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1.  Affective brain areas and sleep disordered breathing 
Progress in brain research  2014;209:275-293.
The neural damage accompanying the hypoxia, reduced perfusion, and other consequences of sleep-disordered breathing found in obstructive sleep apnea, heart failure (HF), and congenital central hypoventilation syndrome (CCHS), appears in areas that serve multiple functions, including emotional drives to breathe, and involve systems that serve affective, cardiovascular, and breathing roles. The damage, assessed with structural magnetic resonance imaging (MRI) procedures, shows tissue loss or water content and diffusion changes indicative of injury, and impaired axonal integrity between structures; damage is preferentially unilateral. Functional MRI responses in affected areas also are time- or amplitude- distorted to ventilatory or autonomic challenges. Among the structures injured are the insular, cingulate, and ventral medial prefrontal cortices, as well as cerebellar deep nuclei and cortex, anterior hypothalamus, raphé, ventrolateral medulla, basal ganglia and, in CCHS, the locus coeruleus. Raphé and locus coeruleus injury may modify serotonergic and adrenergic modulation of upper airway and arousal characteristics. Since both axons and gray matter show injury, the consequences to function, especially to autonomic, cognitive, and mood regulation, are major. Several affected rostral sites, including the insular and cingulate cortices and hippocampus, mediate aspects of dyspnea, especially in CCHS, while others, including the anterior cingulate and thalamus, participate in initiation of inspiration after central breathing pauses, and the medullary injury can impair baroreflex and breathing control. The ancillary injury associated with sleep-disordered breathing to central structures can elicit multiple other distortions in cardiovascular, cognitive, and emotional functions in addition to effects on breathing regulation.
PMCID: PMC4060533  PMID: 24746053
Obstructive Sleep Apnea; Congenital Central Hypoventilation Syndrome; Heart Failure; Hypothalamus; Medulla; Brainstem; Magnetic Resonance Imaging; Dyspnea
2.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
PMCID: PMC4140093  PMID: 24929828
3.  Rhinolithiasis Due to Supernumerary Ectopic Tooth: Very Rare Case 
An ectopic supernumerary tooth causing the formation of rhinolith was never reported before in the medical literature. A 30 years old male patient presented to our hospital with one sided nasal obstruction, recurrent epistaxis, and nasal discharge. Anterior rhinoscopy, nasal endoscopy and X-ray paranasal sinuses revealed a rhinolith in the left nasal cavity. Preoperative evaluation and post operative examination of the specimen proved that the nidus of rhinolith was a supernumerary ectopic tooth.
Electronic supplementary material
The online version of this article (doi:10.1007/s12070-012-0493-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3851516  PMID: 24427605
Supernumerary teeth; Ectopic tooth; Rhinolith
4.  Neural and Physiological Responses to a Cold Pressor Challenge in Healthy Adolescents 
Journal of neuroscience research  2013;91(12):1618-1627.
Abnormal autonomic function is common in pediatric diseases. Assessment of central mechanisms underlying autonomic challenges may reveal vulnerabilities antecedent to system failure. Our objective was to characterize central markers and physiological responses to a cold pressor challenge in normal children as a critical step for establishing such screening. We performed functional magnetic resonance imaging (fMRI), and collected physiological measures during cold application to the foot in 24 healthy adolescents (15.5±0.4 years; 13 male). The protocol included a 120s baseline, 120s right-foot cold water immersion (4°C), and 120s recovery. Analyses included heart rate (HR) cross-correlations with fMRI signals. Cold application increased HR 13% 5-7s after onset, which remained elevated throughout the challenge. Respiratory rate transiently increased (peak 22%), then declined (nadir 12% below baseline), before normalizing at 75s. Cold onset rapidly increased somatosensory cortex and medullary signals, which fell after 25s. Right anterior insular cortex signals increased early, followed after 20s by the left anterior insula, with HR declining 8s later. Amygdalae signals also rose, but signals declined in the posterior cingulate cortex, caudate nucleus, hippocampus, and hypothalamus. Declining signals appeared late in the cerebellar fastigial nuclei (60-120s), and in the pons and thalamus. Somatosensory cortex, fastigial nuclei, and hypothalamic responses were principally left-sided, with bilateral responses elsewhere. Late left anterior insula responses likely underlie the HR decline; the late cerebellar pattern may modulate recovery. The laterality, timing and amplitude of normative responses, and rostral response differentiation indicate the complex integration of adolescent autonomic processing, and provide indices for pathological comparisons.
