Renin-angiotensin system and associated gene polymorphisms in myocardial infarction in young South African Indians.

The renin-angiotensin system plays an important role in cardiovascular regulation. Abnormalities in genetic components of this system, such as the angiotensin-converting enzyme (ACE) gene, angiotensin II type 1 (AT1) receptor gene and angiotensinogen (AGT) gene, may cause a variety of adverse cardiovascular effects. It was the aim of this study, therefore, to investigate the involvement of the ACE insertion/deletion (I/D), AT1 receptor 1166 A->C and AGT M235T polymorphisms as predisposing factors for myocardial infarction (MI) in 195 young South African Indians (C AT1 receptor polymorphism with respect to both genotype and allelotype (p > 0.70), or in the genotype or allele frequency distribution of the AGT M235T polymorphism (p > 0.44). However, a significant in crease was noted for both the AT1 receptor C variant (p = 0.025) and the AGT T variant (p = 0.047) in hypertensive patients compared with those who were normotensive. In conclusion, results of this study indicate that the ACE I/D, the 1166 A->C AT1 receptor and AGT M235T polymorphisms do not confer any increased risk for MI in young South African Indians.

P53 codon 72 polymorphism and human papillomavirus type in relation to cervical cancer in South African women.

The usefulness of the arginine (Arg) residue at codon 72 of the p53 tumor suppressor gene as a marker for the risk of cervical cancer remains unclear. Studies to date have focused mainly on Caucasian subjects despite marked ethnic variations in both the p53 polymorphism and the frequency of cervical carcinoma. Furthermore, not all studies have taken into account the type of human papillomavirus (HPV) infection present. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we determined the p53 codon 72 status in 281 black South African women with cervical cancer and 340 ethnically matched healthy control subjects. In addition, HPV DNA was confirmed in 190 cervical tumors and the viral type determined. Results showed that overall more cancer patients than control subjects had an Arg allele at codon 72 with respect to both genotype and allelotype (P < 0.05). A significantly higher (P < 0.001) Arg allele frequency (55%) was also observed in patients whose tumors contained low or intermediate risk HPV DNA compared with control subjects (31%); the Arg homozygosity rate was 34% and 9% in patients and controls, respectively (P < 0.001). In contrast, patients harboring HPV 16/18 infections showed no differences in p53 status compared with controls. It would appear that, in the absence of HPV 16/18 infections, the Arg allele at codon 72 of the p53 tumor suppressor gene may constitute a risk factor for carcinogenesis of the cervix.

Central airways stenosis in school-aged children: differential diagnosis from asthma.

UNLABELLED: This study assessed the value of spirometry and chest X-rays in the diagnosis of airways stenosis in the tracheal or laryngeal regions at school age. A series of 14 patients was studied. Six of them had vascular ring anomalies, four subglottic stenosis, two aberrant innominate artery, one tracheal stenosis and one a laryngeal web. Four patients were suffering from chronic cough and ten from dyspnoea, noisy breathing and cough upon physical exercise. Two had had their symptoms since infancy and five since 3-6 y of age, whereas seven had had their first symptoms at school age. Nine patients had previously been suspected of having asthma, and five of them had been using inhaled corticosteroids, one inhaled sodium cromoglycate and one peroral terbutaline without any effect. The ratio of forced expiratory volume in 1 s (FEV1) to peak expiratory flow (PEF) was abnormally high in most of the patients. All six children with vascular ring anomalies also had an abnormal aortic configuration on a chest X-ray, and narrowing of the trachea was seen in two of the four with subglottic stenosis. Two children had both chest X-rays and spirometry values within the normal limits. CONCLUSION: The results show that children with stenosis in the laryngeal or tracheal region may not have their first symptoms until school age. Many patients are falsely suspected of having asthma. Simple spirometry and chest X-rays will help the physician to make the correct diagnosis in these patients.

Brain single photon emission computed tomography at term age for predicting cerebral palsy after preterm birth.

