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1.  Progesterone vs placebo therapy for women with epilepsy 
Neurology  2012;78(24):1959-1966.
Objective:
To assess progesterone treatment of intractable seizures in women with partial epilepsy.
Methods:
This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles.
Results:
There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3.
Conclusion:
There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures.
Classification of evidence:
This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.
doi:10.1212/WNL.0b013e318259e1f9
PMCID: PMC3369508  PMID: 22649214
2.  Physician and Patient Assessment of Triamcinolone Acetonide Spray for Steroid-responsive Dermatoses 
Objective: To assess the clinical outcomes of triamcinolone acetonide spray for steroid-responsive dermatoses using investigator and patient global assessment scores and evaluate patient satisfaction. Design: This open-label, single-center, noncomparator study enrolled 42 patients (aged 18 years or older) with dermatoses. Patients were instructed to use triamcinolone acetonide spray 1 to 4 times daily, depending on investigator instructions, for up to 28 days. Measurements: Investigators and patients scored the overall severity of dermatoses based on a global assessment scale. Investigators also rated signs and symptoms of dermatoses and evaluated clinical outcomes based on an improvement assessment scale. Patient satisfaction with treatment was assessed at the end of treatment or at Day 28 using a questionnaire. Patients were evaluated on Days 7, 14, 21, and 28. Complete clearing of dermatoses warranted early discontinuation from the study. Results: Triamcinolone acetonide spray effectively improved dermatoses scores, clinical outcomes, and signs and symptoms of dermatoses. More than 80 percent of patients entered the study with moderate or severe dermatoses. Within 14 days, none had severe dermatoses, and by 28 days, 64 percent of patients were completely clear or almost clear. From the patient perspective, 51.3 percent experienced improvement in only three days, and 84.6 percent experienced improvement in seven days. An overwhelming number of patients (95%) preferred triamcinolone acetonide spray over creams and ointments, and more than half experienced a cooling effect upon contact with the spray. Conclusion: Triamcinolone acetonide spray is an effective topical corticosteroid that should be considered for patients with steroid-responsive dermatoses of all ranges of severity.
PMCID: PMC2922713  PMID: 20725566
3.  Intravesical capsaicin for treatment of detrusor hyperreflexia. 
An intravesical instillation of 100 ml 1 or 2 mmol/l capsaicin has been used to treat detrusor hyperreflexia giving rise to intractable urinary incontinence in 12 patients with spinal cord disease and two other patients with detrusor overactivity of non-spinal origin. Nine patients, all of whom had spinal cord disease, showed some improvement in bladder function. The benefit was only shortlived and partial in four, but the remaining five achieved complete continence while performing intermittent self catheterisation. Urodynamic studies in these nine patients showed an increase in mean (SD) bladder capacity from 106 (57) to 302 (212) ml and a fall in the maximum detrusor pressure from 54 (20) to 36 (10) cm of water. There were no short term ill effects from the instillation and the improvement in bladder function lasted for between three weeks to six months, when in some patients it was repeated. The improvement in bladder behaviour shown in this study can be interpreted as showing that capsaicin sensitive afferents play an important part in the pathogenesis of detrusor hyperreflexia in spinal humans. Intravesical capsaicin seems a promising means of treating intractable detrusor hyperreflexia and studies with this substance may shed new light on other disorders of detrusor activity that cause incontinence.
PMCID: PMC1072443  PMID: 8126498
6.  GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans 
Muscle microvascular surface area determines substrate and hormonal exchanges between plasma and muscle interstitium. GLP-1 (glucagon-like peptide-1) regulates glucose-dependent insulin secretion and has numerous extrapancreatic effects, including a salutary vascular action. To examine whether GLP-1 recruits skeletal and cardiac muscle microvasculature in healthy humans, 26 overnight-fasted healthy adults received a systemic infusion of GLP-1 (1.2 pmol/kg of body mass per min) for 150 min. Skeletal and cardiac muscle MBV (microvascular blood volume), MFV (microvascular flow velocity) and MBF (microvascular blood flow) were determined at baseline and after 30 and 150 min. Brachial artery diameter and mean flow velocity were measured and total blood flow was calculated before and at the end of the GLP-1 infusion. GLP-1 infusion raised plasma GLP-1 concentrations to the postprandial levels and suppressed plasma glucagon concentrations with a transient increase in plasma insulin concentrations. Skeletal and cardiac muscle MBV and MBF increased significantly at both 30 and 150 min (P < 0.05). MFV did not change in skeletal muscle, but decreased slightly in cardiac muscle. GLP-1 infusion significantly increased brachial artery diameter (P < 0.005) and flow velocity (P = 0.05) at 150 min, resulting in a significant increase in total brachial artery blood flow (P < 0.005). We conclude that acute GLP-1 infusion significantly recruits skeletal and cardiac muscle microvasculature in addition to relaxing the conduit artery in healthy humans. This could contribute to increased tissue oxygen, nutrient and insulin delivery and exchange and therefore better prandial glycaemic control and tissue function in humans.