PMCID: PMC4040139  PMID: 24105663
Blood pressure; Magnetic resonance imaging; Heart rate; Respiratory rate; Autonomic
5.  Visual Assessment of Brain Magnetic Resonance Imaging Detects Injury to Cognitive Regulatory Sites in Patients with Heart Failure 
Journal of cardiac failure  2013;19(2):94-100.
Heart failure (HF) patients exhibit depressive and executive function impairments that contribute to HF mortality. Using specialized magnetic resonance imaging (MRI) analysis procedures, brain changes appear in areas regulating these functions (mammillary bodies, hippocampi, and frontal cortex). However, specialized MRI procedures are not part of standard clinical assessment for HF (which is usually a visual evaluation), and it is unclear whether visual examination can detect changes in these structures.
Methods and Results
Using brain MRI, we visually examined the mammillary bodies and frontal cortex for global and hippocampi for global and regional tissue changes in 17 HF and 50 control subjects. Significant global changes emerged in the right mammillary body (HF vs. control scores; 1.18±1.13 vs. 0.52±0.74; P=.024), right hippocampus (1.53±0.94 vs. 0.80±0.86; P=0.005), and left frontal cortex (1.76±1.03 vs. 1.24±0.77; P=0.034) between groups. Comparison of the visual method with specialized MRI techniques corroborates right hippocampal and left frontal cortical, but not mammillary body, atrophy.
Visual examination of brain MRI can detect damage in HF in areas regulating depression and executive function, including the right hippocampus and left frontal cortex. Visual MRI assessment may facilitate evaluation of injury to these structures and the assessment of the impact of potential treatments for this damage.
PMCID: PMC4249656  PMID: 23384634
Mammillary body; hippocampus; frontal cortex; atrophy
6.  Socioeconomic Status and Childhood Asthma in Urban Minority Youths. The GALA II and SAGE II Studies 
Rationale: The burden of asthma is highest among socioeconomically disadvantaged populations; however, its impact is differentially distributed among racial and ethnic groups.
Objectives: To assess the collective effect of maternal educational attainment, annual household income, and insurance type on childhood asthma among minority, urban youth.
Methods: We included Mexican American (n = 485), other Latino (n = 217), and African American (n = 1,141) children (aged 8–21 yr) with and without asthma from the San Francisco Bay Area. An index was derived from maternal educational attainment, annual household income, and insurance type to assess the collective effect of socioeconomic status on predicting asthma. Logistic regression stratified by racial and ethnic group was used to estimate adjusted odds ratios (aOR) and their 95% confidence intervals (CI). We further examined whether acculturation explained the socioeconomic-asthma association in our Latino population.
Measurements and Main Results: In the adjusted analyses, African American children had 23% greater odds of asthma with each decrease in the socioeconomic index (aOR, 1.23; 95% CI, 1.09–1.38). Conversely, Mexican American children have 17% reduced odds of asthma with each decrease in the socioeconomic index (aOR, 0.83; 95% CI, 0.72–0.96) and this relationship was not fully explained by acculturation. This association was not observed in the other Latino group.
Conclusions: Socioeconomic status plays an important role in predicting asthma, but has different effects depending on race and ethnicity. Further steps are necessary to better understand the risk factors through which socioeconomic status could operate in these populations to prevent asthma.
PMCID: PMC3863734  PMID: 24050698
asthma; health status disparities; minority health; educational status; poverty
7.  Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance 
Diabetes  2013;62(11):3887-3900.
Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.
PMCID: PMC3806607  PMID: 24159000
8.  Evaluation of Publicly Financed and Privately Delivered Model of Emergency Referral Services for Maternal and Child Health Care in India 
PLoS ONE  2014;9(10):e109911.
