Chordin Is a Modifier of Tbx1 for the Craniofacial Malformations of 22q11 Deletion Syndrome Phenotypes in Mouse

Point mutations in TBX1 can recapitulate many of the structural defects of 22q11 deletion syndromes (22q11DS), usually associated with a chromosomal deletion at 22q1.2. 22q11DS often includes specific cardiac and pharyngeal organ anomalies, but the presence of characteristic craniofacial defects is highly variable. Even among family members with a single TBX1 point mutation but no cytological deletion, cleft palate and low-set ears may or may not be present. In theory, such differences could depend on an unidentified, second-site lesion that modifies the craniofacial consequences of TBX1 deficiency. We present evidence for such a locus in a mouse model. Null mutations of chordin have been reported to cause severe defects recapitulating 22q11DS, which we show are highly dependent on genetic background. In an inbred strain in which chordin−/− is fully penetrant, we found a closely linked, strong modifier—a mutation in a Tbx1 intron causing severe splicing defects. Without it, lack of chordin results in a low penetrance of mandibular hypoplasia but no cardiac or thoracic organ malformations. This hypomorphic Tbx1 allele per se results in defects resembling 22q11DS but with a low penetrance of hallmark craniofacial malformations, unless chordin is mutant. Thus, chordin is a modifier for the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11DS

Children with pertussis inform the investigation of other pertussis cases among contacts

BACKGROUND: The number of reported pertussis has increased in the last two decades. However, many cases of pertussis may be underreported or not diagnosed. The World Health Organization estimates that pertussis causes 200,000-400,000 deaths each year, most deaths are in infants and in developing countries. Infants with pertussis can indicate an undetected source cases in the community. METHODS: At a University Hospital in Brazil individuals that had frequent contacts with a child with confirmed pertussis (the index case) and had recent history of cough were enrolled into the study. Nasopharyngeal swabs were collected from every contact that had cough within the last 21 days. Cases confirmation followed the guidelines of the Center for Disease Control and Prevention-Atlanta, USA. RESULTS: Pertussis diagnosis was confirmed in 51 children, (considered the index cases). Among the index cases, 72.5% (37/51) were under 6 months of age; culture for Bordetella pertussis was positive in 78.4% (40/51). Pertussis was confirmed in 39% (107/276) of the contacts of 51 index cases. Among these contacts identified as a pertussis case, 40.2% (43/107) were between 6 months and 111/2 years of age and 59.8% (64/107) were older than 111/2 years of age. Pertussis was confirmed by culture in 11.2% (12/107) of them and by epidemiologic linkage in 88.8% (95/107). Each index case allowed identifying two new cases of pertussis. CONCLUSION: Public health authorities should consider implementing early recognition of pertussis index cases and searching for pertussis cases among the contacts. Treatment of the cases and prophylaxis of the contacts is fundamental to control outbreaks in the community

Health worker densities and immunization coverage in Turkey: a panel data analysis

<p>Abstract</p> <p>Background</p> <p>Increased immunization coverage is an important step towards fulfilling the Millennium Development Goal of reducing childhood mortality. Recent cross-sectional and cross-national research has indicated that physician, nurse and midwife densities may positively influence immunization coverage. However, little is known about relationships between densities of human resources for health (HRH) and vaccination coverage within developing countries and over time. The present study examines HRH densities and coverage of the Expanded Programme on Immunization (EPI) in Turkey during the period 2000 to 2006.</p> <p>Methods</p> <p>The study is based on provincial-level data on HRH densities, vaccination coverage and provincial socioeconomic and demographic characteristics published by the Turkish government. Panel data regression methodologies (random and fixed effects models) are used to analyse the data.</p> <p>Results</p> <p>Three main findings emerge: (1) combined physician, nurse/midwife and health officer density is significantly associated with vaccination rates – independent of provincial female illiteracy, GDP per capita and land area – although the association was initially positive and turned negative over time; (2) HRH-vaccination rate relationships differ by cadre of health worker, with physician and health officers exhibiting significant relationships that mirror those for aggregate density, while nurse/midwife densities are not consistently significant; (3) HRH densities bear stronger relationships with vaccination coverage among more rural provinces, compared to those with higher population densities.</p> <p>Conclusion</p> <p>We find evidence of relationships between HRH densities and vaccination rates even at Turkey's relatively elevated levels of each. At the same time, variations in results between different empirical models suggest that this relationship is complex, affected by other factors that occurred during the study period, and warrants further investigation to verify our findings. We hypothesize that the introduction of certain health-sector policies governing terms of HRH employment affected incentives to provide vaccinations and therefore relationships between HRH densities and vaccination rates. National-level changes experienced during the study period – such as a severe financial crisis – may also have affected and/or been associated with the HRH-vaccination rate link. While our findings therefore suggest that the size of a health workforce may be associated with service provision at a relatively elevated level of development, they also indicate that focusing on per capita levels of HRH may be of limited value in understanding performance in service provision. In both Turkey and elsewhere, further investigation is needed to corroborate our results as well as gain deeper understanding into relationships between health worker densities and service provision.</p

