Genetic factors in non-syndromic congenital heart malformations.

The genetic defect in most patients with non-syndromic congenital heart malformations (CHM) is unknown, although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs sporadically. The multifactorial inheritance hypothesis of common diseases suggesting that the cumulative effect of multiple genetic and environmental risk factors leads to disease, might also apply for CHM.

Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

Background: The VACTERL association is a non-random association of congenital defects with an unknown aetiology in the majority of patients.

Methods: A male newborn is reported with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of this patient overlaps with that of X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced.

Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations.

Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported.

Autosomal dominant syndrome of mental retardation, hypotelorism, and cleft palate resembling Schilbach-Rott syndrome.

We present a family segregating for an autosomal dominant syndrome of hypotelorism, cleft palate/uvula, high-arched palate and mild mental retardation. Although these findings may suggest a form of holoprosencephaly, no holoprosencephaly was found on MRI of the proposita. Results of genetic studies were normal including FISH for deletion of 22q11, karyotype analysis, fragile X testing, high-resolution comparative genomic hybridization and SEPT9, SHH mutation analysis.

Cornelia de lange syndrome: a recognizable fetal phenotype.

We describe a fetus with Cornelia de Lange syndrome diagnosed after termination of pregnancy at 21 weeks. Prenatally, growth retardation, diaphragmatic hernia, cystic hygroma and a right hand with only three rays were diagnosed by ultrasound in the second trimester of pregnancy. Postnatal magnetic resonance imaging confirmed the prenatal findings, and the presence of the typical dysmorphic features led to the diagnosis of Cornelia de Lange syndrome.

Inhibition of dendritic cell maturation by group A Streptococcus.

Background: Exposure to group A Streptococcus (GAS) has been shown to induce maturation of dendritic cells (DC).

Methods: To identify bacterial determinants that modulate DC activation in response to GAS infection, we analyzed the induction of maturation in human monocyte-derived DC following exposure to GAS clinical isolates.

Results: Unexpectedly, only 6 of 24 GAS strains tested induced surface expression of major histocompatibility complex class II and costimulatory molecules CD80 and CD83 to levels consistent with DC maturation.

Influence of haptic guidance in learning a novel visuomotor task.

In (re)learning of movements, haptic guidance can be used to direct the needed adaptations in motor control. Haptic guidance influences the main driving factors of motor adaptation, execution error, and control effort in different ways. Human-control effort is dissipated in the interactions that occur during haptic guidance.

First locus for primary pulmonary vein stenosis maps to chromosome 2q.

Aims: Primary pulmonary vein stenosis (PVS) is a rare cardiac abnormality that exhibits a high morbidity and mortality rate. The disease is characterized by obstruction of the pulmonary venous blood flow owing to congenital hypoplasia of individual extra-pulmonary veins. We describe a consanguineous Turkish family with four affected siblings with primary PVS in association with prenatal lymphatic abnormalities.

Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years.

CsrRS regulates group B Streptococcus virulence gene expression in response to environmental pH: a new perspective on vaccine development.

To identify factors involved in the response of group B streptococci (GBS) to environmental pH, we performed a comparative global gene expression analysis of GBS at acidic and neutral pHs. We found that the transcription of 317 genes was increased at pH 5.5 relative to that at pH 7.

Oculoglandular syndrome caused by Yersinia pseudotuberculosis in a dairy goat.

An outbreak of ocular disease in a herd of housed dairy goats was characterized by severe granulomatous conjunctivitis and ipsilateral parotid and submandibular lymphadenopathy. In one case submitted for post-mortem examination, Yersinia pseudotuberculosis was isolated from both the conjunctiva and submandibular lymph node. Histopathological examination identified severe chronic active suppurative and lymphoplasmacytic conjunctivitis and suppurative and necrotizing lymphadenitis associated with bacteria of yersinial morphology.

Autosomal dominant inheritance of cardiac valves anomalies in two families: extended spectrum of left-ventricular outflow tract obstruction.

Only a limited number of families with clear monogenic inheritance of nonsyndromic forms of congenital valve defects have been described. We describe two multiplex pedigrees with a similar nonsyndromic form of heart valve anomalies that segregate as an autosomal dominant condition. The first family is a three-generation pedigree with 10 family members affected with congenital defects of the cardiac valves, including six patients with aortic stenosis and/or aortic regurgitation.

Induction of group A Streptococcus virulence by a human antimicrobial peptide.

Group A streptococci (Streptococcus pyogenes or GAS) freshly isolated from individuals with streptococcal sore throat or invasive ("flesh-eating") infection often grow as mucoid colonies on primary culture but lose this colony appearance after laboratory passage. The mucoid phenotype is due to abundant production of the hyaluronic acid capsular polysaccharide, a key virulence determinant associated with severe GAS infections. These observations suggest that signal(s) from the human host trigger increased production of capsule and perhaps other virulence factors during infection.

PerR confers phagocytic killing resistance and allows pharyngeal colonization by group A Streptococcus.

The peroxide response transcriptional regulator, PerR, is thought to contribute to virulence of group A Streptococcus (GAS); however, the specific mechanism through which it enhances adaptation for survival in the human host remains unknown. Here, we identify a critical role of PerR-regulated gene expression in GAS phagocytosis resistance and in virulence during pharyngeal infection. Deletion of perR in M-type 3 strain 003Sm was associated with reduced resistance to phagocytic killing in human blood and by murine macrophages in vitro.

Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

Background: Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation.

Methods: TCF4 mutational analysis was performed in 117 patients with PTHS-like features.

Results: In total, 16 novel mutations were identified.

Mutations in sarcomeric protein genes not only lead to cardiomyopathy but also to congenital cardiovascular malformations.

Noncompaction of the ventricular myocardium is associated with de novo mutation in the beta-myosin heavy chain gene Budde et al. (2007) PLoS ONE 2: e1362 Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy Xin et al. (2007) Am J Med Genet 143: 2662-2667 Alpha-cardiac actin mutations produce atrial septal defects Matsson et al.

Effects of the new fixed-subsidy system for prosthetic dental care in Germany: results of descriptive research.

Objective: To detail how provision of prosthetic treatments altered in Germany following changes in legislation on 1 January 2005, enacted as part of the health system modernisation law (GMG). This legislation directs health insurance companies to fix subsidies on dental prostheses based on diagnostic findings. The goal of the reform is to ensure that insured persons can select any medically recognised form of prosthetic treatment without losing their right to a health insurance subsidy.

Functional characterisation of the TSC1-TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3.

Burden and economic cost of group A streptococcal pharyngitis.

Objective: Our aim was to describe the morbidity, medical costs, and nonmedical costs associated with group A streptococcal pharyngitis in school-aged children.

Methods: Our study population included parents of children diagnosed as having group A streptococcal pharyngitis at 2 pediatric practice sites in the Boston, Massachusetts, metropolitan area. Telephone interviews were conducted with parents of eligible children, who were asked questions about health care utilization, medications, and time missed from work or school, for calculation of medical and nonmedical costs associated with illness.