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1.  Effects of Educational Music Therapy on State Hope for Recovery in Acute Care Mental Health Inpatients: A Cluster-Randomized Effectiveness Study 
Frontiers in Psychology  2016;7:1569.
Background: There has been an increasing emphasis on recovery as the expectation for people with mental health disorders.
Purpose: The purpose of this effectiveness study is to determine if group-based educational music therapy can immediately impact state hope for recovery in acute care mental health patients. Research questions included: will acute care mental health inpatients who participate in a single music therapy session have higher agency and pathway aspects of state hope for recovery than patients in a control condition? Will there be differences in state hope for recovery as a result of hope-oriented songwriting or lyric analysis interventions?
Method: Participants (N = 169) were cluster randomized to one of three single-session conditions: lyric analysis, songwriting, or wait-list control.
Results: There was no significant between-group difference. However, both music therapy conditions tended to have slightly higher mean pathway, agency, and total state hope scores than the control condition even within the temporal parameters of a single music therapy session. There was no between-group difference in the songwriting and lyric analysis interventions.
Conclusion: Although not significant, results support that educational music therapy may impact state hope for recovery within the temporal parameters of a single session. The specific type of educational music therapy intervention did not affect results. Implications for practice, limitations, and suggestions for future research are provided.
doi:10.3389/fpsyg.2016.01569
PMCID: PMC5054018  PMID: 27774084
hope; educational; mental health; music therapy; acute psychiatric patients; recovery; state hope
2.  Obstacles to implementation of an intervention to improve surgical services in an Ethiopian hospital: a qualitative study of an international health partnership project 
Background
Access to safe surgical care represents a critical gap in healthcare delivery and development in many low- and middle-income countries, including Ethiopia. Quality improvement (QI) initiatives at hospital level may contribute to closing this gap. Many such quality improvement initiatives are carried out through international health partnerships. Better understanding of how to optimise quality improvement in low-income settings is needed, including through partnership-based approaches. Drawing on a process evaluation of an intervention to improve surgical services in an Ethiopian hospital, this paper offers lessons to help meet this need.
Methods
We conducted a qualitative process evaluation of a quality improvement project which aimed to improve access to surgical services in an Ethiopian referral hospital through better management. Data was collected longitudinally and included: 66 in-depth interviews with surgical staff and project team members; observation (135 h) in the surgery department and of project meetings; project-related documentation. Thematic analysis, guided by theoretical constructs, focused on identifying obstacles to implementation.
Results
The project largely failed to achieve its goals. Key barriers related to project design, partnership working and the implementation context, and included: confusion over project objectives and project and partner roles and responsibilities; logistical challenges concerning overseas visits; difficulties in communication; gaps between the time and authority team members had and that needed to implement and engage other staff; limited strategies for addressing adaptive—as opposed to technical—challenges; effects of hierarchy and resource scarcity on QI efforts. While many of the obstacles identified are common to diverse settings, our findings highlight ways in which some features of low-income country contexts amplify these common challenges.
Conclusion
We identify lessons for optimising the design and planning of quality improvement interventions within such challenging healthcare contexts, with specific reference to international partnership-based approaches. These include: the need for a funded lead-in phase to clarify and agree goals, roles, mutual expectations and communication strategies; explicitly incorporating adaptive, as well as technical, solutions; transparent management of resources and opportunities; leadership which takes account of both formal and informal power structures; and articulating links between project goals and wider organisational interests.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-016-1639-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12913-016-1639-4
PMCID: PMC4987978  PMID: 27530439
Quality improvement; Surgery; Patient safety; Partnership; Ethiopia
3.  Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial 
Background
In Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV-positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy.
Methods/design
In order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation.
Discussion
Given the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies.
Trial registration
ClinicalTrials.gov, NCT02400021
doi:10.1186/s40814-016-0087-6
PMCID: PMC5153916  PMID: 27965866
HIV; Pregnancy; Protease inhibitors; Progesterone supplementation; Low birth weight; Preterm birth; RCT; Feasibility; Pilot study
4.  Cell Surface Human Airway Trypsin-Like Protease Is Lost During Squamous Cell Carcinogenesis 
Journal of cellular physiology  2016;231(7):1476-1483.
