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2.  Assessment of Population-Based HIV RNA Levels in a Rural East African Setting Using a Fingerprick-Based Blood Collection Method 
Population-based human immunodeficiency virus (HIV) RNA metrics can help estimate antiretroviral therapy effectiveness within a community. We developed a fingerprick-based viral load technique and measured population HIV RNA levels in a rural Ugandan community, providing the first report from a resource limited setting.
Background. Population-based human immunodeficiency virus type 1 (HIV-1) RNA levels (viral load [VL]) are proposed metrics for antiretroviral therapy (ART) program effectiveness. We estimated population-based HIV RNA levels using a fingerprick-based approach in a rural Ugandan community implementing rapid ART scale-up.
Methods. A fingerprick-based HIV RNA measurement technique was validated against standard phlebotomy. This technique was deployed during a 5-day community-wide health campaign in a 6300-person community. Assessments included rapid HIV antibody testing, VL, and CD4+ T-cell count via fingerprick. We estimated population HIV RNA levels and the prevalence of undetectable RNA, assessed predictors of VL via linear regression, and mapped RNA levels within community geographic units.
Results. During the community-wide health campaign, 179 of 2282 adults (7.8%) and 10 of 1826 children (0.5%) tested seropositive for HIV. Fingerprick VL was determined in 174 of 189 HIV-positive persons (92%). The mean log(VL) was 3.67 log (95% confidence interval [CI], 3.50–3.83 log copies/mL), median VL was 2720 copies/mL (interquartile range, <486–38 120 copies/mL), and arithmetic mean VL was 64 064 copies/mL. Overall, 64 of 174 of individuals had undetectable RNA (37% [95% CI, 30%–44%]), 24% had VL 486–10 000; 25% had VL 10 001–100 000; and 15% had VL>100 000 copies/mL. Among participants taking ART, 83% had undetectable VL.
Conclusions. We developed and implemented a fingerprick VL testing method and provide the first report of population HIV RNA levels in Africa. In a rural Ugandan community experiencing ART scale-up, we found evidence of population-level ART effectiveness, but found a substantial population to be viremic, in need of ART, and at risk for transmission.
doi:10.1093/cid/cis881
PMCID: PMC3552523  PMID: 23243180
population HIV-RNA levels; viral load; fingerprick; ART effectiveness; epidemiology
3.  Uptake of Community-Based HIV Testing during a Multi-Disease Health Campaign in Rural Uganda 
PLoS ONE  2014;9(1):e84317.
Background
The high burden of undiagnosed HIV in sub-Saharan Africa is a major obstacle for HIV prevention and treatment. Multi-disease, community health campaigns (CHCs) offering HIV testing are a successful approach to rapidly increase HIV testing rates and identify undiagnosed HIV. However, a greater understanding of population-level uptake is needed to maximize effectiveness of this approach.
Methods
After community sensitization and a census, a five-day campaign was performed in May 2012 in a rural Ugandan community. The census enumerated all residents, capturing demographics, household location, and fingerprint biometrics. The CHC included point-of-care screening for HIV, malaria, TB, hypertension and diabetes. Residents who attended vs. did not attend the CHC were compared to determine predictors of participation.
Results
Over 12 days, 18 census workers enumerated 6,343 residents. 501 additional residents were identified at the campaign, for a total community population of 6,844. 4,323 (63%) residents and 556 non-residents attended the campaign. HIV tests were performed in 4,795/4,879 (98.3%) participants; 1,836 (38%) reported no prior HIV testing. Of 2674 adults tested, 257 (10%) were HIV-infected; 125/257 (49%) reported newly diagnosed HIV. In unadjusted analyses, adult resident campaign non-participation was associated with male sex (62% male vs. 67% female participation, p = 0.003), younger median age (27 years in non-participants vs. 32 in participants; p<0.001), and marital status (48% single vs. 71% married/widowed/divorced participation; p<0.001). In multivariate analysis, single adults were significantly less likely to attend the campaign than non-single adults (relative risk [RR]: 0.63 [95% CI: 0.53–0.74]; p<0.001), and adults at home vs. not home during census activities were significantly more likely to attend the campaign (RR: 1.20 [95% CI: 1.13–1.28]; p<0.001).