doi:10.1042/CS20130708
PMCID: PMC4353574  PMID: 24552454
conduit artery; contrast ultrasonography; glucagon-like peptide-1 (GLP-1); microvascular recruitment
7.  Very-low-energy diet for type 2 diabetes: An underutilized therapy? 
Background
Current approaches to the management of type 2 diabetes focus on the early initiation of novel pharmacologic therapies and bariatric surgery.
Objective
The purpose of this study was to revisit the use of intensive, outpatient, behavioral weight management programs for the management of type 2 diabetes.
Design
Prospective observational study of 66 patients with type 2 diabetes and BMI ≥ 32 kg/m2 who enrolled in a program designed to produce 15% weight reduction over 12 weeks using total meal replacement and low- to moderate-intensity physical activity.
Results
Patients were 53 ± 7 years of age (mean ± SD) and 53% were men. After 12 weeks, BMI fell from 40.1 ± 6.6 to 35.1 ± 6.5 kg/m2. HbA1c fell from 7.4 ± 1.3% to 6.5 ± 1.2% (57.4 ± 12.3 to 47.7 ± 12.9 mmol/mol) in patients with established diabetes: 76% of patients with established diabetes and 100% of patients with newly diagnosed diabetes achieved HbA1c <7.0% (53.0 mmol/mol). Improvement in HbA1c over 12 weeks was associated with higher baseline HbA1c and greater reduction in BMI.
Conclusions
An intensive, outpatient, behavioral weight management program significantly improved HbA1c in patients with type 2 diabetes over 12 weeks. The use of such programs should be encouraged among obese patients with type 2 diabetes.
doi:10.1016/j.jdiacomp.2014.03.014
PMCID: PMC4350259  PMID: 24849710
8.  Functional effects of mutations in the tropomyosin-binding sites of tropomodulin1 and tropomodulin3 
Cytoskeleton (Hoboken, N.J.)  2014;71(7):395-411.
Tropomodulins (Tmods) interact with tropomyosins (TMs) via two TM-binding sites and cap the pointed ends of TM-coated actin filaments. To study the functional interplay between TM binding and TM-actin filament capping by Tmods, we introduced disabling mutations into the first, second, or both TM-binding sites of full-length Tmod1 (Tmod1-L27G, Tmod1-I131D, and Tmod1-L27G/I131D, respectively) and full-length Tmod3 (Tmod3-L29G, Tmod3-L134D, and Tmod3-L29G/L134D, respectively). Tmod1 and Tmod3 showed somewhat different TM-binding site utilization, but nearly all TM binding was abolished in Tmod1-L27G/I131D and Tmod3-L29G/L134D. Disruption of Tmod-TM binding had a modest effect on Tmod1's ability and no effect on Tmod3's ability to stabilize TM-actin pointed ends against latrunculin A-induced depolymerization. However, disruption of Tmod-TM binding did significantly impair the ability of Tmod3 to reduce elongation rates at pointed ends with α/βTM, albeit less so with TM5NM1, and not at all with TM5b. For Tmod1, disruption of Tmod-TM binding only slightly impaired its ability to reduce elongation rates with α/βTM and TM5NM1, but not at all with TM5b. Thus, Tmod-TM binding has a greater influence on Tmods’ ability to inhibit subunit association as compared to dissociation from TM-actin pointed ends, particularly for α/βTM, with Tmod3's activity being more dependent on TM binding than Tmod1's activity. Nevertheless, disruption of Tmod1-TM binding precluded Tmod1 targeting to thin filament pointed ends in cardiac myocytes, suggesting that the functional effects of Tmod-TM binding on TM-coated actin filament capping can be significantly modulated by the in vivo conformation of the pointed end or other factors in the intracellular environment.
doi:10.1002/cm.21179
PMCID: PMC4347929  PMID: 24922351
9.  “Insight” in Pigeons: Absence of Means-End Processing in Displacement Tests 
Animal cognition  2013;17(2):207-220.