Endothelial Neuropilin Disruption in Mice Causes DiGeorge Syndrome-Like Malformations via Mechanisms Distinct to Those Caused by Loss of Tbx1

The spectrum of human congenital malformations known as DiGeorge syndrome (DGS) is replicated in mice by mutation of Tbx1. Vegfa has been proposed as a modifier of DGS, based in part on the occurrence of comparable phenotypes in Tbx1 and Vegfa mutant mice. Many additional genes have been shown to cause DGS-like phenotypes in mice when mutated; these generally intersect in some manner with Tbx1, and therefore impact the same developmental processes in which Tbx1 itself is involved. In this study, using Tie2Cre, we show that endothelial-specific mutation of the gene encoding the VEGFA coreceptor neuropilin-1 (Nrp1) also replicates the most prominent terminal phenotypes that typify DGS. However, the developmental etiologies of these defects are fundamentally different from those caused by absence of TBX1. In Tie2Cre/Nrp1 mutants, initial pharyngeal organization is normal but subsequent pharyngeal organ growth is impaired, second heart field differentiation is normal but cardiac outflow tract cushion organization is distorted, neural crest cell migration is normal, and palatal mesenchyme proliferation is impaired with no change in apoptosis. Our results demonstrate that impairment of VEGF-dependent endothelial pathways leads to a spectrum of DiGeorge syndrome-type malformations, through processes that are distinguishable from those controlled by Tbx1

Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with congenital and late-onset features. Testing for the genomic content of copy number variations (CNVs) may help elucidate the 22q11.2 deletion mechanism and the variable clinical expression of the syndrome including the high (25%) risk for schizophrenia. We used genome-wide microarrays to assess CNV content and the parental origin of 22q11.2 deletions in a cohort of 100 adults with 22q11.2DS (44 with schizophrenia) and controls. 22q11.2DS subjects with schizophrenia failed to exhibit de novo CNVs or any excess of novel inherited CNVs outside the 22q11.2 region. There were no significant effects of parental origin of the 22q11.2 deletion, deletion length, parental age or family history on expression of schizophrenia. There was no evidence for a general increase of de novo CNVs in 22q11.2DS. A novel finding was the relative paucity of males with de novo 22q11.2 deletions of paternal origin (P = 0.019). The Y chromosome may play a mediating role in the mechanism of 22q11.2 deletion events during spermatogenesis, resulting in the previously observed excess of maternal de novo 22q11.2 deletions. Hemizygosity of the 22q11.2 region appears to be the major CNV-related risk factor for schizophrenia in 22q11.2DS. The results reinforce the need for further efforts to identify specific molecular mechanisms underlying this expression and to identify the 1% of patients with schizophrenia who carry 22q11.2 deletions

A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review

<p>Abstract</p> <p>Background</p> <p>Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date.</p> <p>Methods</p> <p>We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents.</p> <p>Results</p> <p>Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial <it>de novo </it>1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping.</p> <p>Conclusion</p> <p>The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors.</p