Emergency referral services (ERS) are being strengthened in India to improve access for institutional delivery. We evaluated a publicly financed and privately delivered model of ERS in Punjab state, India, to assess its extent and pattern of utilization, impact on institutional delivery, quality and unit cost.
Data for almost 0.4 million calls received from April 2012 to March 2013 was analysed to assess the extent and pattern of utilization. Segmented linear regression was used to analyse month-wise data on number of institutional deliveries in public sector health facilities from 2008 to 2013. We inspected ambulances in 2 districts against the Basic Life Support (BLS) standards. Timeliness of ERS was assessed for determining quality. Finally, we computed economic cost of implementing ERS from a health system perspective.
On an average, an ambulance transported 3–4 patients per day. Poor and those farther away from the health facility had a higher likelihood of using the ambulance. Although the ERS had an abrupt positive effect on increasing the institutional deliveries in the unadjusted model, there was no effect on institutional delivery after adjustment for autocorrelation. Cost of operating the ambulance service was INR 1361 (USD 22.7) per patient transported or INR 21 (USD 0.35) per km travelled.
Emergency referral services in Punjab did not result in a significant change in public sector institutional deliveries. This could be due to high baseline coverage of institutional delivery and low barriers to physical access. Choice of interventions for reduction in Maternal Mortality Ratio (MMR) should be context-specific to have high value for resources spent. The ERS in Punjab needs improvement in terms of quality and reduction of cost to health system.
PMCID: PMC4215978  PMID: 25360798
9.  CTAB-mediated, single-step preparation of competent Escherichia coli, Bifidobacterium sp. and Kluyveromyces lactis cells 
Meta Gene  2014;2:807-818.
An efficient and reproducible method for transformation depends on the competency of the organism. We have developed a simple method for the preparation of competent Escherichia coli, Kluyveromyces lactis, and Bifidobacterium sp. by using a buffer containing cetyl trimethyl ammonium bromide (CTAB) and permits efficient uptake of plasmid DNA and ligation-reaction products. Cells are harvested, washed, mixed with 1–10 μg/ml CTAB, incubated, and followed by a buffer wash. For long-term storage of competent cells, bacteria may be frozen in 10% glycerol without the addition of other components. The transformation process is very simple; plasmid DNA and the cells are mixed and incubated for 5–60 min at 4 °C; no heat pulse is required, and the duration of incubation at 4 °C is not crucial.
•We developed a simple and rapid procedure for the preparation of competent E. coli, Bifidobacterium sp., and K. lactis.•CTAB permits efficient uptake of plasmid, as well as ligation reaction products.•The equal transformation efficiencies were observed with cells harvested at late exponential and stationary phases.•CTAB treated cells are used for transformation by heat shock, electroporation, etc.
PMCID: PMC4287956  PMID: 25606463
Transformation; CTAB; TSS method of transformation; CaCl2 method; Competency; FACS
10.  Regional cerebral blood flow alterations in obstructive sleep apnea 
Neuroscience letters  2013;555:159-164.
Obstructive sleep apnea (OSA) is a condition characterized by upper airway muscle atonia with continued diaphragmatic efforts, resulting in repeated airway obstructions, periods of intermittent hypoxia, large thoracic pressure changes, and substantial shifts in arterial pressure with breathing cessation and resumption. The hypoxic exposure and hemodynamic changes likely induce the structural and functional deficits found in multiple brain areas, as shown by magnetic resonance imaging (MRI) procedures. Altered cerebral blood flow (CBF) may contribute to these localized deficits; thus, we examined regional CBF, using arterial spin labeling procedures, in 11 OSA (age, 49.1±12.2 years; 7 male) and 16 control subjects (42.3±10.2 years; 6 male) with a 3.0-Tesla MRI scanner. CBF maps were calculated, normalized to a common space, and regional CBF values across the brain quantified. Lowered CBF values emerged near multiple bilateral brain sites in OSA, including the corticospinal tracts, superior cerebellar peduncles, and pontocerebellar fibers. Lateralized, decreased CBF appeared near the left inferior cerebellar peduncles, left tapetum, left dorsal fornix/stria terminalis, right medial lemniscus, right red nucleus, right midbrain, and midline pons. Regional CBF values in OSA are significantly reduced in major sensory and motor fiber systems and motor regulatory sites, especially in structures mediating motor coordination; those reductions are often lateralized. The asymmetric CBF declines in motor regulatory areas may contribute to loss of coordination between upper airway and diaphragmatic musculature, and lead to further damage in the syndrome.
