In Very Young Infants Severity of Acute Bronchiolitis Depends On Carried Viruses

Background

RT amplification reaction has revealed that various single viruses or viral co-infections caused acute bronchiolitis in infants, and RV appeared to have a growing involvement in early respiratory diseases. Because remaining controversial, the objective was to determine prospectively the respective role of RSV, RV, hMPV and co-infections on the severity of acute bronchiolitis in very young infants.

Methods and Principal Findings

209 infants (median age: 2.4 months) were enrolled in a prospective study of infants <1 year old, hospitalized for a first episode of bronchiolitis during the winter epidemic season and with no high risk for severe disease. The severity was assessed by recording SaO₂% at admission, a daily clinical score (scale 0–18), the duration of oxygen supplementation and the length of hospitalization. Viruses were identified in 94.7% by RT amplification reaction: RSV only (45.8%), RV only (7.2%), hMPV only (3.8%), dual RSV/RV (14.3%), and other virus only (2%) or coinfections (9%). RV compared respectively with RSV and dual RSV/RV infection caused a significant less severe disease with a lower clinical score (5[3.2–6] vs. 6[4–8], p = 0.01 and 5.5[5–7], p = 0.04), a shorter time in oxygen supplementation (0[0–1] days vs. 2[0–3] days, p = 0.02 and 2[0–3] days, p = 0.03) and a shorter hospital stay (3[3–4.7] days vs.6 [5–8] days, p = 0.001 and 5[4–6] days, p = 0.04). Conversely, RSV infants had also longer duration of hospitalization in comparison with RSV/RV (p = 0.01) and hMPV (p = 0.04). The multivariate analyses showed that the type of virus carried was independently associated with the duration of hospitalization.

Conclusion

This study underlined the role of RV in early respiratory diseases, as frequently carried by young infants with a first acute bronchiolitis. RSV caused the more severe disease and conversely RV the lesser severity. No additional effect of dual RSV/RV infection was observed on the severity.     

Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

Introduction

Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.

Methods

Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).

Results

78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7–6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7–9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0–2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8–5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs).

Conclusions

HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.     

Taenia solium Cysticercosis Hotspots Surrounding Tapeworm Carriers: Clustering on Human Seroprevalence but Not on Seizures

Background

Neurocysticercosis accounts for 30%–50% of all late-onset epilepsy in endemic countries. We assessed the clustering patterns of Taenia solium human cysticercosis seropositivity and seizures around tapeworm carriers in seven rural communities in Peru.

Methodology

The presence of T. solium–specific antibodies was defined as one or more positive bands in the enzyme-linked immunoelectrotransfer blot (EITB). Neurocysticercosis-related seizures cases were diagnosed clinically and had positive neuroimaging or EITB.

Principal Findings

Eleven tapeworm carriers were identified by stool microscopy. The seroprevalence of human cysticercosis was 24% (196/803). Seroprevalence was 21% >50 m from a carrier and increased to 32% at 1–50 m (p = 0.047), and from that distance seroprevalence had another significant increase to 64% at the homes of carriers (p = 0.004). Seizure prevalence was 3.0% (25/837) but there were no differences between any pair of distance ranges (p = 0.629, Wald test 2 degrees of freedom).

Conclusion/Significance

We observed a significant human cysticercosis seroprevalence gradient surrounding current tapeworm carriers, although cysticercosis-related seizures did not cluster around carriers. Due to differences in the timing of the two outcomes, seroprevalence may reflect recent T. solium exposure more accurately than seizure frequency.     

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

Background

We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients.

Methods

Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4).

Results

The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5×the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0–1], 2 and [3]–[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values.

Conclusions

We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy.     

Duration,Pattern of Breastfeeding and Postnatal Transmission of HIV: Pooled Analysis of Individual Data from West and South African Cohorts

Background

Both breastfeeding pattern and duration are associated with postnatal HIV acquisition; their relative contribution has not been reliably quantified.

