A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.     

Exercise improves biomarkers of health and stress in animals fed ad libitum

Voluntary and forced exercise decrease morbidity and mortality in laboratory animals. Caloric restriction has similar effects on health and unique benefits on life span. Nonetheless, in most experiments, animals do not have access to physical activity and are fed ad libitum (AL). We hypothesized that with regular access to either unlimited running wheel exercise (EX) or limited physical activity (PA), key biomarkers of health would be enhanced enough to counter some consequences of a sedentary AL lifestyle. This 16-month study compared body weight, tumor number and size, tissue lesions, oxidative stress, and reactive stress in (1) sedentary animals with no access to physical activity (SED); (2) animals with access to hour-long, twice weekly activity in a large box (PA); and (3) animals with access every other day to a running wheel (EX). At the end of the study, EX body weight was 8-9% lower than PA and SED. In addition, EX had no kidney lesions versus 50% in PA and SED, and had smaller tumor size (10+/-2 vs. 14+/-4 and 30+/-4 mm). Exhaustive exercise lowered glutathione/oxidized glutathione ratio in EX and PA, but in SED, the ratio was depressed even in resting animals. In all treatments, prolactin (PRL) levels were lower in resting animals than in acutely exercised animals. In conclusion, EX had the most favorable health biomarkers while SED had the least. PA did not confer gross health benefits different than the SED group, but was biochemically more similar to EX animals.     

Control of spread of Methicillin Resistant Staphylococcus aureus (MRSA) in Burns Units

Results of four years' studies from a number of hospitals in Kenya have shown that nosocomial infections in burns units are due to Methicillin Resistant Staphylococcus aureus (MRSA). Through chromosomal DNA and plasmid DNA, the stain is highly resistant to sulphonamide ointment and other antibiotics. 90% of patients admitted in burns units get colonized or infected with MRSA. The strain prolongs the duration of patients in hospitals. The burns degenerate to second and third degree burns, thereby necessitating skin grafting. The environment has been found to be contaminated with this strain with some staff members having chronic throat infections. Minocycline was found to be effective in treating the infected staff members. Cleaning this environment with Sodium dichloroisocyanurate (precepts)/Sodium hypochlorite (JIK) reduced drastically the mechanical transmission of bacteria in the units. The duration of stay of the patient was reduced. This shows that MRSA which is spread in government and private hospitals can cheaply be controlled by the proper use of disinfectants, antiseptics, and use of effective antibiotics when necessary.     

Teratoma and medulloblastoma of the cerebellum: a case

The majority of intracranial teratoma are localized in pineal and sellar regions. In cerebellum, the teratoma is quite rare, the association with medulloblastoma is exceptional and was differentiated from medullomyoblastoma. We report one case of 5 years old boy with intracranial hypertension for 3 months. The cerebral computed tomography showed a tumor in the fourth ventricle. The histologic study of surgical specimens found a proliferation of component of medulloblastoma adjacent to mature teratoma with smooth and striated muscles, chondroid component, adipose tissue and epithelial elements. Our objective is to discuss the diagnosis, the hitogenesis and the prognosis of this tumor.     

Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson’s disease

Rare monogenic forms of Parkinson's disease (PD) are promoting our understanding of the molecular pathways involved in the common, non-Mendelian forms of the disease. Here, we focus on PARK7, an autosomal recessive form of early-onset parkinsonism caused by mutations in the DJ-1 gene. We first review the genetics of this form and the rapidly expanding knowledge about the structure and biochemical properties of the DJ-1 protein. We also discuss how DJ-1 dysfunction might lead to neurodegeneration, and the implications of this novel piece of information for the pathogenesis of the common PD forms. Although much work remains to be done to clarify the biology of DJ-1, its proposed activity as a molecular chaperone and/or as oxidative sensor appear intriguing in the light of the current theories on the pathogenesis of PD.     

Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Sfax-Tunisia (1993-1998)

Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Sfax-Tunisia (1993-1998). The choice of antimicrobial therapy for the treatment of bacteremia is often empirical and based on the knowledge of susceptibility profiles of the most common bacteria causing such infections. This study determines the bacterial etiology of bacteremic episodes and antimicrobial susceptibility patterns recorded at a teaching hospital, from January 1993 to December 1998. We collected 2979 strains responsible for bacteremia. Gram negative bacteria were predominant (60%). The organisms recovered most frequently were Staphylococcus aureus (18.9%), Escherichia coli (14.7%), Klebsiella pneumoniae (14%) and Pseudomonas aeruginosa (7.6%). The incidence of resistance to methicillin were 17.4% for Staphylococcus aureus and 26.8% for coagulase negative Staphylococcus. No resistance to glycopeptides was observed among the enterococci and staphylococci studied. 27.7% of enterobacteriaceae were resistant to third generation cephalosporins. Imipenem was the most active agent against gram negative bacteria. To carry out a surveillance of bacteremic episodes occurring at every hospital, it is necessary to provide valuable information which should be the basis for effective empiric therapy.     

The gene for hereditary multiple exostoses does not map to the Langer-Giedion region (8q23-q24).

Hereditary multiple exostoses is a dominantly inherited skeletal disorder which alters enchondral bone during growth and is characterised by exostoses of the juxta-epiphyseal regions. Using polymorphic DNA probes, we have been able to exclude the disease gene from close proximity to the 8q24.1 region where a dominant syndrome with multiple exostoses, the trichorhinophalangeal syndrome type II (TRP II, Langer-Giedion syndrome, MIM 15025), has been previously localised (pairwise linkage Z = -8.96 at theta = 0 with probe L48 at locus D8S51). Multipoint linkage analysis using probes L48, L24, and L1 consistently excluded the HME gene from a large area of the distal long arm of chromosome 8, spanning the smallest region of overlap assigned to the TRP II gene. These studies support the clinical view that HME and TRP II are distinct entities.     

Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers

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Receptors for neurohypophyseal hormones along the rat nephron: 125I-labelled d(CH2)5[Tyr(Me)2, Thr4, Orn8, Tyr-NH 2 9 ] vasotocin binding in microdissected tubules

A microassay was developed to measure the binding of the labelled monoiodinated analogue [1-(mercapto-,-cyclopentamethylenepropionic acid), 2-O-mithyltyrosine, 4-threonine, 8-ornithine, 9-¹²⁵I-tyrosylamide]vasotocin ¹²⁵I-d(CH₂)₅[Tyr (Me)², Thr⁴, Tyr-NH ₂ ⁹ ]OVT to isolated nephron segments microdissected from collagenase-treated rat kidneys. When determined using 1.7 nM labelled ligand at 4° C, specific binding sites (expressed at 10^–18 mol ¹²⁵I-d(CH₂)₅[Tyr (Me)², Thr⁴, Tyr-NH ₂ ⁹ ]OVT bound/mm tubule length) were found in medullary thick ascending limbs (MTAL), 1.67±0.49; cortical thick ascending limbs, 2.20±0.80; cortical collecting ducts, 2.39±0.86; outer medullary collecting ducts (OMCD), 2.54±0.53 and inner medullary collecting ducts, 5.33±0.40, whereas no specific binding could be detected in glomeruli and proximal tubules. Specific ¹²⁵I-d(CH₂)₅[Tyr (Me)², Thr⁴, Tyr-NH ₂ ⁹ ]OVT binding to OMCD was saturable with incubation time and reversible after elimination of free labelled ligand (the association and dissociation rate constants at 4° C were 1.06×10⁷ M^–1 min^–1 and 1.95×10^–2 min^–1 respectively). The stereospecificity of MTAL and OMCD binding sites was assessed in competitive experiments revealing the following recognition pattern for a series of eight vasopressin analogues:ddAVP>AVP>d(CH₂)₅-[Tyr (Me)², Thr⁴, Tyr-NH ₂ ⁹ ]OVT=AVT=OT>d(CH₂)₅[Tyr(Me)²]AVP=[Thr⁴, Gly⁷]OT>[Phe², Orn⁸]VT, whereas pharmacological concentrations of insulin and glucagon did not impair radioligand binding. These results indicate that the detected labelled binding sites might correspond mainly to physiological V₂ vasopressin receptors.