Cancer progression is accompanied by increased levels of extracellular proteases that are capable of remodeling the extracellular matrix, as well as cleaving and activating growth factors and receptors that are involved in pro-cancerous signaling pathways. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression, however, the expression or function of the TTSP Human Airway Trypsin-like protease (HAT) in carcinogenesis has not been examined. In the present study we aimed to determine the expression of HAT during squamous cell carcinogenesis. HAT transcript is present in several tissues containing stratified squamous epithelium and decreased expression is observed in carcinomas. We determined that HAT protein is consistently expressed on the cell surface in suprabasal/apical layers of squamous cells in healthy cervical and esophageal epithelia. To assess whether HAT protein is differentially expressed in normal tissue versus tissue in different stages of carcinogenesis, we performed a comprehensive immunohistochemical analysis of HAT protein expression levels and localization in arrays of paraffin embedded human cervical and esophageal carcinomas compared to the corresponding normal tissue. We found that HAT protein is expressed in the non-proliferating, differentiated cellular strata and is lost during the dedifferentiation of epithelial cells, a hallmark of squamous cell carcinogenesis. Thus, HAT expression may potentially be useful as a marker for clinical grading and assessment of patient prognosis in squamous cell carcinomas.
doi:10.1002/jcp.25173
PMCID: PMC4933652  PMID: 26297835
5.  The Association of Nonalcoholic Fatty Liver Disease, Obesity, and Metabolic Syndrome, with Systemic Inflammation and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2015;239(2):629-633.
Introduction
We characterized the association of 3 metabolic conditions – obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) – with increased inflammation and subclinical atherosclerosis.
Methods
We conducted cross-sectional analysis of 3,976 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with adequate CT imaging to diagnose NAFLD. Obesity was defined as BMI ≥30 kg/m2, metabolic syndrome by AHA/NHLBI criteria, and NAFLD using non-contrast cardiac CT and a liver/spleen attenuation ratio (L/S) <1. Increased inflammation was defined as high sensitivity C-reactive protein (hsCRP) ≥2 mg/L and subclinical atherosclerosis as coronary artery calcium (CAC) >0. We studied the association of a stepwise increase in number of these metabolic conditions (0–3) with increased inflammation and CAC, stratifying results by gender and ethnicity.
Results
Mean age of participants was 63 (±10) years, 45% were male, 37% white, 10% Chinese, 30% African American, and 23% Hispanic. Adjusting for obesity, metabolic syndrome and traditional risk factors, NAFLD was associated with a prevalence odds ratio for hsCRP ≥2 mg/L and CAC >0 of 1.47 (1.20–1.79) and 1.37 (1.11–1.68) respectively. There was a positive interaction between female gender and NAFLD in the association with hsCRP ≥2 mg/L (p= 0.006), with no interaction by race. With increasing number of metabolic conditions, there was a graded increase in prevalence odds ratios of hsCRP ≥2 mg/L and CAC >0.
Conclusion
NAFLD is associated with increased inflammation and CAC independent of traditional risk factors, obesity and metabolic syndrome. There is a graded association between obesity, metabolic syndrome, and NAFLD with inflammation and CAC.
doi:10.1016/j.atherosclerosis.2015.02.011
PMCID: PMC4406399  PMID: 25683387
6.  Staphylococcus pettenkoferi bacteremia: A case report and review of the literature 
In 2002, the coagulase-negative staphylococci species Staphylococcus pettenkoferi was first described. In addition to an overview of the laboratory detection of uncommon coagulase-negative staphylococci, this report describes, to the author’s knowledge, the first case of S pettenkoferi bacteremia in Canada.
Staphylococcus pettenkoferi is a relatively recently described coagulase-negative staphylococci species first described in 2002. Since then, nine additional cases of infection caused by this species have been reported in various countries around the world, including Germany, Belgium, France, South Korea, Italy, Brazil and Mexico. The present report describes a case of S pettenkoferi peripheral line-associated bacteremia. To our knowledge, the present report is the first description of human infection caused by S pettenkoferi in Canada. The present report also provides an overview of the laboratory detection of uncommon coagulase-negative staphylococci.
PMCID: PMC4692301  PMID: 26744589
Bacteremia; Coagulase negative; MALDI-ToF; Staphylococcus pettenkoferi
7.  The Relationship of Coronary Artery Calcium To Coronary Heart Disease Events is Similar in Young and Elderly Participants in The Multi-Ethnic Study of Atherosclerosis: A Secondary Analysis of a Prospective Population-based Cohort 
Mayo Clinic proceedings  2014;89(10):1350-1359.