PMCID: PMC3891908  PMID: 24076138
Arterial spin labeling; Cerebral hemodynamics; Motor coordination; Sensory control; Hypoxemia
11.  Floristic Diversity and Distribution Pattern of Plant Communities along Altitudinal Gradient in Sangla Valley, Northwest Himalaya 
The Scientific World Journal  2014;2014:264878.
Himalayas are globally important biodiversity hotspots and are facing rapid loss in floristic diversity and changing pattern of vegetation due to various biotic and abiotic factors. This has necessitated the qualitative and quantitative assessment of vegetation here. The present study was conducted in Sangla Valley of northwest Himalaya aiming to assess the structure of vegetation and its trend in the valley along the altitudinal gradient. In the forest and alpine zones of the valley, 15 communities were recorded. Study revealed 320 species belonging to 199 genera and 75 families. Asteraceae, Rosaceae, Apiaceae, and Ranunculaceae were dominant. Among genera, Artemisia followed by Polygonum, Saussurea, Berberis, and Thalictrum were dominant. Tree and shrub's density ranged from 205 to 600 and from 105 to 1030 individual per hectare, respectively, whereas herbs ranged from 22.08 to 78.95 individual/m2. Nearly 182 species were native to the Himalaya. Maximum altitudinal distribution of few selected climate sensitive species was found to be highest in northeast and north aspects. This study gives an insight into the floristic diversity and community structure of the fragile Sangla Valley which was hitherto not available.
PMCID: PMC4212538  PMID: 25383363
12.  Potent Malaria Transmission-Blocking Antibody Responses Elicited by Plasmodium falciparum Pfs25 Expressed in Escherichia coli after Successful Protein Refolding 
Infection and Immunity  2014;82(4):1453-1459.
Production of Pfs25, a Plasmodium falciparum transmission-blocking vaccine target antigen, in functional conformation with the potential to elicit effective immunogenicity still remains a major challenge. In the current study, codon-harmonized recombinant Pfs25 (CHrPfs25) was expressed in Escherichia coli, and purified protein after simple oxidative refolding steps retained reduction-sensitive conformational epitopes of transmission-blocking monoclonal antibodies. CHrPfs25 formulated in several adjuvants elicited strong immunogenicity in preclinical studies in mice. Antibodies elicited after immunization recognized native Pfs25 on the surface of live gametes of P. falciparum and demonstrated complete malaria transmission-blocking activity. The transmission-blocking efficacy was 100% even after a 1:128 dilution of sera from immunized mice in the complete Freund's adjuvant and Montanide ISA51 groups and after a 1:16 dilution of sera from mice in the alum group. The blocking was mediated by antibodies; purified IgG at concentrations as low as 31.25 μg/ml exhibited 100% transmission blocking in membrane feeding assays employing two different species of mosquitoes, Anopheles gambiae and Anopheles stephensi. This study provides the first evidence for successful expression of biologically functional rPfs25 in E. coli. The extremely potent malaria transmission-blocking activity of antibodies elicited by immunization with purified protein provides strong support for further evaluation of E. coli-derived CHrPfs25 as a malaria transmission-blocking vaccine in human clinical trials.
