Krishna P. Reddy

Intestinal cytokines in children with pervasive developmental disorders.

Abstract Objective A relationship between autism and gastrointestinal (GI) immune dysregulation has been postulated based on incidence of GI complaints as well as macroscopically observed lymphonodular hyperplasia and microscopically determined enterocolitis in pediatric patients with autism. To evaluate GI immunity, we quantitatively assessed levels of proinflammatory cytokines, interleukin (IL)-6, IL-8, and IL-1β, produced by intestinal biopsies of children with pervasive developmental disorders. Methods Fifteen patients, six with pervasive developmental disorders and nine age-matched controls, presenting for diagnostic colonoscopy were enrolled. Endoscopic biopsies were organ cultured, supernatants were harvested, and IL-6, IL-8, and IL-1β levels were quantified by ELISA. Tissue histology was evaluated by blinded pathologists. Results Concentrations of IL-6 from intestinal organ culture supernatants of patients with pervasive developmental disorders (median 318.5 pg/ml, interquartile range 282.0–393.0 pg/ml) when compared with controls (median 436.9 pg/ml, interquartile range 312.6–602.5 pg/ml) were not significantly different ( p = 0.0987). Concentrations of IL-8 (median 84,000 pg/ml, interquartile range 16,000–143,000 pg/ml) when compared with controls (median 177,000 pg/ml, interquartile range 114,000–244,000 pg/ml) were not significantly different ( p = 0.0707). Concentrations of IL-1β (median 0.0 pg/ml, interquartile range 0.0–94.7 pg/ml) when compared with controls (median 0.0 pg/ml, interquartile range 0.0–60.2 pg/ml) were not significantly different ( p = 0.8826). Tissue histology was nonpathological for all patients. Conclusions We have demonstrated no significant difference in production of IL-6, IL-8, and IL-1β between patients with pervasive developmental disorders and age-matched controls. In general, intestinal levels of IL-6 and IL-8 were lower in patients with pervasive developmental disorders than in age-matched controls. These data fail to support an association between autism and GI inflammation.

Prolonged Infectiousness of Tuberculosis Patients in a Directly Observed Therapy Short-Course Program with Standardized Therapy

BACKGROUND Effective tuberculosis control is compromised by a lack of clarity about the timeframe of viable Mycobacterium tuberculosis shedding after treatment initiation under programmatic conditions. This study quantifies time to conversion from smear and culture positivity to negativity in unselected tuberculosis patients receiving standardized therapy in a directly observed therapy short-course (DOTS) program. METHODS Longitudinal cohort study following up 93 adults initiating tuberculosis therapy in Lima, Peru. Baseline culture and drug susceptibility tests (DSTs) were performed using the MBBacT, proportion, and microscopic observation drug susceptibility (MODS) methods. Smear microscopy and MODS liquid culture were performed at baseline and weekly for 4 weeks then every other week for 26 weeks. RESULTS Median conversion time from culture positivity to culture negativity of 38.5 days was unaffected by baseline smear status. Patients with fully susceptible tuberculosis had a median time to culture conversion of 37 days; 10% remained culture positive at day 60. Delayed culture conversion was associated with multidrug resistance, regardless of DST method used; non-multidrug resistance as defined by the proportion method and MODS (but not MBBacT) was also associated with delay. Persistent day 60 smear positivity yielded positive and negative predictive values of 67% and 92%, respectively, for detecting multidrug resistance. CONCLUSIONS Smear and culture conversion in treated tuberculosis patients takes longer than is conventionally believed, even with fully susceptible disease, and must be accounted for in tuberculosis treatment and prevention programs. Persistent day 60 smear positivity is a poor predictor of multidrug resistance. The industrialized-world convention of universal baseline DST for tuberculosis patients should become the standard of care in multidrug resistance-affected resource-limited settings.

Microscopic observation drug susceptibility assay for tuberculosis screening before isoniazid preventive therapy in HIV-infected persons

BACKGROUND Active tuberculosis (TB) must be excluded before initiating isoniazid preventive therapy (IPT) in persons infected with human immunodeficiency virus (HIV), but currently used screening strategies have poor sensitivity and specificity and high patient attrition rates. Liquid TB culture is now recommended for the detection of Mycobacterium tuberculosis in individuals suspected of having TB. This study compared the efficacy, effectiveness, and speed of the microscopic observation drug susceptibility (MODS) assay with currently used strategies for TB screening before IPT in HIV-infected persons. METHODS A total of 471 HIV-infected IPT candidates at 3 hospitals in Lima, Peru, were enrolled in a prospective comparison of TB screening strategies, including laboratory, clinical, and radiographic assessments. RESULTS Of 435 patients who provided 2 sputum samples, M. tuberculosis was detected in 27 (6.2%) by MODS culture, 22 (5.1%) by Lowenstein-Jensen culture, and 7 (1.6%) by smear. Of patients with any positive microbiological test result, a MODS culture was positive in 96% by 14 days and 100% by 21 days. The MODS culture simultaneously detected multidrug-resistant TB in 2 patients. Screening strategies involving combinations of clinical assessment, chest radiograph, and sputum smear were less effective than 2 liquid TB cultures in accurately diagnosing and excluding TB (P<.01). Screening strategies that included nonculture tests had poor sensitivity and specificity. CONCLUSIONS MODS culture identified and reliably excluded cases of pulmonary TB more accurately than other screening strategies, while providing results significantly faster than Lowenstein-Jensen culture. Streamlining of the ruling out of TB through the use of liquid culture-based strategies could help facilitate the massive up-scaling of IPT required to reduce HIV and TB morbidity and mortality.