Objective
To evaluate the relationship of coronary artery calcium (CAC) to coronary heart disease (CHD) events among young and elderly individuals.
Participants and Methods
This is a secondary analysis of data from a prospective, multi-ethnic, population-based cohort study designed to study subclinical atherosclerosis. A total of 6809 persons aged 45 to 84 years old without known cardiovascular disease at baseline were enrolled from July 2000-September 2002. All participants had CAC scoring performed, and were followed up for a median of 8.5 years. The main outcome measures studied were CHD events, defined as myocardial infarction, definite angina or probable angina followed by revascularization, resuscitated cardiac arrest or death attributable to coronary heart disease.
Results
Comparing individuals with CAC=0 to those with CAC > 100, there was an increased incidence of CHD events from 1 to 21/1000 person-years, and 2 to 23/1000 person-years in the 45-54 and 75-84 year old age groups respectively. Compared to CAC=0, CAC 1-100 and CAC >100 impart an increased multi-variable adjusted CHD event risk in both the 45-54 and 75-84 year old age groups [HR (95% CI): 45-54 years old, CAC 1-100: 2.3 (0.9-5.8), CAC>100: 12.4 (5.1-30.0); 75-84 years old, CAC 1-100: 5.4 (1.2-23.8), CAC>100: 12.1 (2.9-50.2)].
Conclusions
Increased CAC imparts an increased CHD risk in younger and elderly individuals, suggesting that once CAC is known chronologic age has less importance. The utility of CAC scoring as a risk-stratification tool extends both to younger and elderly patients.
doi:10.1016/j.mayocp.2014.05.017
PMCID: PMC4424047  PMID: 25236430
coronary artery calcium; coronary artery disease; aging
8.  Efficacy of Cardiac Resynchronization in Acutely Infarcted Canine Hearts with Electro-mechanical Dyssynchrony 
Background
Patients with acute MI, left bundle branch block (LBBB), and marked LV decompensation suffer nearly 50% early mortality. Whether CRT improves hemodynamic status in this condition is unknown. We tested CRT in this setting, using a canine model of delayed lateral wall activation combined with 2-hours of coronary artery occlusion-reperfusion.
Objective
To evaluate the acute hemodynamic effects of CRT during and immediately after myocardial infarction.
Methods
Adult dogs (n=8) underwent open-chest 2-hour mid-left anterior descending artery occlusion (LAD) followed by 1-hour reperfusion. Four pacing modes were compared: right atrial pacing, pseudo-left bundle block (RV-pacing), and CRT with the left-ventricular (LV) lead positioned at either the lateral wall (LW-CRT) or peri-infarct zone (PIZ-CRT). Continuous LV pressure-volume data, regional segment length, and proximal LAD flow rates were recorded.
Results
At baseline, both RVP and PIZ-CRT reduced anterior wall regional work by ~50% (versus RA pacing). During coronary occlusion, this territory became dyskinetic, and dyskinesis rose further with both CRT modes as compared to pseudo-LBBB. Global cardiac output, stroke work, and ejection fraction all still improved by 11–23%. After reperfusion, both CRT modes elevated infarct-zone regional work and blood flow by ~10% over pseudo-LBBB, and improved global function.
Conclusion
CRT improves global chamber systolic function in chambers with delayed lateral wall activation during and following sustained coronary occlusion. It does so while modestly augmenting infarct-zone dyskinesis during occlusion and improving regional function and blood-flow upon reperfusion. These findings support CRT in the setting of early post-MI dyssynchronous heart failure.
doi:10.1016/j.hrthm.2014.05.036
PMCID: PMC4188793  PMID: 24887137
myocardial infarction; acute heart failure; cardiac resynchronization therapy
9.  Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles 
Molecular Biology of the Cell  2015;26(14):2664-2672.
Although dynactin was believed to be a bidirectional facilitator of axonal transport, here mycalolide B is identified as a dynactin dissociator and shown to selectively abolish retrograde axonal transport of dense-core vesicles in hippocampal and Drosophila neurons. Thus dynactin has a strict obligatory unidirectional role in axonal transport.
