Congenital and Postnatal CMV and EBV Acquisition in HIV-Infected Zimbabwean Infants

Background

HIV-infected infants in sub-Saharan Africa have rapid disease progression. We hypothesized that co-infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) increases mortality in HIV-infected infants.

Methods

257 antiretroviral therapy-naïve HIV-infected Zimbabwean infants were tested for CMV and EBV at 6 weeks of age by real-time PCR; if positive, birth samples were retrieved where available to distinguish congenital and postnatal infection. The impact of co-infection on mortality through 6 months was estimated using Kaplan-Meier and Cox proportional hazards methods.

Results

At 6 weeks, 203/257 (79%) HIV-infected infants were CMV-positive; 27 (11%) had congenital CMV, 108 (42%) postnatal CMV and 68 (26%) indeterminate timing of infection. By 6 months, 37/108 (34%) infants with postnatal CMV versus 16/54 (30%) CMV-negative infants died (adjusted hazard ratio (aHR) 1.1 [95%CI 0.6, 2.2]). At 6 weeks, 33/257 (13%) HIV-infected infants had EBV co-infection; 6 (2%) had congenital EBV, 18 (7%) postnatal EBV and 9 (4%) indeterminate timing of infection. By 6 months, 5/18 (28%) infants with postnatal EBV versus 72/224 (32%) EBV-negative infants died (aHR 0.8 [95%CI 0.3, 2.3]).

Conclusions

The vast majority of HIV-infants had acquired CMV by 6 weeks, and EBV co-infection occurred earlier than expected, with one in eight HIV-infected infants positive for EBV by 6 weeks. There was a high prevalence of congenital CMV infection and we identified 6 infants with congenital EBV infection, which has not previously been reported in Africa or in the context of HIV infection. Neither CMV nor EBV co-infection was associated with increased mortality.     

Seroprevalence of Cytomegalovirus,Epstein Barr Virus and Varicella Zoster Virus among Pregnant Women in Bradford: A Cohort Study

Objective

To estimate the seroprevalence of cytomegalovirus (CMV), Epstein Barr virus (EBV) and varicella zoster virus (VZV) among pregnant women in Bradford by ethnic group and country of birth.

Methods

A stratified random sample of 949 pregnant women enrolled in the Born in Bradford birth cohort was selected to ensure sufficient numbers of White UK born women, Asian UK born women and Asian women born in Asia. Serum samples taken at 24-28 weeks’ gestation were tested for CMV IgG, EBV IgG and VZV IgG. Each woman completed a questionnaire which included socio-demographic information.

Results

CMV seroprevalence was 49% among the White British women, 89% among South Asian UK born women and 98% among South Asian women born in South Asia. These differences remained after adjusting for socio-demographic factors. In contrast, VZV seroprevalence was 95% among women born in the UK but significantly lower at 90% among South Asian women born in Asia. EBV seroprevalence was 94% overall and did not vary by ethnic group/country of birth.

Conclusions

Although about half of White British women are at risk of primary CMV infection in pregnancy and the associated increased risk of congenital infection, most congenital CMV infections are likely to be in children born to South Asian women with non-primary infection during pregnancy. South Asian women born in South Asia are at risk of VZV infection during pregnancy which could produce congenital varicella syndrome or perinatal chickenpox. Differences in CMV and VZV seroprevalence by ethnic group and country of birth must be taken into account when universal immunisation against these viruses is contemplated.     

Cerebral oxygenation is highly sensitive to blood pressure variability in sick preterm infants

Objectives

The significance of blood pressure variability (BPV) for cerebral oxygenation in extremely preterm infants has not been explored, though BPV may well be associated with end organ injury. We hypothesized that increased BPV in sick preterm infants, by exceeding the cerebral autoregulatory capacity, is associated with cerebral oxygenation changes which closely follow the blood pressure fluctuations. We assessed the autoregulatory capacity in the early postnatal period, by determining the correlation between BPV (mmHg²) and coherence of mean arterial blood pressure (MABP mmHg) and cerebral oxygenation (tissue oxygenation index, TOI %).

