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Biomedical subjects

M Yaqoob

Publications and source records attributed to M Yaqoob.

At least 37 records · Page 2Linked to original sources
PubMed1998

Linkage analysis excludes familial congenital hypothyroidism from chromosome 21.

Congenital hypothyroidism (CH) is a heterogeneous disorder with largely unknown causes, affecting 1/3000-1/4000 new-borns. Individuals with Down syndrome have a much higher incidence of CH than the normal population, probably due to the extra copy of chromosome 21. Moreover, a girl has recently been described with CH and an interstitial deletion of proximal 21q, possibly revealing a recessive disease allele on the undeleted chromosome. To establish whether chromosome 21 is also involved in the etiology of familial cases of presumably autosomal recessive CH, we investigated 22 families with recessive CH, using 10 microsatellite markers from 21q. Linkage analysis allowing for heterogeneity revealed no signs of linkage even in a small proportion of the families, and two-point analysis of the markers made it possible to exclude the long arm of chromosome 21 from containing any major disease-causing gene.

Adult↗
PubMed1997

Genetic and linkage analysis of familial congenital hypothyroidism: exclusion of linkage to the TSH receptor gene.

Congenital hypothyroidism affects 1/3000-4000 newborns. The causes of this group of disorders are still largely unknown. Although most cases are sporadic some families have several affected children and/or consanguineous parents, suggesting autosomal recessive inheritance. Furthermore, there is a murine strain (hyt) with congenital hypothyroidism and autosomal recessive inheritance, whose phenotype appears to be identical with the corresponding human disease. In the hyt mouse, the disease is caused by a mutation in the thyroid-stimulating hormone receptor (TSHR) gene, making this gene a likely candidate also for the human disease. The human TSHR gene was mapped on radiation hybrid panels and closely linked flanking markers D14S287 and D14S616 were identified. On the Genebridge 4 panel, D14S287 was found to be located 8.5 cR (corresponding to 2.3 cM) proximal to the TSHR gene, and D14S616 was found to be located 4.4 cR (1.2 cM) distal to the TSHR gene. These markers were analyzed in 23 families, most of them with two or more children affected by congenital hypothyroidism and some with appreciable consanguinity of the parents. Assuming homogeneity, the two-point lod score at theta = 0.1 was -4.8 for D14S287 and -5.8 for D14S616, and thus linkage to the TSHR gene was excluded. Even when the data were analyzed with allowance for heterogeneity, there was no evidence of linkage. Our conclusion is that if mutation of the TSHR gene causes familial congenital hypothyroidism in humans, it affects only a small proportion of the cases.

Adult↗
PubMed1997

Serum hyaluronan levels follow disease activity in vasculitis.

Hyaluronan (HA) is a high molecular weight polysaccharide present in the extracellular matrix of most tissues. It is a major component of loose connective tissues such as skin, synovial fluid and the vitreous body, and during embryonic development, tissue repair, tumor growth and at inflammatory sites. Increased serum concentrations have been reported in association with tissue damage, certain inflammatory diseases, notably rheumatoid arthritis and scleroderma, liver malfunction and in some malignancies. Currently there are no serological markers available that monitor the extent of tissue damage in vasculitis. We therefore, conducted this study to investigate the significance of serum HA in patient with systemic vasculitis (SV). Ten patients with SV and acute renal failure had elevated HA levels compared to normal age and gender matched controls (n = 31) (mean +/- SD: 673.8 +/- 495.14 micrograms/l and 90.26 +/- 37.18 micrograms/l, respectively; p < 0.001]. Eight of these patients were studied longitudinally for ten days, after pulse steroids, during which serum HA levels fell paralleling clinical improvement, despite the persistence of positive perinuclear-anti-neutrophil cytoplasmic antibody (p-ANCA) serology in three patients. In two patients, the clinical course was complicated by sepsis which was accompanied by an acute rise in serum HA. One patient suffered a relapse of vasculitis, with lung hemorrhage and a sudden rise in HA (> 2,000 micrograms/l), but c-ANCA serology remained normal. Serum HA was also measured in a further ten patients in clinical remission from SV and found to be within the normal range (82.44 +/- 39.06 micrograms/l). One patient, with equivocal clinical relapse after transplantation, exhibited high p-ANCA (404 IU) but serum HA remained normal (ten readings over six months 0-163 micrograms/l). Little change was seen in symptoms, or HA and ANCA serology, following plasma exchange. These preliminary data indicate that serum HA is raised in active vasculitis and may be a useful adjunctive marker of disease activity and extent of tissue damage.

