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author:("Pham, luxu")
1.  The pathogenesis of obstructive sleep apnea 
Journal of Thoracic Disease  2015;7(8):1358-1372.
Obstructive sleep apnea (OSA) is a major source of cardiovascular morbidity and mortality, and represents an increasing burden on health care resources. Understanding underlying pathogenic mechanisms of OSA will ultimately allow for the development of rational therapeutic strategies. In this article, we review current concepts about the pathogenesis of OSA. Specifically, we consider the evidence that the upper airway plays a primary role in OSA pathogenesis and provide a framework for modelling its biomechanical properties and propensity to collapse during sleep. Anatomical and neuromuscular factors that modulate upper airway obstruction are also discussed. Finally, we consider models of periodic breathing, and elaborate generalizable mechanisms by which upper airway obstruction destabilizes respiratory patterns during sleep. In our model, upper airway obstruction triggers a mismatch between ventilatory supply and demand. In this model, trade-offs between maintaining sleep stability or ventilation can account for a full range of OSA disease severity and expression. Recurrent arousals and transient increases in airway patency may restore ventilation between periods of sleep, while alterations in neuromuscular and arousal responses to upper airway obstruction may improve sleep stability at still suboptimal levels of ventilation.
PMCID: PMC4561284  PMID: 26380762
Obstructive sleep apnea (OSA); upper airway; inspiratory flow limitation; Starling resistor
2.  Acute effects of ambient ozone on mortality in Europe and North America: results from the APHENA study 
The “Air Pollution and Health: A Combined European and North American Approach” (APHENA) project is a collaborative analysis of multi-city time-series data on the association between air pollution and adverse health outcomes. The main objective of APHENA was to examine the coherence of findings of time-series studies relating short-term fluctuations in air pollution levels to mortality and morbidity in 125 cities in Europe, the US, and Canada. Multi-city time-series analysis was conducted using a two-stage approach. We used Poisson regression models controlling for overdispersion with either penalized or natural splines to adjust for seasonality. Hierarchical models were used to obtain an overall estimate of excess mortality associated with ozone and to assess potential effect modification. Potential effect modifiers were city-level characteristics related to exposure to other ambient air pollutants, weather, socioeconomic status, and the vulnerability of the population. Regionally pooled risk estimates from Europe and the US were similar; those from Canada were substantially higher. The pooled estimated excess relative risk associated with a 10 µg/m3 increase in 1 h daily maximum O3 was 0.26 % (95 % CI, 0.15 %, 0.37 %). Across regions, there was little consistent indication of effect modification by age or other effect modifiers considered in the analysis. The findings from APHENA on the effects of O3 on mortality in the general population were comparable with previously reported results and relatively robust to the method of data analysis. Overall, there was no indication of strong effect modification by age or ecologic variables considered in the analysis.
PMCID: PMC3668792  PMID: 23734168
Ozone; Mortality; Time-series; Multi-city; Cardiovascular; Respiratory
3.  Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): Implications to manganese-induced parkinsonism 
Journal of neurochemistry  2008;107(5):1236-1247.
The long-term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally-exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using Positron Emission Tomography (PET) in the non-human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg (n=4), 5.0-6.7 mg Mn/kg (n=5), or 8.3-10.0 mg Mn/kg (n=3) for 7-59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine-induced DA release measured by PET is markedly impaired in the striatum of Mn-exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post-mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.
PMCID: PMC3675778  PMID: 18808452
manganese; dopamine release; Positron Emission Tomography; parkinsonism; non-human primate; striatum
4.  Fine Particulate Air Pollution and Hospital Admission for Cardiovascular and Respiratory Diseases 
Evidence on the health risks associated with short-term exposure to fine particles (particulate matter ≤2.5 μm in aerodynamic diameter [PM2.5]) is limited. Results from the new national monitoring network for PM2.5 make possible systematic research on health risks at national and regional scales.
To estimate risks of cardiovascular and respiratory hospital admissions associated with short-term exposure to PM2.5 for Medicare enrollees and to explore heterogeneity of the variation of risks across regions.