Conclusions
CHCs provide a rapid approach to testing a majority of residents for HIV in rural African settings. However, complementary strategies are still needed to engage young, single adults and achieve universal testing.
doi:10.1371/journal.pone.0084317
PMCID: PMC3879307  PMID: 24392124
4.  The Effect of a “Universal Antiretroviral Therapy” Recommendation on HIV RNA Levels Among HIV-Infected Patients Entering Care With a CD4 Count Greater Than 500/µL in a Public Health Setting 
A recommendation by San Francisco General Hospital in January 2010 to initiate antiretroviral therapy in all human immunodeficiency virus (HIV)–infected patients led to a rapid increase in HIV RNA suppression among patients with a CD4 cell count of >500 cells/μL after clinic enrollment.
Background. On 1 January 2010, a large, publicly funded clinic in San Francisco announced a “universal ART” approach to initiate antiretroviral therapy (ART) in all human immunodeficiency virus (HIV)-infected persons. The effect of changing guidance on real-world patient outcomes has not been evaluated.
Methods. We evaluated untreated adult patients (defined as going >90 days without ART use) visiting clinic from 2001 to 2011. The cumulative incidence of HIV RNA suppression (viral load, <500 copies/mL), stratified by CD4 cell count at entry and calendar dates representing guideline issuance, were estimated using a competing risk framework. A multivariate Poisson-based model identified factors associated with HIV RNA suppression 6 months after clinic entry.
Results. Of 2245 adults, 87% were male, and the median age was 39 years (interquartile range, 33–45 years). In 534 patients entering clinic with a CD4 cell count of >500 cells/µL, the 1-year incidence of HIV RNA suppression was 10.1% (95% confidence interval [CI], 6.6%–14.6%) before 4 April 2005; 9.1% (95% CI, 3.6%–17.4%) from 4 April 2005 to 1 December 2007; 14.1% (95% CI, 7.5%–22.8%) from 1 December 2007 to the universal ART recommendation and 52.8% (95% CI, 38.2%–65.4%) after. After adjustment, the SFGH policy was associated with a 6-fold increase in the probability of HIV RNA suppression 6 months after clinic entry.
Conclusions. Recommendations to initiate ART in all HIV-infected patients increased the rate of HIV RNA suppression for patients enrolling in care with a CD4 cell count of >500 cells/µL and may foreshadow national trends given the March 2012 revision of national treatment guidelines to favor ART initiation for persons with CD4 cell counts of >500 cells/µL.
doi:10.1093/cid/cis750
PMCID: PMC3501330  PMID: 22955429
5.  Epidemiology and awareness of hypertension in a rural Ugandan community: a cross-sectional study 
BMC Public Health  2013;13:1151.
Background
Hypertension is one of the largest causes of preventable morbidity and mortality worldwide. There are few population-based studies on hypertension epidemiology to guide public health strategies in sub-Saharan Africa. Using a community-based strategy that integrated screening for HIV and non-communicable diseases, we determined the prevalence, awareness, treatment rates, and sociodemographic factors associated with hypertension in rural Uganda.
Methods
A household census was performed to enumerate the population in Kakyerere parish in Mbarara district, Uganda. A multi-disease community-based screening campaign for hypertension, diabetes, and HIV was then conducted. During the campaign, all adults received a blood pressure (BP) measurement and completed a survey examining sociodemographic factors. Hypertension was defined as elevated BP (≥140/≥90 mmHg) on the lowest of three BP measurements or current use of antihypertensives. Prevalence was calculated and standardized to age distribution. Sociodemographic factors associated with hypertension were evaluated using a log-link Poisson regression model with robust standard errors.
Results
Community participation in the screening campaign was 65%, including 1245 women and 1007 men. The prevalence of hypertension was 14.6%; awareness of diagnosis (38.1%) and current receipt of treatment (20.6%) were both low. Age-standardized to the WHO world standard population, hypertension prevalence was 19.8%, which is comparable to 21.6% in the US and 18.4% in the UK. Sociodemographic factors associated with hypertension included increasing age, male gender, overweight, obesity, diabetes, alcohol consumption, and family history. Prevalence of modifiable factors was high: 28.3% women were overweight/obese and 24.1% men consumed ≥10 alcoholic drinks per month.
