The spirit of Dakar: a call for action on malaria.
Explore the source record for details and available documents.
Africa↗
Biomedical subjects
M Schwartz
Publications and source records attributed to M Schwartz.
Segregation of a familial balanced (12;10) insertion resulting in Dup(10)(q21.2q22.1) and Del(10)(q21.2q22.1) in first cousins.
An interchromosomal insertion in 3 generations of a family was ascertained through two developmentally delayed first cousins. Cytogenetic analysis using G-banding and chromosome painting showed an apparently balanced direct insertion of chromosome 10 material into chromosome 12, ins(12;10)(q15;q21.2q22.1), in the mothers and grandfather of these children. The proposita inherited only the derivative 10 chromosome, resulting in deletion of 10q21.2 --> 22.1 while her cousin inherited only the derivative 12, resulting in duplication of 10q21.2 --> 22.1. A comparison of the proposita with published deletion cases suggests a pattern of anomalies attributable to deletion of the 10q21 --> q22 region: developmental delay, hypotonia, a heart murmur, telecanthus, broad nasal root and ear abnormalities. This is the first report of a nontandem duplication of the 10q21 --> q22 region. The phenotype of the cousin with the duplication does not overlap greatly with published tandem 10q duplications. Finally, this report reaffirms the importance of obtaining family studies of patients with interstitial chromosomal abnormalities.
Chromosomes, Human, Pair 10↗
Expression of GTP-dependent and GTP-independent tissue-type transglutaminase in cytokine-treated rat brain astrocytes.
Tissue-type transglutaminases (TGases) were recently shown to exert dual enzymatic activities; they catalyze the posttranslational modification of proteins by transamidation, and they also act as guanosine triphosphatase (GTPase). Here we show that a tissue-type TGase is expressed in rat brain astrocytes in vitro, and is induced by the inflammation-associated cytokines interleukin-1beta and to a lesser extent by tumor necrosis factor-alpha. Induction is accompanied by overexpression and appearance of an additional shorter clone, which does not contain the long 3'-untranslated region and encodes for a novel TGase enzyme whose C terminus lacks a site that affects the enzyme's interaction with guanosine triphosphate (GTP). Expression of two clones revealed that the long form is inhibited noncompetitively by GTP, but the short form significantly less so. The different affinities for GTP may account for the difference in physiological function between these two enzymes.
Amino Acid Sequence↗
Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene.
Choroideremia (CHM) is an X-linked recessive eye disease that results from mutations involving the Rab escort protein-1 (REP-1) gene. In 18 patients deletions of different sizes have been found. Two females suffering from CHM were reported to have translocations that disrupt the REP-1 gene. In 22 patients, small mutations have been identified. Interestingly, these are all nonsense, frameshift or splice-site mutations; with one possible exception, missense mutations have not been found. This comprises all the known mutations in the disease.
Adaptor Proteins, Signal Transducing↗
Serine for glycine substitutions in the C-terminal third of the alpha 1(I) chain of collagen I in five patients with nonlethal osteogenesis imperfecta.
Explore the source record for details and available documents.
Adolescent↗
(G586V) substitutions in the alpha 1 and alpha 2 chains of collagen I: effect of alpha-chain stoichiometry on the phenotype of osteogenesis imperfecta?
Osteogenesis imperfecta (OI) is a congenital disease of connective tissue, most often caused by single amino acid substitutions of glycine residues within the triple helical region of collagen I. Collagen I consists of two alpha 1 chains and one alpha 2 chain. Thus, a substitution in the alpha 1(I) chain is thought to affect the function of the collagen molecule more than would a similar substitution in the alpha 2(I) chain, thereby causing more severe OI. Theoretically this hypothesis may be tested by comparing patients with identical substitutions in different alpha-chains. We present a Gly586Val substitution in the alpha 1(I) chain, and compare our findings to those resulting from Gly586Val substitutions in the alpha 2(I) chain (Forlino et al., 1994; Bateman et al., 1991). Our proband had lethal OI type II. Most alpha-chains of collagen I produced by his cultured fibroblasts were overmodified. The denaturation temperature of the abnormal collagen was 1.5 degrees C below normal. Cyanogen bromide cleavage and subsequent sequencing revealed a G-to-T base substitution at nucleotide 2420 of COL1A1, resulting in a Gly586Val substitution. The collagen findings were almost identical to those reported by Bateman et al. (1991) and Forlino et al. (1994), but the clinical phenotypes were different: the patients with the alpha 2(I) substitutions had OI type IV and III and not the lethal OI type II of our proband. It is known that identical biochemical aberrations in the same chain may have different phenotypic effects, both within families and between non-related patients. This must be taken into account in our cautious proposal that substitutions in the alpha 1(I) chain may have more serious consequences than similar substitutions in the alpha 2(I) chain.