Design, Setting, and Participants
A national database comprising daily time-series data daily for 1999 through 2002 on hospital admission rates (constructed from the Medicare National Claims History Files) for cardiovascular and respiratory outcomes and injuries, ambient PM2.5 levels, and temperature and dew-point temperature for 204 US urban counties (population >200 000) with 11.5 million Medicare enrollees (aged >65 years) living an average of 5.9 miles from a PM2.5 monitor.
Main Outcome Measures
Daily counts of county-wide hospital admissions for primary diagnosis of cerebrovascular, peripheral, and ischemic heart diseases, heart rhythm, heart failure, chronic obstructive pulmonary disease, and respiratory infection, and injuries as a control outcome.
There was a short-term increase in hospital admission rates associated with PM2.5 for all of the health outcomes except injuries. The largest association was for heart failure, which had a 1.28% (95% confidence interval, 0.78%–1.78%) increase in risk per 10-μg/m3 increase in same-day PM2.5. Cardiovascular risks tended to be higher in counties located in the Eastern region of the United States, which included the Northeast, the Southeast, the Midwest, and the South.
Short-term exposure to PM2.5 increases the risk for hospital admission for cardiovascular and respiratory diseases.
PMCID: PMC3543154  PMID: 16522832
5.  Pituitary Stalk Interruption Syndrome in 53 Postpubertal Patients: Factors Influencing the Heterogeneity of Its Presentation 
PLoS ONE  2013;8(1):e53189.
Pituitary stalk interruption syndrome (PSIS) may induce an isolated growth hormone (GH) deficiency or multiple hypothalamic-pituitary (HP) deficiencies. Patients with multiple HP deficiencies, primarily those with adrenocorticotropin (ACTH) deficiency, are at increased risk of morbidity and mortality. Our objective was to identify the factors influencing each symptom and the MRI features of the syndrome to enhance its diagnosis and genetic analysis.
This study was a retrospective, single-center, case-cohort study of 53 patients with PSIS who had reached pubertal age.
Patients were classified as having an isolated GH deficiency (n = 24, Group 1) or HP deficiencies (n = 29, Group 2); of these, 19 had complete HP deficiency, and 10 had GH deficiency associated with TSH (n = 4), TSH and ACTH (n = 3), TSH and gonadotropin (n = 1) deficiencies or amenorrhea (n = 2). The following features were less frequent in Group 1 than in Group 2: breech presentation (4% vs 35%, P = 0.008), hypoglycemia (0% vs 59%, P<0.00001), micropenis (13% vs 69%, P<0.003), hypothalamic origin (0% vs 52%, P<0.000001), ophthalmic malformation (8% vs 38%, P<0.02) and psychomotor delay (0% vs 31%, P<0.004). The frequencies of all other malformations were similar in both groups (37% vs 59%). A visible pituitary stalk was characteristic of patients belonging to Group 1 (P<0.0002). The GH peak was greater in Group 1 than in Group 2 (P<0.0003), as was the anterior pituitary height (P = 0.01).
The factors that best discriminate patients with multiple HP deficiencies from those with an isolated GH deficiency are breech presentation, hypoglycemia, and micropenis. No patient with an isolated GH deficiency had psychomotor delay, but associated malformations and/or syndromes, with the exception of ophthalmic disorders, occurred with similar frequencies in both groups. We have also shown that each of the above characteristics is associated with a given HP deficiency and/or malformation/syndrome in the majority of cases.
PMCID: PMC3538767  PMID: 23308160
6.  MR-guided High Intensity Focused Ultrasound Treatment for Symptomatic Uterine Leiomyomata: Long-term Outcomes 
Academic Radiology  2011;18(8):970-976.
To evaluate the long-term clinical outcomes of MR-guided high intensity focused ultrasound (MR-g HIFU) treatments for symptomatic uterine leiomyomata.
Patients were recruited for a prospective study for MR-g HIFU treatments of symptomatic leiomyomata, with up to three-year follow-up. The study was approved by the institutional review board and was HIPPA compliant. Clinical assessments were obtained at 3 months, 6 months, 1, 2 and 3 years after MR-g HIFU, as well as uterine fibroid symptom severity scores (SSS) and health-related quality of life questionnaires (UFS-QOL). MRI was performed at each follow-up to assess the efficacy of the treatment at 6 months, 1 year, 2 years and 3 years.