Conclusions
We found a substantial burden of hypertension in rural Uganda. Awareness and treatment of hypertension is low in this region. Enhanced community-based education and prevention efforts tailored to addressing modifiable factors are needed.
doi:10.1186/1471-2458-13-1151
PMCID: PMC3890617  PMID: 24321133
Hypertension; Epidemiology; Blood pressure; Non-communicable disease; Community health; Health campaign; Public health; Sub-Saharan Africa; Uganda; Rural
6.  Protective effect of Lannea coromandelica Houtt. Merrill. against three common pathogens 
Background:
Ayurvedic text reports suggested Lannea coromandelica is used in various microbial origin disorders like dysentery, sore eyes and leprosy, genital wounds.
Objective:
The present study was designed to investigate the antimicrobial effect of L. coromandelica Houtt. Merrill. (Anacardiaceae) on microbes which cause female reproductive tract infection.
Materials and Methods:
Ethanolic and aqueous bark extract (Ext.) of L. coromandelica were screened against strains of Streptococcus pyogens, Staphylococcus aureus, and Candida albicans. Antimicrobial assay had been done with agar well diffusion method.
Results:
Ethanolic extracts [100% (16 mg), 75% (12 mg) and 50% (8 mg)] of L. coromandelica exhibited zone of inhibition (ZI) 19.21 mm, 18.45 mm, 16.41 mm and 18.12 mm, 17.35 mm, 16.35 mm against S. aureus and S. pyogens, respectively. However, only 100% and 75% ethanolic extract showed (ZI-19.18 mm, 16.29 mm) activity against C. albicans. Nevertheless, aqueous extract (100%) showed higher antifungal activity (ZI-16.97 mm). Ciprofloxacin and amphotericin B were used as a standard drugs in the present study.
Conclusion:
The results demonstrated that L. coromandelica Houtt. Merrill. have antibacterial activity against S. pyogens, S. aureus and antifungal property against C. albicans. Our findings corroborate the ethnobotanical use of L. coromandelica in traditional medicine system (Ayurveda) of India.
doi:10.4103/0975-9476.123706
PMCID: PMC3891178  PMID: 24459389
Agar well diffusion method; antibacterial; antifungal; ayurveda; Candida albicans; female reproductive tract infection; Lannea coromandelica; Staphylococcus aureus; Streptococcus pyogens
7.  Evaluation on the responses of succinate dehydrogenase, isocitrate dehydrogenase, malate dehydrogenase and glucose-6-phosphate dehydrogenase to acid shock generated acid tolerance in Escherichia coli 
Background:
Escherichia coli have an optimum pH range of 6-7 for growth and survival that's why, called neutrophiles. The ΔpH across the cytoplasmic membrane is linked to cellular bioenergetics and metabolism of the body which is the major supplier of the proton motive force, so homeostasis of cellular pH is essential. When challenged by low pH, protons enter the cytoplasm; as a result, mechanisms are required to alleviate the effects of lowered cytoplasmic pH.
Materials and Methods:
The activities of Succinate dehydrogenase, isocitrate dehydrogenase, malate dehydrogenase and glucose-6-phosphate dehydrogenase in acid shocked cells of E. coli DH5 α and E. coli W3110 subjected to pH 3, 4, and 5 by two types of acidification, like external (using 0.1 N HCl), external along with the monensin (1 μM) and cytoplasmic acidification using the sodium benzoate as an acid permeant (20 mM) which is coupled to the electron transport chain by the reducing power, as yet another system possessed by E. coli as an armor against harsh acidic environments.
Result:
Results showed that an exposure to acidic environment (pH 3, 4 and 5) for a short period of time increased the activities of these dehydrogenases in all types of acidification except cytoplasmic acidification, which shows that higher recycling of reducing power results in pumping out of protons from the cytoplasm through the electron transport chain complexes, thereby restoring the cytoplasmic pH of the bacteria in the range of 7.4-7.8.
Conclusion:
Study indicates that acid shocked E. coli for a period of 2 h can survive for a sustained period.
doi:10.4103/2277-9175.115799
PMCID: PMC3814565  PMID: 24223390
Acid tolerance; dehydrogenases; electron transport chain; external acidification; internal acidification and intracellular pH
8.  Leveraging Rapid Community-Based HIV Testing Campaigns for Non-Communicable Diseases in Rural Uganda 
PLoS ONE  2012;7(8):e43400.
Background
The high burden of undiagnosed HIV in sub-Saharan Africa limits treatment and prevention efforts. Community-based HIV testing campaigns can address this challenge and provide an untapped opportunity to identify non-communicable diseases (NCDs). We tested the feasibility and diagnostic yield of integrating NCD and communicable diseases into a rapid HIV testing and referral campaign for all residents of a rural Ugandan parish.