Methodology and Principal Findings

Pooled data from 2 cohorts: in urban West Africa where breastfeeding cessation at 4 months was recommended but exclusive breastfeeding was rare (Ditrame Plus, DP); in rural South Africa where high rates of exclusive breastfeeding were achieved, but with longer duration (Vertical Transmission Study, VTS). 18-months HIV postnatal transmission (PT) was estimated by Kaplan-Meier in infants who were HIV negative, and assumed uninfected, at age >1 month. Censoring with (to assess impact of mode of breastfeeding) and without (to assess effect of breastfeeding duration) breastfeeding cessation considered as a competing event. Of 1195 breastfed infants, not HIV-infected perinatally, 38% DP and 83% VTS children were still breastfed at age 6 months. By age 3 months, 66% of VTS children were exclusively breastfed since birth and 55% of DP infants predominantly breastfed (breastmilk+water-based drinks). 18-month PT risk (95%CI) in VTS was double that in DP: 9% (7–11) and 5% (3–8), respectively (p = 0.03). However, once duration of breastfeeding was allowed for in a competing risk analysis assuming that all children would have been breastfed for 18-month, the estimated PT risk was 16% (8–28) in DP and 14% (10–18) in VTS (p = 0.32). 18-months PT risk was 3.9% (2.3–6.5) among infants breastfed for less than 6 months, and 8.7% (6.8–11.0) among children breastfed for more than 6 months; crude hazard ratio (HR): 2.1 (1.2–3.7), p = 0.02; adjusted HR 1.8 (0.9–3.4), p = 0.06. In individual analyses of PT rates for specific breastfeeding durations, risks among children exclusively breastfed were very similar to those in children predominantly breastfed for the same period. Children exposed to solid foods during the first 2 months of life were 2.9 (1.1–8.0) times more likely to be infected postnatally than children never exposed to solids this early (adjusted competing risk analysis, p = 0.04).

Conclusions

Breastfeeding duration is a major determinant of postnatal HIV transmission. The PT risk did not differ between exclusively and predominantly breastfed children; the negative effect of mixed breastfeeding with solids on PT were confirmed.     

Family Characteristics as Risk Factors for Childhood Acute Lymphoblastic Leukemia: A Population-Based Case-Control Study

Background

To date, few risk factors for childhood acute lymphoblastic leukemia (ALL) have been confirmed and the scientific literature is full of controversial “evidence.” We examined if family characteristics, particularly maternal and paternal age and number of older siblings, were risk factors for childhood acute lymphoblastic leukemia (ALL).

Methodology/Principal Findings

In this population-based nationwide matched case-control study, patients 0–14 years of age with ALL diagnosed 1991–2006 and registered in the Swiss Childhood Cancer Registry were linked with their census records of 1990 and 2000. Eight controls per case were selected from the census. The association between family characteristics and ALL was analyzed by conditional logistic regressions. We found that increasing maternal age was associated with incidence of ALL in the offspring (OR per 5-year increase in maternal age 1.18, 95% CI 1.05–1.31; p = 0.004), remaining stable (trend OR 1.14, 95% CI 0.99–1.31; p = 0.060) after adjustment for other risk factors. The association with paternal age was weaker (OR per 5-year increase 1.14, 95% CI 1.01–1.28, p = 0.032) and disappeared after adjustments. Number of older siblings was not associated with risk of ALL in the overall group of children aged 0–14 years at diagnosis. However, we found a negative trend between number of older siblings and ALL diagnosed at age 0–4 years (OR per sibling 0.85, 95% CI 0.68–1.06; p = 0.141) and a positive trend for ALL diagnosed at age 5–9 (OR 1.34, 95% CI 1.05–1.72; p = 0.019), with some evidence for an effect modification (p-value for interaction  = 0.040).

Conclusions

As in other studies, increasing maternal, but not paternal age was associated with risk of ALL. We found only a weak association with the number of older siblings, suggesting a delay in disease manifestation rather than a decrease in incidence.     

Low CD10 mRNA Expression Identifies High-Risk Ductal Carcinoma In Situ (DCIS)

Purpose

Optimal management of breast ductal carcinoma in situ (DCIS) is controversial, and many patients are still overtreated. The local death of myoepithelial cells (MECs) is believed to be a pre-requisite to tumor invasion. We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS. The aim of our study was to retrospectively evaluate the prognostic value of CD10 in DCIS.

Experimental Design

CD10 expression was evaluated by quantitative RT-PCR and immunohistochemistry using paraffin-embedded samples of normal breast tissue (n = 11); of morphologically normal ducts associated with DCIS (n = 10); and of DCIS without an invasive component (n = 154).

