Maintaining skills in general practice.
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Australia↗
Biomedical subjects
R W Watts
Publications and source records attributed to R W Watts.
The influence of obesity on the relationship between body mass index and the distance to the epidural space from the skin.
This study confirms that distance to the epidural space from the skin at the L3-4 interspace is only moderately correlated with body mass index in obstetric patients. A similar moderate linear correlation was found in the non-obstetric patients. However, in obese patients (BMI > 25), distance to epidural space from the skin correlated poorly with body mass index.
Adult↗
Comparison of felodipine and enalapril monotherapy in essential hypertension.
This study compared the efficacy and tolerability of monotherapy with felodipine and enalapril in patients with essential hypertension using a double-blind randomised crossover design. Thirty-five subjects (22 male, 13 female--ages: median 48 years, range 31-69 years) entered the randomised phases of the study and 32 subjects completed the study. Following a 4-week run-in placebo phase, the treatments were felodipine ("Plendil ER") 5-20 mg and enalapril 5-20 mg orally once daily for 8 weeks, each with matching placebos. Dose titration was at 2 and/or 4 weeks in each phase. Number of subjects with each different end-of-phase dose were for felodipine: 5 mg--8, 10 mg--11, 20 mg--13 and enalapril: 5 mg--6, 10 mg--9, 20 mg--17. Predose supine blood pressure (mean +/- SEM) was reduced in both active treatment phases compared with the run-in phase (159 + 2/101 +/- 1), but there was no significant difference in blood pressure between the active phases: felodipine 143 +/- 2/90 +/- 1 and enalapril 146 +/- 2/92 +/- 1. The most common adverse effects were for felodipine: headache, flushing, ankle swelling; and for enalapril: cough. Felodipine and enalapril as once daily monotherapy are thus of similar antihypertensive efficacy but with predictably different adverse effect profiles.
Adolescent↗
The GP proceduralist.
For many doctors, the more procedural nature of rural practices is a source of satisfaction. Performing procedural skills, however, requires appropriate training and a career-long commitment to critical analysis of performance. Many rural doctors have been able to document high quality application of their skills. The author of this paper discusses how he has approached the task.
Australia↗
Alanine glyoxylate aminotransferase deficiency: biochemical and molecular genetic lessons from the study of a human disease.
The decision to treat a patient with primary hyperoxaluria type 1 (PHI) by combined liver and kidney transplantation, the former to correct the metabolic lesion which was then thought to be deficiency of cytoplasmic 2-oxoglutarate:glyoxylate carboligase, and the latter to replace the organ which is destroyed, provided an opportunity to investigate the disease by modern biochemical methods. It was shown that 2-oxoglutarate:glyoxylate carboligase (the first decarboxylating component of 2-oxoglutarate dehydrogenase) is entirely mitochondrial so that deficiency of a cytoplasmic form of this enzyme could not be the cause of PHI. The deficient enzyme proved to be hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT). The disease can be diagnosed enzymologically on percutaneous liver biopsies and this is possible for the fetus in utero. There are four types of genetically determined heterogeneity in PHI:(1) responsiveness and non-responsiveness to pharmacological doses of pyridoxine, in terms of an effect on the rate of oxalate production; (2) the presence or absence of residual catalytic AGT activity; (3) CRM+ and CRM-variants; (4) locational variation by virtue of which the enzyme (AGT) is mitochondrial and not peroxisomal. About one third of patients with PHI have residual AGT activity and at least a large proportion of these have mitochondrial and not peroxisomal AGT. The molecular features which guide peroxisomal and mitochondrial enzymes from their sites of synthesis into the appropriate organelle are reviewed and the possibilities for genetic variation in the relevant parts of the AGT molecule are discussed. The gene directing the synthesis of AGT has been cloned and sequenced, as has the AGT cDNA from a patient with mitochondrial AGT. Three point mutations causing amino acid substitution in the predicted AGT protein sequence have been identified: proline----leucine at residue 11, glycine----arginine at residue 170 and isoleucine----methionine at residue 340. The present evidence based on screening PHI patients and control subjects suggest that the substitution at residue 11, which cosegregates with that at residue 340, generates an amphiphilic alpha-helix which resembles mitochondrial targeting sequences but that misrouting of all the newly synthesized AGT into mitochondria requires the substitution at residue 170 which may act by impeding the entry of the enzyme into peroxisomes. The recognition of enzyme locational heterogeneity in PHI due to mutations affecting leader sequences should encourage a search for similar metabolic lesions in other inborn errors of metabolism affecting peroxisomal and/or mitochondrial enzymes.