In order to assess the predictive value of neonatal brain perfusion with single photon emission computed tomography (SPET) with regard to neuromotor outcome at a corrected age of 18 months, 34 infants with birth weight <1,500 g and gestation age <34 weeks underwent brain technetium-99m ethylcysteinate dimer (99Tc(m)-ECD) SPET at term age. The perfusion defects were estimated by visual interpretation. Consecutive semiquantitative assessment was made in 26 cases and reference values for the tracer were collected from images of 17 preterm infants with normal outcome after the follow-up period. Relative regional cortical (frontal, sensorimotor, parietal and occipital), cerebellar and thalamic perfusion levels were evaluated in middle sagittal slices and hemispheric asymmetries in transaxial slices. Perfusion defects predicted cerebral palsy (CP) (n = 11) with 82% sensitivity, 70% specificity and 74% accuracy, the corresponding figures for ultrasound (US) being 73, 83 and 79%, respectively. The sensitivity of SPET in predicting moderate or severe CP (n = 7) was 100% and the specificity 67%, the corresponding figures for US being 71% and 74%, respectively. Brain SPET seems to identify the most severe forms of CP in preterm infants very well at term age, but cannot identify all mild ones. In addition to a low specificity, the radiation exposure restricts usefulness of the method for clinical purposes.

Collagen Ialpha1 and vitamin D receptor gene polymorphisms in South African whites, blacks and Indians.

OBJECTIVE: To determine whether polymorphic differences exist between black, white and Indian South Africans in genes associated with bone mineral density and osteoporosis. DESIGN: Genes selected were the vitamin D receptor (Apa I and Taq I polymorphisms) and collagen (Sp I transcription factor polymorphism) using standard molecular biology techniques. SETTING: Department of Chemical Pathology, Nelson R Mandela School of Medicine, University of Natal, Durban, South Africa. SUBJECTS: Healthy male and female blood donors living in the Durban metropolitan region, South Africa. The group comprised black Africans (n=264), white Caucasians (n=247) and Asians of Indian origin (n=194). RESULTS: No significant differences in genotypes were seen between white and Indian subjects. Blacks had a significantly higher frequency of the TT Taq I genotype and a significantly lower frequency of the Ss Sp I genotype. No ss genotype was detected in blacks. CONCLUSION: The very low frequency of the collagen Sp I s allele and higher frequency of the VDR T allele in blacks may be associated with the lower incidence of osteoporosis in this ethnic group.

Apolipoprotein E polymorphism in South African Zulu women with preeclampsia.

OBJECTIVES: Apolipoprotein E may contribute to the hypertiglyceridemia and consequent endothelial dysfunction of preeclampsia. We carried out a study to determine whether the apolipoprotein E genotype plays any role as a risk factor for preeclampsia in a black South African population with a high incidence of preeclampsia. DESIGN: A descriptive, prospective study design was used. SETTING: King Edward VIII Hospital, a tertiary care, referral academic hospital in Durban, South Africa. PATIENTS AND PARTICIPANTS: One hundred three South African Zulu women with preeclampsia and 110 healthy normotensive women attending the antenatal clinic were recruited. MAIN OUTCOME MEASURES: The relationship between the apolipoprotein E allele and genotype frequencies to preeclampsia as well as adverse perinatal outcome. RESULTS: The frequencies of varepsilon2 and varepsilon4 alleles (0. 19 and 0.25, respectively) were much higher than those reported in other population groups. However, there was no significant difference in the apolipoprotein E genotype and allele frequencies between the study and the control groups. The varepsilon2/2 genotype was associated with increased risk of perinatal death (p = 0.047). CONCLUSION: The study suggests that, despite the high incidence of both preeclampsia and the varepsilon2 and varepsilon4 alleles in South African Zulu women, apolipoprotein E genotype does not appear to be a risk factor for preeclampsia in this population.

The p53 codon 72 polymorphism in black South African women and the risk of cervical cancer.

The p53 codon 72 genotype was examined in blood samples taken from 121 Zulu-speaking black South African women with histologically proven squamous carcinoma of the cervix. Freshly biopsied tumour tissue was also available for human papillomavirus subtyping from 100 of these women. A control group consisted of 251 healthy race-matched women attending a contraceptive service facility. The results show that there were no statistically significant differences in the frequency of the homozygous arginine genotype between patients with cancer of cervix, irrespective of human papillomavirus status, and healthy controls. This finding suggests that the arginine allele does not predispose towards viral tumour genesis in this population, and supports the findings of research done in other ethnic groups.

Activity-based costing in radiology. Application in a pediatric radiological unit.