Cells, Cultured↗
X-linked adrenal hypoplasia in a large Greenlandic family. Detection of a missense mutation (N4401) in the DAX-1 gene; implication for genetic counselling and carrier diagnosis.
X-linked congenital adrenal hypoplasia (AHC) is a developmental disorder of the human adrenal gland that results in profound hormonal deficiencies, which are lethal if untreated. Hypogonadotropic hypogonadism (HHG) is frequently associated with this disorder. The gene (DAX-1) responsible for the disease has recently been isolated. It encodes a protein with large similarity to members of the nuclear hormone receptor superfamily. Several different mutations in this gene have been found in patients suffering from AHC. We have identified a missense mutation (N440I) in three patients with AHC and HHG, all belonging to a large Greenlandic family. A total of 42 individuals has been tested for this mutation. We have diagnosed 10 women as carriers, and have excluded 22 women with a 25-50% risk from being carriers, emphasizing the rapid impact of molecular genetic techniques.
Adolescent↗
Mutations in the gene encoding 21-hydroxylase detected by solid-phase minisequencing.
We have developed an assay based on solid-phase minisequencing to screen for the following seven point mutations in the gene CYP21 encoding 21-hydroxylase: Pro30Leu, I2-splice, Ile172Asn, Cluster-E6, Val281Leu, Gln318Stop, and Arg356Trp. 5'-Biotinylated PCR products of CYP21 are bound to streptavidin-coated microtiter wells, where the minisequencing reaction takes place after denaturation of DNA. Depending on the sequence investigated, one specific 3H-labelled deoxyribonucleotide is incorporated to extend a detection primer. By using an appropriate set of detection primers, it is possible to screen the gene for several mutations within the same PCR amplificate. This fast and reliable method very clearly distinguishes between DNA from homozygous mutant, heterozygous, and normal individuals and is well suited for routine diagnosis of patients with 21-hydroxylase deficiency and for carrier detection.
Amino Acid Sequence↗
Do gravid women with preeclampsia-eclampsia ever require plasmapheresis?
Explore the source record for details and available documents.
Diagnosis, Differential↗
The Society of Thoracic Surgeons National Cardiac Surgery Database: current risk assessment.
BACKGROUND: The Society of Thoracic Surgeons National Cardiac Surgery Database has recently completed gathering patient data from 1990 through 1994. Using information from more than 300,000 patients undergoing isolated coronary artery bypass grafting in this period, new risk models of operative mortality were developed. METHODS: Logistic regression analysis was used to develop a risk model for each calendar year. A standard "training set/test set" approach was used for each model. RESULTS: Five validation techniques were used to evaluate the reliability of the risk models. All models were found to predict operative mortality with good accuracy in this population. CONCLUSIONS: The new risk models for isolated coronary artery bypass operations serve as reliable predictors of operative mortality for the most recent harvest of patient data from The Society of Thoracic Surgeons National Cardiac Surgery Database.
Coronary Artery Bypass↗
Adolescent suicidal behaviours: a population-based study of risk.
BACKGROUND: Reports of adolescent suicidal behaviour have generally derived from clinical settings but population-based studies are likely to provide a clearer epidemiological view. METHODS: Non-fatal suicidal behaviours were studied in 1699 Australian 15- to 16-year-old secondary school students at 44 schools in the state of Victoria, Australia. Self-reported episodes of self-harm were characterized using items from the Beck Suicide Intent Scale. RESULTS: The 12 month weighted prevalence estimate for deliberate self-harm was 5.1%. The commonest forms were self-laceration (1.7%), self-poisoning (1.5%) and deliberate recklessness (1.8%). Self-poisoning and self-laceration were commoner in girls. The prevalence of 'true suicide attempts' was 0.2%. Most self-harmers did not perceive death as likely, plan self-harming episodes at length or inform others of the episodes. Psychiatric morbidity had the strongest association with self-harm, an association which held for all subtypes. Antisocial behaviour and substance abuse were associated with self-harm in girls but not boys. Sexual activity was independently associated with self-harm in both genders. CONCLUSIONS: Deliberate self-harm was common but the great majority of episodes were not 'true suicide attempts'. It is, therefore, possible that attributable mortality and morbidity may be greater in self-harmers without definite suicidal intent.