Study Design

Thirty-two preterm infants of mean gestational age of 26.3 (±1.5) weeks were studied on the first 3 postnatal days. Spectral analysis (Coherence and transfer-function gain analysis) was used to calculate coherence of MABP and TOI; BPV was quantified using power spectral density of MABP.

Results

Overall, maximum Coherence showed a trend for positive correlation with BPV (n = 32, p = 0.06). Infants identified as clinically unstable with documented brain injury (n = 7) had high Coherence values at low BPV. Separate analysis of stable infants (excluding the 7 critically ill infants) revealed a significant association between maximum Coherence and BPV (n = 25, p = 0.006).

Conclusions

Fluctuation in cerebral oxygenation is closely associated with increased BPV in preterm infants undergoing intensive care. Moreover, in the critically sick preterm infant, blood pressure-dependent variations in cerebral oxygenation occur even with relatively lower BPV, suggesting they have severely impaired autoregulation, and placing them at greater vulnerability to cerebral injury arising from blood pressure fluctuations.     

Relationship between the COMT-Val158Met and BDNF-Val66Met Polymorphisms,Childhood Trauma and Psychotic Experiences in an Adolescent General Population Sample

Objective

Psychotic experiences occur at a much greater prevalence in the population than psychotic disorders. There has been little research to date, however, on genetic risk for this extended psychosis phenotype. We examined whether COMT or BDNF genotypes were associated with psychotic experiences or interacted with childhood trauma in predicting psychotic experiences.

Method

Psychiatric interviews and genotyping for COMT-Val158Met and BDNF-Val66Met were carried out on two population-based samples of 237 individuals aged 11-15 years. Logistic regression was used to examine for main effects by genotype and childhood trauma, controlling for important covariates. This was then compared to a model with a term for interaction between genotype and childhood trauma. Where a possible interaction was detected, this was further explored in stratified analyses.

Results

While childhood trauma showed a borderline association with psychotic experiences, COMT-Val158Met and BDNF-Val66Met genotypes were not directly associated with psychotic experiences in the population. Testing for gene x environment interaction was borderline significant in the case of COMT-Val158Met with individuals with the COMT-Val158Met Val-Val genotype, who had been exposed to childhood trauma borderline significantly more likely to report psychotic experiences than those with Val-Met or Met-Met genotypes. There was no similar interaction by BDNF-Val66Met genotype.

Conclusion

The COMT-Val158Met Val-Val genotype may be a genetic moderator of risk for psychotic experiences in individuals exposed to childhood traumatic experiences.     

Critical Serum Creatinine Values in Very Preterm Newborns

Background

Renal failure in neonates is associated with an increased risk of mortality and morbidity. But critical values are not known.

Objective

To define critical values for serum creatinine levels by gestational age in preterm infants, as a predictive factor for mortality and morbidity.

Study Design

This was a retrospective study of all preterm infants born before 33 weeks of gestational age, hospitalized in Nantes University Hospital NICU between 2003 and 2009, with serum creatinine levels measured between postnatal days 3 to 30. Children were retrospectively randomized into either training or validation set. Critical creatinine values were defined within the training set as the 90^th percentile values of highest serum creatinine (HSCr) in infants with optimal neurodevelopmental at two years of age. The relationship between these critical creatinine values and neonatal mortality, and non-optimal neural development at two years, was then assessed in the validation set.

Results and Conclusion

The analysis involved a total of 1,461 infants (gestational ages of 24-27 weeks (n=322), 28-29 weeks (n=336), and 30-32 weeks (803)), and 14,721 creatinine assessments. The critical values determined in the training set (n=485) were 1.6, 1.1 and 1.0 mg/dL for each gestational age group, respectively. In the validation set (n=976), a serum creatinine level above the critical value was significantly associated with neonatal mortality (Odds ratio: 8.55 (95% confidence interval: 4.23-17.28); p<0.01) after adjusting for known renal failure risk factors, and with non-optimal neurodevelopmental outcome at two years (odds ratio: 2.06 (95% confidence interval: 1.26-3.36); p=0.004) before adjustment. Creatinine values greater than 1.6, 1.1 and 1.0 mg/dL respectively at 24-27, 28-29, 30-32 weeks of gestation were associated with mortality before and after adjustment for risk factors, and with non-optimal neurodevelopmental outcome, before adjustment.     

