Immune status and the efficacy of adjuvant radiotherapy for patients with localized Merkel cell carcinoma of the head and neck.

PURPOSE: Immunosuppressed (IS) patients are at increased risk for developing Merkel cell carcinoma (MCC) with worsened outcomes compared to immunocompetent (IC) patients. We sought to determine the effects of immune status on the efficacy of adjuvant RT regarding OS for patients with stage I, II or III (localized) MCC of the head and neck. METHODS/PATIENTS: The National Cancer Database was queried for patients with resected, localized MCC of the head and neck with known immune status. Kaplan-Meier methods were used to describe OS. Log-rank tests, multivariable Cox regression models and interaction effect testing were used to compare OS by subgroup categorized by patient and treatment factors including immune status and adjuvant RT receipt. RESULTS: A total of 892 (89.6%) IC and 104 (10.4%) IS patients with MCC of the head and neck were included. Adjuvant RT was associated with improved 3-year OS rate for both IS patients (49.4% vs. 35.5%, p = 0.0467) and stage I/II IC patients (72.4% vs. 62.9%, p = 0.0092). Adjuvant RT was associated with decreased hazard of death (HR 0.77, 95% CI 0.62-0.95). Interaction effect testing did not demonstrate a difference in the efficacy of adjuvant RT on OS between IC and IS status (p = 0.157). CONCLUSIONS: In this NCDB analysis, adjuvant RT was associated with decreased hazard of death for patients with localized MCC of the head and neck regardless of immune status and should be considered for both IS and IC patients.

Fifteen-year trends and predictors of preparation for pregnancy in women with pre-conception Type 1 and Type 2 diabetes: a population-based cohort study.

AIMS: To investigate trends in indicators of preparation for pregnancy in women with Type 1 and Type 2 diabetes and explore their predictors. METHODS: Data on 2293 pregnancies delivered during 1996-2010 by women with Type 1 (n = 1753) and Type 2 (n = 540) diabetes were obtained from the Northern Diabetes in Pregnancy Survey. Multiple logistic regression was used to analyse the relationship between potential predictors and three indicators of inadequate pregnancy preparation: non-attendance for pre-conception care; no pre-conception folate consumption; and peri-conception HbA(1c) ≥ 53 mmol/mol (≥ 7%). RESULTS: Overall, 40.3% of women with diabetes attended pre-conception care, 37.4% reported pre-conception folate consumption, and 28.2% had adequate peri-conception HbA1c . For all patients, pre-conception folate consumption improved over time, while peri-conception glucose control did not. Attendance for pre-conception care for women with Type 1 diabetes significantly declined. Residence in deprived areas, smoking and younger maternal age (for women aged < 35 years) were independently associated with all three indicators of inadequate preparation for pregnancy. Additional predictors of inadequate peri-conception HbA(1c) were: Type 1 diabetes (adjusted odds ratio 5.51, 95% CI 2.71-11.22), longer diabetes history (adjusted odds ratio 1.16, 95% CI 1.09-1.23 per year increase for those with < 15 years' diabetes duration), non-white ethnicity (adjusted odds ratio 3.13, 95% CI 1.23-7.97) and higher BMI (adjusted odds ratio 1.05, 95% CI 1.01-1.09 per 1-kg/m(2) increase). Non-attendance for pre-conception care was additionally associated with Type 2 diabetes (P = 0.003) and multiparity (P < 0.0001). CONCLUSIONS: There are socio-demographic inequalities in preparation for pregnancy among women with diabetes. Women with Type 2 diabetes were less likely to attend pre-conception care. Pre-conception services need to be designed to maximize uptake in all groups.

HbA(1c) and birthweight in women with pre-conception type 1 and type 2 diabetes: a population-based cohort study.