Axonal transport is critical for maintaining synaptic transmission. Of interest, anterograde and retrograde axonal transport appear to be interdependent, as perturbing one directional motor often impairs movement in the opposite direction. Here live imaging of Drosophila and hippocampal neuron dense-core vesicles (DCVs) containing a neuropeptide or brain-derived neurotrophic factor shows that the F-actin depolymerizing macrolide toxin mycalolide B (MB) rapidly and selectively abolishes retrograde, but not anterograde, transport in the axon and the nerve terminal. Latrunculin A does not mimic MB, demonstrating that F-actin depolymerization is not responsible for unidirectional transport inhibition. Given that dynactin initiates retrograde transport and that amino acid sequences implicated in macrolide toxin binding are found in the dynactin component actin-related protein 1, we examined dynactin integrity. Remarkably, cell extract and purified protein experiments show that MB induces disassembly of the dynactin complex. Thus imaging selective retrograde transport inhibition led to the discovery of a small-molecule dynactin disruptor. The rapid unidirectional inhibition by MB suggests that dynactin is absolutely required for retrograde DCV transport but does not directly facilitate ongoing anterograde DCV transport in the axon or nerve terminal. More generally, MB's effects bolster the conclusion that anterograde and retrograde axonal transport are not necessarily interdependent.
doi:10.1091/mbc.E14-11-1564
PMCID: PMC4501363  PMID: 26023088
10.  Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis 
European Heart Journal  2013;35(33):2232-2241.
Aims
We sought to evaluate the impact of coronary artery calcium (CAC) in individuals at the extremes of risk factor (RF) burden.
Methods and results
6698 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) were followed for coronary heart disease (CHD) events over mean 7.1 ± 1 years. Annualized CHD event rates were compared among each RF category (0, 1, 2, or ≥3) after stratification by CAC score (0, 1–100, 101–300, and >300). The following traditional modifiable RFs were considered: cigarette smoking, LDL cholesterol ≥3.4 mmol/L, low HDL cholesterol, hypertension, and diabetes. There were 1067 subjects (16%) with 0 RFs, whereas 1205 (18%) had ≥3 RFs. Among individuals with 0 RFs, 68% had CAC 0, whereas 12 and 5% had CAC >100 and >300, respectively. Among individuals with ≥3 RFs, 35% had CAC 0, whereas 34 and 19% had CAC >100 and >300, respectively. Overall, 339 (5.1%) CHD events occurred. Individuals with 0 RFs and CAC >300 had an event rate 3.5 times higher than individuals with ≥3 RFs and CAC 0 (10.9/1000 vs. 3.1/1000 person-years). Similar results were seen across categories of Framingham risk score.
Conclusion
Among individuals at the extremes of RF burden, the distribution of CAC is heterogeneous. The presence of a high CAC burden, even among individuals without RFs, is associated with an elevated event rate, whereas the absence of CAC, even among those with many RF, is associated with a low event rate. Coronary artery calcium has the potential to further risk stratify asymptomatic individuals at the extremes of RF burden.
doi:10.1093/eurheartj/eht508
PMCID: PMC4150068  PMID: 24366919
Coronary artery calcium; Risk factors; Coronary heart disease
11.  Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons 
Introduction
Synaptic dysfunction and intracellular transport defects are early events in Alzheimer’s disease (AD). Extracellular amyloid β (Aβ) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Meanwhile, intraneuronal accumulation of Aβ precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. However, the links between intracellular Aβ, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood.
Results
We compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aβ into extracellular space and the latter accumulates Aβ oligomers within cells. First we investigated the effects of intracellular Aβ oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We found that intracellular Aβ oligomers caused a reduction in mushroom, or mature spines, independently of tau. We also found that intracellular Aβ oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. A reduction in BDNF transport by intracellular Aβ oligomers was also observed in tau knockout neurons.
Conclusions
Our findings indicate that intracellular Aβ oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aβ-induced spine loss and transport defects require tau.
doi:10.1186/s40478-015-0230-2
PMCID: PMC4546183  PMID: 26293809
12.  Breastfeeding, lung volumes and alveolar size at school-age 
BMJ Open Respiratory Research  2015;2(1):e000081.
Background
Previous studies found larger lung volumes at school-age in formerly breastfed children, with some studies suggesting an effect modification by maternal asthma. We wanted to explore this further in children who had undergone extensive lung function testing. The current study aimed to assess whether breastfeeding was associated with larger lung volumes and, if so, whether all compartments were affected. We also assessed association of breastfeeding with apparent diffusion coefficient (ADC), which measures freedom of gas diffusion in alveolar-acinar compartments and is a surrogate of alveolar dimensions. Additionally, we assessed whether these effects were modified by maternal asthma.