Results

CD10 immunostaining was only observed in MECs in normal tissue and in DCIS. Normal tissue showed high mRNA expression levels of CD10, whereas DCIS showed a variable range. After a median follow-up of 6 years, DCIS with CD10 expression below the levels observed in normal tissue (71%) demonstrated a higher risk of local relapse (HR = 1.88; [95CI:1.30–2.70], p = 0.001) in univariate analysis. No relapse was observed in patients expressing high CD10 mRNA levels (29%) similar to the ones observed in normal tissue. In multivariate analysis including known prognostic factors, low CD10 mRNA expression remained significant (HR = 2.25; [95%CI:1.24–4.09], p = 0.008), as did the recently revised Van Nuys Prognostic Index (VNPI) score (HR = 2.03; [95%CI:1.23–3.35], p = 0.006).

Conclusion

The decrease of CD10 expression in MECs is associated with a higher risk of relapse in DCIS; this knowledge has the potential to improve DCIS management.     

Realtime PCR Is More Sensitive than Multiplex PCR for Diagnosis and Serotyping in Children with Culture Negative Pneumococcal Invasive Disease

Background

Pneumococcal serotyping is usually performed by Quellung reaction, considered the gold standard test. However the method cannot be used on culture-negative samples. Molecular methods can be a useful alternative. The aim of the study was to evaluate the use of Multiplex-sequential-PCR (MS-PCR) or Realtime-PCR on blood samples for diagnosis and serotyping of invasive pneumococcal disease (IPD) in a pediatric clinical setting.

Methodology/Principal Findings

Sensitivity and specificity of MS-PCR and Realtime-PCR have been evaluated both on 46 well characterized pneumococcal isolates and on 67 clinical samples from children with culture-negative IPD. No difference in sensitivity and specificity between MS-PCR and Realtime PCR was found when the methods were used on isolates: both methods could type 100% isolates and the results were always consistent with culture-based methods. On the contrary, when used on clinical samples 43/67 (64.2%) were typeable by MS-PCR and 61/67 (91.0%) by Realtime-PCR (p = 0.0004,K Cohen 0.3, McNemar''s p<0.001). Non-typeability by MS-PCR was associated in 18/20 cases (90.0%) with low bacterial load. The difference between the two methods was present both when they were used on normally sterile fluids (respectively 31/33 (93.9%) typeable samples for Realtime-PCR and 24/33 (72.7%) for MS-PCR, p = 0.047, 95%CL 0.03–0.98; K Cohen 0.3; McNemar''s p = 0.0016) and when they were used on nasopharyngeal swabs (respectively 30/34 (88.2%) typeable samples for Realtime-PCR and 19/34 (55.9%) for MS-PCR, p = 0.007, 95%CL 0.04–0.66); the presence of multiple pneumococcal serotypes in nasopharyngeal swabs was found more frequently by Realtime PCR (19/30; 63.3%) than by Multiplex-sequential PCR (3/19; 15.8%; p = 0.003;95%CL 1.87–39.97).

Conclusions/Significance

In conclusion, both MS-PCR and Realtime PCR can be used for pneumococcal serotyping of most serotypes/serogroups directly on clinical samples from culture-negative patients but Realtime-PCR appears more sensitive.     

Non-Alcoholic Fatty Liver Disease Is Closely Associated with Sub-Clinical Inflammation: A Case-Control Study on Asian Indians in North India

Objectives

Association between sub-clinical inflammation and non-alcoholic fatty liver disease (NAFLD) has not been studied in Asian Indians. In this case-control study, we aimed to analyse association of NAFLD with the sub-clinical inflammation and metabolic profile in Asian Indians in north India.

Methods

Ultrasound diagnosed 120 cases of NAFLD were compared to 152 healthy controls without NAFLD. Anthropometric profile [body mass index (BMI), waist circumference (WC), hip circumference (HC)], high-sensitivity C-reactive protein (hs-CRP), metabolic profile [fasting blood glucose (FBG), lipid profile] and hepatic function tests [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] were recorded.