Fifty one leiomyomata in 40 patients were treated. All patients were treated within the FDA guidelines with leiomyomata localized on MR and treated with sonication. The mean baseline volume of treated leiomyomata was 336.9 cm3. The mean improvement scores for tSSS was 47.8 (p<.001) and for tUFS-QOL was 39.8 (p<.001) at 3 years. The mean volume decrease in treated leiomyomata was 32.0% (p<.001), and, in uterus, the volume decrease was 27.7% (p<.001) at three years. There were no long-term complications.
Long-term follow-up data from MR-g HIFU treatments show sustained symptomatic relief among enrolled patients. Although the results are preliminary, MR-g HIFU for the treatment of uterine leiomyomata may result in acceptable long-term outcomes at three years.
PMCID: PMC3401073  PMID: 21718955
7.  Clinical, Biological and Genetic Analysis of 8 Cases of Congenital Isolated Adrenocorticotrophic Hormone (ACTH) Deficiency 
PLoS ONE  2011;6(10):e26516.
Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency may be rare, but it could be an underestimated cause of neonatal death. Our objective was to shorten the time between first symptoms and diagnosis.
This single-centre retrospective case-cohort study was carried out on eight consecutive patients.
Two had the neonatal form and 6 the late onset form. Six were admitted to an intensive care unit at least once for seizures with hypoglycemia, major hypothermia, fever, and/or collapsus. The 2 neonatal cases presented with hypoglycemia and in a state of “apparent death” at birth or hypothermia (29°C) at 6 days. All 6 late onset cases had also been admitted to an emergency department 1–3 times, but had left hospital incorrectly diagnosed. Their first symptoms were noted at 3–12.3 years, and they were diagnosed at 3.3–14.4 years. All had hypoglycemia, and 4 had had seizures. The presenting symptoms were vomiting and/or abdominal pain, asthenia, irritability, difficulty with physical activities, and anorexia. The school performance of 4 deteriorated. Two underwent psychotherapy and treatment for depression, which was stopped when Hydrocortisone® replacement therapy began.
The plasma concentrations in spontaneous hypoglycemia were: ACTH<5 to 17.1 pg/mL, with concomitant cortisol <3.5 to 37 ng/mL. The plasma dehydroepiandrosterone sulfate (DHAS) concentrations were low in the 7 evaluated. The coding sequence of TPIT was normal in all.
Several unexplained symptoms in a child, mainly gastro-intestinal symptoms and seizures due to hypoglycemia, may indicate ACTH deficiency. A low or normal basal plasma ACTH despite concomitant low cortisol at 8 a.m. and/or in spontaneous hypoglycemia, associated with low DHAS, in a patient not given corticosteroids is highly suggestive of ACTH deficiency. The isolated character of ACTH deficiency must be confirmed by determining the other hypothalamic-pituitary functions, and Hydrocortisone® replacement therapy initiated in emergency.
PMCID: PMC3196582  PMID: 22028893
8.  Neighborhood Socioeconomic Status, Depression, and Health Status in the Look AHEAD (Action for Health in Diabetes) Study 
BMC Public Health  2011;11:349.
Depression and diminished health status are common in adults with diabetes, but few studies have investigated associations with socio-economic environment. The objective of this manuscript was to evaluate the relationship between neighborhood-level SES and health status and depression.
Individual-level data on 1010 participants at baseline in Look AHEAD (Action for Health in Diabetes), a trial of long-term weight loss among adults with type 2 diabetes, were linked to neighborhood-level SES (% living below poverty) from the 2000 US Census (tracts). Dependent variables included depression (Beck Inventory), and health status (Medical Outcomes Study (SF-36) scale). Multi-level regression models were used to account simultaneously for individual-level age, sex, race, education, personal yearly income and neighborhood-level SES.
Overall, the % living in poverty in the participants' neighborhoods varied, mean = 11% (range 0-67%). Compared to their counterparts in the lowest tertile of neighborhood poverty (least poverty), those in the highest tertile (most poverty) had significantly lower scores on the role-limitations(physical), role limitations(emotional), physical functioning, social functioning, mental health, and vitality sub-scales of the SF-36 scale. When evaluating SF-36 composite scores, those living in neighborhoods with more poverty had significantly lower scores on the physical health (β-coefficient [β] = -1.90 units, 95% CI: -3.40,-0.039), mental health (β = -2.92 units, -4.31,-1.53) and global health (β = -2.77 units, -4.21,-1.33) composite scores.
