. Adductor dysfunction is the most common cause of groin pain in athletes, with the adductor longus being the tendon most commonly involved. The most reproducible finding for adductor longus tendinopathy is tenderness along the tendon with passive abduction and resisted hip adduction in extension. Magnetic resonance imaging and injection of a corticosteroid and anesthetic into the proximal muscle-tendon junction are both helpful in confirming the diagnosis. Nonoperative treatment may consist of protected weight bearing, ice application, ultrasonography, electrical stimulation, and gentle stretching with progressive strengthening. However, nonoperative management is not always successful. In these instances, surgical treatment can be quite effective. We present the indications, surgical technique, and rehabilitation protocol of adductor tenotomy for chronic tendinopathy. This can prove a useful tool for the treatment of recalcitrant groin pain attributable to the adductor longus.
PMCID: PMC4044507  PMID: 24904780
16.  Osmotic therapies added to antibiotics for acute bacterial meningitis 
Every day children and adults throughout the world die from acute community-acquired bacterial meningitis, particularly in low-income countries. Survivors are at risk of deafness, epilepsy and neurological disabilities. Osmotic therapies have been proposed as an adjunct to improve mortality and morbidity from bacterial meningitis. The theory is that they will attract extra-vascular fluid by osmosis and thus reduce cerebral oedema by moving excess water from the brain into the blood. The intention is to thus reduce death and improve neurological outcomes.
To evaluate the effects on mortality, deafness and neurological disability of osmotic therapies added to antibiotics for acute bacterial meningitis in children and adults.
Search methods
We searched CENTRAL 2012, Issue 11, MEDLINE (1950 to November week 3, 2012), EMBASE (1974 to November 2012), CINAHL (1981 to November 2012), LILACS (1982 to November 2012) and registers of ongoing clinical trials (April 2012). We also searched conference abstracts and contacted researchers in the field.
Selection criteria
Randomised controlled trials testing any osmotic therapy in adults or children with acute bacterial meningitis.
Data collection and analysis
Two review authors independently screened the search results and selected trials for inclusion. We collected data from each study for mortality, deafness, seizures and neurological disabilities. Results are presented using risk ratios (RR) and 95% confidence intervals (CI) and grouped according to whether the participants received steroids or not.
Main results
Four trials were included comprising 1091 participants. All compared glycerol (a water-soluble sugar alcohol) with a control; in three trials this was a placebo, and in one a small amount of 50% dextrose. Three trials included comparators of dexamethasone alone or in combination with glycerol. As dexamethasone appeared to have no modifying effect, we aggregated results across arms where both treatment and control groups received corticosteroids and where both treatment and control groups did not.
Compared to placebo, glycerol may have little or no effect on death in people with bacterial meningitis (RR 1.09, 95% confidence interval (CI) 0.89 to 1.33, 1091 participants, four trials, low-quality evidence); or on death and neurological disability combined (RR 1.04, 95% CI 0.86 to 1.25).
Glycerol may have little or no effect on seizures during treatment for meningitis (RR 1.08, 95% CI 0.90 to 1.30, 909 participants, three trials, low-quality evidence).
Glycerol may reduce the risk of subsequent deafness (RR 0.60, 95% CI 0.38 to 0.93, 741 participants, four trials, low-quality evidence).
Authors’ conclusions
The only osmotic diuretic to have undergone randomised evaluation is glycerol. Data from trials to date have not demonstrated benefit on death, but it may reduce deafness. Osmotic diuretics, including glycerol, should not be given to adults and children with bacterial meningitis unless as part of carefully conducted randomised controlled trial.
