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T H Goodship

Publications and source records attributed to T H Goodship.

At least 19 recordsLinked to original sources
PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗
PubMed2000

Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1.

Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults. There is a 30-50-fold increased incidence of VUR in first-degree relatives of probands, compared with the general population. We report the results of the first genomewide search of VUR and RN; we studied seven European families whose members exhibit apparently dominant inheritance. We initially typed 387 polymorphic markers spaced, on average, at 10 cM throughout the genome; we used the GENEHUNTER program to provide parametric and nonparametric linkage analyses of affected individuals. The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16. Saturation with markers at 1-cM intervals increased the NPL to 5.94 (P=.00009). Hence, VUR maps to a locus on chromosome 1. There was evidence of genetic heterogeneity at the chromosome 1 locus, and 12 additional loci were identified genomewide, with P<.05. No significant linkage was found to 6p, where a renal and ureteric malformation locus has been reported, or to PAX2, mutations of which cause VUR in renal-coloboma syndrome. Our results support the hypothesis that VUR is a genetic disorder.

Chromosome Mapping↗
PubMed2000

Long-term follow-up of patients presenting to adult nephrologists with chronic pyelonephritis and 'normal' renal function.

We studied the natural history, and therefore prognosis, of patients with chronic pyelonephritis presenting to adult nephrologists with a plasma or serum creatinine <90 mmol/l. From the Newcastle chronic pyelonephritis database, 255 patients with radiologically-proven disease were reviewed. Median follow-up was 95 months (95%CI 82. 3-109.3). Plasma creatinine was < or =90 micromol/l (P(Cr)< or =90 group) at presentation in 138. At presentation, hypertension, bilateral disease and proteinuria were less frequent in the P(Cr)< or =90 group (hypertension 19% vs. 32%, p<0.05; bilateral disease 25% vs. 70%, p<0.001; proteinuria 18% vs. 60%, p<0.001). With the exception of two patients, the renal prognosis of this group was excellent. Patients over the age of 18 years presenting to adult nephrologists with a diagnosis of chronic pyelonephritis and a creatinine < or =90 micromol/l can be reassured that the chances of developing end-stage renal failure in the future are very small. Most could be referred back to their general practitioner for long-term follow-up.

Adult↗
PubMed1999

Acidosis and nutrition.

In recent years there has been increasing evidence for the deleterious effect of acidosis on a number of fundamental systems of the body including nutrition [1, 2]. Approximately 70 mmol of hydrogen ions are produced daily by the body, and to maintain acid-base balance there must be an equivalent net acid secretion by the kidney. It is remarkable that extracellular fluid (ECF) pH is maintained within a very narrow range of 7.35-7.45 (35-45 nM), reflecting the fundamental importance of pH on many aspects of basic cellular function particularly proteins. It is important to differentiate between the terms acidosis and acidemia. The former is a pathophysiologic process tending to acidify body fluids, whereas the latter occurs when the ECF hydrogen ion concentration is above the normal range. It is possible to be acidotic (with a reduced serum bicarbonate) but not acidemic because of appropriate buffering of hydrogen ions. The major extracellular buffer is the carbonic acid/hydrogen carbonate system with plasma proteins and hemoglobin contributing significantly less. The major intracellular buffer is protein followed by bone [3]. The type of acidosis seen in patients with chronic renal failure changes with decreasing GFR; initially a non-anion gap acidosis is observed secondary to the loss of bicarbonate from the proximal tubule and impaired excretion in the distal tubule. With increasing severity of renal impairment, failure to excrete organic and inorganic acids results in an increased anion gap [4, 5].

Acidosis↗
PubMed1999

Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency.

BACKGROUND: In a recent study of three families we have found that inherited haemolytic uraemic syndrome (HUS) maps to a region of chromosome 1q containing the gene for complement factor H. In one of these families and also in a case of sporadic D-HUS, we have identified mutations in the factor H gene. A further family with inherited HUS has therefore been investigated. METHODS: DNA extracted from the family members and DNA extracted from archival post-mortem material from a deceased family member, was studied. Review of renal biopsies and study of complement components was also undertaken. RESULTS: This family demonstrates an inherited deficiency of complement factor H. Non-diarrhoeal HUS has affected at least two family members with half normal levels of factor H. CONCLUSION: These findings represent further evidence of the association between factor H dysfunction and HUS.

Adolescent↗
PubMed1998

Factor H--US?