The understanding of functional relations between action and consequence is a critical component of intelligence. To examine this linkage in pigeons, we investigated their understanding of the relations of the elements tested in an extension of Köhler's box-stacking task to this species (Epstein et al. 1984). In the experiments, the pigeons had to move a spatially displaced box under an out-of-reach target. Experiment 1 successfully replicated and extended the previous finding showing that when separately trained to move a box and stand on it to peck the target, pigeons can synthesize these behaviors to solve the single-box displacement problem quickly on their first attempt. Experiment 2 tested whether pigeons, when given a simultaneous choice among two boxes with identical reinforcement histories, would selectively choose the box with the correct functional affordance (i.e., permitting standing) to solve the problem rather than a nonfunctional one. Their extensive, equivalent, and undirected behavior in moving both boxes during these tests suggests the pigeons did not possess a means-end understanding of the functional properties of the boxes. Instead, their results were consistent with an analysis of their earlier synthetic behavior as being due to the temporal and spatial relations of the physical elements in the task and their prior learned behaviors.
doi:10.1007/s10071-013-0653-8
PMCID: PMC3894253  PMID: 23774955
10.  A hand surgeon’s guide to common onychodystrophies 
Hand (New York, N.Y.)  2013;9(1):24-28.
The human fingernail contributes to the precise dexterity of the fingers, enhances sensibility, allows manipulation of fine objects, and shields the fingertip from traumatic injury. Nail abnormalities are a common incidental finding in the course of a hand surgeon’s daily practice. These abnormalities may be clues to systemic, dermatologic, traumatic, and infectious processes that would benefit from further evaluation and treatment. The purpose of this review is to discuss common nail dystrophies and their related diagnoses.
doi:10.1007/s11552-013-9564-z
PMCID: PMC3928370  PMID: 24570633
Fingernail; Onychodystrophies
11.  Efficacy and safety of an extended nevirapine regimen in infants of breastfeeding mothers with HIV-1 infection for prevention of HIV-1 transmission (HPTN 046): 18-month results of a randomized, double-blind, placebo-controlled trial 
Summary
Background
HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18 month outcomes.
Methods
Randomized, placebo-controlled trial in four African countries. Infant diagnostic HIV testing was done regularly from birth, through 18 months. Kaplan-Meier analysis was used to assess 18 month cumulative infant HIV infection, HIV infection/or death and mortality rates.
Results
Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower, among infants receiving daily NVP from 6 weeks to 6 months 1.1% (95% CI 0.2-1.8%), compared to placebo: 2.4% (95% CI 1.3-2.6%), p=0.049; but not significantly lower thereafter. Eighteen month postnatal infection rates were low: 2.2% [95% CI 1.1-3.3%] versus 3.1% [95% CI 1.9-4.4%], respectively, p=0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18 month postnatal infection rates (0.5%, 95% CI 0.0-1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI 1.9-5.5%); and infants of mothers with CD4 >350/mm3 not receiving ART (4.8%, 95% CI 2.7-6.8%), (p=0.46). There were no differences in adverse events between study arms.
Conclusion
This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age six weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.
doi:10.1097/QAI.0000000000000052
PMCID: PMC3945386  PMID: 24189151
nevirapine; infant HIV prophylaxis; PMTCT
12.  Challenges and Ideas from a Research Program on High Quality, Evidence-Based Practice in School Mental Health 
Objective
Reviews the progression of a research program designed to develop, implement and study the implementation of “achievable” evidence-based practices (EBPs) in schools. Reviews challenges encountered and ideas to overcome them to enhance this avenue of research.
Method
Presents two federally funded randomized controlled trials involving comparison of a four-component targeted intervention (Quality Assessment and Improvement, Family Engagement and Empowerment, Modular Evidence-Based Practice, Implementation Support) versus a comparison intervention focused on Personal Wellness. In both studies primary aims focused on changes in clinician attitudes and behavior, including the delivery of high quality, evidence-based practices and secondary aims focused on student level impacts.
Results
A number of challenges, many not reported in the literature are reviewed, and ideas for overcoming them are presented.
Conclusions
Given the reality that the majority of youth mental health services are delivered in schools and the potential of school mental health (SMH) services to provide a continuum of mental health care from promotion to intervention, it is critical that the field consider and address the logistical and methodological challenges associated with implementing and studying EBP implementation by clinicians.
doi:10.1080/15374416.2013.833097
PMCID: PMC3954908  PMID: 24063310
school mental health; quality; family engagement and empowerment; evidence-based practices; challenges
14.  Staphylococcus aureus bloodstream infection: A pooled analysis of five prospective, observational studies 
The Journal of infection  2013;68(3):242-251.