PMCID: PMC3996551  PMID: 23543568
Adrenal Cortex Hormones [therapeutic use]; Anti-Bacterial Agents [therapeutic use]; Combined Modality Therapy [methods]; Community-Acquired Infections [complications; metabolism; mortality; therapy]; Deafness [prevention & control]; Dexamethasone [therapeutic use]; Diuretics, Osmotic [*therapeutic use]; Epilepsy [prevention & control]; Glucose [therapeutic use]; Glycerol [*therapeutic use]; Intracranial Pressure [physiology]; Meningitis, Bacterial [complications; metabolism; mortality; *therapy]; Osmosis [physiology]; Osmotic Pressure [physiology]; Randomized Controlled Trials as Topic; Adolescent; Adult; Child; Humans
19.  Genetic basis for nitrate resistance in Desulfovibrio strains 
Nitrate is an inhibitor of sulfate-reducing bacteria (SRB). In petroleum production sites, amendments of nitrate and nitrite are used to prevent SRB production of sulfide that causes souring of oil wells. A better understanding of nitrate stress responses in the model SRB, Desulfovibrio vulgaris Hildenborough and Desulfovibrio alaskensis G20, will strengthen predictions of environmental outcomes of nitrate application. Nitrate inhibition of SRB has historically been considered to result from the generation of small amounts of nitrite, to which SRB are quite sensitive. Here we explored the possibility that nitrate might inhibit SRB by a mechanism other than through nitrite inhibition. We found that nitrate-stressed D. vulgaris cultures grown in lactate-sulfate conditions eventually grew in the presence of high concentrations of nitrate, and their resistance continued through several subcultures. Nitrate consumption was not detected over the course of the experiment, suggesting adaptation to nitrate. With high-throughput genetic approaches employing TnLE-seq for D. vulgaris and a pooled mutant library of D. alaskensis, we determined the fitness of many transposon mutants of both organisms in nitrate stress conditions. We found that several mutants, including homologs present in both strains, had a greatly increased ability to grow in the presence of nitrate but not nitrite. The mutated genes conferring nitrate resistance included the gene encoding the putative Rex transcriptional regulator (DVU0916/Dde_2702), as well as a cluster of genes (DVU0251-DVU0245/Dde_0597-Dde_0605) that is poorly annotated. Follow-up studies with individual D. vulgaris transposon and deletion mutants confirmed high-throughput results. We conclude that, in D. vulgaris and D. alaskensis, nitrate resistance in wild-type cultures is likely conferred by spontaneous mutations. Furthermore, the mechanisms that confer nitrate resistance may be different from those that confer nitrite resistance.
PMCID: PMC4001038  PMID: 24795702
sulfate-reducing bacteria; sulfide control; Desulfovibrio; nitrite; nitrate inhibition; stress response; functional genomics; fitness profiling
20.  The Potential of Accelerating Early Detection of Autism through Content Analysis of YouTube Videos 
PLoS ONE  2014;9(4):e93533.
Autism is on the rise, with 1 in 88 children receiving a diagnosis in the United States, yet the process for diagnosis remains cumbersome and time consuming. Research has shown that home videos of children can help increase the accuracy of diagnosis. However the use of videos in the diagnostic process is uncommon. In the present study, we assessed the feasibility of applying a gold-standard diagnostic instrument to brief and unstructured home videos and tested whether video analysis can enable more rapid detection of the core features of autism outside of clinical environments. We collected 100 public videos from YouTube of children ages 1–15 with either a self-reported diagnosis of an ASD (N = 45) or not (N = 55). Four non-clinical raters independently scored all videos using one of the most widely adopted tools for behavioral diagnosis of autism, the Autism Diagnostic Observation Schedule-Generic (ADOS). The classification accuracy was 96.8%, with 94.1% sensitivity and 100% specificity, the inter-rater correlation for the behavioral domains on the ADOS was 0.88, and the diagnoses matched a trained clinician in all but 3 of 22 randomly selected video cases. Despite the diversity of videos and non-clinical raters, our results indicate that it is possible to achieve high classification accuracy, sensitivity, and specificity as well as clinically acceptable inter-rater reliability with nonclinical personnel. Our results also demonstrate the potential for video-based detection of autism in short, unstructured home videos and further suggests that at least a percentage of the effort associated with detection and monitoring of autism may be mobilized and moved outside of traditional clinical environments.
PMCID: PMC3989176  PMID: 24740236
21.  Einthoven dissertation prizes 2013 
Netherlands Heart Journal  2014;22(5):249-252.
PMCID: PMC4016325  PMID: 24718898
22.  Bronchial Wall Measurements in Patients after Lung Transplantation: Evaluation of the Diagnostic Value for the Diagnosis of Bronchiolitis Obliterans Syndrome 
PLoS ONE  2014;9(4):e93783.
To prospectively evaluate quantitative airway wall measurements of thin-section CT for the diagnosis of Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation.
Materials and Methods
In 141 CT examinations, bronchial wall thickness (WT), the wall area percentage (WA%) calculated as the ratio of the bronchial wall area and the total area (sum of bronchial wall area and bronchial lumen area) and the difference of the WT on inspiration and expiration (WTdiff) were automatically measured in different bronchial generations. The measurements were correlated with the lung function parameters. WT and WA% in CT examinations of patients with (n = 25) and without (n = 116) BOS, were compared using the unpaired t-test and univariate analysis of variance, while also considering the differing lung volumes.