Acute Kidney Injury↗
PubMed1996

Nitric oxide kinetics during hypoxia in proximal tubules: effects of acidosis and glycine.

In the present study, we directly monitored nitric oxide (NO) with an amperometric NO-sensor in suspensions of rat proximal tubules. Hypoxia-stimulated NO generation was characterized by an initial rise and a subsequent sustained increase which preceded cell membrane damage as assessed by lactic dehydrogenase (LDH) release. In contrast, the NO concentration remained unmeasurable in normoxic controls. Nitro-L-arginine-methyl ester (L-NAME) prevented the hypoxia-induced increase in NO in a dose dependent manner in parallel with incremental cytoprotection. The hypoxia-induced elevation in NO and the associated membrane injury were both markedly prevented by extracellular acidosis (pH 6.95). In vitro proximal tubular nitric oxide synthase (NOS) activity (3H-arginine to 3H-citrulline assay) was pH dependent with optimum activity at pH 8.0 and greatly reduced activity at acidic pH even in the presence of calcium and co-factors. However, glycine, a well recognized cytoprotective agent, did not attenuate the NO concentration during hypoxia. The present study therefore provides direct evidence that NO is generated by rat proximal tubules during hypoxia and demonstrates that the protective effect of low pH against hypoxic rat tubular injury is associated with an inhibition of this NO production.

Acidosis, Renal Tubular↗
PubMed1996

5-amino salicylic acid absorption and metabolism in ulcerative colitis patients receiving maintenance sulphasalazine, olsalazine or mesalazine.

BACKGROUND: All 5-aminosalicylic acid (5-ASA) preparations are potentially nephrotoxic, but there has been concern that newer delivery systems may increase this risk, either because of altered absorption or altered metabolism. Previous studies of 5-ASA absorption and excretion have usually either been performed in healthy controls or have only examined short-term therapy. 5-ASA and N-acetyl-5-ASA have therefore been measured in blood samples, and N-acetyl-5-ASA in urine samples, from patients with ulcerative colitis on long-term maintenance with different 5-ASA preparations and compared with sensitive markers of renal damage. METHODS: Patients receiving mesalazine (Asacol) (n = 13), sulphasalazine (n = 12) or olsalazine (Dipentum) (n = 8), all at doses within the recommended range were studied. Six-hour and trough serum concentrations of 5-ASA and N-acetyl-5-ASA and 24-h urinary excretion of N-acetyl-5-ASA were measured by high-performance liquid chromatography. RESULTS: Absorption of 5-ASA, assessed as 24-h excretion of N-acetyl-5-ASA expressed as molar % of ingested dose, was greater in patients receiving mesalazine, 23.25 +/- 10.65% (mean +/- s.d.; n = 13), than those receiving sulphasalazine (11.16 +/- 10.52%, n = 12; P = 0.003) or olsalazine (9.70 +/- 3.89%, n = 8; P < 0.002). The ratio of 5-ASA: N-acetyl-5-ASA in the serum 6 h after dose was also greater with mesalazine (1.02 +/- 0.44, mean +/- s.d.) than sulphasalazine (0.54 +/- 0.44, P < 0.02) or olsalazine (0.38 +/- 0.44, P < 0.005). Urinary markers of tubular damage were increased in four of 33 patients, but showed no correlation with concentration of 5-ASA or N-acetyl-5-ASA in serum and N-acetyl-5-ASA in urine, nor with lifetime dose or average daily dose of 5-ASA. CONCLUSIONS: In patients with ulcerative colitis receiving maintenance 5-ASA therapy there was greater absorption and less acetylation of 5-ASA from mesalazine (Asacol) compared with sulphasalazine or olsalazine, but no evidence from this study that this resulted in increased nephrotoxicity.