Impact of Pregnancy-Associated Malaria on Infant Malaria Infection in Southern Benin

Background

Infants of mothers with placental Plasmodium falciparum infections at delivery are themselves more susceptible to malaria attacks or to infection in early life.

Methodology/ Principal Findings

To assess the impact of either the timing or the number of pregnancy-associated malaria (PAM) infections on the incidence of parasitemia or malaria attacks in infancy, we followed 218 mothers through pregnancy (monthly visits) up to delivery and their infants from birth to 12 months of age (fortnightly visits), collecting detailed clinical and parasitological data. After adjustment on location, mother’s age, birth season, bed net use, and placental malaria, infants born to a mother with PAM during the third trimester of pregnancy had a significantly increased risk of infection (OR [95% CI]: 4.2 [1.6; 10.5], p = 0.003) or of malaria attack (4.6 [1.7; 12.5], p = 0.003). PAM during the first and second trimesters had no such impact. Similarly significant results were found for the effect of the overall number of PAM episodes on the time to first parasitemia and first malaria attack (HR [95% CI]: 2.95 [1.58; 5.50], p = 0.001 and 3.19 [1.59; 6.38], p = 0.001) respectively.

Conclusions/ Significance

This study highlights the importance of protecting newborns by preventing repeated episodes of PAM in their mothers.     

Prolonged Seasonality of Respiratory Syncytial Virus Infection among Preterm Infants in a Subtropical Climate

Objective

There is limited epidemiological data on the seasonality of respiratory syncytial virus (RSV) infection in subtropical climates, such as in Taiwan. This study aimed to assess RSV seasonality among children ≤24 months of age in Taiwan. We also assessed factors (gestational age [GA], chronologic age [CA], and bronchopulmonary dysplasia [BPD]) associated with RSV-associated hospitalization in preterm infants to confirm the appropriateness of the novel Taiwanese RSV prophylactic policy.

Study Design

From January 2000 to August 2010, 3572 children aged ≤24-months were admitted to Taipei Mackay Memorial Hospital due to RSV infection. The monthly RSV-associated hospitalization rate among children aged ≤24 months was retrospectively reviewed. Among these children, 378 were born preterm. The associations between GA, CA, and BPD and the incidence of RSV-associated hospitalization in the preterm infants were assessed.

Results

In children aged ≤24 months, the monthly distribution of RSV-associated hospitalization rates revealed a prolonged RSV season with a duration of 10 months. Infants with GAs ≤32 weeks and those who had BPD had the highest rates of RSV hospitalization (P<0.001). Preterm infants were most vulnerable to RSV infection within CA 9 months.

Conclusions

Given that Taiwan has a prolonged (10-month) RSV season, the American Academy of Pediatrics'' recommendations for RSV prophylaxis are not directly applicable. The current Taiwanese guidelines for RSV prophylaxis, which specify palivizumab injection (a total six doses until CA 8–9 months) for preterm infants (those born before 28^6/7 weeks GA or before 35^6/7 weeks GA with BPD), are appropriate. This prophylaxis strategy may be applicable to other countries/regions with subtropical climates.     

Breastfeeding Progression in Preterm Infants Is Influenced by Factors in Infants,Mothers and Clinical Practice: The Results of a National Cohort Study with High Breastfeeding Initiation Rates

Background and Aim

Many preterm infants are not capable of exclusive breastfeeding from birth. To guide mothers in breastfeeding, it is important to know when preterm infants can initiate breastfeeding and progress. The aim was to analyse postmenstrual age (PMA) at breastfeeding milestones in different preterm gestational age (GA) groups, to describe rates of breastfeeding duration at pre-defined times, as well as analyse factors associated with PMA at the establishment of exclusive breastfeeding.