Alanine Transaminase↗
Obstetric epidural services in rural South Australia.
A survey of sixty South Australian country hospitals found that 35 units had more than 25 deliveries per year (total deliveries 4,247, which is 21.5% of total live births in South Australia during 1989). Twenty-five of these units had an epidural service (71%) and the overall epidural rate was 16.7%, 9.5% provided by general practitioner anaesthetists and 7.2% by specialists. General practitioner anaesthetists were involved more in the medium-sized units (50-200 deliveries per year), whereas specialists provided more services in the larger regional units and the small units as visitors. The epidural rate varied between 6-20% depending on the size of the unit. Most country regions in South Australia have reasonable access to an epidural service. The more geographically isolated areas are being serviced by general practitioner anaesthetists.
Analgesia, Epidural↗
A five-year prospective analysis of the efficacy, safety and morbidity of epidural anaesthesia performed by a general practitioner anaesthetist in an isolated rural hospital.
During a five-year period, 324 epidurals were performed by a general practitioner anaesthetist in an isolated rural hospital. Of these 160 were for obstetric purposes, 72% in primagravida patients, the majority in early and established labour (median cervical dilatation of 3.0 cm). The median epidural insertion time was seven minutes: 80% were free of all complications, there were no dural taps and there was a failure rate of 2%. The median visual analogue pain score (VAPS) was 8.3 prior to insertion and at peak of epidural blockade it was reduced to 0.5. Ten per cent of patients had unblocked segments, half of these were corrected and 90% of patients had even blocks. Despite higher pain scores in the 6-10 cm cervical dilatation group, epidural analgesia was just as effective when compared to the 0.5 cm group. Seventy-seven percent of women interviewed the day after delivery were fully satisfied with the epidural: 19% said it was considerable help, 2% some help and 2% said no help at all. During epidural caesarean section (n = 72), 75% of patients were comfortable, 17% had some discomfort and 7% required general or spinal anaesthesia. The incidence of hypotension (systolic blood pressure less than 90 mmHg), was 24.6% with a median ephedrine dose of 10 mg; however, with a greater than 20% drop in systolic blood pressure, the dose of ephedrine required to maintain blood pressure increased in a log-dose fashion. For women who received epidurals in labour, the caesarean section rate was 25%, instrumental vaginal delivery 34% and spontaneous vaginal delivery 41%. There were no adverse neonatal outcomes.
Anesthesia Department, Hospital↗
Low arylsulphatase A activity and choreoathetotic syndrome in three siblings: differentiation of pseudodeficiency from metachromatic leukodystrophy.
We report on a family with a sibship of three children for whom the diagnosis of "an unusual form of metachromatic leukodystrophy (MLD)" had been suggested earlier. The patients had choreiform movements and dystonic posturing accompanied by dysarthria since childhood. The availability of the polymerase chain reaction enabled us to show that the three siblings have a pseudodeficiency genotype (ASAp/ASAp). There was no abnormal sulphatiduria, and we propose that the neurological disease and low arylsulphatase A activity are unrelated to one another in this family. A diagnosis of MLD carries very serious implications, and we recommend that gene amplification by polymerase chain reaction and hybridization with allele-specific oligonucleotide probes should be used to corroborate the diagnosis, especially when there is no abnormal sulphatiduria and when metachromatic material cannot be demonstrated in a sural nerve biopsy.
Adolescent↗
Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. The European Study Group on Transplantation in Hyperoxaluria Type 1.
