An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome

OBJECTIVE: To investigate genetic susceptibility to recurrent fevers, generalized severe myalgia, and migratory erythema in an Israeli Arab child with no family history of similar disease. METHODS: DNA sequencing of exons 1-6 of the TNFRSF1A gene (formerly TNFR1) was performed in the patient and his parents to determine the presence of the autosomal-dominant tumor necrosis factor receptor-associated periodic syndrome (TRAPS); informative markers spanning the TNFRSF1A locus were used to genotype all available members of the patient's family. The TNFRSF1A gene was subsequently screened in 69 healthy Arab controls and 96 Caucasian controls. Formal forensic paternity testing was performed on the child. RESULTS: We found a de novo missense mutation in exon 3 of the TNFRSF1A gene, involving a novel C-->T transition encoding a Cys70Arg (C70R) variant, in the Israeli Arab patient. Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded. This mutation was not present in the parents or siblings, or among the 69 healthy Arab controls. However, another TNFRSF1A variant, Pro46Lys (P46L), was present in 1 of the Arab controls. CONCLUSION: We have identified a TNFRSF1A mutation associated with periodic fever in an Arab patient, and a TNFRSF1A variant, which is variably pathogenic in Caucasians, in an Arab control. This is the first report of a de novo mutation in periodic fevers in general, and also of TRAPS in the Arab population. These findings demonstrate the need to include TRAPS in the differential diagnosis of recurrent fevers in this population.     

Norethisterone treatment to control timing of the IVF cycle

The use of norethisterone to control the timing of the precedingmenstrual cycle and in consequence the timing of the in-vitrofertilization (IVF) cycle has been evaluated in a therapeuticIVF programme in which oocyte recovery was limited to 2 dayseach week. A consecutive series of 181 cycles after norethisteroneand 29 untreated controls were compared. Menstruation occurred2– 3 days after norethisterone as planned in 82% of patientsoverall and in 87% of patients whose menstrual cycle lengthvaried by no more than 2 days about the median. Norethisteronetreatment did not significantly affect the outcome of IVF treatmentcompared with the controls in respect to cycles abandoned (12versus 0%, respectively), peak follicular diameter (mean 18.1mm versus 18.3 mm 48 h before laparoscopy), oocyte recoveryrate (4.6 versus 4.5 per patient), oocyte morphology (63% versus52% mature), or fertilization rate (72 versus 65% of matureoocytes). Clinical pregnancies were too few for comparison (rates27 versus 9% per laparoscopy) but the overall rate (23%) indicatedeffectiveness of the methods. Prior norethisterone treatmentappears to be an effective and useful means of controlling thetiming of the oocyte recovery in IVF treatment.     

Exclusion of the familial Mediterranean fever locus as a susceptibility region for autosomal dominant familial Hibernian fever.

Autosomal dominant periodic fevers constitute a range of syndromes characterised by recurrent attacks of fever and abdominal pain. Familial Hibernian fever (FHF) has been described in only one United Kingdom based family, but two other Irish families have been found with similar clinical features. FHF resembles familial Mediterranean fever (FMF) in several clinical features, but the mode of inheritance of FHF is dominant whereas FMF is recessive. We have investigated whether autosomal dominant periodic fevers, in particular FHF, map to the FMF susceptibility locus (MEFV) on chromosome 16p13.3. We have used informative microsatellite markers flanking this locus to genotype members of the three families mentioned above. Two point and multipoint lod scores definitively excluded linkage to MEFV in the two larger families. A haplotype study confirmed these findings, indicating that FHF is genotypically as well as phenotypically distinct from FMF.     

Fragile X chromosome: clinical and cytogenetic studies on cases from seven families.

Results of detailed clinical and cytogenetic studies on 13 mentally retarded males and two heterozygous females (one normal and one retarded) are reported. Reference is made to technical modifications to enhance the incidence of expression of the fragile X. The addition of excess methionine to the fibroblast cultures (final concentration of 115 mg/l medium TC 199) was found to be particularly valuable, increasing the incidence of expression up to four-fold, and enabling the demonstration of the fragile X in fibroblasts when it could not be demonstrated in blood cultures in at least one case. Studies on replication patterns of the X chromosomes in the two heterozygous females showed that the fragile X chromosome was genetically active in a significantly greater proportion of cells (74%) in the mentally retarded female, whereas the normal X was active in a similar proportion (72%) in the carrier with normal intelligence.     

A population-based study of anxiety as a precursor for depression in childhood and adolescence

Background  

Anxiety and depression co-occur in children and adolescents with anxiety commonly preceding depression. Although there is some evidence to suggest that the association between early anxiety and later depression is explained by a shared genetic aetiology, the contribution of environmental factors is less well examined and it is unknown whether anxiety itself is a phenotypic risk factor for later depression. These explanations of the association between early anxiety and later depression were evaluated.     

Medicare managed care and the need for quality measurement

With the increasing penetration of managed care as health insurance coverage for Medicare beneficiaries, accountability for quality of care is being demanded. While HEDIS 2.5 has become the standard for assessing the performance of health plans in caring for their commercial members, no such standard exists for Medicare enrollees. U.S. Quality Algorithms, the performance measurement subsidiary of U.S. Healthcare, has developed the Medicare Quality Report Card as a tool for performance assessment and quality improvement. This article describes how the measures of quality important to the Medicare population were chosen, how the measures were calculated, and how they have been used in programs designed to improve the quality of care for U.S. Healthcare Medicare members.     

Safe method for isolation of prion protein and diagnosis of Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease (CJD) is a fatal progressive infectious encephalopathy of humans characterized by spongiform degeneration of the brain. Detection of protease-resistant low molecular weight proteins, referred to as ‘prions’, in the brain is essential for diagnosis. Protease-based methods for prion detection are problematic due to variable susceptibility of prion proteins to proteinase-K digestion. Since CJD brain samples are infectious at all stages of the prion extraction process, we set out to develop a laboratory safe method for prion purification. We lysed the tissues with guanidine thiocyanate followed by phenol extraction of the proteins. Western blotting using prion-specific MAB 3F4 revealed primarily low molecular weight unglycosylated prion (UGP) bands in all CJD cases (19) while the predominant banding in all normal brains (14) represented glycosylated prion (GP). Density readings of the blots revealed the UGP/GP ratio to be significantly different in CJD versus normal brains, with an inverse UGP/GP ratio in CJD. Using this method, we discovered one previously undiagnosed CJD case when we screened 19 brains from the Louisiana State University Alzheimer disease brain bank. Our method is a safe and reliable way of detecting abnormal prion proteins (p < 0.0001) and is adaptable to both diagnostic and research laboratories.