Methods
We analysed data from 111 children and young adults aged 11–21 years, who had participated in detailed lung function testing, including spirometry, plethysmography and measurement of ADC of 3Helium (3He) by MR. Information on breastfeeding came from questionnaires applied in early childhood (age 1–4 years). We determined the association between breastfeeding and these measurements using linear regression, controlling for potential confounders.
Results
We did not find significant evidence for an association between duration of breastfeeding and lung volumes or alveolar dimensions in the entire sample. In breastfed children of mothers with asthma, we observed larger lung volumes and larger average alveolar size than in non-breastfed children, but the differences did not reach significance levels.
Conclusions
Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.
doi:10.1136/bmjresp-2015-000081
PMCID: PMC4499711  PMID: 26180638
Paediatric asthma
13.  Efficacy of WHO recommendation for continued breastfeeding and maternal cART for prevention of perinatal and postnatal HIV transmission in Zambia 
Introduction
To prevent mother-to-child transmission (MTCT) of HIV in developing countries, new World Health Organization (WHO) guidelines recommend maternal combination antiretroviral therapy (cART) during pregnancy, throughout breastfeeding for 1 year and then cessation of breastfeeding (COB). The efficacy of this approach during the first six months of exclusive breastfeeding has been demonstrated, but the efficacy of this approach beyond six months is not well documented.
Methods
A prospective observational cohort study of 279 HIV-positive mothers was started on zidovudine/3TC and lopinavir/ritonavir tablets between 14 and 30 weeks gestation and continued indefinitely thereafter. Women were encouraged to exclusively breastfeed for six months, complementary feed for the next six months and then cease breastfeeding between 12 and 13 months. Infants were followed for transmission to 18 months and for survival to 24 months. Text message reminders and stipends for food and transport were utilized to encourage adherence and follow-up.
Results
Total MTCT was 9 of 219 live born infants (4.1%; confidence interval (CI) 2.2–7.6%). All breastfeeding transmissions that could be timed (5/5) occurred after six months of age. All mothers who transmitted after six months had a six-month plasma viral load >1,000 copies/ml (p<0.001). Poor adherence to cART as noted by missed dispensary visits was associated with transmission (p=0.04). Infant mortality was lower after six months of age than during the first six months of life (p=0.02). The cumulative rate of infant HIV infection or death at 18 months was 29/226 (12.8% 95 CI: 7.5–20.8%).
Conclusions
Maternal cART may limit MTCT of HIV to the UNAIDS target of <5% for eradication of paediatric HIV within the context of a clinical study, but poor adherence to cART and follow-up can limit the benefit. Continued breastfeeding can prevent the rise in infant mortality after six months seen in previous studies, which encouraged early COB.
doi:10.7448/IAS.18.1.19352
PMCID: PMC4490793  PMID: 26140453
breastfeeding transmission of HIV; vertical transmission; option B+; infant survival; efficacy of WHO guidelines; perinatal transmission of HIV
14.  Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons 
Molecular Biology of the Cell  2015;26(6):1058-1071.
Intracellular Ca2+ dysregulation and transport disruption precede cell death in Alzheimer's disease. Mechanisms of AβO-induced Ca2+ elevation are identified that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects. The results challenge dogmatic views on mechanisms of AβO toxicity and subcellular sites of action.
Disruption of fast axonal transport (FAT) and intracellular Ca2+ dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca2+-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca2+ elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca2+ influx through axonal voltage-gated Ca2+ channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca2+ release from the ER. This work establishes a novel role for Ca2+ dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD.
doi:10.1091/mbc.E14-12-1612
PMCID: PMC4357506  PMID: 25609087
15.  The Use of Coronary Artery Calcium Testing to Guide Aspirin Utilization for Primary Prevention: Estimates from the Multi-Ethnic Study of Atherosclerosis 
Background
Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are low to intermediate risk.