AIMS/HYPOTHESIS: To investigate clinical and sociodemographic predictors of birthweight in singletons born to women with type 1 or type 2 diabetes. METHODS: Normally formed singleton live births and intrapartum stillbirths, born to women with pre-conception diabetes during 1996-2008, were identified from the population-based Northern Diabetes in Pregnancy Survey (n = 1,505). Associations between potential predictors and birthweight were analysed by multiple regression. RESULTS: Potentially modifiable independent predictors of increase in birthweight were pre-pregnancy care (adjusted regression coefficient [b] = 87.1 g; 95% CI 12.9, 161.3), increasing third-trimester HbA(1c) ≤7% (53 mmol/mol) (b = 310.5 g per 1% [11 mmol/mol]; 95% CI 246.3, 374.7) and increasing maternal BMI (b = 9.5 g per 1 kg/m(2); 95% CI 3.5, 15.5). Smoking during pregnancy (b = -145.1 g; 95% CI -231.4, -58.8), later gestation at first antenatal visit (b = -15.0 g; 95% CI -26.9, -3.0) and higher peri-conception HbA(1c) (b = -48.2 g; 95% CI -68.8, -27.6) were independently associated with birthweight reduction. Pre-pregnancy nephropathy (b = -282.7 g; 95% CI -461.8, -103.6) and retinopathy (b = -175.5 g; 95% CI -269.9, -81.0) were independent non-modifiable predictors of reduced birthweight, while greater maternal height was a non-modifiable predictor of increasing birthweight (b = 17.8 g; 95% CI 12.3, 23.2). Other predictors of birthweight increase were male sex, multiparity and increasing gestational age at delivery. Type or duration of diabetes, socioeconomic status and ethnicity were not associated with continuous birthweight. CONCLUSIONS/INTERPRETATION: Poor glycaemic control before and throughout pregnancy is associated with abnormal fetal growth, with increasing peri-conception HbA(1c) predicting weight reduction and increasing third-trimester HbA(1c) predicting increased birthweight. Women with microvascular complications of diabetes may require increased surveillance to detect fetal growth restriction.

Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study.

AIMS: The aim of this study was to quantify the risk of major congenital anomaly, and to assess the influence of peri-conception HbA(1c) and other clinical and socio-demographic factors on the risk of congenital anomaly occurrence in offspring of women with type 1 and type 2 diabetes diagnosed before pregnancy. METHODS: This was a population-based cohort study using linked data from registers of congenital anomaly and diabetes in pregnancy. A total of 401,149 singleton pregnancies (1,677 in women with diabetes) between 1996 and 2008 resulting in live birth, fetal death at ≥20 weeks' gestation or termination of pregnancy for fetal anomaly were included. RESULTS: The rate of non-chromosomal major congenital anomaly in women with diabetes was 71.6 per 1,000 pregnancies (95% CI 59.6, 84.9), a relative risk of 3.8 (95% CI 3.2, 4.5) compared with women without diabetes. There was a three- to sixfold increased risk across all common anomaly groups. In a multivariate analysis, peri-conception glycaemic control (adjusted OR [aOR] 1.3 [95% CI 1.2, 1.4] per 1% [11 mmol/mol] linear increase in HbA(1c) above 6.3% [45 mmol/mol]) and pre-existing nephropathy (aOR 2.5 [95% CI 1.1, 5.3]) were significant independent predictors of congenital anomaly. Associations with gestation at booking (aOR 1.1 [95% CI 1.0, 1.1]) and parity (aOR 1.6 [95% CI 1.0, 2. 5]) were not significant. Unadjusted risk was higher for women from deprived areas or who did not take folate. Type and duration of diabetes, ethnicity, age, BMI, preconception care, smoking and fetal sex were not associated with congenital anomaly risk. CONCLUSIONS: Peri-conception glycaemia is the most important modifiable risk factor for congenital anomaly in women with diabetes. The association with nephropathy merits further study.

Analysis of airway epithelial regeneration and repair following endobronchial brush biopsy in sheep.

Understanding the fundamental processes involved in repairing the airway wall following injury is fundamental to understanding the way in which these processes are perturbed during disease pathology. Indeed complex diseases such as asthma and chronic obstructive pulmonary disease (COPD) have at their core evidence of airway wall remodeling processes that play a crucial functional role in these diseases. The authors sought to understand the dynamic cellular events that occur during bronchial airway epithelial repair in sheep. The injury was induced by endobronchial brush biopsy (BBr), a process that causes epithelial débridement and induces a consequential repair process. In addition, the current experimental protocol allowed for the time-dependent changes in airway wall morphology to be studied both within and between animals. The initial débridement was followed by evidence of dedifferentiation in the intact epithelium at the wound margins, followed by proliferation of cells both within the epithelium and in the deeper wall structures, notably in association with the submucosal glands and smooth muscle bundles. Seven days after injury, although the airway wall was thickened at the site of damage, the epithelial layer was intact, with evidence of redifferentiation. These studies, in demonstrating broad agreement with previous studies in small animals, indicate the wider relevance of this system as a comparative model and should provide a solid basis upon which to further characterize the critical cellular and molecular interactions that underlie both effective restitution and pathological repair.