The data provided by 14 European centres concerning 22 combined liver-kidney and two isolated liver grafts performed in primary hyperoxaluria type 1 (PH1) were discussed at a workshop which drew the following main conclusions: 1. In end-stage renal failure due to PH1 1-year kidney graft survival rate is far better after combined liver-kidney transplantation than after kidney transplantation alone. This may be due to enhanced renal graft tolerance induced by the simultaneously grafted liver, in addition to the reduced risk of oxalate-induced damage to the kidney graft because the oxalate overproduction has been corrected. 2. Prolonged dialysis using conventional regimes gives rise to extensive systemic oxalosis, especially oxalate osteopathy, which leads to long-lasting excretion of large amounts of oxalate even after oxalate synthesis has been normalised by liver-kidney transplantation, with the risk of jeopardising the success of the kidney graft. In addition, oxalate arteriopathy may endanger the recipient's life. 3. Patients whose GFR is in the range of 25-60 ml/min per 1.73 m2 should be followed up closely, with sequential assessments based on the rate of loss of overall renal function and the plasma and urine oxalate values. An isolated liver transplantation should be considered once the disease has been shown to be following an aggressive course. If this strategy is not followed, planning for an elective liver-kidney graft should begin when GFR decreases to about 25 ml/min per 1.73 m2 and the operation should be as soon as possible. 4. As orthotopic liver transplantation involves the removal of the recipient's biochemically defective but otherwise normal liver, the diagnosis of PH1 should be unequivocally established in every case by the measurement of alanine: glyoxylate aminotransferase enzyme activity in a preoperative liver biopsy.
Adolescent↗
[Which transplantation strategies in primary hyperoxaluria type 1?].
The following main conclusions concerning the transplantation strategies to be adopted in primary hyperoxaluria type 1 (PH1) were drawn from the data collected from 22 patients who received combined liver-kidney grafts and 2 patients who received isolated liver grafts in Europe from June 1984 to March 1990. In end-stage renal failure due to PH1 liver-kidney transplantation yields better results than conventional renal transplantation. An isolated liver graft should be planned in patients with GFR between 25 and 60 ml/min/1.73 m2 whereas a combined liver-kidney graft is to be recommended as soon as the GFR falls below 25 ml/min/1.73 m2. Such patients should not be maintained on dialysis for more than a few months since they would unavoidably develop oxalosis with the risk of disabling lesions in the skeleton and cardiovascular system. Besides, oxalosis would be regularly followed by long-standing hyperoxaluria, with the risk of damage to the kidney graft, despite the correction of the enzyme deficit brought up by the liver graft.
Glomerular Filtration Rate↗
Treatment of type 1 Gaucher's disease affecting bone with aminohydroxypropylidene bisphosphonate (pamidronate).
Two patients with Type 1 (adult) Gaucher's disease and major skeletal involvement with multiple fractures have been treated with the second generation bisphosphonate pamidronate for extensive periods. There was evidence of an immediate reduction in bone resorption, with increased calcium absorption (delayed in Patient 1), improved calcium balance and maintained or improved bone density indices in the axial and peripheral skeleton. There was no evidence of immediate relapse on treatment cessation. No toxic effects of pamidronate treatment were identified and subjective skeletal pain diminished in both patients. Histomorphometry of transiliac bone biopsies obtained before the start of treatment, after double in vivo tetracycline labelling, represents one of the earliest reports of the quantitative findings in iliac bone invaded by Gaucher cells.
Adult↗
Liver and kidney transplantation in the treatment of primary hyperoxaluria.
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Adolescent↗
Combined hepatic and renal transplantation in primary hyperoxaluria type I: clinical report of nine cases.
