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1.  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
2.  Efficacy of Cardiac Resynchronization in Acutely Infarcted Canine Hearts with Electro-mechanical Dyssynchrony 
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.
To evaluate the acute hemodynamic effects of CRT during and immediately after myocardial infarction.
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.
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.
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.
PMCID: PMC4188793  PMID: 24887137
myocardial infarction; acute heart failure; cardiac resynchronization therapy
3.  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.
PMCID: PMC4501363  PMID: 26023088
4.  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.
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.
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.
PMCID: PMC4150068  PMID: 24366919
Coronary artery calcium; Risk factors; Coronary heart disease
5.  Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons 
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.
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.
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.
PMCID: PMC4546183  PMID: 26293809
6.  Breastfeeding, lung volumes and alveolar size at school-age 
BMJ Open Respiratory Research  2015;2(1):e000081.
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.
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.
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.
Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.
PMCID: PMC4499711  PMID: 26180638
Paediatric asthma
7.  Efficacy of WHO recommendation for continued breastfeeding and maternal cART for prevention of perinatal and postnatal HIV transmission in Zambia 
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.
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.
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%).
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.
PMCID: PMC4490793  PMID: 26140453
breastfeeding transmission of HIV; vertical transmission; option B+; infant survival; efficacy of WHO guidelines; perinatal transmission of HIV
8.  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.
PMCID: PMC4357506  PMID: 25609087
9.  The Use of Coronary Artery Calcium Testing to Guide Aspirin Utilization for Primary Prevention: Estimates from the Multi-Ethnic Study of Atherosclerosis 
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.
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.
PMCID: PMC4412344  PMID: 24803472
Aspirin; imaging; prevention; coronary disease
10.  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.
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.
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.
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.
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.
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.
PMCID: PMC4024837  PMID: 24831208
cardiac CT; coronary artery calcium; coronary artery disease; revacularization
11.  Diurnal cortisol amplitude and fronto-limbic activity in response to stressful stimuli 
Psychoneuroendocrinology  2009;34(5):694-704.
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.
PMCID: PMC4250041  PMID: 19135805
Amygdala; Medial prefrontal cortex; Hippocampus; Cortisol; Neuroimaging; Stress
12.  Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice 
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.
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.
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.
PMCID: PMC4232697  PMID: 25344697
tau; Amyloid precursor protein; O-GlcNAc; Thiamet-G
14.  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.
PMCID: PMC4264589  PMID: 25030058
progesterone; protease inhibitors; lopinavir; small for gestational age; low birth weight; HIV; pregnancy
15.  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.
PMCID: PMC4096628  PMID: 21075593
anxiety disorders; panic disorder; posttraumatic stress disorder; subgenual cingulate cortex; ventral striatum; extended amygdala; brainstem; neuroimaging
16.  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.
PMCID: PMC3697077  PMID: 23340029
fitness; obesity; metabolic syndrome; liver fat; inflammation
18.  Increased Incidence of Tuberculosis in Zimbabwe, in Association with Food Insecurity, and Economic Collapse: An Ecological Analysis 
PLoS ONE  2014;9(2):e83387.
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.
Prospective databases from two mission hospitals, which were geographically widely separated, and remained open during the crisis, were reviewed.
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).
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.
PMCID: PMC3914787  PMID: 24505245
19.  CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II, Open-Label, Dose-Escalation Study 
The Oncologist  2013;18(1):25-26.
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.
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.
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.
CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.
PMCID: PMC3556251  PMID: 23299770
20.  Relation of Uric Acid to Serum Levels of High-Sensitivity C-Reactive Protein, Triglycerides, and High-Density Lipoprotein Cholesterol and to Hepatic Steatosis 
The American journal of cardiology  2012;110(12):1787-1792.