Methods
A five-day, multi-disease campaign, offering diagnostic, preventive, treatment and referral services, was performed in May 2011. Services included point-of-care screening for HIV, malaria, TB, hypertension and diabetes. Finger-prick diagnostics eliminated the need for phlebotomy. HIV-infected adults met clinic staff and peer counselors on-site; those with CD4≤100/µL underwent intensive counseling and rapid referral for antiretroviral therapy (ART). Community participation, case-finding yield, and linkage to care three months post-campaign were analyzed.
Results
Of 6,300 residents, 2,323/3,150 (74%) adults and 2,020/3,150 (69%) children participated. An estimated 95% and 52% of adult female and male residents participated respectively. Adult HIV prevalence was 7.8%, with 46% of HIV-infected adults newly diagnosed. Thirty-nine percent of new HIV diagnoses linked to care. In a pilot subgroup with CD4≤100, 83% linked and started ART within 10 days. Malaria was identified in 10% of children, and hypertension and diabetes in 28% and 3.5% of adults screened, respectively. Sixty-five percent of hypertensives and 23% of diabetics were new diagnoses, of which 43% and 61% linked to care, respectively. Screening identified suspected TB in 87% of HIV-infected and 19% of HIV-uninfected adults; 52% percent of HIV-uninfected TB suspects linked to care.
Conclusions
In an integrated campaign engaging 74% of adult residents, we identified a high burden of undiagnosed HIV, hypertension and diabetes. Improving male attendance and optimizing linkage to care require new approaches. The campaign demonstrates the feasibility of integrating hypertension, diabetes and communicable diseases into HIV initiatives.
doi:10.1371/journal.pone.0043400
PMCID: PMC3423366  PMID: 22916256
9.  Use of Lasers for the Management of Refractory Cases of Hidradenitis Suppurativa and Pilonidal Sinus 
Background:
Hidradinitis suppurativa (HS) and pilonidal sinus (PNS) are chronic inflamatory skin diseases, often refractory to treatment and search for a new treatment is on. We tried deroofing with the help of carbon dioxide laser in patients of HS and PNS, however there was recurrence.
Aim:
To evaluate a technique combining the use of CO2 laser and long pulse 1064 nm Neodymium-doped Yttrium Aluminium Garnet (Nd:YAG) laser for the treatment of HS and PNS.
Materials and Methods:
In 4 patients with HS and 5 patients with PNS, we performed procedure in two steps: first destroying the hair follicles with long pulse Nd yag 1064 laserfollowed by deroofing with carbon di oxide laser. Follow up was done upto 3 years.
Results:
All patients with HS were females in the age group of 30-40 years. In PNS, 2 male patients were of age less than 20, two male patients of age more than 20 and one females of age less than 20. None of the HS or PNS patients showed recurrence.
Conclusion:
The deroofing with CO2 laser along with hair follicle removal with long pulse Nd:YAG laser is an effective minimally invasive tissue saving surgical intervention for the treatment of refractory HS and PNS lesions.
doi:10.4103/0974-2077.101377
PMCID: PMC3483576  PMID: 23112515
Hidradenitis suppurativa; PNS-pilonidal sinus; Carbon dioxide laser; Long pulse Nd:YAG Laser
10.  Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes 
The Journal of Infectious Diseases  2011;203(8):1174-1181.
Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain.
Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model.
Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001).
Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.
doi:10.1093/infdis/jiq167
PMCID: PMC3107558  PMID: 21451005
11.  Blue cures blue but be cautious 
Methemoglobinemia is a disorder characterized by the presence of >1% methemoglobin (metHb) in the blood. Spontaneous formation of methemoglobin is normally counteracted by protective enzyme systems, for example, nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase. Methemoglobinemia is treated with supplemental oxygen and methylene blue (1–2 mg/kg) administered slow intravenously, which acts by providing an artificial electron acceptor for NADPH methemoglobin reductase. But known or suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency is a relative contraindication to the use of methylene blue because G6PD is the key enzyme in the formation of NADPH through pentose phosphate pathway and G6PD-deficient individuals generate insufficient NADPH to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. So, we should be careful using methylene blue in methemoglobinemia patient before G6PD levels.