PURPOSE AND PATIENTS AND METHODS: The purpose of this article is to report the experience of three centers with combined hepatic and renal transplantation for pyridoxine-resistant primary hyperoxaluria type I (alanine:glyoxylate aminotransferase [EC 2.6.1.44] deficiency), with particular emphasis on the selection criteria and timing of the operation. Nine patients with this inherited disease were treated by combined hepatic and renal transplantation. The former replaces the enzyme-deficient organ while the latter replaces the functionally affected organ. RESULTS: One patient with gross systemic oxalosis died in the immediate postoperative period and another died 8 weeks postoperatively of a generalized cytomegalovirus infection, having shown evidence of biochemical correction. One patient with particularly severe osteodystrophy at the time of the operation died 14 months postoperatively from renal failure due to progressive calcium oxalate nephrocalcinosis involving the transplanted kidney, plus thromboembolic disease. He also had very extensive systemic oxalosis. An additional patient with severe osteodystrophy died 9 months postoperatively. One patient developed hyper-rejection of the kidney and died later of gastrointestinal hemorrhage. The four long-term survivors (22 to 38 months) have remained asymptomatic from the standpoint of their renal disease, with resolution of any manifestations of systemic oxalosis that they may have had. They are either employed or continuing their education. CONCLUSIONS: A prolonged period of end-stage renal failure treated by dialysis regimens that are suitable for non-hyperoxaluric renal failure and extensive systemic oxalosis, particularly oxalotic osteodystrophy, are poor prognostic features. We propose that hepatic transplantation should be considered as definitive treatment before end-stage renal failure develops. This should be supplemented by renal transplantation with vigorous pre- and perioperative hemodialysis to deplete the body stores of oxalate. Although some authorities would reserve hepatic transplantation for patients in whom renal transplantation has failed, we suggest that combined liver and kidney transplantation is appropriate in patients who have never had a renal graft. Furthermore, the time has come to consider hepatic transplantation before any irreversible renal damage has occurred in these patients.
Adolescent↗
Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency.
Complete hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency causes the Lesch-Nyhan syndrome, an X-linked, purine metabolism disorder manifested by hyperuricemia, hyperuricaciduria, and neurologic dysfunction. Partial HPRT deficiency causes hyperuricemia and gout. One requirement for understanding the molecular basis of HPRT deficiency is the determination of which amino acids in this salvage enzyme are necessary for structural or catalytic competence. In this study we have used the PCR coupled with direct sequencing to determine the nucleotide and subsequent amino acid changes in 22 subjects representing 17 unrelated kindreds from the United Kingdom. These mutations were confirmed by using either RNase mapping or Southern analyses. In addition, experiments were done to determine enzyme activity and electrophoretic mobility, and predictive paradigms were used to study the impact of these amino acid substitutions on secondary structure.
Chromosome Deletion↗
What treatment do you advise for a small child with hyperoxaluria presenting with renal calculi?
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Child↗
Treatment of renal failure in the primary hyperoxalurias.
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Adult↗
Purine synthesis de novo and salvage in hypoxanthine phosphoribosyltransferase-deficient mice.
Extreme degrees of hypoxanthine phosphoribosyltransferase (HPRT) deficiency in man are associated with gross sex-linked neurological dysfunction, gout and urinary stones (the Lesch-Nyhan or 'complete HPRT-deficiency' syndrome). The less severe degrees of enzyme deficiency (sex-linked recessive gout and/or urolithiasis or the 'partial HPRT-deficiency' syndrome) may be associated with minor neurological manifestations. Whole body purine synthesis de novo is accelerated in both these groups of patients. A strain of mice with an experimentally produced mutation at the HPRT locus showed some residual 'apparent HPRT activity' in brain, liver, testicular, splenic, kidney and ovarian tissues but not in erythrocyte haemolysates. The mutation removes exons 1 and 2 of the coding region of the gene together with the promotor and about 10 kb of upstream sequence from the gene. It is therefore possible that the observed 'apparent HPRT activity' in these mice is due to the operation of an alternative metabolic pathway. Purine synthesis de novo was markedly accelerated in their brain, testicular, splenic and kidney tissues. It was not accelerated in the liver tissue of male mice hemizygous for the mutation and the degree of acceleration in the female homozygotes only just reached statistical significance at the p = 0.02 level. This observation casts doubt on the importance of modulations in the rate of hepatic purine synthesis de novo as a mechanism for maintaining a steady supply of purines for translocation to other organs.
Adenine Phosphoribosyltransferase↗