Absorption↗
PubMed1996

Retention of an albumin-bound furan dicarboxylic acid in patients with chronic renal failure or after a kidney transplant.

BACKGROUND: 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) is a furan dicarboxylic acid which accumulates in the plasma of patients with renal impairment. 5-Propyl FPA is an inhibitor of the binding of drugs to albumin and is also implicated in other aspects of the uraemic syndrome. METHODS: Plasma concentrations of propyl FPA have been measured in non-dialysis-dependent, chronic renal failure patients and in renal transplant patients by high-performance liquid chromatography. Concentrations of haemoglobin, albumin and creatinine were also determined. RESULTS: There was a positive correlation between serum creatinine and 5-propyl FPA and a negative correlation between haemoglobin concentration and 5-propyl FPA in chronic renal failure patients. There was a negative correlation between 5-propyl FPA and duration of transplant only when the serum creatinine was >200 microM. The mean plasma concentration of 5-propyl FPA in chronic renal failure patients with plasma creatinine CONCLUSIONS: This retention of 5-propyl FPA may therefore reflect a specific tubular defect in renal transplant patients treated with cyclosporin and points to the possibility that 5-propyl FPA may serve as a marker of tubular dysfunction.

Adult↗
PubMed1996

Selective labelling of bradykinin receptor subtypes in WI38 human lung fibroblasts.

1. Binding of the B1 bradykinin receptor radioligand, [3H]-des-Arg10-kallidin (-KD) and the B2 receptor radioligand [3H]-bradykinin (-BK) was investigated in membranes prepared from WI38 human foetal lung fibroblasts. 2. One-site analysis of the saturation data for [3H]-des-Arg10-KD gave an equilibrium dissociation constant (KD) value of 0.51 +/- 0.12 nM and a maximum receptor density (Bmax) of 260 +/- 49 fmol mg-1 of protein. [3H]-des-Arg10-KD binding was displaced by ligands in the order: des-Arg10-KD > KD > > des-Arg9[Leu8]-BK > des-Arg9-BK > Hoe 140 > > BK, implying that it was binding selectively to B1 receptors. 3. One-site analysis of the binding of [3H]-BK to W138 membranes indicated that it had a KD value of 0.25 +/- 0.06 nM and a Bmax of 753 +/- 98 fmol mg-1 of protein. The potencies for displacement of [3H]-BK binding were: Hoe 140 > > BK = KD > > > des-Arg10-KD = des-Arg9[Leu8]-BK = des-Arg9-BK, which was consistent with binding to B2 receptors. 4. This is the first characterization of [3H]-des-Arg10-KD binding to include both kinetic and equilibrium data, and demonstrates that [3H]-des-Arg10-KD has a high affinity for human B1 bradykinin receptors and is sufficiently selective to be used as a radioligand for B1 receptors in human cells or tissues expressing an excess of B2 BK receptors.

Bradykinin↗
PubMed1996

Accumulation of the endogenous L-arginine analogue NG-monomethyl-L-arginine in human end-stage renal failure patients on regular haemodialysis.

We measured plasma levels of L-arginine, its analogue NG-monomethyl-L-arginine (L-NMMA), and related amino acids in normal subjects and uraemic patients (n = 31), before and after haemodialysis. Plasma levels of L-arginine were reduced to less than half of normal values in uraemic subjects compared with controls, and were not affected by haemodialysis. L-NMMA was not detectable in non-uraemic subjects, but markedly elevated in uraemic patients. In parallel, we used human red blood cells as a model to study the effect of L-NMMA upon the transport of L-arginine. L-NMMA trans-stimulated L-arginine transport significantly, confirming that L-arginine and L-NMMA share common transport pathways. Our results suggest altered L-arginine metabolism and the presence of an increased concentration of a NO synthase inhibitor in uraemia. We propose that alterations in plasma L-arginine levels and increased production of L-arginine analogues will alter NO synthesis and may help to explain some pathological changes seen in uraemia.

Adult↗
PubMed1996

Monitoring of endothelial leucocyte adhesion molecule-1 in anti-neutrophil-cytoplasmic-antibody-positive vasculitis.