Summary
Objectives
Staphylococcus aureus bacteraemia is a common, often fatal infection. Our aim was to describe how its clinical presentation varies between populations and to identify common determinants of outcome.
Methods
We conducted a pooled analysis on 3395 consecutive adult patients with S. aureus bacteraemia. Patients were enrolled between 2006 and 2011 in five prospective studies in 20 tertiary care centres in Germany, Spain, United Kingdom, and United States.
Results
The median age of participants was 64 years (interquartile range 50–75 years) and 63.8% were male. 25.4% of infections were associated with diabetes mellitus, 40.7% were nosocomial, 20.6% were caused by methicillin-resistant S. aureus (MRSA), although these proportions varied significantly across studies. Intravenous catheters were the commonest identified infective focus (27.7%); 8.3% had endocarditis. Crude 14 and 90-day mortality was 14.6% and 29.2%, respectively. Age, MRSA bacteraemia, nosocomial acquisition, endocarditis, and pneumonia were independently associated with death, but a strong association was with an unidentified infective focus (adjusted hazard ratio for 90-day mortality 2.92; 95% confidence interval 2.33 to 3.67, p < 0.0001).
Conclusion
The baseline demographic and clinical features of S. aureus bacteraemia vary significantly between populations. Mortality could be reduced by assiduous MRSA control and early identification of the infective focus.
doi:10.1016/j.jinf.2013.10.015
PMCID: PMC4136490  PMID: 24247070
Staphylococcus aureus bloodstream infection; Bacteraemia; Mortality; Pooled analysis
15.  Immunogenicity of ALVAC-HIV vCP1521 in Infants of HIV-1 Infected Women in Uganda (HPTN 027): the first pediatric HIV vaccine trial in Africa 
Objective
Maternal-to-child-transmission of HIV-1 infection remains a significant cause of HIV-1 infection despite successful prevention strategies. Testing protective HIV-1 vaccines remains a critical priority. The immunogenicity of ALVAC-HIV vCP1521 (ALVAC) in infants born to HIV-1 infected women in Uganda was evaluated in the first pediatric HIV-1 vaccine study in Africa.
Design
HPTN 027 was a randomized, double blind, placebo-controlled phase I trial to evaluate the safety and immunogenicity of ALVAC in 60 infants born to HIV-1 infected mothers with CD4 counts > 500 cell/μL that were randomized to the ALVAC vaccine or placebo. ALVAC-HIV vCP1521 is an attenuated recombinant canarypox virus expressing HIV-1 clade E env, clade B gag and protease gene products.
Methods
Infants were vaccinated at birth, 4, 8 and 12 weeks of age with ALVAC or placebo. Cellular and humoral immune responses were evaluated using IFN-γ ELISpot, CFSE proliferation, intracellular cytokine staining, binding and neutralizing antibody assays. Fisher's exact test was used to compare positive responses between study arms.
Results
Low levels of antigen specific CD4 and CD8 T cell responses (intracellular cytokine assay) were detected at 24 months (CD4 – 6/36 vaccine vs. 1/9 placebo; CD8 – 5/36 vaccine vs. 0/9 placebo) of age. There was a non-significant trend toward higher cellular immune response rates in vaccine recipients compared to placebo. There were minimal binding antibody responses and no neutralizing antibodies detected.
Conclusions
HIV-1 exposed infants are capable of generating low levels of cellular immune responses to ALVAC vaccine, similar to responses seen in adults.
doi:10.1097/01.qai.0000435600.65845.31
PMCID: PMC4171956  PMID: 24091694
HIV vaccine; infants; immunogenicity; Africa; HIV prevention
16.  Patient transitions relevant to individuals requiring ongoing ventilatory assistance: A Delphi study 
Distinguishing patient cohorts that require ongoing mechanical ventilation has been made problematic by the use of various terms, which, in turn, leads to difficulty in comparative studies and uncertainty in the timing of clinical decision making. Consensus conferences have achieved little in terms of standardizing transition terms and information that can be broadly applied to include the many clinical specialities reflecting the continuum of care. Accordingly, this study aimed to identify the defining features of key transition points for individuals requiring ongoing ventilator assistance based on expert-derived consensus.
BACKGROUND:
Various terms, including ‘prolonged mechanical ventilation’ (PMV) and ‘long-term mechanical ventilation’ (LTMV), are used interchangeably to distinguish patient cohorts requiring ventilation, making comparisons and timing of clinical decision making problematic.
OBJECTIVE:
To develop expert, consensus-based criteria associated with care transitions to distinguish cohorts of ventilated patients.