doi:10.4103/0975-7406.90112
PMCID: PMC3249703  PMID: 22219589
G6PD deficiency; methemoglobinemia; methylene blue
12.  Strengthening TB surveillance system in India: Way forward for improving estimates of TB incidence 
One of the key indicators used under India’s TB control program is the DOTS case detection rate of new sputum smear positive TB whose estimates in India are based on incidence estimates derived from Styblo’s rule. Styblo’s rule was formulated in an era without well-established tuberculosis control program, effective tuberculosis drugs, and emergence of TB-HIV coinfection, so today it does not reflect the true incidence of TB. Considering various loopholes in different methods of measurement of incidence (prevalence surveys of disease/ infection, vital registration system and Styblo’s rule), strengthening of existing surveillance system is the best tool to obtain correct estimates of tuberculosis incidence in India.
doi:10.4103/0970-2113.80325
PMCID: PMC3109834  PMID: 21712922
Indicator; Styblo’s rule; surveillance; tuberculosis
13.  Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009 
PLoS ONE  2010;5(12):e15510.
Background
Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009.
Methodology/Principal Findings
We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27).
Conclusions
Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.
doi:10.1371/journal.pone.0015510
PMCID: PMC3000814  PMID: 21170322
14.  Plasma levels of retinoids, carotenoids and tocopherols in patients with mild obstructive sleep apnoea 
Respirology (Carlton, Vic.)  2009;14(8):1134-1142.
Background and objective
OSA is associated with increased incidence of cardiovascular diseases. Pathogenic mechanisms of vascular diseases include thickened vascular walls due to the increased number of smooth muscle cells (SMC). Retinoic acid (RA) suppresses the growth of SMC, and reduced retinoid levels are associated with vascular diseases. Oxidant signalling promotes SMC growth, thus antioxidant levels may also influence the development of cardiovascular diseases. The present study tested the hypothesis that plasmas from OSA patients contain altered levels of retinoids, carotenoids and tocopherols.
Methods
Plasma samples were taken before and after sleep from patients with OSA (mostly mild) without known cardiovascular diseases and from control subjects. Levels of retinoids, carotenoids and tocopherols were measured using sensitive gas chromatograph-mass spectrometry and high pressure liquid chromatography methods and total antioxidant capacity was assessed fluorometrically.
Results
Results showed that plasmas from patients with OSA had significantly lower retinyl palmitate and 9-cis RA compared with control subjects, while levels of retinol, all-trans RA and 13-cis RA were indifferent. All-trans β-carotene and 9-cis β-carotene were also lower in OSA patients. Levels of all-trans RA and 13-cis RA in OSA patients were reduced after sleep compared with before sleep. OSA patients showed significantly higher δ-tocopherol compared with controls. Treatment of cultured human vascular SMC with post-sleep OSA patient plasmas promoted cell growth, but not in controls.
Conclusions
Mild OSA exhibits altered levels of specific retinoids, carotenoids and tocopherols, which may be markers and/or mediators for the increased susceptibility of patients to vascular diseases.
doi:10.1111/j.1440-1843.2009.01623.x
PMCID: PMC2804104  PMID: 19761534
antioxidant; carotenoid; retinoid; sleep apnoea; tocopherol
15.  When to Start Antiretroviral Therapy 
Current HIV/AIDS Reports  2010;7(2):60-68.
The question of when to start combination antiretroviral therapy for treatment-naïve patients has always been controversial. This is particularly true in the current era, with major guidelines recommending very different treatment strategies. Despite a lack of clarity regarding the optimal time to begin therapy, there has been a recent shift toward earlier initiation. This more aggressive approach is driven by several observations. First, effective viral suppression with therapy can prevent non-AIDS-related morbidity and mortality. Second, therapy can prevent irreversible harm to the human immune system. Third, therapy may prevent transmission of HIV to others, and thus have a potential public health benefit. For patients who are motivated and willing to initiate early treatment, the collective benefits of early therapy may outweigh the well-documented risks of antiretroviral medications.