Phylogeography and molecular epidemiology of Papaya ringspot virus.

Papaya ringspot virus (PRSV) is the most important virus affecting papaya and cucurbit plants in tropical and subtropical areas. PRSV isolates are divided into biotypes P and W: both the P and W types naturally infect plants in the family Cucurbitaceae, whereas the P type naturally infects papaya (Carica papaya). Understanding the origin and nature of the PRSV genetic diversity and evolution is critical for the implementation of control strategies based on cross-protection and the deployment of transgenic plants that show resistance to virus isolates highly similar to the transgene. The molecular epidemiology of PRSV was evaluated by analyzing the nucleotide sequence of the capsid protein (CP) and helper component-proteinase (HC-Pro) genes of isolates from around the world, including newly characterized ones from Colombia and Venezuela, using a relaxed molecular clock-based approach and a phylogeographic study. Our results confirm previous estimates on the origin of PRSV around 400 years ago and suggest distinct dispersion events from the Indian Peninsula to the rest of Asia, via Thailand, and subsequently to the Americas. A historical reconstruction of the P- and W-type characters in the phylogenetic study supports the need to revise the hypothesis that PRSV-P derives from PRSV-W since our results suggest that the ancestral state could be either of the two biotypes. Moreover, estimates of epidemic growth predict an increasing genetic diversity of the virus over time that has direct implications for control strategies of PRSV based on cross-protection and the use of transgenic plants.

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung.

We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

Lifecourse predictors of adult respiratory function: results from the Newcastle Thousand Families Study.

BACKGROUND: Impaired development in utero is suggested to increase the risk of poor respiratory health in adulthood, although a consensus has not been reached. A possible explanation for discrepancies between previous studies is inconsistent controlling for potential confounding factors, particularly childhood infections. Also, little is known regarding the relative importance of factors operating at different stages of the lifecourse. We have used detailed longitudinal data from the Newcastle Thousand Families cohort to assess the impact of birth weight, and various other factors acting throughout the lifecourse, on predicting forced expiratory volume in 1 s (FEV(1)). METHODS: Detailed information was collected prospectively during childhood, including birth weight, childhood infections and socioeconomic circumstances. At age 49-51 years, 412 study members attended for clinical examination and measurement of FEV(1). These data were analysed in relation to a range of factors from across the lifecourse using linear regression models. RESULTS: After adjustment for all other significant variables, increasing birth weight, standardised for sex and gestational age (p = 0.011), being breast fed for more than 4 weeks (p = 0.017), less frequent childhood lower respiratory tract infections (LRTI) (p = 0.015), non- smoking (p<0.001), lower body fat percentage (p = 0.010), male sex (p<0.001), no history of asthma (p = 0.013) and greater adult height (p<0.001) were all independently associated with higher adult FEV(1). CONCLUSION: Adult lung function is influenced by numerous factors during an individual's lifetime, acting both directly and indirectly throughout the lifecourse. As expected, sex, height and smoking were the most important predictors of FEV(1), but birth weight, breast feeding and childhood LRTIs also contributed significantly.

Alterations of microsomal monooxygenase system and carcinogen metabolism by streptozotocin-induced diabetes in rats.

The effects of diabetes on the liver microsomal monooxygenase enzymes and carcinogen metabolism have been studied in rats. Treatment with streptozotocin causes a marked enhancement in microsomal N-nitrosodimethylamine (NDMA) demethylase activity. The enhancement is due mainly to the induction of a high affinity NDMA demethylase (Km, approximately 0.05 mM) which is accompanied by the induction of a protein species with mol. wt. of 50,000. The treatment also induces aniline hydroxylase whose activity is in parallel with NDMA demethylase. Streptozotocin-induced diabetes also increases the metabolism of N-nitrosomethylethylamine but not that of N-nitrosomethylaniline or N-nitrosomethylbenzylamine. On the other hand, diabetes decreases the metabolism of benzo[a]pyrene, benzphetamine, and ethylmorphine. The result suggest that diabetes causes an alteration of the composition of cytochrome P-450 isozymes; the forms efficient in metabolizing NDMA are increased while certain other forms of cytochrome P-450 are decreased.