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K Morgan

Publications and source records attributed to K Morgan.

At least 163 records · Page 9Linked to original sources
PubMed1995

Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs.

The candidate region for spinal muscular atrophy (SMA) has been defined as a 750 kb interval on 5q13. In this study, we performed allelic association studies in 154 German SMA families with the multicopy markers Ag1-CA (D5S1556); C212 (D5F149S1/S2) and correlated genotype data with deletion of candidate genes. Both multicopy markers recognize 0-3 alleles pro chromosome. Deletions were detected for all copies of the markers Ag1-CA (C272) and C212 in 13 of 88 (15%) type I SMA patients and three of 48 (6%) type II patients. In all informative cases, the deletion was inherited from one parent. In two further cases (one type I and one type III SMA), de novo deletions of only one copy of Ag1-CA and C212 were found. In both cases the patients were homozygously deleted for the survival motor neuron (SMN) gene (exons 7 and 8) but only the type I SMA patient was deleted for the neuronal apoptosis inhibitory protein (NAIP) gene (exons 5 and 6). A third case (type II SMA) showed de novo deletion of SMN, but not of Ag1-CA, C212 and NAIP. Specific alleles of Ag1-CA and C212 showed significant association with SMA, particularly in type I SMA. When the number of marker copies defines genotypes, 1,1 (one allele on each chromosome) is found to be increased in type I SMA (50%) and 1,2 (one allele on one chromosome and two alleles on the other one) in type II SMA (60%). The 2,2 genotype (two alleles on each chromosome) was found in 4% of type I and II patients. By comparison, pooled normal genotype frequencies were 20, 44 and 36%, respectively. These results suggest a strong correlation between genotype and severity of disease. Based on these data we propose a model which indicates that type I SMA patients are composed of two severe alleles, type II of a mild and a severe, and type III of two mild alleles. Correlation of Ag1-CA genotype with deletion of the XS2G3/NAIP genes indicates that most patients with a deletion have a 1,1 genotype. Owing to the physical proximity of these markers, we propose that a large deletion occurs on type I SMA chromosomes that removes DNA between C212 and XS2G3/NAIP and that type II SMA results from compound heterozygosity for mild (small deletion) and severe mutations.

Alleles↗
PubMed1995

Use of videocinematography to assess morphological qualities of conventionally cultured and cocultured embryos.

Videocinematography and image analysis procedures were utilized to evaluate the effect of conventional and coculture methodologies on morphological parameters in human embryos derived from in-vitro fertilization (IVF). Following 24-30 h of in-vitro development, cocultured embryos had more acceptable morphological features and less fragmentation present than embryos cultured in medium alone. Cocultured embryos were more advanced at the time of replacement when compared with conventionally cultured embryos. Zona pellucida variation (> or = 20%) also occurred more frequently in cocultured embryos. The morphological characteristic most enhanced after coculture was blastomere expansion. Patients who became pregnant across both culture treatments had a higher proportion of morphologically normal embryos replaced than patients who failed to achieve an ongoing pregnancy. Clinical pregnancy rate for patients following coculture was 49%, which was greater (P < 0.05) than the 29% detected for patients with embryos in the conventional culture group.

Animals↗
PubMed1995

The effect of ambient temperature and saline loading on changes in plasma and urine electrolytes (Na+ and K+) following exercise.

In this study 4 Standardbred geldings (age 3-8 years, weight 431-531 kg) were used. The horses were fed a hay and oat diet and the total sodium intake was about 32 mg/kg bwt (690 mmol/day). An exercise test (ET) which contained 3 phases was performed. Phase I consisted of 23.5 min of mainly submaximal exercise, Phase 2 of 2 h of box rest and Phase 3 of 26 min of exercise including an intensive trot over 2600 m at 90% of VO2max. The ET was repeated 3 times: the first at 20 degrees C (30-40% RH), the second at 35 degrees C (30-40% RH) and the third at 35 degrees C (30-40% RH) after a nasogastric administration of 10 litres of 0.9% NaCl solution (35 degrees C and saline load [+ F]). Blood samples were taken before, during and after exercise. To measure fluid loss, horses were weighted before and after the ETs. Total urine output was determined 2 days before the ET (control), throughout the exercise day and for 2 days after (recovery days). There were an increase in blood and rectal temperatures after both exercise phases and a significant higher blood temperature was observed after exercise at 35 degrees C compared to 20 degrees C. The horses lost about 2% of their bodyweight (bwt) during the ETs. The plasma protein concentration increased during the exercise phases and remained elevated 2 h after exercise at both 20 degrees C and 35 degrees C, even though the horses had free access to water. The plasma protein concentration had returned to pre-exercise levels 26 h post exercise. After the saline load, total plasma protein concentration fell and increased only at the end of each exercise phase. The major mechanism regulating fluid balance after exercise seemed to be a lowered urinary excretion since water intake did not increase significantly. Urinary potassium excretion was positive throughout the experiment. During control days there was a positive sodium balance, shown by a urinary sodium excretion of 260 mmol/day. Post exercise urinary sodium excretion fell and remained very low until the second day of recovery, except after saline loading. In addition, plasma sodium was lowered 26 h after exercise at 35 degrees C. This study shows that with a daily salt intake of 38 g it will take several days to compensate for a sodium loss caused by sweating. Therefore, it is recommended that extra salt be given during the exercise day. In the experimental situation, pre-exercise saline supplementation was beneficial since the recovery time was shortened.