Methods

The study was part of a prospective survey of a national Danish cohort of preterm infants based on questionnaires and structured telephone interviews, including 1,221 mothers and their 1,488 preterm infants with GA of 24–36 weeks.

Results

Of the preterm infants, 99% initiated breastfeeding and 68% were discharged exclusively breastfed. Breastfeeding milestones were generally reached at different PMAs for different GA groups, but preterm infants were able to initiate breastfeeding at early times, with some delay in infants less than GA 32 weeks. Very preterm infants had lowest mean PMA (35.5 weeks) at first complete breastfeed, and moderate preterm infants had lowest mean PMA at the establishment of exclusive breastfeeding (36.4 weeks). Admitting mothers to the NICU together with the infant and minimising the use of a pacifier during breastfeeding transition were associated with 1.6 (95% CI 0.4–2.8) and 1.2 days (95% CI 0.1–2.3) earlier establishment of exclusive breastfeeding respectively. Infants that were small for gestational age were associated with 5.6 days (95% CI 4.1–7.0) later establishment of exclusive breastfeeding.

Conclusion

Breastfeeding competence is not developed at a fixed PMA, but is influenced by multiple factors in infants, mothers and clinical practice. Admitting mothers together with their infants to the NICU and minimising the use of pacifiers may contribute to earlier establishment of exclusive breastfeeding.     

Neonatal Mortality and Long-Term Outcome of Infants Born between 27 and 32 Weeks of Gestational Age in Breech Presentation: The EPIPAGE Cohort Study

Objective

To determine whether breech presentation is an independent risk factor for neonatal morbidity, mortality, or long-term neurologic morbidity in very preterm infants.

Design

Prospective population-based cohort.

Population

Singletons infants without congenital malformations born from 27 to 32 completed weeks of gestation enrolled in France in 1997 in the EPIPAGE cohort.

Methods

The neonatal and long-term follow-up outcomes of preterm infants were compared between those in breech presentation and those in vertex presentation. The relation of fetal presentation with neonatal mortality and neurodevelopmental outcomes was assessed using multiple logistic regression models.

Results

Among the 1518 infants alive at onset of labor included in this analysis (351 in breech presentation), 1392 were alive at discharge. Among those eligible to follow up and alive at 8 years, follow-up data were available for 1188 children. Neonatal mortality was significantly higher among breech than vertex infants (10.8% vs. 7.5%, P = 0.05). However the differences were not significant after controlling for potential confounders. Neonatal morbidity did not differ significantly according to fetal presentation. Severe cerebral palsy was less frequent in the group born in breech compared to vertex presentation but there was no difference after adjustment. There was no difference according to fetal presentation in cognitive deficiencies/learning disabilities or overall deficiencies.

Conclusion

Our data suggest that breech presentation is not an independent risk factor for neonatal mortality or long-term neurologic deficiencies among very preterm infants.     

Maternal Prepregnancy Body Mass Index and Gestational Weight Gain on Offspring Overweight in Early Infancy

Objective

The aim of the present study was to evaluate the association of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) with anthropometry in the offspring from birth to 12 months old in Tianjin, China.

Methods

Between 2009 and 2011, health care records of 38,539 pregnant women had been collected, and their children had been measured body weight and length at birth, 3, 6, 9 and 12 months of age. The independent and joint associations of pre-pregnancy BMI and GWG based on the Institute of Medicine (IOM) guidelines with anthropometry in the offspring were examined using General Linear Model and Logistic Regression.

Results

Prepregnancy BMI and maternal GWG were positively associated with Z-scores for birth weight-for-gestational age, birth length-for-gestational age, and birth weight-for-length. Infants born to mothers with excessive GWG had the greatest changes in Z-scores for weight-for-age from birth to Month 3, and from Month 6 to Month 12, and the greatest changes in Z-scores for length-for-age from birth to months 3 and 12 compared with infants born to mothers with adequate GWG. Excessive GWG was associated with an increased risk of offspring overweight or obesity at 12 months old in all BMI categories except underweight.