Intestinal interleukin-13 in pediatric inflammatory bowel disease patients.

Background:Interleukin-13 (IL-13) is a multifunctional cytokine whose net principle action is to diminish inflammatory responses. Dysregulation of IL-13 production has been proposed to contribute to intestinal inflammation in inflammatory bowel disease (IBD) patients. Previous studies implicate IL-13 in IBD pathogenesis; however, they fail to accurately reflect in vivo intestinal IL-13 production. We evaluate IL-13, IL-6, and IL-1β elaborations from colonic organ cultures of pediatric IBD patients Methods:Endoscopic lamina propria biopsies or surgical specimens from pediatric patients with IBD were organ cultured and supernatants evaluated by enzyme-linked immunosorbent assay for IL-1β, IL-6, and IL-13. Results:IL-13 concentrations were significantly reduced in ulcerative colitis (UC) patients when compared with normal controls (P = 0.002) and Crohn disease (CD) patients (P = 0.001). End-stage UC patients at colectomy had lower intestinal IL-13 production than all other UC patients (P = 0.002). No significant correlation was found between IL-13 concentration and histologic disease severity (P = 0.134). Conclusions:Diminished intestinal IL-13 production is present in UC patients and wanes further with clinical disease progression. These findings suggest that UC patients may be differentiated from CD patients by intestinal IL-13 quantitation, and UC patients may benefit from IL-13 enhancing therapies.

Lung Cancer Mortality Associated With Smoking and Smoking Cessation Among People Living With HIV in the United States

Importance Lung cancer has become a leading cause of death among people living with human immunodeficiency virus (HIV) (PLWH). Over 40% of PLWH in the United States smoke cigarettes; HIV independently increases the risk of lung cancer. Objective To project cumulative lung cancer mortality by smoking exposure among PLWH in care. Design Using a validated microsimulation model of HIV, we applied standard demographic data and recent HIV/AIDS epidemiology statistics with specific details on smoking exposure, combining smoking status (current, former, or never) and intensity (heavy, moderate, or light). We stratified reported mortality rates attributable to lung cancer and other non–AIDS-related causes by smoking exposure and accounted for an HIV-conferred independent risk of lung cancer. Lung cancer mortality risk ratios (vs never smokers) for male and female current moderate smokers were 23.6 and 24.2, respectively, and for those who quit smoking at age 40 years were 4.3 and 4.5. In sensitivity analyses, we accounted for nonadherence to antiretroviral therapy (ART) and for a range of HIV-conferred risks of death from lung cancer and from other non–AIDS-related diseases (eg, cardiovascular disease). Main Outcomes and Measures Cumulative lung cancer mortality by age 80 years (stratified by sex, age at entry to HIV care, and smoking exposure); total expected lung cancer deaths, accounting for nonadherence to ART. Results Among 40-year-old men with HIV, estimated cumulative lung cancer mortality for heavy, moderate, and light smokers who continued to smoke was 28.9%, 23.0%, and 18.8%, respectively; for those who quit smoking at age 40 years, it was 7.9%, 6.1%, and 4.3%; and for never smokers, it was 1.6%. Among women, the corresponding mortality for current smokers was 27.8%, 20.9%, and 16.6%; for former smokers, it was 7.5%, 5.2%, and 3.7%; and for never smokers, it was 1.2%. ART-adherent individuals who continued to smoke were 6 to 13 times more likely to die from lung cancer than from traditional AIDS-related causes, depending on sex and smoking intensity. Due to greater AIDS-related mortality risks, individuals with incomplete ART adherence had higher overall mortality but lower lung cancer mortality. Applying model projections to the approximately 644 200 PLWH aged 20 to 64 in care in the United States, 59 900 (9.3%) are expected to die from lung cancer if smoking habits do not change. Conclusions and Relevance Those PLWH who adhere to ART but smoke are substantially more likely to die from lung cancer than from AIDS-related causes.