Animals↗
PubMed1995

The hospital admissions study in England: are there alternatives to emergency hospital admission?

STUDY OBJECTIVE: To assess the potential for substituting alternative forms of care for admission to an acute hospital in particular groups of patients. DESIGN: A screening tool, the intensity-severity-discharge review system with adult criteria (ISD-A), developed for hospital utilisation review in the USA, was used in a cohort of hospital admissions to identify a group of patients who could potentially have been treated outside the acute hospital. These patients were further assessed by a panel of general practitioners (GPs) to determine the most appropriate alternative form of care. A cost analysis was performed on the results obtained. SETTING: General medicine and geriatric specialties in one acute hospital in the south western region. PATIENTS: Patients comprised a sample of 701 admitted to general medical and geriatric specialties. MAIN RESULTS: The screening tool identified 19.7% of admissions for whom there was potential for treatment outside the acute hospital. Assessment by the GP panel reduced this potential to between 9.8% and 15.0% of emergency admissions. The alternatives most frequently identified as "most appropriate" were the community hospital/GP bed and the urgent outpatient assessment (within either 24 or 48 hours). Potential resource savings based on the average cost were relatively small. This potential seemed to be greater for the alternative of the urgent outpatient assessment. CONCLUSIONS: Potential exists for treating a proportion of patients in lower intensity alternatives to the acute hospital. If this potential were exploited few resource savings would occur.

Cohort Studies↗
PubMed1995

Molecular biology of diabetes insipidus.

The identification, characterization, and mutational analysis of three different genes, namely the prepro-arginine-vasopressin-neurophysin II gene (prepro-AVP-NPII), the arginine-vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin-2, AQP2), provide the basis for our understanding of three different hereditary forms of diabetes insipidus: autosomal dominant neurogenic diabetes insipidus, X-linked nephrogenic diabetes insipidus, and autosomal recessive nephrogenic diabetes insipidus, respectively. These advances provide diagnostic tools for physicians caring for these patients.

Amino Acid Sequence↗
PubMed1995

Symptomatic fluid retention in patients on continuous peritoneal dialysis.

The clinical features, pathogenesis, management, prognosis, and predictors of symptomatic fluid gain (SFR) were analyzed for 71 episodes occurring in 66 patients on continuous peritoneal dialysis, 94.4% on continuous ambulatory peritoneal dialysis (CAPD) and 5.6% on continuous cycling peritoneal dialysis. Compared with a control group of 149 CAPD patients, the SFR group had a higher percentage of diabetics (64 versus 46%) and a higher frequency of noncompliance with fluid restriction (76 versus 22%), salt restriction (74 versus 23%), and performance of dialysis (30 versus 7%) (all at P < or = 0.015). Peripheral edema (100%), pulmonary congestion (80%), pleural effusions (76%), and systolic (83%) and diastolic (66%) hypertension were the most common manifestations of SFR. The annual hospitalization rate for SFR was 4.1 +/- 5.8 days per patient. SFR resulted in the discontinuation of CAPD in 10 patients and death in 1 patient. Serum sodium concentration was not different between dry and maximal weight in the SFR group. Thirty-eight (58%) of SFR and 61 (41%) of control patients were evaluated by peritoneal equilibration tests (PET). SFR patients had lower PET drain volume (2.08 +/- 0.47 versus 2.54 +/- 0.23 L) and a higher frequency of high peritoneal solute transport (32.2 versus 2.4%). In this group, logistic regression identified dietary noncompliance, low PET drain volume, and young age as independent predictors of SFR. Response to management and preventive measures was inconsistent. The best results were obtained by the use of short dwell exchanges with hypertonic dialysate in compliant patients with high peritoneal solute transport. SFR has serious consequences in CAPD. (ABSTRACT TRUNCATED AT 250 WORDS)

Diet, Sodium-Restricted↗
PubMed1995

Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome.

The fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Fragile X premutations are not associated with any clinical phenotype but are at high risk of expanding to full mutations causing the disease when they are transmitted by a carrier woman. There is no reliable estimate of the prevalence of women who are carriers of fragile X premutations. We have screened 10,624 unselected women by Southern blot for the presence of FMR1 premutation alleles and have confirmed their size by PCR analysis. We found 41 carriers of alleles with 55-101 CGG repeats, a prevalence of 1/259 women (95% confidence interval 1/373-1/198). Thirty percent of these alleles carry an inferred haplotype that corresponds to the most frequent haplotype found in fragile X males and may indeed constitute premutations associated with a significant risk of expansion on transmission by carrier women. We identified another inferred haplotype that is rare in both normal and fragile X chromosomes but that is present on 13 (57%) of 23 chromosomes carrying FMR1 alleles with 53-64 CGG repeats. This suggests either (1) that this haplotype may be stable or (2) that the associated premutation-size alleles have not yet reached equilibrium in this population and that the incidence of fragile X syndrome may increase in the future.

Alleles↗
PubMed1995

Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene.

The most common mycobacterial disease in humans is tuberculosis, and there is evidence for genetic factors in susceptibility to tuberculosis. In the mouse, the Bcg gene controls macrophage priming for activation and is a major gene for susceptibility to infection with mycobacteria. A candidate gene for Bcg was identified by positional cloning and was designated "natural resistance-associated macrophage protein gene" (Nramp1), and the human homologue (NRAMP1) has recently been cloned. Here we report on (1) the physical mapping of NRAMP1 close to VIL in chromosome region 2q35 by PCR analysis of somatic cell hybrids and YAC cloning and (2) the identification of nine sequence variants in NRAMP1. Of the four variants in the coding region, there were two missense mutations and two silent substitutions. The missense mutations were a conservative alanine-to-valine substitution at codon 318 in exon 9 and an aspartic acid-to-asparagine substitution at codon 543 in the predicted cytoplasmic tail of the NRAMP1 protein. A microsatellite was located in the immediate 5' region of the gene, three variants were in introns, and one variant was located in the 3' UTR. The allele frequencies of each of the nine variants were determined in DNA samples of 60 Caucasians and 20 Asians. In addition, we have physically linked two highly polymorphic microsatellite markers, D2S104 and D2S173, to NRAMP1 on a 1.5-Mb YAC contig. These molecular markers will be useful to assess the role of NRAMP1 is susceptibility to tuberculosis and other macrophage-mediated diseases.

Alleles↗
PubMed1994

Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites.

The mouse chromosome 1 locus Bcg (Ity, Lsh) controls the capacity of the tissue macrophage to restrict the replication of antigenically unrelated intracellular parasites and therefore determines the natural resistance (BCG-R, dominant) or susceptibility (BCG-S, recessive) of inbred mouse strains to infection with diverse pathogens, including several Mycobacterium species, Salmonella typhimurium, and Leishmania donovani. We have used a positional cloning strategy based on genetic and physical mapping, YAC cloning, and exon trapping to isolate a candidate gene for Bcg (Nramp) that encodes a predicted macrophage-specific transport protein. We have analyzed a total of 27 inbred mouse strains of BCG-R and BCG-S phenotypes for the presence of nucleotide sequence variations within the coding portion of Nramp and have carried out haplotype typing of the corresponding chromosome 1 region in these mice, using 11 additional polymorphic markers mapping in the immediate vicinity of Nramp. cDNA cloning and nucleotide sequencing identified 5 nucleotide sequence variations within Nramp in the inbred strains; while 4 of these represented silent sequence polymorphisms, one G to A substitution at nucleotide position 783 resulted in the non-conservative replacement of Gly105 to Asp105 within the second predicted transmembrane domain (TM2) of the Nramp protein. An absolute association of this allelic variation and Bcg phenotype was observed in the 20 BCG-R strains (Gly105) and 7 BCG-S strains (Asp105) tested. Moreover, sequence analysis of the corresponding region of the Nramp gene from distantly related species indicated strong amino acid sequence conservation of TM2, including an invariant glycine at position 105. Haplotype mapping using sequence polymorphism identified within Nramp and additional RFLPs and SSLPs from the region revealed that although the 20 BCG-R strains analyzed showed diverse allelic combinations for these markers, the 7 BCG-S strains tested share a conserved core haplotype of 2.2 Mb overlapping and including Nramp. Taken together, these results suggest that (1) Gly105 is the wildtype form of Nramp and that the nonconservative substitution to Asp105 underlies the BCG-S phenotype, and (2) Bcg8 alleles carry the same Gly105-->Asp105 mutation and are identical by descent.

Alleles↗
PubMed1994

Tau immunoreactivity and SDS solubility of two populations of paired helical filaments that differ in morphology.

To further understand the processes that lead to the formation of neurofibrillary tangles from paired helical filaments (PHF) in Alzheimer brains, we studied two morphologically distinct fractions of PHF separated on sucrose density gradient. In a fraction with mostly short and non-aggregated PHF, the majority of filaments could be solubilized in SDS. In a fraction containing primarily PHF aggregated into clusters or bundles, sometimes resembling neurofibrillary tangles, filaments were less soluble in SDS. Immunogold labelling with a panel of tau-immunoreactive antibodies demonstrated that N-terminal epitopes of tau were preserved in the short filaments, but were reduced or absent in aggregated filaments. In contrast, C-terminal epitopes were present in both fractions. Furthermore, the accessibility of the microtubule-binding domain to immunolabelling was markedly impaired in short and non-aggregated filaments compared to aggregated filaments. These results are consistent with proteolytic degradation of the N-terminal epitopes and preservation of the C-terminal epitopes and the microtubule-binding domain of tau in the aggregated filaments. Partial proteolysis may be involved in the generation of aggregated PHF in neurofibrillary tangles.

Aged↗
PubMed1994

In vivo measurement of tumor blood oxygenation by near-infrared spectroscopy: immediate effects of pentobarbital overdose or carmustine treatment.

Near-infrared (NIR) spectroscopy was used to measure blood oxygen saturation (SO2) in vivo, in normal rat brain and in subcutaneously-implanted rat 9L gliosarcoma. Changes in cranial and tumor blood SO2 were measured during lethal pentobarbital overdose. After sacrifice, SO2 of cranial blood fell rapidly to a mean of 5.0% of the pre-sacrifice values, whereas SO2 of tumor blood stabilized at a mean of 72.4% of the pre-sacrifice values. This suggests that oxygen consumption by tumor is very low compared to brain. Cranial blood had a higher SO2 than tumor blood before sacrifice (p = 0.03), and a lower SO2 after sacrifice (p = 0.02). The magnitude of the change in SO2 after sacrifice was greater in normal brain than in tumor (p = 0.02), showing that brain tissue uses a greater proportion of the oxygen in ischemic blood than does tumor tissue. To determine the effect of carmustine (BCNU) treatment on tumor and cranial blood SO2, we compared BCNU-treated rats with sham-treated rats. Continuous NIR measurements before and immediately following treatment (ie. over 30-60 min) showed that tumor blood SO2 tended to increase after BCNU treatment, whereas SO2 tended to decrease following sham-treatment. The difference in SO2 between treated and control tumors was significant at 60 min (p = 0.02). Thus BCNU treatment can potentially result in immediate increases in tumor oxygenation. The increase in treated tumor blood SO2 occurred despite the fact that there was no change in cranial blood SO2 even at day 4 following treatment. Tumor blood SO2 was inversely correlated with tumor size (p = 0.001), confirming that blood is more poorly oxygenated in large tumors.

Animals↗
PubMed1994

Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.

Women who carry mutations in the BRCA1 gene on chromosome 17q have an 85% lifetime risk of breast cancer, and a 60% risk of ovarian cancer. We have identified BRCA1 mutations in 12 of 30 (40%) Canadian families with breast and/or ovarian cancer, including six of the eight families (75%) that contained two cases of early-onset breast cancer and two cases of ovarian cancer. Six frameshift mutations account for all 12 mutant alleles, including nucleotide insertions (two mutations) and deletions (four mutations). Four independent families carried the same 1 basepair (bp) insertion mutation in codon 1755 and four other families shared a 2 bp deletion mutation in codons 22-23. These families were not known to be related, but haplotype analysis suggests that the carriers of each of these mutations have common ancestors.

Amino Acid Sequence↗
PubMed1994

Linkage disequilibrium analysis of childhood-onset spinal muscular atrophy (SMA) in the French-Canadian population.

Spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. The gene responsible for childhood SMA has been mapped to the q11.2-q13.3 region of chromosome 5. We have extended our linkage studies of SMA in the French-Canadian population to include microsatellite markers at the D5S125, D5S351, D5S435, JK53CA1/2 and MAP1B loci. These markers span about 4 cM of the SMA candidate region. We observed significant evidence for linkage between SMA and all the markers tested. The analysis of recombinant chromosomes provide evidence for the following genetic order: D5S125-D5S435-MAP1B-3'-JK53CA1/2 and places D5S351 proximal to JK53CA1/2. Furthermore, we confirm the current localization of the SMA gene distal to D5S435. Finally, we provide demonstration of significant linkage disequilibrium between childhood-onset SMA and four of the five marker loci, D5S125, D5S435, D5S351 and JK53CA1/2. Analysis of SMA-region haplotypes suggests that there may be a predominant SMA allele that is present on about 17% of SMA chromosomes in this sample of the French-Canadian population. We conclude that the observed linkage disequilibrium is likely due to genetic drift among regions of Quebec, consistent with this population's early history.

Age of Onset↗