Conclusions

Maternal prepregnancy overweight/obesity and excessive GWG were associated with greater weight gain and length gain of offspring in early infancy. Excessive GWG was associated with increased infancy overweight and obesity risk.     

Plasma Cytokine Levels Fall in Preterm Newborn Infants on Nasal CPAP with Early Respiratory Distress

Introduction

Early nCPAP seems to prevent ventilator-induced lung injury in humans, although the pathophysiological mechanisms underlying this beneficial effect have not been clarified yet.

Objective

To evaluate plasma levels IL-1β, IL-6, IL-8, IL-10, and TNF-α immediately before the start of nCPAP and 2 hours later in preterm infants.

Methods

Prospective cohort including preterm infants with 28 to 35 weeks gestational age with moderate respiratory distress requiring nCPAP. Extreme preemies, newborns with malformations, congenital infections, sepsis, surfactant treatment, and receiving ventilatory support in the delivery room were excluded. Blood samples were collected right before and 2 hours after the start of nCPAP.

Results

23 preterm infants (birth weight 1851±403 grams; GA 32.3±1.7 weeks) were treated with nCPAP. IL-1β, IL-10, TNF-α levels were similar, IL-8 levels were reduced in 18/23 preterm infants and a significant decrease in IL-6 levels was observed after 2 hours of nCPAP. All newborns whose mothers received antenatal steroids had lower cytokine levels at the onset of nCPAP than those whose mothers didn’t receive it; this effect was not sustained after 2 hours of nCPAP.

Conclusion

Early use nCPAP is not associated with rising of plasma pro-inflammatory cytokines and it seems to be a less harmful respiratory strategy for preterm with moderate respiratory distress.     

Recurrence of Preeclampsia in Northern Tanzania: A Registry-Based Cohort Study

Objective

Preeclampsia occurs in about 4 per cent of pregnancies worldwide, and may have particularly serious consequences for women in Africa. Studies in western countries have shown that women with preeclampsia in one pregnancy have a substantially increased risk of preeclampsia in subsequent pregnancies. We estimate the recurrence risks of preeclampsia in data from Northern Tanzania.

Methods

A prospective cohort study was designed using 19,811 women who delivered singleton infants at a hospital in Northern Tanzania between 2000and2008. A total of 3,909 women were recorded with subsequent deliveries in the hospital with follow up through 2010. Adjusted recurrence risks of preeclampsia were computed using regression models.

Results

The absolute recurrence risk of preeclampsia was25%, which was 9.2-fold (95% CI: 6.4 - 13.2) compared with the risk for women without prior preeclampsia. When there were signs that the preeclampsia in a previous pregnancy had been serious either because the baby was delivered preterm or had died in the perinatal period, the recurrence risk of preeclampsia was even higher. Women who had preeclampsia had increased risk of a series of adverse pregnancy outcomes in future pregnancies. These include perinatal death (RR= 4.3), a baby with low birth weight (RR= 3.5), or a preterm birth (RR= 2.5). These risks were only partly explained by recurrence of preeclampsia.

Conclusions

Preeclampsia in one pregnancy is a strong predictor for preeclampsia and other adverse pregnancy outcomes in subsequent pregnancies in Tanzania. Women with previous preeclampsia may benefit from close follow-up during their pregnancies.     

A Phase I Randomized Clinical Trial of Candidate Human Immunodeficiency Virus type 1 Vaccine MVA.HIVA Administered to Gambian Infants

Background

A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.

Trial Design

We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.

Methods

Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.

Results

From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.

Conclusions

A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group.