Soluble endothelial leucocyte adhesion molecule-1 (ELAM-1) has been shown to act as a neutrophil chemoattractant and may also represent a specific marker of endothelial cell damage or activation. Nine patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis (p-ANCA: n = 4, c-ANCA: n = 5) were prospectively monitored for disease activity by serial serum ELAM-1, C-reactive proteins (CRPs), von Willebrand factor (vWF) and ANCA levels. Six patients presented acutely with biopsy-proven renal vasculitis. One patient on dialysis, one in remission with stable renal function and one renal transplant patient developed clinical and serological relapse. Seven patients had abnormally high ELAM-1 (>60 ng/ml) levels at presentation. These fell within normal limits a week following pulse methyl prednisolone therapy. This preceded a fall in CRP, vWF and subsequent clinical remission. p-ANCA serology remained positive in 3 cases. One patient relapsed with rising ELAM-1 levels. Two patients developed erroneously positive ANCA serology but serum ELAM-1 remained normal. Six patients with chronic renal impairment of non-vasculitic origin who presented acutely with septicaemia had normal serum ELAM-1 levels (mean +/- SD: 31 +/- 10 ng/ml) at presentation and during the subsequent clinical course. These preliminary findings are encouraging, especially when ELAM-1 is combined with ANCA monitoring in vasculitis. However, further data from larger controlled studies are needed to validate the utility of ELAM-1 in the monitoring of patients with vasculitis.

Adult↗
PubMed1995

Case report: the diagnostic value of contrast-enhanced computed tomography in acute bilateral renal cortical necrosis.

Acute bilateral renal cortical necrosis is a relatively rare cause of acute renal failure accounting for only 2% of cases in the Western World. The pathophysiology of this condition is complex, but ultimately leads to the destruction of the renal cortex with sparing of the renal medulla. A definitive diagnosis is based on renal histology. In this report we describe a patient in whom this diagnosis was made using contrast-enhanced computed tomography as renal biopsy was contraindicated.

Acute Kidney Injury↗
PubMed1995

Carbohydrate analysis of the B2 bradykinin receptor from rat uterus.

The B2 bradykinin receptor purified from rat uterus has an apparent molecular mass of 81 kDa. This is higher than the value of 42 kDa estimated from the sequence data of rat and human B2 receptors. Carbohydrate analysis of the rat B2 bradykinin receptor indicated that it was a sialoglycoprotein with three N-linked complex oligosaccharide side chains. This was consistent with the sequence, which has three potential glycosylation sites. The receptor did not appear to possess O-linked carbohydrate side chains. Removal of the N-linked carbohydrates with endo-beta-N-acetylglucosaminidase yielded a core protein of 42-44 kDa. The presence of these N-linked carbohydrates explains the discrepancy between the molecular size of the purified receptor protein and that estimated from the sequence. The sequence of the rat receptor suggests an isoelectric point of about pH 7.0, but the purified receptor had an isoelectric point of pH 4.5-4.7. Sialic acid residues on the N-linked side chains are likely to be responsible for the acidic nature of the rat receptor. Carbohydrate does not appear to play a role in ligand-receptor interactions, as deglycosylation did not alter the affinity of the B2 bradykinin receptor for bradykinin or the B2-selective antagonist HOE-140.

Acetylglucosaminidase↗
PubMed1995

Severe mental retardation in 2 to 24-month-old children in Lahore, Pakistan: a prospective cohort study.

Severe mental retardation (developmental quotient (DQ) < 50) was investigated in 1303 children from 2 to 24 months of age, born during 1984-87 in four population groups representing different socio-economic levels in and around Lahore, Pakistan. The incidence per 1000 live births was 22 in the periurban slum, 9 in the urban slum, 7 in the village and 4 in the upper middle class group. The aetiology was prenatal in 79%, perinatal in 14% and untraceable in 7% of cases. Down's syndrome was the most common cause of severe mental retardation (36%). Impairments were studied at 2 years of age. Impairment of language was present in all, while locomotor dysfunction was seen in 89% of cases. Epilepsy and cerebral palsy were each present in 22% of cases. Mortality among these severely mentally retarded children was 36%.

Asphyxia Neonatorum↗
PubMed1995

Tubular damage in microalbuminuric patients with primary glomerulonephritis and diabetic nephropathy.