doi:10.1007/s11904-010-0044-6
PMCID: PMC2856854  PMID: 20425559
HIV; Antiretroviral therapy; Early treatment; “When to start”; Clinical trials; Observational studies; Non-AIDS conditions; “Test and treat”; Systemic inflammation; T cell activation
16.  Regulation of Bcl-xL Expression in Lung Vascular Smooth Muscle 
Pulmonary hypertension is characterized by thickened pulmonary arterial walls due to increased number of pulmonary artery smooth muscle cells (PASMC). Apoptosis of PASMC may play an important role in regulating the PASMC number and may be useful for reducing pulmonary vascular thickening. The present study examined the regulation of an anti-apoptotic protein Bcl-xL. Bcl-xL expression was found to be increased in the pulmonary artery of chronic hypoxia–treated rats with pulmonary vascular remodeling. Adenovirus-mediated gene transfer of Bcl-xL indeed showed that this protein has anti-apoptotic activities in PASMC. Treatment of remodeled pulmonary artery with sodium nitroprusside (SNP) reduced Bcl-xL expression by targeting the bcl-xL promoter. The bcl-xL promoter contains two GATA elements, and SNP decreases the GATA-4 DNA-binding activity. Overexpression of GATA-4 attenuated the SNP-mediated suppression of Bcl-xL expression, providing direct evidence for the role of GATA-4 in Bcl-xL gene transcription. We established that SNP targets the 250 proximal region of the gata4 promoter and suppresses its gene transcription. Thus, inducers of pulmonary hypertension enhance anti-apoptotic Bcl-xL gene transcription, which can be suppressed by targeting gata4 gene transcription.
doi:10.1165/rcmb.2006-0359OC
PMCID: PMC1868666  PMID: 17272823
apoptosis; genes; pulmonary hypertension; smooth muscle
17.  Oxidative stress and oxidant signaling in obstructive sleep apnea and associated cardiovascular diseases 
Free radical biology & medicine  2006;40(10):1683-1692.
Obstructive sleep apnea (OSA) has emerged as a major public health problem and increasing evidence indicates that untreated OSA can lead to the development of various cardiovascular disorders. One important mechanism by which OSA may promote cardiovascular diseases is intermittent hypoxia, in which patients are subjected to repeated episodes of brief oxygen desaturation in the blood, followed by reoxygenation. Such cycles of hypoxia/reoxygenation may result in the generation of reactive oxygen species. Some studies have demonstrated the presence of oxidative stress in OSA patients as well as in animals subjected to intermittent hypoxia. Further, modulations of nitric oxide and biothiol status might also play important roles in the pathogenesis of OSA-associated diseases. Reactive oxygen species and redox events are also involved in the regulation of signal transduction for oxygen-sensing mechanisms. This review summarizes currently available information on the evidence for and against the occurrence of oxidative stress in OSA and the role of reactive oxygen species in cardiovascular changes associated with OSA.
doi:10.1016/j.freeradbiomed.2006.01.008
PMCID: PMC1995030  PMID: 16678006
Free radical; Intermittent hypoxia; Nitric oxide; Oxidative stress; Reactive oxygen species; Sleep apnea; Superoxide
18.  Regulation of Bcl-xL expression in lung vascular smooth muscle 
Pulmonary hypertension is characterized by thickened pulmonary arterial walls due to increased number of pulmonary artery smooth muscle cells (PASMC). Apoptosis of PASMC may play important roles in regulating the PASMC number and may be useful for reducing pulmonary vascular thickening. The present study examined the regulation of an anti-apoptotic protein Bcl-xL. Bcl-xL expression was found to be increased in the pulmonary artery of chronic hypoxia treated rats with pulmonary vascular remodeling. Adenovirus-mediated gene transfer of Bcl-xL indeed showed that this protein has anti-apoptotic activities in PASMC. Treatment of remodeled pulmonary artery with sodium nitroprusside (SNP) reduced Bcl-xL expression by targeting the bcl-xL promoter. The bcl-xL promoter contains two GATA elements, and SNP decreases the GATA-4 DNA binding activity. Overexpression of GATA-4 attenuated the SNP-mediated suppression of Bcl-xL expression, providing direct evidence for the role of GATA-4 in Bcl-xL gene transcription. We identified that SNP targets the 250 proximal region of the gata4 promoter and suppresses its gene transcription. Thus, inducers of pulmonary hypertension enhance anti-apoptotic Bcl-xL gene transcription, which can be suppressed by targeting the gata4 gene transcription.
doi:10.1165/rcmb.2006-0359OC
PMCID: PMC1868666  PMID: 17272823
Apoptosis; Genes; Pulmonary hypertension; Smooth muscle
19.  Assessment of the Epidemic Potential of a New Strain of Rotavirus Associated with the Novel G9 Serotype Which Caused an Outbreak in the United States for the First Time in the 1995-1996 Season 
Journal of Clinical Microbiology  2004;42(4):1434-1438.