Varicella: epidemiological aspects and vaccination coverage in the Veneto Region

<p>Abstract</p> <p>Background</p> <p>With the control of many infections through national vaccination programmes, varicella is currently the most widespread preventable childhood disease in industrialized nations. In 2005 varicella vaccination was added to the Veneto Region routine immunization schedule for all children at 14 months of age and 12 year-old susceptible adolescents through an active and a free of charge offer. To evaluate parameters at the start of the programme, we conducted a study to describe the epidemiology of varicella infection and coverage rates for varicella vaccine in the Veneto Region (North-East Italy).</p> <p>Methods</p> <p>We examined incidence rates and median age of case patients in the Veneto Region for 2000-2007 period using two data sources: the mandatory notification of infections diseases and the Italian Paediatric Sentinel Surveillance System of Vaccine Preventable Diseases. Corrected coverage rates were calculated from data supplied by the Public Health and Screening Section of the Regional Department for Prevention.</p> <p>Results</p> <p>In the Veneto Region from 2000 to 2007, a total of 99,351 varicella cases were reported through mandatory notifications, mostly in children under 15 years of age. The overall standardised annual incidence ranged from 2.0 to 3.3 per 1,000 population, with fluctuations from year to year. The analysis by geographic area showed a similar monthly incidence rate in Italy and in the Veneto Region. The vaccination average adherence rate was 8.2% in 2004 cohort, 63.5% in 2005 cohort and 86.5% in 2006 cohort. Corrected coverage rates were 8.1% in 2004 cohort, 59.9% in 2005 cohort and 70.0% in 2006 cohort, respectively.</p> <p>Conclusion</p> <p>Data from passive and active surveillance systems confirm that varicella is a common disease which each year affects a large proportion of the population, mainly children. Uptake of the varicella vaccination programme was strikingly good with average coverage rates of about 70% after only 3 years. Sustained implementation of existing vaccine policies is needed to warrant any significant reduction of varicella incidence in the Veneto Region. Continued surveillance will be important to monitor the impact of the recently introduced mass vaccination policy.</p

Detection of small RNAs in Bordetella pertussis and identification of a novel repeated genetic element

Background: Small bacterial RNAs (sRNAs) have been shown to participate in the regulation of gene expression and have been identified in numerous prokaryotic species. Some of them are involved in the regulation of virulence in pathogenic bacteria. So far, little is known about sRNAs in Bordetella, and only very few sRNAs have been identified in the genome of Bordetella pertussis, the causative agent of whooping cough. Results: An in silico approach was used to predict sRNAs genes in intergenic regions of the B. pertussis genome. The genome sequences of B. pertussis, Bordetella parapertussis, Bordetella bronchiseptica and Bordetella avium were compared using a Blast, and significant hits were analyzed using RNAz. Twenty-three candidate regions were obtained, including regions encoding the already documented 6S RNA, and the GCVT and FMN riboswitches. The existence of sRNAs was verified by Northern blot analyses, and transcripts were detected for 13 out of the 20 additional candidates. These new sRNAs were named Bordetella pertussis RNAs, bpr. The expression of 4 of them differed between the early, exponential and late growth phases, and one of them, bprJ2, was found to be under the control of BvgA/BvgS two-component regulatory system of Bordetella virulence. A phylogenetic study of the bprJ sequence revealed a novel, so far undocumented repeat of ~90 bp, found in numerous copies in the Bordetella genomes and in that of other Betaproteobacteria. This repeat exhibits certain features of mobil

Crk and CrkL adaptor proteins: networks for physiological and pathological signaling

The Crk adaptor proteins (Crk and CrkL) constitute an integral part of a network of essential signal transduction pathways in humans and other organisms that act as major convergence points in tyrosine kinase signaling. Crk proteins integrate signals from a wide variety of sources, including growth factors, extracellular matrix molecules, bacterial pathogens, and apoptotic cells. Mounting evidence indicates that dysregulation of Crk proteins is associated with human diseases, including cancer and susceptibility to pathogen infections. Recent structural work has identified new and unusual insights into the regulation of Crk proteins, providing a rationale for how Crk can sense diverse signals and produce a myriad of biological responses