PMCID: PMC3993404  PMID: 24421036
13.  Genetic diversity in Capsicum germplasm based on microsatellite and random amplified microsatellite polymorphism markers 
A sound knowledge of the genetic diversity among germplasm is vital for strategic germplasm collection, maintenance, conservation and utilisation. Genomic simple sequence repeats (SSRs) and random amplified microsatellite polymorphism (RAMPO) markers were used to analyse diversity and relationships among 48 pepper (Capsicum spp.) genotypes originating from nine countries. These genotypes covered 4 species including 13 germplasm accessions, 30 improved lines of 4 domesticated species and 5 landraces derived from natural interspecific crosses. Out of 106 SSR markers, 25 polymorphic SSR markers (24 %) detected a total of 76 alleles (average, 3.04; range, 2–5). The average polymorphic information content (PIC) was 0.69 (range, 0.29–0.92). Seventeen RAMPO markers produced 87 polymorphic fragments with average PIC of 0.63 (range, 0.44–0.81). Dendrograms based on SSRs and RAMPOs generated two clusters. All 38 Capsicum annuum genotypes and an interspecific landrace clustered together, whereas nine non-annuum (three Capsicum frutescens, one Capsicum chinense, one Capsicum baccatum and four interspecific landraces) genotypes clustered separately. Genetic variation within non-annuum genotypes was greater than the C. annuum genotypes. Distinctness of interspecific derivative landraces grown in northeast India was validated; natural crossing between sympatric Capsicum species has been proposed as the mechanism of their origin.
Electronic supplementary material
The online version of this article (doi:10.1007/s12298-013-0185-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3781276  PMID: 24431527
Capsicum; SSR; RAMPO; Interspecific derivatives; Sympatric population
14.  Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: The GALA II Study 
Atopy varies by ethnicity even within Latino groups. This variation may be due to environmental, socio-cultural or genetic factors.
To examine risk factors for atopy within a nationwide study of U.S. Latino children with and without asthma.
Aeroallergen skin test repsonse was analyzed in 1830 US latino subjects. Key determinants of atopy included: country / region of origin, generation in the U.S., acculturation, genetic ancestry and site to which individuals migrated. Serial multivariate zero inflated negative binomial regressions, stratified by asthma status, examined the association of each key determinant variable with the number of positive skin tests. In addition, the independent effect of each key variable was determined by including all key variables in the final models.
In baseline analyses, African ancestry was associated with 3 times as many positive skin tests in participants with asthma (95% CI:1.62–5.57) and 3.26 times as many positive skin tests in control participants (95% CI: 1.02–10.39). Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, Puerto Rican [exp(β) (95%CI): 1.31(1.02–1.69)] and mixed ethnicity [exp(β) (95%CI):1.27(1.03–1.56)] asthmatics had a greater probability of positive skin tests compared to Mexican asthmatics. Ancestry associations were abrogated by recruitment site, but not region of origin.
Puerto Rican ethnicity and mixed origin were associated with degree of atopy within U.S. Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.
PMCID: PMC3788073  PMID: 23684070
Latino; atopy; region of origin; genetic ancestry; immigration; skin test; aeroallergen
15.  Sleep-disordered breathing: effects on brain structure and function 
Sleep-disordered breathing is accompanied by neural injury that affects a wide range of physiological systems which include processes for sensing chemoreception and airflow, driving respiratory musculature, timing circuitry for coordination of breathing patterning, and integration of blood pressure mechanisms with respiration. The damage also occurs in regions mediating emotion and mood, as well as areas regulating memory and cognitive functioning, and appears in structures that serve significant glycemic control processes. The injured structures include brain areas involved in hormone release and action of major neurotransmitters, including those playing a role in depression. The injury is reflected in a range of structural magnetic resonance procedures, and also appears as functional distortions of evoked activity in brain areas mediating vital autonomic and breathing functions. The damage is preferentially unilateral, and includes axonal projections; the asymmetry of the injury poses unique concerns for sympathetic discharge and potential consequences for arrhythmia. Sleep-disordered breathing should be viewed as a condition that includes central nervous system injury and impaired function; the processes underlying injury remain unclear.
PMCID: PMC3778068  PMID: 23643610
Obstructive sleep apnea; magnetic resonance imaging; autonomic; neural injury; hypoxia; dyspnea; congenital central hypoventilation
16.  Profile of Microbial Keratitis after Corneal Collagen Cross-Linking 
BioMed Research International  2014;2014:340509.