Results

Metabolic parameters [FBG, total cholesterol (TC), serum triglycerides (TG),low-density lipoprotein (LDL-c)], hs-CRP and prevalence of the metabolic syndrome were higher in cases as compared to controls (p-value<0.05 for all). The median (range) of hs-CRP (mg/L) for cases [2.6(0.2–13.4)] were significantly higher than in controls [1.4(0.03–11.4), p = 0.01]. Similarly, higher values of hs-CRP were obtained when subgroups of cases with obesity, abdominal obesity and the metabolic syndrome were compared to controls [2.75 (0.03–14.3) vs. 1.52 (0.04–14.3), p = 0.0010; 2.8 (0.03–14.3) vs. 1.5 (0.06–14.3), p = 0.0014 and 2.7 (0.5–14.3) vs. 1.6 (0.06–8.5), p = 0.0013, respectively. On multivariate logistic regression analysis BMI (p = 0.001), WC (p = 0.001), FBG (p = 0.002), TC (p = 0.008), TG (p = 0.002), blood pressure (p = 0.005), metabolic syndrome (p = 0.001) and hs-CRP (p = 0.003) were significantly and independently associated with NAFLD. After adjusting for significant variables, the association between high hs-CRP and NAFLD remained large and statistically significant [adjusted OR = 1.17, 95% confidence interval (CI) = 1.05–1.29]. An increase in 1 mg/dl of hs-CRP level calculated to increase the risk of developing NAFLD by 1.7 times as compared to controls after adjusting for significant variables associated with NAFLD.

Conclusions

In this cohort of Asian Indians in North India, presence of NAFLD showed independent relationships with sub-clinical inflammation.     

Natural Killer Cells in Obesity: Impaired Function and Increased Susceptibility to the Effects of Cigarette Smoke

Background

Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independantly associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects.

Methodology and Principal Findings

Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg/m²) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +/− 13% vs 42% +/−12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01).

Conclusions/Significance

Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.     

CD40: Novel Association with Crohn's Disease and Replication in Multiple Sclerosis Susceptibility

Background

A functional polymorphism located at −1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves'' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves'' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn''s disease (CD) lesions.

Methodology

Genotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry.

Principal Findings

The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01–1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06–1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93–1.17)].

Conclusion

The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.     

Demographic and Clinical Features of Dengue Fever in Pakistan from 2003–2007: A Retrospective Cross-Sectional Study

Background

Demographic features of dengue fever have changed tremendously in Pakistan over the past two decades. Small scale studies from all over the country have reported different aspects of individual outbreaks during this time. However, there is scarcity of data looking at the overall trend of dengue virus infection in the country. In this study, we examined annual trends, seasonality, and clinical features of dengue fever in the Pakistani population.

Methods

Demographic information and dengue IgM status of all patients tested for dengue IgM antibody at Aga Khan University Hospital from January 2003 to December 2007 were analyzed to look for trends of IgM-positive cases in Pakistan. In addition, clinical and biochemical parameters were abstracted retrospectively from medical records of all patients hospitalized with IgM-proven dengue fever between January 2006 and December 2007. These patients were categorized into dengue fever and dengue hemorrhagic fever according to the WHO severity grading scale.

Results

Out of a total of 15040 patients (63.2% male and 36.8% female), 3952 (26.3%) tested positive for dengue IgM antibody. 209 IgM proven dengue patients were hospitalized during the study period. During 2003, IgM positive cases were seen only during the months of July-December. In contrast, such cases were detected throughout the year from the 2004–2007. The median age of IgM positive patients decreased every year from 32.0 years in 2003 to 24.0 years in 2007 (p<0.001). Among hospitalized patients, nausea was the most common presenting feature found in 124/209 (59.3%) patients. Children presented with a higher median body temperature than adults (p = 0.010). In addition, neutropenia was seen more commonly in children while raised serum ALT levels were seen more commonly in adults (both p = 0.006). While a low total white cell count was more common in patients with dengue fever as compared to Dengue Hemorrhagic Fever (p = 0.020), neutropenia (p = 0.019), monocytosis (p = 0.001) and raised serum ALT level (p = 0.005) were observed more commonly in the latter group.

Conclusions

Dengue virus is now endemic in Pakistan, circulating throughout the year with a peak incidence in the post monsoon period. Median age of dengue patients has decreased and younger patients may be more susceptible. Total and differential leukocyte counts may help identify patients at risk of hemorrhage.     

Fecal Calprotectin Excretion in Preterm Infants during the Neonatal Period

Background

Fecal calprotectin has been proposed as a non-invasive marker of intestinal inflammation in inflammatory bowel disease in adults and children. Fecal calprotectin levels have been reported to be much higher in both healthy full-term and preterm infants than in children and adults.