Adolescent↗
Radiosurgery for arteriovenous malformations: the University of Toronto experience.
BACKGROUND: From July 1989 to February 1996, 130 patients underwent stereotactic radiosurgery. We report the results of the first 50 patients eligible for a minimum of three years of follow-up. METHODS: Twenty women and 30 men, (mean age: 37.5 years) were treated by dynamic rotation on a 6 MV linear accelerator. Prior treatment was embolization in seventeen, surgery in three and embolization and surgery in six. All had DSA and enhanced CT scanning, while some had MRI. Forty-seven treatments used a single isodose. Restricting eloquent normal tissue to 15 Gy, margin doses (at 50-90% isodose) were 12 Gy (one patient); 15 Gy (sixteen patients); 20 Gy (31 patients); 25 Gy (two patients). Maximum diameters were: < 1.5 cm (12 patients); < 2.0 cm (nine patients); < 2.5 cm (twelve patients); < 3.0 cm (thirteen patients; 3.0 cm (four patients). RESULTS: Forty-five patients were evaluable at three years, with thirty-nine having angiography. Twenty-five had angiographically confirmed obliterations; two had parenchymal AVMs obliterated but with residual dural components; four had MRI evidence of obliteration (refused angiography). One patient acutely had a seizure; one patient (with hemorrhages, resection, and embolizations preceding two applications of radiosurgery, separated by 3.5 years) had worsening of memory. CONCLUSIONS: Our uncorrected (five patients unevaluable at three years) and corrected angiographically confirmed obliteration rates are 54% and 60% respectively. Our follow-up (98% accounting of cohort; 78% angiographic rate) and explicit derivation of denominators help delineate the efficacy of radiosurgery at these doses.
Adult↗
Prediction of obliteration of arteriovenous malformations after radiosurgery: the obliteration prediction index.
OBJECTIVE: To describe the response to single dose photon stereotactic radiosurgery of arteriovenous malformations (AVMs) so that the probability of success or failure of treatment may be predicted for the individual patient. METHOD: The obliteration prediction index (OPI) was calculated for AVMs by dividing the marginal dose of radiation in Gray (Gy) by the lesion diameter in centimetres in cohorts of 42 patients treated with the modified linear accelerator at Toronto-Sunnybrook Regional Cancer Centre and 394 patients treated with the gamma unit at the Royal Hallamshire Hospital, Sheffield, United Kingdom. Patients were grouped into ranges by OPI and the proportion of success and failure was calculated for each group. An exponential function [P = 1-A.e(-B.OPI)] was fitted to the data by the least squares method. RESULTS: Despite systematic differences in radiation treatment, that is, marginal doses of 15 and 20 Gy in Toronto and most Sheffield patients with a marginal dose of 25 Gy, the resultant data points exhibited similar behaviour. CONCLUSION: The function [P = 1-A.e(-B.OPI)] partly describes the biological effect of radiation and is independent of the radiation device used. Radiosurgery centres can use this model to facilitate predictions of successful treatment for individual patients.
Follow-Up Studies↗
Compound heterozygosity in the glutaryl-CoA dehydrogenase gene with R227P mutation in one allele is associated with no or very low free glutarate excretion.
Explore the source record for details and available documents.
Alleles↗
NMDA-receptor antagonist protects neurons from secondary degeneration after partial optic nerve crush.
Damage resulting from a partial acute lesion of white matter in the central nervous system (CNS) gradually spreads also to neurons that escaped the primary injury, resulting in their degeneration. Such spreading has been referred to as secondary degeneration. In order to demonstrate that this degeneration is indeed secondary to that caused by the acute insult, as well as to investigate the mechanism underlying the spread of damage and ways in which to protect neurons from such damage, we have proposed the use of partial lesion of the rodent optic nerve as a model. In this model we examined whether an antagonist of a receptor-mediated channel, shown to be beneficial in gray matter lesions, can protect neurons from undergoing secondary degeneration following white matter lesion. A well-calibrated partial crush lesion inflicted on the optic nerve of adult rats was immediately followed by a single intraperitoneal injection of the N-methyl-D-aspartate receptor antagonist, MK-801 (1 mg/kg). Protection of neurons from secondary degeneration was assessed by retrograde labeling and by measurement of the visual evoked potential (VEP) response to light. Two weeks after the injury, the mean number of neurons that were still intact was about threefold higher in the MK-801-treated group than in the saline-treated control group, indicating a treatment-induced protection of neurons that had escaped primary injury. A positive VEP response to light was obtained in 90% of the MK-801 treated animals and in only 50% of injured controls. The questions regarding whether the secondary degeneration of initially spared neurons starts in their cell bodies or in their axons, and consequently the identity of the primary site of their protection by MK-801, are discussed in relation to the absence of N-methyl-D-aspartate receptors on nerve fibers. The present findings may have implications for both acute and chronic injuries of the CNS.
Analysis of Variance↗
Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy.
In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and cBCD541 respectively) on normal and SMA chromosomes. This has enabled us to establish haplotypes with regard to SMN and cBCD541, and estimate their frequencies, on both types of chromosomes. Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of cBCD541. We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of cBCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of cBCD541 were identified. We could not confirm the hypothesis that the presence of more copies of cBCD541 is correlated to a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of cBCD541 were found to differ significantly between normal and SMA chromosomes. This distribution can be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. This first report of a direct haplotype analysis of SMN and cBCD541 should help clarify the role of cBCD541 in the pathogenesis of SMA.
Centromere↗
A comparison of donor and recipient site sensation in free tissue reconstruction of the oral cavity.
In patients who undergo oral cavity reconstruction, loss of sensation plays a vital role in producing disturbances in postoperative oral function. Microsurgical techniques have provided a method of addressing this deficit through the use of sensate cutaneous free flaps in which microneural anastomoses are performed between a sensory nerve supplying the flap, and a recipient nerve in the head and neck. The purpose of this study was to compare the cutaneous sensation of the radial forearm flap and lateral arm flap donor sites, the two most commonly used intraoral sensate flaps. For comparison, sensation was also determined in five intraoral sites: the tip of tongue, lateral tongue, cheek, gingiva, and hard palate. Sensation was evaluated at the two potential donor sites in 66 random subjects using static and moving two-point discrimination, thermal sensation differences, and Semmes-Weinstein monofilament pressures. In the same subjects Semmes-Weinstein monofilament pressures were used to evaluate intraoral sensation. Information was recorded on age, sex, smoking and denture status. All four sensory evaluations demonstrated that the lateral arm flap donor site was more sensitive than the radial forearm donor site. Thermal sensitivity differentials (0.52 vs. 0.40 degrees C, p < 0.001), static two-point discrimination (15.4 vs. 15.0 mm, p < 0.2), moving two-point discrimination (5.8 vs. 4.8 mm, p < 0.03), and Semmes-Weinstein monofilament pressures (5.10 vs. 4.08 g per square millimeter, p < 0.001) all indicated a more sensitive lateral arm flap donor site. Older subjects had significantly decreased sensation at both donor sites based on static two-point discrimination and Semmes-Weinstein monofilament testing. No sex differences were noted. Based on Semmes-Weinstein monofilament testing in the mouth, the tip of the tongue is the most sensitive area (2.26 g per square millimeter), followed by the hard palate (3.60 g per square millimeter), the lateral tongue (4.08 g per square millimeter), the cheek (4.77 g per square millimeter), and the gingiva (8.06 g per square millimeter). Smokers had significantly decreased sensation at the tip of tongue and hard palate. Denture wearers had significantly diminished sensation in all intraoral locations except the lateral tongue. Older patients had significantly diminished sensation at all intraoral sites. No sex differences were noted. The lateral arm flap donor site is a more sensitive region than the radial forearm flap donor site. However, the lateral arm flap donor site is less sensitive than the tip of tongue and hard palate, while the radial forearm flap donor site is less sensitive than the tip of tongue, hard palate, lateral tongue, and cheek. This suggests that for certain locations, intraoral sensate flaps may require measures such as sensory reeducation protocols to approach normal recipient site sensation.
Adult↗