Measurements could be performed in 2,978 bronchial generations. WT, WA%, and WTdiff did not correlate with the lung function parameters (r<0.5). The WA% on inspiration was significantly greater in patients with BOS than in patients without BOS, even when considering the dependency of the lung volume on the measurements. WT on inspiration and expiration and WA% on expiration did not show significant differences between the groups.
WA% on inspiration was significantly greater in patients with than in those without BOS. However, WA% measurements were significantly dependent on lung volume and showed a high variability, thus not allowing the sole use of bronchial wall measurements to differentiate patients with from those without BOS.
PMCID: PMC3979715  PMID: 24713820
23.  Exome capture from saliva produces high quality genomic and metagenomic data 
BMC Genomics  2014;15:262.
Targeted capture of genomic regions reduces sequencing cost while generating higher coverage by allowing biomedical researchers to focus on specific loci of interest, such as exons. Targeted capture also has the potential to facilitate the generation of genomic data from DNA collected via saliva or buccal cells. DNA samples derived from these cell types tend to have a lower human DNA yield, may be degraded from age and/or have contamination from bacteria or other ambient oral microbiota. However, thousands of samples have been previously collected from these cell types, and saliva collection has the advantage that it is a non-invasive and appropriate for a wide variety of research.
We demonstrate successful enrichment and sequencing of 15 South African KhoeSan exomes and 2 full genomes with samples initially derived from saliva. The expanded exome dataset enables us to characterize genetic diversity free from ascertainment bias for multiple KhoeSan populations, including new exome data from six HGDP Namibian San, revealing substantial population structure across the Kalahari Desert region. Additionally, we discover and independently verify thirty-one previously unknown KIR alleles using methods we developed to accurately map and call the highly polymorphic HLA and KIR loci from exome capture data. Finally, we show that exome capture of saliva-derived DNA yields sufficient non-human sequences to characterize oral microbial communities, including detection of bacteria linked to oral disease (e.g. Prevotella melaninogenica). For comparison, two samples were sequenced using standard full genome library preparation without exome capture and we found no systematic bias of metagenomic information between exome-captured and non-captured data.
DNA from human saliva samples, collected and extracted using standard procedures, can be used to successfully sequence high quality human exomes, and metagenomic data can be derived from non-human reads. We find that individuals from the Kalahari carry a higher oral pathogenic microbial load than samples surveyed in the Human Microbiome Project. Additionally, rare variants present in the exomes suggest strong population structure across different KhoeSan populations.
PMCID: PMC4051168  PMID: 24708091
Exomes; KhoeSan; Genetic diversity; Metagenomics; Microbiome
24.  Regional variation in IIM myosin heavy chain expression in the temporalis muscle of female and male baboons(Papio anubis) 
Archives of oral biology  2012;58(4):435-443.
The purpose of this study was to determine whether high amounts of fast/type II myosin heavy chain (MyHC) in the superficial as compared to the deep temporalis muscle of adult female and male baboons(Papio anubis) correlates with published data on muscle function during chewing. Electromyograpic (EMG) data show a regional specialization in activation from low to high amplitude activity during hard/tough object chewing cycles in the baboon superficial temporalis (Wall et al., 2007, 2008). A positive correlation between fast/type II MyHC amount and EMG activity will support the high occlusal force hypothesis.
Deep anterior temporalis (DAT), superficial anterior temporalis (SAT), and superficial posterior temporalis (SPT) muscle samples were analyzed using SDS-PAGE gel electrophoresis to test the prediction that SAT and SPT will show high amounts of fast/type II MyHC compared to DAT. Serial muscle sections were incubated against NOQ7.5.4D and MY32 antibodies to determine the breadth of slow/type I versus fast/type II expression within each section.
Type I and type IIM MyHCs comprise nearly 100% of the MyHCs in the temporalis muscle. IIM MyHC was the overwhelmingly predominant fast MyHC, though there was a small amount of type IIA MyHC (≤5%) in DAT in two individuals. SAT and SPT exhibited a fast/type II phenotype and contained large amounts of IIM MyHC whereas DAT exhibited a type I/type II (hybrid) phenotype and contained a significantly greater proportion of MyHC-I. MyHC-I expression in DAT was sexually dimorphic as it was more abundant in females.
The link between the distribution of IIM MyHC and high relative EMG amplitudes in SAT and SPT during hard/tough object chewing cycles is evidence of regional specialization in fiber type to generate high occlusal forces during chewing. The high proportion of MyHC-I in DAT of females may be related to a high frequency of individual fiber recruitment in comparison to males.
PMCID: PMC3593987  PMID: 23102552
Myosin Type Composition; Mastication; Muscle; Anatomy

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