Trial Registration

ClinicalTrials.gov NCT00982579 The Pan African Clinical Trials Registry PACTR2008120000904116     

Molecular Epidemiology of Tuberculosis in Kaohsiung City Located at Southern Taiwan, 2000-2008

Background

We present the first comprehensive analysis of Mycobacterium tuberculosis (MTB) isolates circulating in southern Taiwan. In this 9-year population-based study, the TB situation in the Kaohsiung region was characterized by genotypic analysis of 421 MTB isolates.

Methods

All 421 isolates of MTB were analyzed by spoligotyping and MIRU-VNTR typing. Drug-resistance patterns were also analyzed.

Results

The percentage of EAI (East African-Indian) strains increased across sampling years (2000–2008) in southern Taiwan, whereas the proportion of Beijing lineages remained unchanged. Clustering was more frequent with EAI genotype infections (odds ratio = 3.6, p<0.0001) when compared to Beijing genotypes. Notably, MTB resistance to streptomycin (STR) had significantly increased over time, but resistance to other antibiotics, including multidrug resistance, had not. Three major genes (gidB, rpsL and rrs) implicated in STR resistance were sequenced and specific mutations identified.

Conclusions

This study revealed that EAI strains were highly transmissible and that STR resistance has increased between 2000 and 2008 in Kaohsiung, Taiwan.     

Transcriptional Modulation of Intestinal Innate Defense/Inflammation Genes by Preterm Infant Microbiota in a Humanized Gnotobiotic Mouse Model

Background and Aims

It is known that postnatal functional maturation of the small intestine is facilitated by microbial colonization of the gut. Preterm infants exhibit defects in gut maturation, weak innate immunity against intestinal infection and increased susceptibility to inflammatory disorders, all of which may be related to the inappropriate microbial colonization of their immature intestines. The earliest microbes to colonize the preterm infant gut encounter a naïve, immature intestine. Thus this earliest microbiota potentially has the greatest opportunity to fundamentally influence intestinal development and immune function. The aim of this study was to characterize the effect of early microbial colonization on global gene expression in the distal small intestine during postnatal gut development.

Methods

Gnotobiotic mouse models with experimental colonization by early (prior to two weeks of life) intestinal microbiota from preterm human infants were utilized. Microarray analysis was used to assess global gene expression in the intestinal epithelium.

Results and Conclusion

Multiple intestinal genes involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication, and immune function are developmental- and intestinal microbiota- regulated. Using a humanized gnotobiotic mouse model, we demonstrate that certain early preterm infant microbiota from prior to 2 weeks of life specifically induce increased NF-κB activation and a phenotype of increased inflammation whereas other preterm microbiota specifically induce decreased NF-κB activation. These fundamental differences correlate with altered clinical outcomes and suggest the existence of optimal early microbial communities to improve health outcomes.     

Hemodynamic and Metabolic Correlates of Perinatal White Matter Injury Severity

Background and Purpose

Although the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.

Methods

We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter.

Results

A spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.

Conclusions

Our results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.     

The chromatin remodeling factor SMARCB1 forms a complex with human cytomegalovirus proteins UL114 and UL44

Background

Human cytomegalovirus (HCMV) uracil DNA glycosylase, UL114, is required for efficient viral DNA replication. Presumably, UL114 functions as a structural partner to other factors of the DNA-replication machinery and not as a DNA repair protein. UL114 binds UL44 (HCMV processivity factor) and UL54 (HCMV-DNA-polymerase). In the present study we have searched for cellular partners of UL114.

Methodology/Principal Findings

In a yeast two-hybrid screen SMARCB1, a factor of the SWI/SNF chromatin remodeling complex, was found to be an interacting partner of UL114. This interaction was confirmed in vitro by co-immunoprecipitation and pull-down. Immunofluorescence microscopy revealed that SMARCB1 along with BRG-1, BAF170 and BAF155, which are the core SWI/SNF components required for efficient chromatin remodeling, were present in virus replication foci 24–48 hours post infection (hpi). Furthermore a direct interaction was also demonstrated for SMARCB1 and UL44.