Rotavirus causes severe morbidity in developed countries and frequent deaths (≥500,000 per year) in less-developed countries. Historically, four serotypes—G1, G2, G3, and G4—have predominated; they are distinguished by one of two surface neutralization antigens (VP7). However, in 1983 and 1984 we described a new rotavirus serotype, designated G9, in five children hospitalized for diarrhea in Philadelphia, Pa. G9 rotavirus was not identified again in the Western Hemisphere until it caused ca. 50% of the rotavirus disease detected in Philadelphia in the 1995-1996 season. This outbreak allowed us to question whether a rotavirus strain completely new to a well-studied community would target either very young infants or older children, cause especially severe disease, or completely displace previously extant serotypes. We observed a significant excess of G9 infections in younger infants (especially in those <6 months old) that might be attributed to the lack of G9-specific antibodies in mothers. Of further note, six of the seven oldest patients with rotavirus diarrhea were infected with the G9 strains (not significant). However, the age distribution of children with rotavirus did not differ over a 5-year study period regardless of the infecting serotype. Patients with diarrhea associated with G9 strains did not have disease more severe than that caused by the G1, G2, or G3 serotype. G9 strains did not displace the other serotypes but were virtually completely replaced by G1 or G2 serotypes in the three subsequent rotavirus seasons. We conclude that the abrupt appearance of this novel rotavirus serotype did not present a special threat to public health in the community.
doi:10.1128/JCM.42.4.1434-1438.2004
PMCID: PMC387540  PMID: 15070985
20.  Great Diversity of Group A Rotavirus Strains and High Prevalence of Mixed Rotavirus Infections in India 
Journal of Clinical Microbiology  2001;39(10):3524-3529.
We previously observed a marked diversity of rotavirus strains and a high prevalence of the uncommon serotype G9 in a small survey of rotavirus strains collected from six centers in India. In the present study, we characterized a larger collection of strains from children hospitalized with severe diarrhea in seven Indian cities between 1996 and 1998. A total of 287 strains were G and P genotyped by reverse transcription-PCR, and some were further characterized by electropherotyping and subgrouping. Of the four strains common globally, three were found in only 43% of samples (P[8], G1, 15%; P[4], G2, 22%; P[8], G4, 6%), whereas G9 strains made up 17% of the total. Three different G9 strains were present: a P[8], G9 strain, which displayed the long electropherotype and subgroup II VP6 specificity, and two P[6], G9 strains, one with the long electropherotype and subgroup II specificity and the other with the short electropherotype and subgroup I specificity. Marked diversity was observed among strains collected from different cities and collected over time. Of the 253 strains that were fully typed, 54 (21%) had a mixed G or P genotype. Serotype G2 strains were detected more often in infections caused by single strains than in mixed infections (P < 0.05), whereas serotype G1 strains were found more often in mixed infections than in infections caused by single strains (P < 0.05). The diversity of rotavirus strains and the high prevalence of mixed infections confirm trends reported earlier and help to better characterize the strains of rotavirus circulating in India. Vaccines under development should clearly target G9 strains, and G9 should be included as one of the common global serotypes.
doi:10.1128/JCM.39.10.3524-3529.2001
PMCID: PMC88383  PMID: 11574567
21.  Use of Lambda Phage S and R Gene Products in an Inducible Lysis System for Vibrio cholerae- and Salmonella enterica Serovar Typhimurium-Based DNA Vaccine Delivery Systems 
Infection and Immunity  2000;68(2):986-989.
Novel methods for adapting DNA vaccine technology to the prevention of mucosal diseases are greatly needed. Here we show that regulated expression of phage lambda lysis genes S and R causes dramatic lysis of both Vibrio cholerae and Salmonella enterica serovar Typhimurium cells with concomitant release of plasmid DNA into the surrounding media. We also used single and double DNase mutant strains to show that secreted V. cholerae DNases can adversely affect the integrity of DNA molecules released upon lysis. These results suggest that incorporation of lambda SR-mediated lysis constructs and DNA stabilizing mutations into candidate live attenuated bacterial vaccines offers a promising approach for the development of effective mucosal DNA delivery vectors for humans.
PMCID: PMC97237  PMID: 10639478

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