Objective

To determine the time course of fecal calprotectin (f-calprotectin) excretion in preterm infants from birth until hospital discharge and to identify factors influencing f-calprotectin levels in the first weeks of life, including bacterial establishment in the gut.

Methodology

F-calprotectin was determined using an ELISA assay in 147 samples obtained prospectively from 47 preterm infants (gestational age, and birth-weight interquartiles 27–29 weeks, and 880–1320 g, respectively) at birth, and at 2-week intervals until hospital discharge.

Principal Findings

Although median f-calprotectin excretion was 138 µg/g, a wide range of inter- and intra-individual variation in f-calprotectin values (from day 3 to day 78) was observed (86% and 67%, respectively). In multivariate regression analysis, f-calprotectin correlated negatively with ante and per natal antibiotic treatment (p = 0.001), and correlated positively with the volume of enteral feeding (mL/kg/d) (p = 0.009), the need to interrupt enteral feeding (p = 0.001), and prominent gastrointestinal colonization by Clostridium sp (p = 0.019) and Staphylococcus sp (p = 0.047).

Conclusion

During the first weeks of life, the high f-calprotectin values observed in preterm infants could be linked to the gut bacterial establishment.     

The Impact of HIV Infection and CD4 Cell Count on the Performance of an Interferon Gamma Release Assay in Patients with Pulmonary Tuberculosis

Background

The performance of the tuberculosis specific Interferon Gamma Release Assays (IGRAs) has not been sufficiently documented in tuberculosis- and HIV-endemic settings. This study evaluated the sensitivity of the QuantiFERON TB-Gold In-Tube (QFT-IT) in patients with culture confirmed pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance.

Methodology/Principal Findings

161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT-IT was positive in 74% (119/161; 95% CI: 67–81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion decreased with increasing CD4 cell count in HIV-positive patients (test for trend p = 0.03). Low CD4 cell count (<300 cells/µl) did not account for all QFT-IT indeterminate nor all negative results. Sensitivity when excluding indeterminate results was 86% (95% CI: 81–92%) and did not differ between HIV-negative and HIV–positive patients (88 vs. 83%, p = 0.39).

Conclusions/Significance

Sensitivity of the QFT-IT for diagnosing active PTB infection was reasonable when excluding indeterminate results and in HIV-negative patients. However, since the test missed more than 10% of patients, its potential as a rule-out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV-infection is prevalent.     

Evidence for STAT4 as a Common Autoimmune Gene: rs7574865 Is Associated with Colonic Crohn's Disease and Early Disease Onset

Background

Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort.

Methodology/Principal Findings

Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn''s disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74–0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63–12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74–1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75–1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction.

Conclusions/Significance

Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.     

Consuming More of Daily Caloric Intake at Dinner Predisposes to Obesity. A 6-Year Population-Based Prospective Cohort Study

Background/Objectives

It has been hypothesized that assuming most of the caloric intake later in the day leads to metabolic disadvantages, but few studies are available on this topic. Aim of our study was to prospectively examine whether eating more of the daily caloric intake at dinner leads to an increased risk of obesity, hyperglycemia, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD).

Subjects/Methods

1245 non-obese, non-diabetic middle-aged adults from a population-based cohort underwent a 3-day food record questionnaire at enrollment. Anthropometric values, blood pressure, blood metabolic variables, and estimated liver fat were measured at baseline and at 6-year follow-up.

Design

Prospective cohort study.

Results

Subjects were divided according to tertiles of percent daily caloric intake at dinner. A significant increase in the incidence rate of obesity (from 4.7 to 11.4%), metabolic syndrome (from 11.1 to 16.1%), and estimated NAFLD (from 16.5 to 23.8%) was observed from the lower to higher tertile. In a multiple logistic regression model adjusted for multiple covariates, subjects in the highest tertile showed an increased risk of developing obesity (OR = 2.33; 95% CI 1.17–4.65; p = 0.02), metabolic syndrome (OR = 1.52; 95% CI 1.01–2.30; p = 0.04), and NAFLD (OR = 1.56; 95% CI 1.10–2.22; p = 0.01).

Conclusions

Consuming more of the daily energy intake at dinner is associated with an increased risk of obesity, metabolic syndrome, and NAFLD.     