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Complement Factor H↗
PubMed1998

Genetic studies into inherited and sporadic hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for factor H lies within the region. Subsequent mutation analysis of the factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of serum factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with factor H deficiency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.

Adult↗
PubMed1997

Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium.

Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium. In this study, the parathyroid response to the correction of acidosis in eight hemodialysis patients was determined by performing dynamic assessment of parathyroid function before and after the correction of acidosis. The parathyroid response to intravenous calcitriol before and after the correction of acidosis was also assessed. After optimal correction of acidosis, there were no significant changes in blood pH, ionized calcium, phosphate, or alkaline phosphatase values, but the level of venous total CO2 increased significantly. Parathyroid hormone/ionized calcium curves were displaced downward after correction of acidosis, but not after the administration of intravenous calcitriol. The correction of metabolic acidosis in hemodialysis patients with secondary hyperparathyroidism can suppress parathyroid hormone secretion by increasing the sensitivity of the parathyroid glands to ionized calcium.

Acidosis↗
PubMed1997

Correction of acidosis in hemodialysis decreases whole-body protein degradation.

Correction of acidosis in hemodialysis (HD) decreases protein degradation. The effect of the correction of chronic metabolic acidosis in chronic renal failure patients treated with HD was determined from the kinetics of infused L-[1-(13)C]leucine. Six HD patients were studied before (acid) and after (bicarbonate) correction of acidosis (pH: acid 7.36 +/- 0.01, bicarbonate 7.40 +/- 0.01, P < 0.005). Leucine appearance from body protein (PD) and leucine disappearance into body protein (PS) decreased significantly with correction of acidosis (PD: acid 180.6 +/- 7.3, bicarbonate 130.9 +/- 7.2 mumol.kg-1.h-1, P < 0.005; PS: acid 172.3 +/- 6.8, bicarbonate 122.0 +/- 6.8 mumol.kg-1.h-1, P < 0.005). There was no significant change in leucine oxidation or plasma amino acid concentrations. These results demonstrate that optimal correction of acidosis in HD is beneficial in terms of protein turnover and may improve long-term nutritional status in HD.

Acidosis↗
PubMed1996

The correction of acidosis does not increase dietary protein intake in chronic renal failure patients.

In normal humans and in patients with chronic renal failure (CRF), acidosis increases whole-body protein degradation. Correction of acidosis reduces protein degradation. The mechanisms underlying these changes in protein metabolism are unclear. However, one possibility is that dietary protein intake is reduced in acidosis and that this causes increased protein degradation. This possibility has not been tested. In this study the effects of acidosis on protein intake in patients with CRF have been assessed using 7-day weighed dietary inventories in the acidotic state (venous bicarbonate 15.6 +/- 1.0 mmol/L) and following treatment with oral sodium bicarbonate (venous bicarbonate 21.0 +/- 1.4 mmol/L). Protein intake was also derived from urinary nitrogen excretion. There was no significant difference in protein intake calculated from dietary records (1.0 +/- 0.09 g/kg/d v 1.06 +/- 0.1 g/ kg/d) or calculated from urinary nitrogen (1.13 +/- 0.07 g/kg/d v 1.06 +/- 0.06 g/kg/d) between the untreated and bicarbonate-treated states in eight patients with CRF. We conclude that acidosis in CRF patients does not affect dietary protein intake and that dietary changes therefore do not contribute significantly to the changes in protein metabolism seen in acidosis.

Acidosis↗
PubMed1996

Correction of acidosis in CAPD decreases whole body protein degradation.

Correction of acidosis in CAPD decreases protein degradation and synthesis but has no effect on leucine oxidation. The effect of the correction of metabolic acidosis in CRF patients treated with CAPD was determined from the kinetics of infused L-[1-13C]leucine. Seven CAPD patients were studied before (acid) and after correction of acidosis (bicarbonate) (pH:acid 7.39 +/- 0.01, bicarbonate 7.41 +/- 0.01, P = 0.005). Leucine appearance from body protein (PD) [corrected] and leucine disappearance into body protein (PS) [corrected] decreased significantly with correction of acidosis. (PS: acid 211.7 +/- 9.8, bicarbonate 142.3 +/- 4.2 micromol x kg-1 x hr-1, P < 0.001; PD: acid 200.6 +/- 8.5, bicarbonate 132.4 +/- 3.7 micromol x kg-1 x hr-1, P < 0.001). There was no significant change in leucine oxidation or plasma amino acid concentrations. These results demonstrate that optimal correction of acidosis in CAPD is beneficial in terms of protein turnover.

Acidosis↗