Ceramide activates JNK to inhibit a cAMP-gated K+ conductance and Cl– secretion in intestinal epithelia

Sphingomyelinases (SMases) hydrolyze membrane sphingomyelin to ceramide and are ex‐pressed by diverse host and microbial cell types popu‐lating mucosal surfaces. Exogenous bacterial SMase acts on the basolateral membrane of polarized human intestinal epithelial cells to repress the cAMP‐induced Cl‐ secretory response, but how this occurs is un‐known. We show here that SMase acts by down‐regulating a cAMP‐gated basolateral membrane K+ conduc‐tance. Neither phosphocholine, ceramide‐1‐phosphate, nor sphingosine‐1‐phosphate recapitulates this effect, indicating that ceramide production is the decisive factor. Basolaterally applied SMase induced the phos‐phorylation of c‐Jun NH2‐terminal kinase (JNK), and inhibition of JNK rescued the effect of SMase on cAMP‐dependant secretion. SMase secreted by normal human fibroblasts specifically recapitulated the effect on cAMP‐induced Cl‐ secretion, indicating that cell types inhabiting the subepithelial space can provide such an activity to the basolateral membrane of intesti‐nal enterocytes in trans. Thus, conversion of sphingo‐myelin to ceramide in basolateral membranes of intes‐tinal cells rapidly activates JNK to inhibit a cAMP‐gated K+ conductance and thereby attenuates Cl‐ secretion. These results define a novel lipid‐mediated pathway for regulation of salt and water homeostasis at mucosal surfaces.—Saslowsky, D. E., Tanaka, N., Reddy, K. P., Lencer, W. I. Ceramide activates JNK to inhibit a cAMP‐gated K+ conductance and Cl‐ secretion in intestinal epithelia. FASEBJ. 23, 259‐270 (2009)

Relationship Between Upper Respiratory Tract Influenza Test Result and Clinical Outcomes Among Critically Ill Influenza Patients

Among critically ill patients with lower respiratory tract (LRT)-confirmed influenza, we retrospectively observed worse 28-day clinical outcomes in upper respiratory tract (URT)-negative versus URT-positive subjects. This finding may reflect disease progression and highlights the need for influenza testing of both URT and LRT specimens to improve diagnostic yield and possibly inform prognosis.

Herpes Zoster Vaccine: Time for a Boost?

O ne in three persons in the US will develop herpes zoster (HZ) during their lifetime, and the risk increases with age. The disease is painful, often debilitating, and costly. Some cases result in postherpetic neuralgia (PHN), a chronic pain condition that can last months to years. In 2006, for the first time, a vaccine to prevent HZ and PHN became available in the US. A large-scale clinical trial in persons aged ≥60 years had shown that the live attenuated vaccine reduced HZ incidence by 51% and PHN incidence by 67% over a median 3.1year follow-up period. Following this success, the Advisory Committee on Immunization Practices (ACIP) recommended one-time HZ vaccination for those ≥60 years of age. However, a follow-up study of the original trial cohort reported a substantial decline in HZ vaccine efficacy over time; by year 11 post-vaccination, there was essentially no protection. If HZ vaccination is successful, and yet protection is shortlived, a key challenge is finding the Bsweet spot^ age at which to vaccinate. Such timing would protect people for the maximum length of time during which they are at highest risk of HZ and its complications. While the question of the optimal age at which to vaccinate remains, so does the related question of whether to administer a booster dose in the face of waning protection. Under the currently recommended strategy, those vaccinated only once at age 60 would be left unprotected after age 70, when the incidence and severity of HZ and PHN are highest. A recently published study reported fairly robust cellmediated immune responses after a booster dose in persons who had received an initial HZ vaccine 10 years earlier. The potential clinical benefit of a booster should be weighed against its added cost. In this issue of the Journal of General InternalMedicine, Le and Rothberg report a methodologically robust and well-timed cost-effectiveness analysis which sought to determine the optimal schedule for the live attenuated HZ vaccine. This work builds upon their previously published and guidelinecited cost-effectiveness analysis of HZ vaccination. The authors updated their well-developed Markov model, newly incorporated data regarding the long-term efficacy of the vaccine, and evaluated strategies entailing booster doses. They examined 11 strategies, including no vaccination, onetime vaccination at various ages, a booster dose after 10 years, and two booster doses 10 years apart. They included a comprehensive list of key input parameters, including HZ incidence and its associated complications and quality-of-life decrements, ageand time-dependent vaccine efficacy, adherence to boosters, and vaccine costs. Model-generated results per strategy included HZ and PHN cases, per-person qualityadjusted life-years (QALYs), and per-person total costs. The authors reported incremental cost-effectiveness ratios (ICERs) and used a commonly cited, albeit somewhat arbitrary (and often considered too low), US threshold where interventions with an ICER <

Using Observational Data to Calibrate Simulation Models

100,000/QALYare considered cost-effective. Among the 11 strategies evaluated, only four were deemed efficient and worthy of further consideration: no vaccination, one-time vaccination at age 70, vaccination at age 70 followed by a booster 10 years later, and vaccination at age 60 followed by boosters 10 and 20 years later. Notably, the ACIP’s currently recommended schedule, one-time vaccination at age 60, was not among the efficient strategies. Vaccination at age 60 followed by two boosters provided the greatest clinical benefit, but its ICER was relatively high, at ∼

Influences of antihypertensive and antihyperlipidemic drugs on the senses of taste and smell: a review

154,000/QALY. Using costeffectiveness benchmarks alone, vaccination at age 70 followed by one booster was the optimal strategy, with an ICER of ∼