Purpose. To report the profile of microbial keratitis occurring after corneal collagen cross-linking (CXL) in keratoconus patients. Methods. A retrospective analysis of 2350 patients (1715 conventional CXL, 310 transepithelial CXL, and 325 accelerated CXL) over 7 years (from January 2007 to January 2014) of progressive keratoconus, who underwent CXL at a tertiary eye care centre, was performed. Clinical findings, treatment, and course of disease of four eyes that developed postprocedural moxifloxacin resistant Staphylococcus aureus (MXRSA) infectious keratitis are highlighted. Results. Four eyes that underwent CXL (0.0017%) had corneal infiltrates. All eyes that developed keratitis had conventional CXL. Corneal infiltrates were noted on the third postoperative day. Gram's stain as well as culture reported MXRSA as the causative agent in all cases. Polymerase chain reaction (PCR) in each case was positive for eubacterial genome. All patients were treated with fortified antibiotic eye drops, following which keratitis resolved over a 6-week period with scarring. All these patients were on long-term preoperative oral/topical steroids for chronic disorders (chronic vernal keratoconjunctivitis, bronchial asthma, and chronic eczema). Conclusion. The incidence of infectious keratitis after CXL is a rare complication (0.0017%). MXRSA is a potential organism for causing post-CXL keratitis and should be identified early and treated aggressively with fortified antibiotics.
PMCID: PMC4180902  PMID: 25302296
17.  Replication and fine mapping of asthma-associated loci in individuals of African ancestry 
Human genetics  2013;132(9):1039-1047.
Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RLML18R1, and 10pl4, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.
PMCID: PMC3975655  PMID: 23666277
18.  Global Brain Blood-Oxygen Level Responses to Autonomic Challenges in Obstructive Sleep Apnea 
PLoS ONE  2014;9(8):e105261.
Obstructive sleep apnea (OSA) is accompanied by brain injury, perhaps resulting from apnea-related hypoxia or periods of impaired cerebral perfusion. Perfusion changes can be determined indirectly by evaluation of cerebral blood volume and oxygenation alterations, which can be measured rapidly and non-invasively with the global blood oxygen level dependent (BOLD) signal, a magnetic resonance imaging procedure. We assessed acute BOLD responses in OSA subjects to pressor challenges that elicit cerebral blood flow changes, using a two-group comparative design with healthy subjects as a reference. We separately assessed female and male patterns, since OSA characteristics and brain injury differ between sexes. We studied 94 subjects, 37 with newly-diagnosed, untreated OSA (6 female (age mean ± std: 52.1±8.1 yrs; apnea/hypopnea index [AHI]: 27.7±15.6 events/hr and 31 male 54.3±8.4 yrs; AHI: 37.4±19.6 events/hr), and 20 female (age 50.5±8.1 yrs) and 37 male (age 45.6±9.2 yrs) healthy control subjects. We measured brain BOLD responses every 2 s while subjects underwent cold pressor, hand grip, and Valsalva maneuver challenges. The global BOLD signal rapidly changed after the first 2 s of each challenge, and differed in magnitude between groups to two challenges (cold pressor, hand grip), but not to the Valsalva maneuver (repeated measures ANOVA, p<0.05). OSA females showed greater differences from males in response magnitude and pattern, relative to healthy counterparts. Cold pressor BOLD signal increases (mean ± adjusted standard error) at the 8 s peak were: OSA 0.14±0.08% vs. Control 0.31±0.06%, and hand grip at 6 s were: OSA 0.08±0.03% vs. Control at 0.30±0.02%. These findings, indicative of reduced cerebral blood flow changes to autonomic challenges in OSA, complement earlier reports of altered resting blood flow and reduced cerebral artery responsiveness. Females are more affected than males, an outcome which may contribute to the sex-specific brain injury in the syndrome.
PMCID: PMC4148259  PMID: 25166862
19.  Early-Life Air Pollution and Asthma Risk in Minority Children. The GALA II and SAGE II Studies 
Rationale: Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications.
Objectives: To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions.
Methods: This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO2), sulfur dioxide, particulate matter not greater than 10 μm in diameter, and particulate matter not greater than 2.5 μm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant.
Measurements and Main Results: After adjustment for confounders, a 5-ppb increase in average NO2 during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04–1.31).
Conclusions: Early-life NO2 exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.
PMCID: PMC3778732  PMID: 23750510
air pollution; minority; children; asthma
20.  Recent Advances in Polyamine Metabolism and Abiotic Stress Tolerance 
BioMed Research International  2014;2014:239621.