METHODS:
A four-round (R), web-based Delphi study with consensus defined as >70% was performed. In R1, participants listed, using free text, criteria perceived to should and should not define seven transitions. Transitions comprised: T1 – acute ventilation to PMV; T2 – PMV to LTMV; T3 – PMV or LTMV to acute ventilation (reverse transition); T4 – institutional to community care; T5 – no ventilation to requiring LTMV; T6 – pediatric to adult LTMV; and T7 – active treatment to end-of-life care. Subsequent Rs sought consensus.
RESULTS:
Experts from intensive care (n=14), long-term care (n=14) and home ventilation (n=10), representing a variety of professional groups and geographical areas, completed all Rs. Consensus was reached on 14 of 20 statements defining T1 and 21 of 25 for T2. ‘Physiological stability’ had the highest consensus (97% and 100%, respectively). ‘Duration of ventilation’ did not achieve consensus. Consensus was achieved on 13 of 18 statements for T3 and 23 of 25 statements for T4. T4 statements reaching 100% consensus included: ‘informed choice’, ‘patient stability’, ‘informal caregiver support’, ‘caregiver knowledge’, ‘environment modification’, ‘supportive network’ and ‘access to interprofessional care’. Consensus was achieved for 15 of 17 T5, 16 of 20 T6 and 21 of 24 T7 items.
CONCLUSION:
Criteria to consider during key care transitions for ventilator-assisted individuals were identified. Such information will assist in furthering the consistency of clinical care plans, research trials and health care resource allocation.
PMCID: PMC4198230  PMID: 24791254
Home ventilation; Long-term mechanical ventilation; Mechanical ventilation; Pediatric ventilation; Prolonged mechanical ventilation; Transition
17.  New Insights into Bacterial Chemoreceptor Array Structure and Assembly from Electron Cryotomography 
Biochemistry  2014;53(10):1575-1585.
Bacterial chemoreceptors cluster in highly ordered, cooperative, extended arrays with a conserved architecture, but the principles that govern array assembly remain unclear. Here we show images of cellular arrays as well as selected chemoreceptor complexes reconstituted in vitro that reveal new principles of array structure and assembly. First, in every case, receptors clustered in a trimers-of-dimers configuration, suggesting this is a highly favored fundamental building block. Second, these trimers-of-receptor dimers exhibited great versatility in the kinds of contacts they formed with each other and with other components of the signaling pathway, although only one architectural type occurred in native arrays. Third, the membrane, while it likely accelerates the formation of arrays, was neither necessary nor sufficient for lattice formation. Molecular crowding substituted for the stabilizing effect of the membrane and allowed cytoplasmic receptor fragments to form sandwiched lattices that strongly resemble the cytoplasmic chemoreceptor arrays found in some bacterial species. Finally, the effective determinant of array structure seemed to be CheA and CheW, which formed a “superlattice” of alternating CheA-filled and CheA-empty rings that linked receptor trimers-of-dimer units into their native hexagonal lattice. While concomitant overexpression of receptors, CheA, and CheW yielded arrays with native spacing, the CheA occupancy was lower and less ordered, suggesting that temporal and spatial coordination of gene expression driven by a single transcription factor may be vital for full order, or that array overgrowth may trigger a disassembly process. The results described here provide new insights into the assembly intermediates and assembly mechanism of this massive macromolecular complex.
doi:10.1021/bi5000614
PMCID: PMC3985956  PMID: 24580139
18.  Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice 
Psychopharmacology  2013;10.1007/s00213-013-3235-1.
Objective
Allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of α5* nAChRs in the effects of nicotine on brain reward systems.
Materials and methods
Effects of acute (0.03125-0.5 mg/kg SC) or chronic (24 mg/kg per day; osmotic minipump) nicotine, and mecamylamine-precipitated withdrawal, on intracranial self-stimulation (ICSS) thresholds were assessed in wildtype and α5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion (CTA) procedure.
Results
Lower nicotine doses (0.03125-0.125 mg/kg) decreased ICSS thresholds in wildtype and α5 knockout mice. At higher doses (0.25-0.5 mg/kg), threshold-lowering effects of nicotine were diminished in wildtype mice, whereas nicotine lowered thresholds across all doses tested in α5 knockout mice. Nicotine (1.5 mg/kg) conditioned a taste aversion to saccharine equally in both genotypes. Mecamylamine (5 mg/kg) elevated ICSS thresholds by a similar magnitude in wildtype and α5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated α5 knockout mice.
