Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review

The new 2017 diagnostic criteria for hypermobile Ehlers–Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.     

Four new adenosine deaminase mutations,altering a zinc-binding histidine,two conserved alanines,and a 5′ splice site

Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + 1G→A) in the 5′ splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme-associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in a helix 4 and β strand 4 of the α/β barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.© 1995 wiley-Liss, Inc.     

Refined genetic mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.3 and evidence of linkage disequilibrium in European families

Chronic distal spinal muscular atrophy (Chronic DSMA, MIM (*)607088) is a rare autosomal recessive disorder characterized by a progressive motor weakness and muscular atrophy, predominating in the distal parts of the limbs. A form of Chronic DSMA gene has been previously mapped to chromosome 11q13 in the 10.3 cM interval defined by loci D11S1889 and D11S1321. By linkage analysis in 12 European Chronic DSMA families, we showed that a disease gene maps to chromosome 11q13.3 (Z(max)=6.66 at theta=0.00 at the DSM4 locus) and suggested that this condition is genetically homogeneous. Recombination events allowed us to reduce the genetic interval to a 2.6 cM region, telomeric to the IGHMBP2 gene, excluding this gene as the disease causing gene in Chronic DSMA. Moreover, partial linkage disequilibrium was found between three rare alleles at loci D11S1369, DSM4 and D11S4184 and the mutant chromosome in European patients. Analysis of the markers at these loci strongly suggests that most Chronic DSMA chromosomes are derived from a single ancestor. Refinement of the Chronic DSMA locus will hopefully allow to test candidate genes and lead to identification of the disease-causing mutations.     

Long-term culture of neurones from human cerebral cortex in serum-free medium

A method for cultivating neurones from the fetal human central nervous system in the absence of glial cells is described. Brain cells from 15-18-week-old human fetuses are plated on polylysine-coated surfaces and grown in a serum-free hormonally-defined medium. About 98% of the cells were identified as neurones using tetanus toxin as a marker. The cultures survive for up to 7 weeks and develop an extremely complex network of neurites.     

HIV infection among patients in U.S. acute care hospitals. Strategies for the counseling and testing of the hospital patients. The Hospital HIV Surveillance Group.

BACKGROUND. Routine, voluntary testing of hospital patients for the human immunodeficiency virus (HIV) has been proposed in order to identify those with early HIV infection in a setting where there is ready access to counseling, appropriate clinical referral, evaluation, and therapy. We studied the pattern of HIV infection among patients in 20 U.S. hospitals, in order to evaluate possible national strategies for the routine, voluntary HIV counseling and testing of hospital patients. METHODS. Blood specimens remaining after clinical use from a systematically selected sample of patients at 20 hospitals in 15 U.S. cities were tested anonymously for antibody to HIV type 1 (HIV-1). Multivariate regression was used to determine which variables best predicted HIV seroprevalence in individual hospitals. Using these data, we estimated the number of HIV-positive patients in all U.S. hospitals and considered the efficiency of routine counseling and testing in different subgroups of patients and hospitals. RESULTS. From September 1989 through October 1991, 9286 of 195,829 specimens (4.7 percent) were positive for HIV-1 in the 20 hospitals. The seroprevalence of HIV at these institutions ranged from 0.2 percent to 14.2 percent. Among HIV-positive patients, 32 percent had symptomatic HIV infection or the acquired immunodeficiency syndrome (AIDS) at the time of admission or evaluation. In the 20 hospitals, HIV seroprevalence was 10.4 times (95 percent confidence interval, 8.8 to 12.0) the AIDS-diagnosis rate (the annual number of patients with new diagnoses of AIDS per 1000 discharges in 1990). In a multivariate model that included 13 hospital-specific variables, only the AIDS-diagnosis rate was associated with the hospital-specific HIV-seroprevalence rate (P less than 0.001). Using these data and the AIDS-diagnosis rates for all U.S. acute care hospitals, we estimated that 225,000 HIV-positive persons were hospitalized (95 percent confidence interval, 190,000 to 260,000) in all 5558 such hospitals in 1990, including 163,000 persons presenting with conditions other than HIV or AIDS (95 percent confidence interval, 130,000 to 196,000). In 1990, in 593 U.S. hospitals with AIDS-diagnosis rates of 1.0 or more per 1000 discharges, HIV testing of patients 15 to 54 years old (3 million patients, or 12.0 percent of all patients in U.S. acute care hospitals) would have identified an estimated 68 percent of all HIV-positive patients (110,000 patients) who were admitted with conditions other than symptomatic HIV infection or AIDS. CONCLUSIONS. We estimate that about 225,000 HIV-positive persons were hospitalized in 1990, of whom only one third were admitted for symptomatic HIV infection or AIDS. Routine, voluntary HIV testing of patients 15 to 54 years old in hospitals with 1 or more patients with newly diagnosed AIDS per 1000 discharges per year could potentially have identified as many as 110,000 patients with HIV infection that was previously unrecognized.     

The mouse genome

The house mouse has been used as a privileged model organism since the early days of genetics, and the numerous experiments made with this small mammal have regularly contributed to enrich our knowledge of mammalian biology and pathology, ranging from embryonic development to metabolic disease, histocompatibility, immunology, behavior, and cancer. Over the past two decades, a number of large-scale integrated and concerted projects have been undertaken that will probably open a new era in the genetics of the species. The sequencing of the genome, which will allow researchers to make comparisons with other mammals and identify regions conserved by evolution, is probably the most important project, but many other initiatives, such as the massive production of point or chromosomal mutations associated with comprehensive and standardized phenotyping of the mutant phenotypes, will help annotation of the approximately 25,000 genes packed in the mouse genome. In the same way, and as another consequence of the sequencing, the discovery of many single nucleotide polymorphisms and the development of new tools and resources, like the Collaborative Cross, will contribute to the development of modern quantitative genetics. It is clear that mouse genetics has changed dramatically over the last 10-15 years and its future looks promising.