Global warming is an alarming problem in agriculture and its effect on yield loss has been estimated to be five per cent for every degree centigrade rise in temperature. Plants exhibit multiple mechanisms like optimizing signaling pathway, involvement of secondary messengers, production of biomolecules specifically in response to stress, modulation of various metabolic networks in accordance with stress, and so forth, in order to overcome abiotic stress factors. Many structural genes and networks of pathway were identified and reported in plant systems for abiotic stress tolerance. One such crucial metabolic pathway that is involved in normal physiological function and also gets modulated during stress to impart tolerance is polyamine metabolic pathway. Besides the role of structural genes, it is also important to know the mechanism by which these structural genes are regulated during stress. Present review highlights polyamine biosynthesis, catabolism, and its role in abiotic stress tolerance with special reference to plant systems. Additionally, a system based approach is discussed as a potential strategy to dissect the existing variation in crop species in unraveling the interacting regulatory components/genetic determinants related to PAs mediated abiotic stress tolerance.
PMCID: PMC4124767  PMID: 25136565
21.  Geospatial Analysis on the Distributions of Tobacco Smoking and Alcohol Drinking in India 
PLoS ONE  2014;9(7):e102416.
Tobacco smoking and binge alcohol drinking are two of the leading risk factors for premature mortality worldwide. In India, studies have examined the geographic distributions of tobacco smoking and alcohol drinking only at the state-level; sub-state variations and the spatial association between the two consumptions are poorly understood.
We used data from the Special Fertility and Mortality Survey conducted in 1998 to examine the geographic distributions of tobacco smoking and alcohol drinking at the district and postal code levels. We used kriging interpolation to generate smoking and drinking distributions at the postal code level. We also examined spatial autocorrelations and identified spatial clusters of high and low prevalence of smoking and drinking. Finally, we used bivariate analyses to examine the spatial correlations between smoking and drinking, and between cigarette and bidi smoking.
There was a high prevalence of any smoking in the central and northeastern states, and a high prevalence of any drinking in Himachal Pradesh, Arunachal Pradesh, and eastern Madhya Pradesh. Spatial clusters of early smoking (started smoking before age 20) were identified in the central states. Cigarette and bidi smoking showed distinctly different geographic patterns, with high levels of cigarette smoking in the northeastern states and high levels of bidi smoking in the central states. The geographic pattern of bidi smoking was similar to early smoking. Cigarette smoking was spatially associated with any drinking. Smoking prevalences in 1998 were correlated with prevalences in 2004 at the district level and 2010 at the state level.
These results along with earlier evidence on the complementarities between tobacco smoking and alcohol drinking suggest that local public health action on smoking might also help to reduce alcohol consumption, and vice versa. Surveys that properly represent tobacco and alcohol consumptions at the district level are recommended.
PMCID: PMC4099149  PMID: 25025379
22.  Differential Responses of the Insular Cortex Gyri to Autonomic Challenges 
Determining insular functional topography is essential for assessing autonomic consequences of neural injury. We examined that topography in the five major insular cortex gyri to three autonomic challenges, the Valsalva, hand grip, and foot cold pressor, using functional magnetic resonance imaging (fMRI) procedures. Fifty-seven healthy subjects (age±std: 47±9 years) performed four 18 s Valsalva maneuvers (30 mmHg load pressure), four hand grip challenges (16 s at 80% effort), and a foot cold pressor (60 s, 4°C), with fMRI scans recorded every 2 s. Signal trends were compared across gyri using repeated measures ANOVA. Significantly (P<0.05) higher signals in left anterior versus posterior gyri appeared during Valsalva strain, and in the first 4 s of recovery. The right anterior gyri showed sustained higher signals up to 2 s post-challenge, relative to posterior gyri, with sub-gyral differentiation. Left anterior gyri signals were higher than posterior areas during the hand grip challenge. All right anterior gyri showed increased signals over posterior up to 12 s post-challenge, with decline in the most-anterior gyrus from 10–24 s during recovery. The left three anterior gyri showed relatively lower signals only during the 90 s recovery of the cold pressor, while the two most-anterior right gyri signals increased only during the stimulus. More-differentiated representation of autonomic signals appear in the anterior right insula for the Valsalva maneuver, a bilateral, more-posterior signal representation for hand grip, and preferentially right-sided, anterior-posterior representation for the cold pressor. The functional organization of the insular cortex is gyri-specific to unique autonomic challenges.