Conclusion
α5* nAChRs are not involved in reward-enhancing effects of lower nicotine doses, the reward-inhibiting effects of nicotine withdrawal, or the general noxious effects of higher nicotine doses. Instead, α5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of α5* nAChR signaling greatly expands the range of nicotine doses that facilitate brain reward activity, which may help explain the increased tobacco addiction vulnerability associated with CHRNA5 risk alleles.
doi:10.1007/s00213-013-3235-1
PMCID: PMC3930613  PMID: 23958943
CHRNA5; α5 nicotinic receptors; nicotine; reward; aversion; habenula; interpeduncular nucleus; conditioned taste aversion
19.  Effects of Motion Sickness Severity on the Vestibular-Evoked Myogenic Potentials 
Background
Motion sickness is a common debilitating condition associated with both actual and perceived motion. Despite the commonality, little is known about the underlying physiological mechanisms. One theory proposes that motion sickness arises from a mismatch between reality and past experience in vertical motions. Physiological tests of the vestibular system, however, have been inconclusive regarding the underlying pathogenesis. Cervical vestibular-evoked myogenic potentials (cVEMPs) arise from the saccule, which responds to vertical motion. If vertical motion elicits motion sickness, the cVEMP should be affected.
Purpose
The purpose of this investigation was to determine if cVEMP characteristics differ among individuals with a range of motion sickness susceptibility from negligible to severe. The hypothesis was that individuals with high susceptibility would have larger cVEMP amplitudes and shorter cVEMP latencies relative to those who are resistant to motion sickness.
Research Design
The study had two parts. The first was quasi-experimental in which participants comprised three groups based on susceptibility to motion sickness (low, mild-moderate, high) as identified on the short version of the Motion Sickness Susceptibility Questionnaire (MSSQ-S). The second part of the study was correlational and evaluated the specific relationships between the degree of motion sickness susceptibility and characteristics of the VEMPs.
Study Sample
A total of 24 healthy young adults (ages 20–24 yr) were recruited from the university and the community without regard to motion sickness severity.
Data Collection and Analysis
Participants took the MSSQ-S, which quantifies susceptibility to motion sickness. The participants had a range of motion sickness susceptibility with MSSQ raw scores from 0.0–36.6, which correspond to percent susceptibility from 0.0–99.3%. VEMPs were elicited by 500 Hz tone-bursts monaurally in both ears at 120 dB pSPL. MSSQ-S percent scores were used to divide the participants into low, mild-moderate, and high susceptibility groups. A fixed general linear model with repeated-measures analysis of variance tested cVEMP characteristics for the susceptibility groups (between participants) and ears (within participants). A univariate analysis of variance tested the cVEMP interaural amplitudes across groups. The second analysis was a regression of the severity of motion sickness in percent on cVEMP characteristics. Significance was defined as p < 0.05.
Results
Participants in the high susceptibility group had significantly higher cVEMP amplitudes than those in the low susceptibility group. cVEMP amplitudes did not differ between ears, and latencies did not differ between the two groups or between ears. Regression analysis on MSSQ-S percent susceptibility by VEMP amplitudes revealed a best-fit cubic function in both ears, with r2 values of more than 42%. The interaural asymmetry ratio was negatively associated with motion sickness susceptibility (r2 = 0.389).
Conclusions
The current study is the first to report that greater susceptibility to motion sickness is associated with larger cVEMP amplitudes and lower interaural cVEMP asymmetries. Larger interaural asymmetries in cVEMPs did not promote motion sickness susceptibility. The cVEMP findings implicate the saccule and its neural pathways in the production of motion sickness and are consistent with the theory that vertical motions elicit motion sickness. Motion sickness susceptibility may contribute to the variability in normative cVEMP amplitudes.
doi:10.3766/jaaa.25.9.4
PMCID: PMC4332880  PMID: 25405837
Vestibular-evoked myogenic potential; motion sickness; saccule; vestibular nerve; inner ear; perception; humans; adults
20.  Being Ready to Treat Ebola Virus Disease Patients 
As the outbreak of Ebola virus disease (EVD) in West Africa continues, clinical preparedness is needed in countries at risk for EVD (e.g., United States) and more fully equipped and supported clinical teams in those countries with epidemic spread of EVD in Africa. Clinical staff must approach the patient with a very deliberate focus on providing effective care while assuring personal safety. To do this, both individual health care providers and health systems must improve EVD care. Although formal guidance toward these goals exists from the World Health Organization, Medecin Sans Frontières, the Centers for Disease Control and Prevention, and other groups, some of the most critical lessons come from personal experience. In this narrative, clinicians deployed by the World Health Organization into a wide range of clinical settings in West Africa distill key, practical considerations for working safely and effectively with patients with EVD.
doi:10.4269/ajtmh.14-0746
PMCID: PMC4347319  PMID: 25510724
21.  Gating Topology of the Proton-Coupled Oligopeptide Symporters 
Structure(London, England:1993)  2015;23(2):290-301.
