The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi

Background: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations.Methods: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation.Results: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi.Conclusions: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells

Reduced prefrontal gyrification in obsessive–compulsive disorder

Structural magnetic resonance imaging (MRI) studies reveal evidence for brain abnormalities in obsessive–compulsive disorder (OCD), for instance, reduction of gray matter volume in the prefrontal cortex. Disturbances of gyrification in the prefrontal cortex have been described several times in schizophrenia pointing to a neurodevelopmental etiology, while gyrification has not been studied so far in OCD patients. In 26 OCD patients and 38 healthy control subjects MR-imaging was performed. Prefrontal cortical folding (gyrification) was measured bilaterally by an automated version of the automated-gyrification index (A-GI), a ratio reflecting the extent of folding, from the slice containing the inner genu of the corpus callosum up to the frontal pole. Analysis of covariance (ANCOVA, independent factor diagnosis, covariates age, duration of education) demonstrated that compared with control subjects, patients with OCD displayed a significantly reduced A-GI in the left hemisphere (p = 0.021) and a trend for a decreased A-GI in the right hemisphere (p = 0.076). Significant correlations between prefrontal lobe volume and A-GI were only observed in controls, but not in OCD patients. In conclusion, prefrontal hypogyrification in OCD patients may be a structural correlate of the impairment in executive function of this patient group and may point to a neurodevelopmental origin of this disease

Therapeutic strategies to slow chronic kidney disease progression

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric, antifibrotic, and anti-inflammatory properties. Intensified blood pressure control, probably aiming for a target blood pressure below the 75th percentile, may exert additional renoprotective effects. Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia, anemia, and disorders of mineral metabolism. Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin, serum lipid, and calcium-phosphorus ion product levels in the normal range

No intention to comply with influenza and pneumococcal vaccination: behavioural determinants among smokers and non-smokers

OBJECTIVE: Smoking increases the risk for influenza and pneumococcal disease, but vaccination uptake is lower among smokers than non-smokers. We therefore aimed to determine reasons for not complying with vaccination among smokers and non-smokers. METHOD: In 2005 a self-administered questionnaire was sent to a random sample of Dutch patients (n=4,000) assessing medical, social and behavioural determinants. Independent factors associated with not complying with influenza and pneumococcal vaccination among smokers and non-smokers were assessed by multivariate logistic regression analysis. RESULTS: In all, 1,725 of 4,000 patients returned the questionnaire (response rate: 43%), 426 (25%) were smokers. Among smokers self-reported flu vaccine uptake was 42% and among non-smokers 52% among both only 0,2% received both vaccines. Most important predictors of not complying in smokers and non-smokers were patient's beliefs not to be susceptible to disease (odds ratio (OR) 4.0, 95% confidence interval (CI): 2.0, 8.0 and OR 2.8, CI: 2.0, 3.9), finding it difficult to go to the GP for vaccination (OR 2.5, CI: 1.3, 4.8 and OR 1.8, CI: 1.3, 2.6) and being against vaccination (OR 2.4 CI: 1.3, 4.4 and OR 1.8, CI: 1.3, 2.6), respectively. CONCLUSION: There are no substantial differences in determinants associated with not complying with influenza and pneumococcal vaccination between smokers and non-smokers but there is a trend towards stronger associations in smokers

Clinical effectiveness of conventional influenza vaccination in asthmatic children.

Influenza immunization rates among young asthmatics remain unsatisfactory due to persistent concern about the impact of influenza and the benefits of the vaccine. We assessed the effectiveness of the conventional inactivated trivalent sub-unit influenza vaccine in reducing acute respiratory disease in asthmatic children. We conducted a two-season retrospective cohort study covering the 1995-6 and 1996-7 influenza outbreaks in 22 computerized primary care practices in The Netherlands. In total, 349 patients aged between 0 and 12 years meeting clinical asthma-criteria were included; 14 children were lost to follow-up in the second season. The occurrence of physician-diagnosed acute respiratory disease episodes including influenza-like illness, pneumonia. bronchitis, bronchiolitis, asthma exacerbation and acute otitis media in vaccinated and unvaccinated children were compared after adjustments for age, prior health care and medication use. The occurrence of acute respiratory disease in unvaccinated children was 28% and 24% in the 1995-6 and 1996-7 season, respectively, and was highest in children under 6 years of age (43%). The overall pooled clinical vaccine effectiveness was 27% (95% confidence interval -7 to 51%, P = 0.11) after adjustments. A statistically higher vaccine protectiveness of 55% (95% CI 20-75%, P = 0.01) was observed among asthmatics under 6 years of age compared with -5% in older children (95% CI -81 to 39%). The occurrence of acute respiratory disease among asthmatic children during influenza epidemics is very high, notably in the youngest. Influenza vaccination may reduce morbidity in asthmatic infants and pre-school children. However, larger, preferably experimental, studies are needed to establish the benefits of vaccination, notably in older asthmatic children