In this selected group of weight loss trial participants, lower neighborhood SES was significantly associated with poorer health status. Whether these associations might influence response to the Look AHEAD weight loss intervention requires further investigation.
PMCID: PMC3111582  PMID: 22182286
9.  Do management strategies for coronary artery disease influence 6 year cognitive outcomes? 
The Annals of thoracic surgery  2009;88(2):445-454.
Previous uncontrolled studies have suggested that there is late cognitive decline after coronary artery bypass grafting that may be attributable to use of the cardiopulmonary bypass pump.
In this prospective, nonrandomized, longitudinal study, we compared cognitive outcomes after on-pump coronary artery bypass surgery (n=152) with: off-pump bypass surgery (n=75); nonsurgical cardiac comparison subjects (n=99); and 69 heart-healthy comparison (HHC) subjects. The primary outcome measure was change from baseline to 72 months in the following cognitive domains: Verbal memory, Visual memory, Visuoconstruction, Language, Motor speed, Psychomotor speed, Attention, Executive function, and a composite Global score.
There were no consistent differences in 72-month cognitive outcomes among the 3 groups with coronary artery disease (CAD). The CAD groups had lower baseline performance, and a greater degree of decline compared to HHC. The degree of change was small with none of the groups having > 0.5 SD decline. None of the groups were substantially worse at 72 months compared to baseline.
Compared to subjects with no vascular disease risk factors, the CAD patients had lower baseline cognitive performance and greater degrees of decline over 72 months, suggesting that in these patients, vascular disease may have an impact on cognitive performance. We found no significant differences in the long-term cognitive outcomes among patients with various CAD therapies, indicating that management strategy for CAD is not an important determinant of long-term cognitive outcomes.
PMCID: PMC2753795  PMID: 19632391
Neurocognitive deficits; Outcomes; CABG; vascular disease
10.  Neighborhood and weight-related health behaviors in the Look AHEAD (Action for Health in Diabetes) Study 
BMC Public Health  2010;10:312.
Previous studies have shown that neighborhood factors are associated with obesity, but few studies have evaluated the association with weight control behaviors. This study aims to conduct a multi-level analysis to examine the relationship between neighborhood SES and weight-related health behaviors.
In this ancillary study to Look AHEAD (Action for Health in Diabetes) a trial of long-term weight loss among individuals with type 2 diabetes, individual-level data on 1219 participants from 4 clinic sites at baseline were linked to neighborhood-level data at the tract level from the 2000 US Census and other databases. Neighborhood variables included SES (% living below the federal poverty level) and the availability of food stores, convenience stores, and restaurants. Dependent variables included BMI, eating patterns, weight control behaviors and resource use related to food and physical activity. Multi-level models were used to account for individual-level SES and potential confounders.
The availability of restaurants was related to several eating and weight control behaviors. Compared to their counterparts in neighborhoods with fewer restaurants, participants in neighborhoods with more restaurants were more likely to eat breakfast (prevalence Ratio [PR] 1.29 95% CI: 1.01-1.62) and lunch (PR = 1.19, 1.04-1.36) at non-fast food restaurants. They were less likely to be attempting weight loss (OR = 0.93, 0.89-0.97) but more likely to engage in weight control behaviors for food and physical activity, respectively, than those who lived in neighborhoods with fewer restaurants. In contrast, neighborhood SES had little association with weight control behaviors.
In this selected group of weight loss trial participants, restaurant availability was associated with some weight control practices, but neighborhood SES was not. Future studies should give attention to other populations and to evaluating various aspects of the physical and social environment with weight control practices.
PMCID: PMC2897795  PMID: 20525373
11.  Subjective memory symptoms in surgical and nonsurgical coronary artery patients: 6-Year follow-up 
The Annals of thoracic surgery  2009;87(1):27-34.
Self-reported cognitive and memory complaints following coronary artery bypass graft surgery (CABG) are common. Several studies have attempted to quantify the incidence of such complaints and to examine the relationship between subjective and objective cognitive functioning, but the etiology and longitudinal course of these self-reports remain unclear.