Summary
Proton-coupled oligopeptide transporters belong to the major facilitator superfamily (MFS) of membrane transporters. Recent crystal structures suggest the MFS fold facilitates transport through rearrangement of their two six-helix bundles around a central ligand binding site; how this is achieved, however, is poorly understood. Using modeling, molecular dynamics, crystallography, functional assays, and site-directed spin labeling combined with double electron-electron resonance (DEER) spectroscopy, we present a detailed study of the transport dynamics of two bacterial oligopeptide transporters, PepTSo and PepTSt. Our results identify several salt bridges that stabilize outward-facing conformations and we show that, for all the current structures of MFS transporters, the first two helices of each of the four inverted-topology repeat units form half of either the periplasmic or cytoplasmic gate and that these function cooperatively in a scissor-like motion to control access to the peptide binding site during transport.
Graphical Abstract
Highlights
•New higher-resolution structure of PepTSo•Salt bridges stabilizing outward-facing conformations are identified•The conserved prolines in helix 8 are shown to be important•The first two helices in each inverted-topology repeat form part of a gate
Fowler et al. use biophysical and modeling approaches to identify salt bridges in two peptide transporters that stabilize their outward-facing conformations. Their results also suggest that the first two helices in each inverted-topology repeat unit forms part of either of the two gates.
doi:10.1016/j.str.2014.12.012
PMCID: PMC4321885  PMID: 25651061
22.  Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy 
The Journal of Clinical Investigation  2014;124(11):4693-4708.
Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
doi:10.1172/JCI75199
PMCID: PMC4347224  PMID: 25250574
23.  Modeling Trajectory of Depressive Symptoms Among Psychiatric Inpatients: A Latent Growth Curve Approach 
Objectives
Changes in the parameters of inpatient psychiatric care have inspired a sizable literature exploring correlates of prolonged intervention as well as symptom change over varying lengths of hospitalization. However, existing data offer limited insight regarding the nature of symptom change over time. Objectives of this longitudinal research were to (a) model the trajectory of depressive symptoms within an inpatient psychiatric sample, (b) identify characteristics associated with unique patterns of change, and (c) evaluate the magnitude of expected gains using objective clinical benchmarks.
Methods
Participants included psychiatric inpatients treated between April 2008 and December 2010. Latent growth curve modeling was used to determine the trajectory of Beck Depression Inventory II depressive symptoms in response to treatment. Age, gender, trauma history, prior hospitalization, and DSM-IV diagnoses were examined as potential moderators of recovery.
Results
Results indicate a nonlinear model of recovery, with symptom reductions greatest following admission and slowing gradually over time. Female gender, probable trauma exposure, prior psychiatric hospitalization, and primary depressive diagnosis were associated with more severe trajectories. Diagnosis of alcohol/substance use, by contrast, was associated with more moderate trajectories. Objective benchmarks occurred relatively consistently across patient groups with clinically significant change occurring between 2–4 weeks post-admission.
Conclusion
The nonlinear trajectory of recovery observed in these data provides insight regarding the dynamics of inpatient recovery. Across all patient groups, symptom reduction was most dramatic in the initial week of hospitalization. However, notable improvement continued for several weeks post-admission. Results suggest timelines for adequate inpatient care are largely contingent on program-specific goals.