Methods and Results
To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were not on aspirin at baseline and were free of diabetes. Using data from median 7.6-year follow-up, five-year number-needed-to-treat (NNT5) estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm (NNH5) estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC ≥ 100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated NNT5 of 173 for individuals <10% FRS and 92 for individuals ≥ 10% FRS, estimated NNH5 of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated NNT5 of 2,036 for individuals <10% FRS and 808 for individuals ≥ 10% FRS, estimated NNH5 of 442 for a major bleed). Gender specific and age-stratified analyses showed similar results.
Conclusion
For the primary prevention of CHD, MESA participants with CAC ≥ 100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin.
doi:10.1161/CIRCOUTCOMES.113.000690
PMCID: PMC4412344  PMID: 24803472
Aspirin; imaging; prevention; coronary disease
16.  Baseline Subclinical Atherosclerosis Burden and Distribution are Associated with the Frequency and Mode of Future Coronary Revascularization: Multi-Ethnic Study of Atherosclerosis (MESA) 
JACC. Cardiovascular imaging  2014;7(5):476-486.
Objectives
We sought to evaluate the impact of coronary artery calcium (CAC) burden and regional distribution on the need for and type of future coronary revascularization (percutaneous [PCI] vs. surgical [CABG]) among asymptomatic individuals.
Background
The need for coronary revascularization and the chosen mode of revascularization are thought to be a function of disease burden and anatomic distribution. The association between the baseline burden and regional distribution of CAC and the risk and type of future coronary revascularization remains unknown.
Methods
6,540 MESA participants (individuals aged 45-84 years, free of known baseline cardiovascular disease) with vessel-specific CAC measurement were followed for median 8.5 (7.7 – 8.6) years. Annualized rates and multivariable adjusted hazard ratios for revascularization and revascularization type were analyzed according to CAC score category, number of vessels with CAC (0-4, including the left main), and by involvement of individual coronary arteries.
Results
A total of 265 revascularizations (4.2%) occurred during follow-up, and 206 (78% of total) were preceded by adjudicated symptoms. Revascularization was uncommon when CAC=0 (0.6%), with graded increase over both rising CAC burden and increasingly diffuse CAC distribution. The revascularization rate per 1,000 person-years for CAC 1-100, 101-400, and >400 was 4.9, 11.7 and 25.4; for 1, 2, 3, and 4 vessels with CAC the rates were 3.0, 8.0, 16.1, and 24.8. In multivariable models adjusting for CAC score, number of vessels with CAC remained predictive of mode of revascularization. Independent predictors of CABG vs. PCI included 3 or 4 vessel CAC, higher CAC burden, and involvement of the left main. Risk for CABG was extremely low with <3 vessel baseline CAC. Results were similar when considering only symptom-driven revascularizations.
Conclusions
In this multi-ethnic cohort of asymptomatic individuals, baseline CAC was highly predictive of future coronary revascularization procedures, with measures of CAC burden and distribution each independently predicting need for PCI vs. CABG over 8.5 year follow-up.
doi:10.1016/j.jcmg.2014.03.005
PMCID: PMC4024837  PMID: 24831208
cardiac CT; coronary artery calcium; coronary artery disease; revacularization
17.  Diurnal cortisol amplitude and fronto-limbic activity in response to stressful stimuli 
Psychoneuroendocrinology  2009;34(5):694-704.
Summary
The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response.
doi:10.1016/j.psyneuen.2008.11.011
PMCID: PMC4250041  PMID: 19135805
Amygdala; Medial prefrontal cortex; Hippocampus; Cortisol; Neuroimaging; Stress
18.  Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice 
Background
Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer’s disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.
Results
We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.
Conclusions
This study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.
doi:10.1186/1750-1326-9-42
PMCID: PMC4232697  PMID: 25344697
tau; Amyloid precursor protein; O-GlcNAc; Thiamet-G
20.  HIV Protease Inhibitor Use During Pregnancy Is Associated With Decreased Progesterone Levels, Suggesting a Potential Mechanism Contributing to Fetal Growth Restriction 
Background. Protease inhibitor (PI)–based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational-age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels.
Methods. PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women.
Results. PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile.
Conclusions. Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes.
doi:10.1093/infdis/jiu393
PMCID: PMC4264589  PMID: 25030058
progesterone; protease inhibitors; lopinavir; small for gestational age; low birth weight; HIV; pregnancy
21.  Differential activity of rostral cingulate and brainstem in Panic Disorder and PTSD 
Journal of anxiety disorders  2010;25(2):251-257.
Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, Posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects.
doi:10.1016/j.janxdis.2010.09.010
PMCID: PMC4096628  PMID: 21075593
anxiety disorders; panic disorder; posttraumatic stress disorder; subgenual cingulate cortex; ventral striatum; extended amygdala; brainstem; neuroimaging
22.  Impact of Fitness Versus Obesity on Routinely Measured Cardiometabolic Risk in Young, Healthy Adults 
The American journal of cardiology  2013;111(7):991-995.
Obesity demonstrates a direct relation with cardiovascular risk and all-cause mortality, while cardiorespiratory fitness demonstrates an inverse relation. In clinical practice, several cardiometabolic (“CM”) risk factors are commonly measured to gauge cardiovascular risk yet the interaction between fitness and obesity with regard CM risk has not been fully explored. We studied 2,634 Brazilian adults referred for an employer-sponsored heath exam. Obesity was defined as BMI >30 kg/m2 or waist circumference > 102cm (men) or >88cm (women) when BMI 25–30kg/m2. Fitness was quantified by stage achieved on an Ellestad treadmill stress test, with those completing stage 4 considered fit. Hepatic steatosis was determined by ultrasound. We compared CM risk factors after stratifying patients into 4 groups: fit/normal weight, fit/obese, unfit/normal weight & unfit/obese. Approximately 22% of patients were obese; 12% were unfit. Fitness and obesity were moderately correlated (ρ=0.38–50). 6.5% of the sample was unfit/normal weight, and 16% fit/obese. In overweight and obese patients, fitness was negatively associated with CM risk (p<0.01 for all values). In fit patients, increasing BMI was positively associated with CM risk (p<0.01 for all values). In instances of discordance between fitness and obesity, obesity was the stronger determinant of CM risk. Fitness and obesity are independently associated with CM risk. The effects of fitness and obesity are additive but obesity is more strongly associated with CM risk when fitness and obesity are discordant. These findings underscore the need for weight loss in obese individuals and suggest an unmeasured benefit of fitness.
doi:10.1016/j.amjcard.2012.12.022
PMCID: PMC3697077  PMID: 23340029
fitness; obesity; metabolic syndrome; liver fat; inflammation
24.  Increased Incidence of Tuberculosis in Zimbabwe, in Association with Food Insecurity, and Economic Collapse: An Ecological Analysis 
PLoS ONE  2014;9(2):e83387.
Background
Zimbabwe underwent a socioeconomic crisis and resultant increase in food insecurity in 2008–9. The impact of the crisis on Tuberculosis (TB) incidence is unknown.
Methods
Prospective databases from two mission hospitals, which were geographically widely separated, and remained open during the crisis, were reviewed.
Results
At the Howard Hospital (HH) in northern Zimbabwe, TB incidence increased 35% in 2008 from baseline rates in 2003–2007 (p<0.01) and remained at that level in 2009. Murambinda Hospital (MH) in Eastern Zimbabwe also demonstrated a 29% rise in TB incidence from 2007 to 2008 (p<0.01) and remained at that level in 2009. Data collected post-crisis at HH showed a decrease of 33% in TB incidence between 2009 to 2010 (p<0.001) and 2010/2011 TB incidence remained below that of the crisis years of 2008/2009 (p<0.01). Antenatal clinic HIV seroprevalence at HH decreased between 2001(23%) to 2011(11%) (p<0.001). Seasonality of TB incidence was analyzed at both MH and HH. There was a higher TB incidence in the dry season when food is least available (September-November) compared to post harvest (April-June) (p<0.001).
Conclusion
This study suggests that an epidemic of TB mirrored socioeconomic collapse and recovery in Zimbabwe. The seasonal data suggests that food security may have been associated with TB incidence both annually and during the crisis in this high HIV prevalence country.
doi:10.1371/journal.pone.0083387
PMCID: PMC3914787  PMID: 24505245
25.  CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II, Open-Label, Dose-Escalation Study 
The Oncologist  2013;18(1):25-26.
Background.
The A3 adenosine receptor (A3AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A3AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC.
Methods.
The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A3AR as a biological predictive marker of response to CF102 were the secondary objectives.
Results.
Eighteen patients received CF102—six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102.
Conclusions.
CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.
doi:10.1634/theoncologist.2012-0211
PMCID: PMC3556251  PMID: 23299770

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