Measures of subjective memory complaints were compared in two groups: 220 CABG patients and 92 nonsurgical cardiac comparisons at 3 months, and 1, 3, and 6 years. At 6 years, additional measures were used to quantify memory self-assessment. The frequency of subjective complaints at each time point was determined and associations with objective cognitive performance as well as depression were examined.
At early (3-month and/or 1-year) follow-up, subjective memory complaints were reported more often by the CABG than the nonsurgical group (45.5% vs. 17.0%, p<0.0001). By 6 years, the frequency of complaints was similar (52%) in both groups. Subjective memory ratings were significantly correlated with performance on several memory tests at 6 years. This relationship was not confounded by depression.
Subjective memory complaints are more frequent early in follow-up in patients undergoing CABG than in controls, but by 6 years they are similar. The increase in subjective complaints over time may be related to progression of underlying cerebrovascular disease. Unlike previous studies, we found that subjective memory assessments were correlated with objective performance on several memory tests. Although subjective memory complaints are more common in patients with depression, they cannot be explained by depression alone.
PMCID: PMC2753233  PMID: 19101263
CABG; neurocognitive deficits; outcomes; brain
12.  Factors that Influence Quality of Life in Rural Children with Asthma and their Parents 
Among rural children with asthma and their parents, this study examined the relationship between parental and child reports of quality of life and described the relationship of several factors such as asthma severity, missed days of work and asthma education on their quality of life.
Two hundred and one rural families with asthma were enrolled in a school-based educational program. Intervention parents and children received interactive asthma workshop(s), asthma devices and literature. Parent and child quality of life measurements were obtained pre and post intervention using Juniper's Paediatric Caregivers Quality of Life and Juniper's Paediatric Quality of Life Questionnaires. Asthma severity was measured using criteria from the National Asthma Education and Prevention Program (NAEPP) guidelines.
There was no association between parent and child total quality of life scores, and mean parental total quality of life scores were higher at baseline and follow-up than those of the children. All the parents' quality of life scores were correlated with parental reports of missed days of work. For all children, emotional quality of life (EQOL) was significantly associated with parental reports of school days missed (p= .03) and marginally associated with parental reports of hospitalizations due to asthma (p=.0.08). Parent's emotional quality of life (EQOL) and activity quality of life (AQOL) were significantly associated with children's asthma severity (EQOL, p=.009, AQOL, p=0.03), but not the asthma educational intervention. None of the child quality of life measurements were associated with asthma severity.
Asthma interventions for rural families should help families focus on gaining and maintaining low asthma severity levels in order for families to enjoy an optimal quality of life. Health care providers should try to assess the child's quality of life at each asthma care visit independently of the parents.
PMCID: PMC2592842  PMID: 18971080
13.  Rural Children with Asthma: Impact of a Parent and Child Asthma Education Program 
The goal of this study was to determine the effectiveness of an asthma educational intervention in improving asthma knowledge, self-efficacy, and quality of life in rural families. Children 6 to 12 years of age (62% male, 56% white, and 22% Medicaid) with persistent asthma (61%) were recruited from rural elementary schools and randomized into the control standard asthma education (CON) group or an interactive educational intervention (INT) group geared toward rural families.
Parent/caregiver and child asthma knowledge, self-efficacy, and quality of life were assessed at baseline and at 10 months post enrollment. Despite high frequency of symptom reports, only 18% children reported an emergency department visit in the prior 6 months. Significant improvement in asthma knowledge was noted for INT parents and young INT children at follow-up (Parent: CON = 16.3; INT = 17.5, p < 0.001; Young children: CON = 10.8, INT = 12.45, p < 0.001). Child self-efficacy significantly increased in the INT group at follow-up; however, there was no significant difference in parent self-efficacy or parent and child quality of life at follow-up. Asthma symptom reports were significantly lower for the INT group at follow-up. For young rural children, an interactive asthma education intervention was associated with increased asthma knowledge and self-efficacy, decreased symptom reports, but not increased quality of life.
PMCID: PMC2276310  PMID: 16393717
asthma education; self-efficacy; quality of life; rural; children

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