Conclusions/Significance

The core SWI/SNF factors required for efficient chromatin remodeling are present in the HCMV replication foci throughout infection. The proteins UL44 and UL114 interact with SMARCB1 and may participate in the recruitment of the SWI/SNF complex to the chromatinized virus DNA. Thus, the presence of the SWI/SNF chromatin remodeling complex in replication foci and its association with UL114 and with UL44 might imply its involvement in different DNA transactions.     

Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphism and Left Ventricular Function in Early Chronic Kidney Disease

Background

Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated.

Methods

140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively.

Results

The median estimated glomerular filtration rate (eGFR) was 50mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively).

Conclusions

eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.     

Respiratory syncytial virus infection is associated with an altered innate immunity and a heightened pro-inflammatory response in the lungs of preterm lambs

Introduction

Factors explaining the greater susceptibility of preterm infants to severe lower respiratory infections with respiratory syncytial virus (RSV) remain poorly understood. Fetal/newborn lambs are increasingly appreciated as a model to study key elements of RSV infection in newborn infants due to similarities in lung alveolar development, immune response, and susceptibility to RSV. Previously, our laboratory demonstrated that preterm lambs had elevated viral antigen and developed more severe lesions compared to full-term lambs at seven days post-infection. Here, we compared the pathogenesis and immunological response to RSV infection in lungs of preterm and full-term lambs.

Methods

Lambs were delivered preterm by Caesarian section or full-term by natural birth, then inoculated with bovine RSV (bRSV) via the intratracheal route. Seven days post-infection, lungs were collected for evaluation of cytokine production, histopathology and cellular infiltration.

Results

Compared to full-term lambs, lungs of preterm lambs had a heightened pro-inflammatory response after infection, with significantly increased MCP-1, MIP-1α, IFN-γ, TNF-α and PD-L1 mRNA. RSV infection in the preterm lung was characterized by increased epithelial thickening and periodic acid-Schiff staining, indicative of glycogen retention. Nitric oxide levels were decreased in lungs of infected preterm lambs compared to full-term lambs, indicating alternative macrophage activation. Although infection induced significant neutrophil recruitment into the lungs of preterm lambs, neutrophils produced less myeloperoxidase than those of full-term lambs, suggesting decreased functional activation.

Conclusions

Taken together, our data suggest that increased RSV load and inadequate immune response may contribute to the enhanced disease severity observed in the lungs of preterm lambs.     

Association of Trichomonas vaginalis and Cytological Abnormalities of the Cervix in Low Risk Women

Objective

Is Trichomonas vaginalis (TV) an inducing factor for the development of (pre-)cancerous lesions of the cervix?

Design

Cross sectional study.

Setting

Screening healthy Belgian women with low infection risk.

Sample

63,251 consecutive liquid based cervical samples.

Methods

Real time quantitative PCR for presence of TV, 18 HPV types and Pap smear analysis of cytologic abnormalities.

Main Outcome Measures

Association of TV and HPV with cervix dysplasia

Results

The overall prevalence of TV DNA was 0.37%, of low risk HPV 2%, of high risk HPV 13.2%, and 8.8 % had cytological abnormalities. Both LR-HPV and HR-HPV were significantly associated with all cytological abnormalities. Presence of TV was associated with LR- and HR-HPV, ASC-US and HSIL, but not with other abnormalities. All women with TV and HSIL also had HR-HPV, while the latter was present in only 59% of women with TV and ASC-US. Amongst HPV negative women, TV was found in 1.3% of women with ASC-US, but only in 0.03% of women with normal cytology (OR 4.2, CL95% 2.1-8.6). In HR-HPV positive women, presence of TV increased the likelihood of cytological abnormalities somewhat (P=0.05), mainly due to an increase in ASC-US and LSIL, but not HSIL.

Conclusions

We conclude that TV infection is associated with both LR and HR-HPV infection of the cervix, as well as with ASC-US and HSIL. TV is a concomitant STI, but is not thought to be a co-factor in the causation of HSIL and cervical cancer. However, TV may cause false positive diagnoses of ASC-US.