Increased uric acid (UA) is strongly linked to cardiovascular disease. However, the independent role of UA is still debated because it is associated with several cardiovascular risk factors including obesity and metabolic syndrome. This study assessed the association of UA with increased high-sensitivity C-reactive protein (hs-CRP), increased ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL), sonographically detected hepatic steatosis, and their clustering in the presence and absence of obesity and metabolic syndrome. We evaluated 3,518 employed subjects without clinical cardiovascular disease from November 2008 through July 2010. Prevalence of hs-CRP ≥3 mg/L was 19%, that of TG/HDL ≥3 was 44%, and that of hepatic steatosis was 43%. In multivariable logistic regression after adjusting for traditional cardiovascular risk factors and confounders, highest versus lowest UA quartile was associated with hs-CRP ≥3 mg/L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.01 to 2.28, p = 0.04), TG/HDL ≥3 (OR 3.29, 95% CI 2.36 to 4.60, p <0.001), and hepatic steatosis (OR 3.10, 95% CI 2.22 to 4.32, p <0.001) independently of obesity and metabolic syndrome. Association of UA with hs-CRP ≥3 mg/L became nonsignificant in analyses stratified by obesity. Ascending UA quartiles compared to the lowest UA quartile demonstrated a graded increase in the odds of having 2 or 3 of these risk conditions and a successive decrease in the odds of having none. In conclusion, high UA levels were associated with increased TG/HDL and hepatic steatosis independently of metabolic syndrome and obesity and with increased hs-CRP independently of metabolic syndrome.
PMCID: PMC3766845  PMID: 22975466
21.  Catch-up Alveolarization in Ex-Preterm Children. Evidence from 3He Magnetic Resonance 
Rationale: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair.
Objectives: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance.
Methods: We recruited schoolchildren aged 10–14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37–42 wk; n = 61); (2) mild preterm (32–36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance.
Measurements and Main Results: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm2/second (95% confidence interval, 0.089–0.095) in the term group. Corresponding values were 0.096 (0.091–0.101), 0.090 (0085–0.095), and 0.089 (0.083–0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders.
Conclusions: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.
PMCID: PMC3734619  PMID: 23491406
alveolar structure; lung acinus; bronchopulmonary dysplasia; neonatal chronic lung disease
22.  Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons 
Molecular Biology of the Cell  2013;24(16):2494-2505.
The role of tau in axonal transport disruption during early-stage Alzheimer disease is controversial. The amyloid-β oligomers markedly impair BDNF transport in primary wild-type and tau-knockout neurons. This occurs by nonexcitotoxic activation of calcineurin, and inhibition of calcineurin rescues transport defects independent of tau.
Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.
PMCID: PMC3744947  PMID: 23783030
24.  Cognitive Outcome of Offspring from Dexamethasone-Treated Pregnancies at Risk for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency 
European Journal of Endocrinology  2012;167(1):103-110.
To test whether dexamethasone (DEX) treatment of pregnancies at risk for congenital adrenal hyperplasia (CAH) impairs cognitive functioning in the offspring.
Observational follow-up of prenatally DEX-exposed offspring and controls.
Study 1 included 140 children age 5-12 years: 67 DEX-exposed (long-term: 8 CAH girls) and 73 unexposed (with 15 CAH girls). Study 2 included 20 participants age 11-24 years: 7 DEX-exposed (long-term: 1 CAH woman) and 13 unexposed (with 4 CAH women). Neuropsychological testing was done in hospital settings or patients' homes. Data analysis aimed at maximizing detection of effects of DEX exposure.
The vast majority of group comparisons were not marginally or conventionally significant. The few significant findings on short-term prenatal DEX exposure suggested more positive than adverse outcomes. By contrast, the few significant findings in females with CAH and long-term DEX exposure indicated slower mental processing than in controls on several neuropsychological variables, although partial correlations of DEX-exposure duration with cognitive outcome did not corroborate this association.
Our studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory, while our findings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about potentially adverse cognitive aftereffects of such exposure. Yet, our studies are not definitive, and replications in larger samples are required.
PMCID: PMC3383400  PMID: 22549088
25.  Treatment of Dry Eye Syndrome with Orally Administered CF101: Data from a Phase 2 Clinical Trial 
Ophthalmology  2010;117(7):1287-1293.
To explore the safety and efficacy of CF101, an A3 adenosine receptor agonist, in patients with moderate-to-severe dry eye syndrome
Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study.
68 patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group.
Patients were orally treated with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week post-treatment observation.
Main Outcome Measures
an improvement of >25% over baseline at week 12 in one of the following parameters: (a) tear break-up time (BUT); (b) superficial punctate keratitis assessed by fluorescein staining (FS); (c) Schirmer tear test 1 (ST1).
clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements and monitoring of adverse events.
A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group.
CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate-to-severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome.
PMCID: PMC3668568  PMID: 20304499

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