doi:10.4088/JCP.12m07842
PMCID: PMC4313384  PMID: 23759452
inpatient treatment; psychiatric hospitalization; depression; symptom trajectory; latent growth curve modeling
24.  The Common Marmoset Genome Provides Insight into Primate Biology and Evolution 
Worley, Kim C. | Warren, Wesley C. | Rogers, Jeffrey | Locke, Devin | Muzny, Donna M. | Mardis, Elaine R. | Weinstock, George M. | Tardif, Suzette D. | Aagaard, Kjersti M. | Archidiacono, Nicoletta | Rayan, Nirmala Arul | Batzer, Mark A. | Beal, Kathryn | Brejova, Brona | Capozzi, Oronzo | Capuano, Saverio B. | Casola, Claudio | Chandrabose, Mimi M. | Cree, Andrew | Dao, Marvin Diep | de Jong, Pieter J. | del Rosario, Ricardo Cruz-Herrera | Delehaunty, Kim D. | Dinh, Huyen H. | Eichler, Evan | Fitzgerald, Stephen | Flicek, Paul | Fontenot, Catherine C. | Fowler, R. Gerald | Fronick, Catrina | Fulton, Lucinda A. | Fulton, Robert S. | Gabisi, Ramatu Ayiesha | Gerlach, Daniel | Graves, Tina A. | Gunaratne, Preethi H. | Hahn, Matthew W. | Haig, David | Han, Yi | Harris, R. Alan | Herrero, Javier M. | Hillier, LaDeana W. | Hubley, Robert | Hughes, Jennifer F. | Hume, Jennifer | Jhangiani, Shalini N. | Jorde, Lynn B. | Joshi, Vandita | Karakor, Emre | Konkel, Miriam K. | Kosiol, Carolin | Kovar, Christie L. | Kriventseva, Evgenia V. | Lee, Sandra L. | Lewis, Lora R. | Liu, Yih-shin | Lopez, John | Lopez-Otin, Carlos | Lorente-Galdos, Belen | Mansfield, Keith G. | Marques-Bonet, Tomas | Minx, Patrick | Misceo, Doriana | Moncrieff, J. Scott | Morgan, Margaret B. | Muthuswamy, Raveendran | Nazareth, Lynne V. | Newsham, Irene | Nguyen, Ngoc Bich | Okwuonu, Geoffrey O. | Prabhakar, Shyam | Perales, Lora | Pu, Ling-Ling | Puente, Xose S. | Quesada, Victor | Ranck, Megan C. | Raney, Brian J. | Deiros, David Rio | Rocchi, Mariano | Rodriguez, David | Ross, Corinna | Ruffier, Magali | Ruiz, San Juana | Sajjadian, S. | Santibanez, Jireh | Schrider, Daniel R. | Searle, Steve | Skaletsky, Helen | Soibam, Benjamin | Smit, Arian F. A. | Tennakoon, Jayantha B. | Tomaska, Lubomir | Ullmer, Brygg | Vejnar, Charles E. | Ventura, Mario | Vilella, Albert J. | Vinar, Tomas | Vogel, Jan-Hinnerk | Walker, Jerilyn A. | Wang, Qing | Warner, Crystal M. | Wildman, Derek E. | Witherspoon, David J. | Wright, Rita A. | Wu, Yuanqing | Xiao, Weimin | Xing, Jinchuan | Zdobnov, Evgeny M. | Zhu, Baoli | Gibbs, Richard A. | Wilson, Richard K.
Nature genetics  2014;46(8):850-857.
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
doi:10.1038/ng.3042
PMCID: PMC4138798  PMID: 25038751
25.  Emerging and Resistant Infections 
Annals of the American Thoracic Society  2014;11(Suppl 4):S193-S200.
The lungs are a major target for infection and a key battleground in the fight against the development of antimicrobial drug–resistant pathogens. Ventilator-associated pneumonia (VAP) is associated with mortality rates of 24–50%. The optimal duration of antibiotic therapy against VAP is unknown, but prolonged courses are associated with the emergence of bacterial resistance. De-escalation strategies in which treatment is discontinued based on signs of clinical resolution, fixed durations of therapy (generally 7–8 d), or serum procalcitonin responses have been shown to decrease antibiotic consumption. Outcomes are comparable to longer treatment courses, with the possible exception of VAP due to nonfermenting, gram-negative bacilli such as Pseudomonas aeruginosa. Staphylococcus aureus is a leading cause of VAP and other infections. Outcomes after S. aureus infection are shaped by the interplay between environmental, bacterial, and host genetic factors. It is increasingly clear that mechanisms of pathogenesis vary in different types of S. aureus infections. Genome-scale studies of S. aureus strains, host responses, and host genetics are redefining our understanding of the pathogenic mechanisms underlying VAP. Genome-sequencing technologies are also revolutionizing our understanding of the molecular epidemiology, evolution, and transmission of influenza. Deep sequencing using next-generation technology platforms is defining the remarkable genetic diversity of influenza strains within infected hosts. Investigators have demonstrated that antiviral drug-resistant influenza may be present prior to the initiation of treatment. Moreover, drug-resistant minor variant influenza strains can be transmitted from person to person in the absence of selection pressure. Studies of lung infections and the causative pathogens will remain at the cutting edge of clinical and basic medical research.
doi:10.1513/AnnalsATS.201402-069PL
PMCID: PMC4200571  PMID: 25148425
pneumonia; ventilator-associated pneumonia; Staphylococcus aureus; influenza

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