PMCID: PMC4077282  PMID: 22342370
Functional magnetic resonance imaging; autonomic nervous system; functional neuroanatomy; Valsalva maneuver; hand grip; cold pressor
23.  Variations in Innervation of Muscles in Anterior Compartment of Arm – A Cadaveric Study 
Aims and Objective: Study was undertaken to observe the variation in the innervation of muscles in the front of arm. The results were compiled. Embryological basis and clinical applications of encountered variations were tried to explain with the help of available literature.
Material and Methods: Thirty upper limbs from fifteen cadavers were dissected to observe the contents of front of arm. Musculocutaneous nerve, median nerve and innervation of the muscles of front of arm were observed.
Results: Variations were observed in 13% of cases. Commonly seen variation was the absence of musculocutaneous nerve and innervation of muscles of front of arm by branches of median nerve. This variation was seen bilaterally in 3.3% of cases and unilaterally in 6.6% cases. Bilateral presence of this variation in one out of fifteen cadavers is rare finding. Variation is more common on right side as compared to the left side.
Conclusion: Bilateral absence of musculocutaneous nerve and innervation of muscles of front of arm from the branches of median nerve is a rare variation. Knowledge of such anatomical variations is of interest to the anatomist and clinician alike. Variations assume significance during surgical exploration of the axilla and can even fail nerve block of infraclavicular part of brachial plexus. Surgeons who perform procedures involving neoplasm or repairing trauma need to be aware of these variations.
PMCID: PMC4079987  PMID: 24995166
Musculocutaneous nerve; Median nerve; Innervation; Muscles
24.  Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in Olive baboons 
Vaccine  2013;31(31):3140-3147.
Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (Olive baboons, Papio anubis). The results showed that at a dose of 2.5 mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5 mg and 1 mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers.
PMCID: PMC3686897  PMID: 23684840
Pfs25; Malaria; Transmission blocking vaccine; DNA vaccine; Electroporation; Prime boost
25.  Neural Alterations Associated with Anxiety Symptoms in >Obstructive Sleep Apnea Syndrome 
Depression and anxiety  2009;26(5):480-491.
Neuropsychological comorbidities, including anxiety symptoms, accompany obstructive sleep apnea (OSA); structural and functional brain alterations also occur in the syndrome. The objective was to determine if OSA patients expressing anxiety symptoms show injury in specific brain sites.
Magnetic resonance T2-relaxometry was performed in 46 OSA and 66 control subjects. Anxiety symptoms were evaluated using the Beck Anxiety Inventory (BAI); subjects with BAI scores > 9 were classified anxious. Whole-brain T2-relaxation maps were compared between anxious and non-anxious groups using analysis of covariance (covariates; age and gender).
Sixteen OSA and seven control subjects showed anxiety symptoms, and 30 OSA and 59 controls were non-anxious. Significantly higher T2-relaxation values, indicating tissue injury, appeared in anxious OSA vs non-anxious OSA subjects in subgenu, anterior, and mid-cingulate, ventral medial prefrontal and bilateral insular cortices, hippocampus extending to amygdala, and temporal, and bilateral parietal cortices. Brain injury emerged in anxious OSA vs non-anxious controls in bilateral insular cortices, caudate nuclei, anterior fornix, anterior thalamus, internal capsule, mid-hippocampus, dorsotemporal, dorsofrontal, ventral medial prefrontal and parietal cortices.
Anxious OSA subjects showed injury in brain areas regulating emotion, with several regions lying outside structures affected by OSA alone, suggesting additional injurious processes in anxious OSA subjects.
PMCID: PMC4041684  PMID: 18828142
Sleep-disordered breathing; Intermittent hypoxia; Hippocampus; Amygdala; Fornix; Magnetic resonance imaging

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