Respiratory Symptoms and Airway Obstruction in HIV-Infected Subjects in the HAART Era

Background

Prevalence and risk factors for respiratory symptoms and airway obstruction in HIV-infected subjects in the era of highly active antiretroviral therapy (HAART) are unknown. We evaluated respiratory symptoms and measured airway obstruction to identify the impact of HAART and other risk factors on respiratory symptoms and pulmonary function.

Methodology/Principal Findings

Two hundred thirty-four HIV-infected adults without acute respiratory symptoms were recruited from an HIV clinic. All subjects were interviewed and performed spirometry. Multivariate linear and logistic regressions were performed to determine predictors of respiratory symptoms, forced expiratory volume in one second (FEV₁) percent predicted, and FEV₁/forced vital capacity (FEV₁/FVC). Thirty-one percent of subjects reported at least one respiratory symptom. Smoking status (current or former versus never) (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.41–5.22, p = 0.003), higher log plasma HIV viral levels (OR = 1.12, 95%CI = 1.02–1.24, p = 0.02), and lower FEV₁/FVC (OR = 1.06 for every 0.01 decrease in FEV₁/FVC, 95%CI = 1.02–1.14, p = 0.001) were independent predictors of respiratory symptoms. Age (p = 0.04), pack-year smoking history (p<0.001), previous bacterial pneumonia (p = 0.007), and HAART use (p = 0.04) were independent predictors of decreased FEV₁/FVC.

Conclusions/Significance

Respiratory symptoms remain common in HIV-infected subjects, especially in those with a smoking history. Subjects who were older, had a greater pack-year history of smoking, or previous bacterial pneumonia had lower FEV₁/FVC ratios. Interestingly, use of HAART was independently associated with a decreased FEV₁/FVC, possibly secondary to an immune response to subclinical infections, increased autoimmunity, or other factors associated with HAART use.     

The Diagnostic and Prognostic Accuracy of Five Markers of Serious Bacterial Infection in Malawian Children with Signs of Severe Infection

Background

Early recognition and prompt and appropriate antibiotic treatment can significantly reduce mortality from serious bacterial infections (SBI). The aim of this study was to evaluate the utility of five markers of infection: C-reactive protein (CRP), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), CD163 and high mobility group box-1 (HMGB1), as markers of SBI in severely ill Malawian children.

Methodology and Principal Findings

Children presenting with a signs of meningitis (n = 282) or pneumonia (n = 95), were prospectively recruited. Plasma samples were taken on admission for CRP, PCT, sTREM-1 CD163 and HMGB1 and the performance characteristics of each test to diagnose SBI and to predict mortality were determined. Of 377 children, 279 (74%) had SBI and 83 (22%) died. Plasma CRP, PCT, CD163 and HMGB1 and were higher in HIV-infected children than in HIV-uninfected children (p<0.01). In HIV-infected children, CRP and PCT were higher in children with SBI compared to those with no detectable bacterial infection (p<0.0005), and PCT and CD163 were higher in non-survivors (p = 0.001, p = 0.05 respectively). In HIV-uninfected children, CRP and PCT were also higher in children with SBI compared to those with no detectable bacterial infection (p<0.0005), and CD163 was higher in non-survivors (p = 0.05). The best predictors of SBI were CRP and PCT, and areas under the curve (AUCs) were 0.81 (95% CI 0.73–0.89) and 0.86 (95% CI 0.79–0.92) respectively. The best marker for predicting death was PCT, AUC 0.61 (95% CI 0.50–0.71).

Conclusions

Admission PCT and CRP are useful markers of invasive bacterial infection in severely ill African children. The study of these markers using rapid tests in a less selected cohort would be important in this setting.     

Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

Background

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis.

Aim

A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome.

Methods

PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment.

Results

Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR = 1.26, 95% CI = 1.09–1.46, p = 0.001; for TT vs. CC, OR = 1.49, 95% CI = 1.13–1.97, p = 0.008; for CT vs. CC, OR = 1.29, 95% CI = 1.10–1.51, p = 0.001; for TT+CT vs. CC, OR = 1.35, 95% CI = 1.13–1.60, p = 0.0008; for TT vs. CT+CC, OR = 0.76, 95% CI = 0.60–0.94, p = 0.01).

Conclusion

The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy.