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Biomedical subjects

A Marshall

Publications and source records attributed to A Marshall.

At least 19 recordsLinked to original sources
PubMed2025

Multi-Polygenic prediction of Frailty and its Trajectories highlights Chronic Pain, Rheumatoid Arthritis, and Educational Attainment pathways.

Frailty is a complex ageing-related trait with a growing evidence base for genetic influence. While a single polygenic score (PGS) for frailty has shown predictive value, few studies have examined the joint effect of multiple genetic risks. This study used a multi-polygenic score (MPS) approach to evaluate the combined and relative contributions of 26 PGSs to frailty, measured via the Frailty Index (FI), in two UK cohorts aged 65 and older: the English Longitudinal Study of Ageing (ELSA) and the Lothian Birth Cohort 1936 (LBC1936). Using elastic net regression with repeated cross-validation, we identified chronic pain and depressive symptoms PGSs as the strongest risk predictors of cross-sectional frailty status, while educational attainment, parental longevity, and rheumatoid arthritis PGSs were protective. Compared to single PGS models, MPS models provided improved prediction of frailty levels, explaining up to 4.7% of variance in frailty status - an improvement over the best single PGS (2.5%). To assess whether PGSs also predicted longitudinal frailty progression, we applied generalized additive mixed models (GAMMs) to model age-related trajectories. In ELSA, five PGSs (chronic pain, depressive symptoms, rheumatoid arthritis, educational attainment, and parental death) significantly interacted with age, influencing the rate of frailty change. In LBC1936, consistent though weaker effects were observed for chronic pain and education PGSs. These findings show that polygenic liability shapes both frailty levels and trajectories in later life. Our results support the use of multi-trait genomic models to improve risk prediction and understanding of frailty's complex aetiology.

Journal Article↗
PubMed1992

Antihypertensive and hemodynamic effects of calcium channel blockade with isradipine after acute exercise.

In a randomized, double-blind, placebo-controlled, crossover study with two 4-week treatment periods, we investigated the effects of calcium channel blockade with 5 mg slow release oral isradipine on postexercise blood pressure and systemic hemodynamics (echocardiography) in ten hypertensive patients. The results show that the combination of exercise and isradipine treatment exerts additive antihypertensive effects in hypertensive patients after exercise. The antihypertensive effect of prior exercise with placebo was related to a significant fall in total peripheral resistance. After exercise during isradipine treatment, total peripheral resistance was lower than with placebo. Thus, isradipine exerts an additional antihypertensive effect during the postexercise period, which appears to be mediated by a further reduction of total peripheral resistance.

Adult↗
PubMed1992

Inactivation of wild-type and rad mutant Caenorhabditis elegans by 8-methoxypsoralen and near ultraviolet radiation.

Survival of wild-type and four radiation-sensitive (rad) mutants of the nematode Caenorhabditis elegans was determined after near-UV irradiation in the presence of 8-methoxypsoralen (8-MOP). Three sets of inactivation profiles were generated for each strain by irradiating synchronous populations of either early embryos, late embryos or first-stage larvae (L1s). Late embryos were consistently the most sensitive. Curiously, none of the four rad mutants were even moderately hypersensitive. Split-dose experiments indicated that DNA-DNA crosslinks were primarily responsible for lethality. Crosslink induction and repair were determined using two different assays. In both cases, little if any repair was observed in wild-type. This lack of repair thus explains why the rad mutants were not hypersensitive to 8-MOP photoinactivation. Since early embryos undergo extensive cell cycling, their resistance to 8-MOP photoinactivation suggests that replication is highly refractory to both monoadducts and crosslinks, as has been demonstrated previously for UV radiation-induced photoproducts (Hartman et al., 1991, Mutat. Res., 255, pp. 163-173).

Animals↗
PubMed1992

Postexercise reflex control of forearm vascular resistance during calcium antagonism with slow-release oral isradipine.

In untreated hypertensive patients, blood pressure is decreased during the hours that follow a single bout of exercise, but the mechanisms involved are as yet unknown. As antihypertensive chemotherapy may interfere with cardiovascular regulation, we investigated the effects of calcium antagonism with isradipine (slow-release oral formulation, SRO) on postexercise blood pressure and on the reflex control of forearm vascular resistance in patients with mild-to-moderate hypertension. The results show that isradipine SRO exerted an additional blood pressure-lowering effect after exercise that was associated with a further decrease in forearm vascular resistance. The reflex changes in forearm vascular resistance were potentiated after exercise, but were not further affected by isradipine SRO. Therefore, isradipine SRO does not interfere with the cardiovascular mechanisms that act to decrease blood pressure after exercise in patients who have hypertension.

Administration, Oral↗
PubMed1989

The DNF15S2 locus at 3p21 is transcribed in normal lung and small cell lung cancer.

Small cell lung cancer (SCLC) has been associated with a deletion of the short arm of chromosome 3. One SCLC cell line, H748, has an interstitial deletion of chromosome 3p and shows allele loss for the DNF15S2 locus detected by the probe lambda H3. Conservation of DNF15S2 sequences in mouse indicated that this human genomic fragment may contain coding sequences. Screening of a normal lung cDNA library with chromosome 3-specific fragments of the lambda H3 probe resulted in the isolation of 18 positive clones. The cDNA clones detect an additional DNA polymorphism that is in linkage disequilibrium with the HindIII polymorphism of the DNF15S2 locus. Sequence analysis indicated that the DNF15S2 locus could potentially code for a previously unreported protein of 67 kDa which has 26 cysteine residues. DNF15S2 is part of the coding region of a 3.3-kb mRNA expressed in lung. Northern analysis indicated that this mRNA was not detectable in one of five SCLC lines. This SCLC line, H128, also lacks the enzyme aminoacylase 1.

Amino Acid Sequence↗
PubMed1988

Rat clusterin isolated from primary Sertoli cell-enriched culture medium is sulfated glycoprotein-2 (SGP-2).

Clusterin, a glycoprotein originally isolated from ram rete testis fluid, is a dimer composed of monomers with non-identical NH2-terminal amino acid sequences. In view of its possible role in cell-cell interactions in the seminiferous epithelium, we sought to identify such a protein in the rat. Using the bioassay developed for the ovine protein, rat clusterin was purified to apparent homogeneity by HPLC from primary Sertoli cell-enriched culture media. This protein is also a heterodimer consisting of monomers of Mr 43,000 (alpha) and Mr 35,000 (beta). NH2-Terminal amino acid sequence analysis indicated that the alpha subunit has a sequence of NH2-SLMPLSHYGPLSFHNMFQPFFDMIHQAQQA and the beta subunit, NH2-EQEFSDNELQELSTQGSRYVNKEIQNAVQG. These two subunits show marked similarity with the corresponding subunits of ram clusterin isolated from rete testis fluid. Using an antibody against the alpha subunit of rat clusterin, a cDNA clone was isolated from a rat testicular lambda gt11 cDNA library. Analyses of the amino acid sequence derived from the isolated rat clusterin cDNA and of the NH2-terminal amino acid sequences indicate that rat clusterin is identical to a Sertoli cell glycoprotein previously designated sulfated glycoprotein-2.

Amino Acid Sequence↗
PubMed1988

Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively.

cDNAs encoding human proteins C and S have been used to screen a panel of mouse-human somatic cell hybrids to determine the chromosomal location of their respective genes. The gene for human protein C is located on chromosome 2, whereas that for protein S is located on chromosome 3. Analysis of human genomic DNA restriction endonuclease fragmentation patterns suggests that the human protein S gene is greater than 40 kb in size and contains a minimum of 11 introns.

Animals↗
PubMed1988

Adult polyglucosan body disease (APBD).

Three patients aged 63, 63 and 74 years had various combinations of progressive lower and upper motor neuron dysfunction, sensory loss, urinary incontinence and dementia. Postmortem examinations in two cases showed moderate cerebral and spinal atrophy, ill-defined areas of incomplete myelin loss in white matter and small necrotic foci in the white matter of gyri, around the basal ganglia and near the dentate nuclei. The main microscopic abnormality was a massive accumulation of PAS-positive polyglucosan bodies (PB) of various sizes and shapes in the cerebral hemispheres, brainstem, cerebellum, spinal cord, nerve roots and nerves. These PB were found in the processes of nerve cells and astrocytes, but not in their perikarya. Similar PB were present in peripheral nerves and in the lungs, heart, liver and kidneys. In the third case, a nerve biopsy revealed several, unusually large, PB in the axons of myelinated fibers. These clinicopathologic features are consistent with adult polyglucosan body disease (APBD) and are distinctive from other conditions in which PB may accumulate. Twelve similar cases have been reported previously. The diagnosis can be made by nerve biopsy. The pathogenesis of APBD is not known, but it may be a polysaccharide storage disease.

Aged↗
PubMed1988

Restriction fragment length polymorphism studies show consistent loss of chromosome 3p alleles in small cell lung cancer patients' tumors.

Previous karyotypic analysis of human small cell lung cancer cell lines has demonstrated a consistent deletion of a portion of the short arm of chromosome 3(p14-23). DNA prepared from tumors and normal tissues obtained from 24 small cell lung cancer and two extrapulmonary small cell cancer patients was hybridized to four probes that detect restriction fragment length polymorphisms within chromosome region 3p14-21. Of the 25 patients who were heterozygous for at least one marker in this region in the DNA from normal tissue, 23 (92%) showed an unequivocal loss of heterozygosity in the DNA from their tumor tissue. From these studies we conclude that loss of alleles from the short arm of chromosome 3 is a consistent finding in unselected small cell lung cancer patients' tumor DNA.

Adult↗
PubMed1987

Assignment of the lactotransferrin gene to human chromosome 3 and to mouse chromosome 9.

Lactotransferrin (LTF), a member of the transferrin family of genes, is the major iron-binding protein in milk and body secretions. The amino acid sequence of LTF consists of two homologous domains homologous to proteins in the transferrin family. Recent isolation of cDNA encoding mouse LTF has expedited the mapping of both mouse and human LTF genes. Southern blot analysis of DNA from mouse-Chinese hamster and human-mouse somatic cell hybrids maps the LTF gene to mouse chromosome 9 and to human chromosome 3, respectively. Furthermore, analysis of cell hybrids containing defined segments of human chromosome 3 demonstrates that the gene is located in the 3q21-qter region. These results suggest that LTF and associated genes of the transferrin family have existed together on the same chromosomal region for 300-500 million years.

Animals↗
PubMed1987

Chromosomal assignments of genes for tissue plasminogen activator and urokinase in mouse.

The genes encoding the two plasminogen activators, tissue plasminogen activator and urokinase, were mapped to mouse chromosomes using probes derived from the respective mouse cDNAs. DNA from mouse-Chinese hamster and mouse-rat somatic cell hybrids was digested with BamHI and EcoRI, respectively, and analyzed by Southern blot hybridization for the segregation of the two genes. Tissue plasminogen activator and urokinase cosegregated with mouse chromosomes 8 and 14, respectively. The plasminogen activator genes thus fall into two syntenic groups that are conserved in human and mouse.

Animals↗
PubMed1987

Hemopexin is localized to human chromosome 11.

Hemopexin, a plasma protein that migrates during electrophoresis with the beta-globulins, transports free heme to sites of its catabolism in the liver. A hemopexin cDNA clone has been utilized for mapping the hemopexin (HPX) gene to human chromosome 11 in the region pter----p11 by somatic cell hybrid analysis.

Animals↗