Tubular damage as suggested by enzymuria and tubular proteinuria is a recognized feature of glomerulonephritis (GN) with clinical proteinuria and both incipient and overt diabetic nephropathy (DN). However, little is known about the presence of tubulopathy in patients with primary GN, microalbuminuria [albumin excretion (AER) 30-300 mg/d] and microhematuria. Three groups were studied. The GN group comprised 17 (2 F) patients with biopsy-proven GN with microalbuminuria. The DN group comprised 35 (14 F) patients with incipient diabetic nephropathy with AER 30-300 mg/d, and controls comprised 38 (15 F) normal subjects with normal AER < 30 mg/d. Serum creatinine, albuminurinuria, transferrinuria, and markers of tubular damage such as urinary excretion of N-acetyl-glucosaminidase (NAG), leucine aminopeptidase (LAP), gamma-glutamyl transferase (gGT), and retinol binding protein (RBP) were measured. GN and DN had comparable degrees of albuminuria, transferrinuria, and LAP excretion, and these were significantly higher than controls. Serum creatinine was significantly higher in GN than DN and controls. DN had significantly higher NAG and RBP, and lower gGT than GN and controls. In both GN and DN groups, both glomerular proteins correlated with each other and NAG correlated significantly to LAP and gGT. Albuminuria correlated to tubular enzymuria in GN group but not in patients with DN. The results suggest that tubular damage is less marked in microalbuminuric patients with GN than those with DN despite similar degree of glomerular proteinuria. The pattern of tubulopathy is also different in the two groups, indicating differences in the pathogenesis of tubular damage in these two clinical settings.

Acetylglucosaminidase↗
PubMed1995

Biochemical markers of basement membrane disturbances and occupational exposure to hydrocarbons and mixed solvents.

To investigate possible mechanisms of hydrocarbon or solvent-induced renal damage, we studied three groups of healthy men employed in a UK manufacturing plant. Group 1 (n = 111) were occupationally exposed to hydrocarbon-based paints, Group 2 (n = 100) were occupationally exposed to petroleum-based mineral oils, and Group 3 (n = 92) had low background occupational exposure to hydrocarbons. Occupational atmospheric exposure levels for toluene, xylene, butanol and oil mist around the time of this study were within UK permissible limits. Group 4 (controls) were males with no known occupational hydrocarbon or solvent exposure (n = 108). Circulating laminin antibodies and the auto-antibody implicated in Goodpasture's syndrome (anti-GBM) were measured, as were serum laminin, a basement membrane turnover marker, and soluble E-selectin, an endothelial activation marker. Group 1 had a significantly greater proportion of subjects with high levels of both anti-laminin antibodies and soluble E-selectin; Group 2 had significantly more subjects with raised anti-GBM antibodies, laminin and soluble E-selectin. Mean levels of soluble E-selectin were increased in Groups 1 and 2. In a small but significant proportion of these workers exposed to hydrocarbons/mixed solvents there are alterations both to basement membranes, resulting in auto-antibody production, and to overlying vascular endothelial cells.

Adult↗
PubMed1995

Effects of haemodialysis and continuous ambulatory peritoneal dialysis on the plasma clearance of an albumin-bound furan dicarboxylic acid.

Organic acids that are strongly bound to albumin are not removed by dialysis and the plasma concentrations of one such substance, a furan dicarboxylic acid (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid: 5-propyl FPA) have been measured by HPLC in healthy subjects (n = 21), patients on regular haemodialysis (n = 30), and patients treated by continuous ambulatory peritoneal dialysis (n = 21). The mean (+/- SD) concentrations of 5-propyl FPA were significantly higher in haemodialysis (95 +/- 44 microM) compared to CAPD patients (28 +/- 19 microM) and both were higher than in healthy individuals (14 +/- 7 microM). Haemoglobin concentrations in CAPD patients were significantly higher than in those on haemodialysis while these patients had significantly higher albumin concentrations than CAPD patients. The concentration of 5-propyl FPA was positively correlated with the duration of dialysis for haemodialysis patients but not for CAPD patients. The lower concentrations of 5-propyl FPA in CAPD patients may at least partly explain the higher haemoglobin levels found in these patients.

Anemia↗