PURPOSE: To get an informative and detailed picture of the resource utilization in a radiology department in order to support its pricing and management. MATERIAL AND METHODS: A system based mainly on the theoretical foundations of activity-based costing (ABC) was designed, tested and compared with conventional costing. The study was performed at the Pediatric Unit of the Department of Radiology, Oulu University Hospital. The material consisted of all the 7,452 radiological procedures done in the unit during the first half of 1994, when both methods of costing where in use. Detailed cost data were obtained from the hospital financial and personnel systems and then related to activity data captured in the radiology information system. RESULTS: The allocation of overhead costs was greatly reduced by the introduction of ABC compared to conventional costing. The overhead cost as a percentage of total costs dropped to one-fourth of total costs, from 57% to 16%. The change of unit costs of radiological procedures varied from -42% to +82%. CONCLUSION: Costing is much more detailed and precise, and the percentage of unspecified allocated overhead costs diminishes drastically when ABC is used. The new information enhances effective departmental management, as the whole process of radiological procedures is identifiable by single activities, amenable to corrective actions and process improvement.

Prematurity-associated nephrocalcinosis and kidney function in early childhood.

To assess the impact of prematurity-associated nephrocalcinosis on kidney function later in life, 20 premature children with neonatal nephrocalcinosis and 20 controls, matched for birth weight and postnatal age but without nephrocalcinosis, were examined (birth weight 905+/-209 vs. 957+/-226 g; study age 4.7+/-1.1 vs. 4.6+/-0.9 years). Distal tubular acidification capacity was measured with the oral acetazolamide test, in which the response was abnormal in 1 out of the 20 children with a history of nephrocalcinosis, but in none of the controls. Urinary calcium and beta(2)-microglobulin excretion were higher in the children with nephrocalcinosis, but no differences were found in fractional excretion of sodium and potassium or tubular reabsorption of phosphate. Estimated creatinine clearance was not different between the groups. Of the 6 children with nephrocalcinosis lasting beyond 2 years of age, 5 had had chronic lung disease neonatally and exhibited a tendency for compensated respiratory acidosis at the time of the examination. Neonatal nephrocalcinosis seems to lead to some signs of renal tubular dysfunction in early childhood of preterm infants. Glomerular function, however, appears not to be specifically disturbed by nephrocalcinosis.

5,10 methylenetetrahydrofolate reductase polymorphism in black South African women with pre-eclampsia.

The polymorphic C677T mutation in the gene encoding 5,10 methylenetetrahydrofolate reductase has been shown to be a risk factor for pre-eclampsia in Japanese and European women when inherited as a homozygous trait. We attempted to verify these findings in a black African population with a high incidence of pre-eclampsia. No difference in frequency of the T-allele was observed in 105 women with pre-eclampsia, compared with 110 healthy pregnant normotensive women. Only one woman with pre-eclampsia was TT homozygous, suggesting that methylenetetrahydrofolate reductase polymorphism is not an important factor in the pathogenesis of pre-eclampsia in black South African women.

PIP: This study aims to determine whether the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) polymorphism plays any role as a risk factor for preeclampsia in black South African women. A total of 105 pregnant women with preeclampsia were included in the study and were subjected to several tests. Test results showed that the MTHFR genotypes and allele frequencies in the study group and control group have no significant difference in the frequencies of the homozygous TT genotype or the T-allele. Among the respondents, only one woman with preeclampsia was homozygous for the C677T mutation. Findings indicate that preeclampsia in black South African women affects 18% of pregnancies. In addition, the C677T mutation cannot be considered an important factor in the pathogenesis of preeclampsia in this study population. Further studies are required for clarifications concerning these issues.

Nephrocalcinosis in full-term infants receiving furosemide treatment for congestive heart failure: a study of the incidence and 2-year follow up.

UNLABELLED: In order to study the incidence and course of nephrocalcinosis in full-term infants with congestive heart failure receiving long-term furosemide treatment, 36 such infants (median age 2.9 months, range 1.2-8.0) and 36 full-term control infants not receiving any diuretics (median age 3.4 months, range 1.1-8.4) were studied by renal ultrasonography and random urine calcium variables. The infants with nephrocalcinosis were followed at 3-6 month intervals up to 2 years of age, or until ultrasonic resolution. Nephrocalcinosis was found in 5 out of the 36 (14%) treated infants, but in none of the controls (P = 0.03). The dose of furosemide was higher in the infants with nephrocalcinosis than in those without (1.9+/-0.6 vs. 1.3+/-0.4 mg/kg per day; P = 0.01). The urinary calcium concentration was higher in the infants receiving furosemide than in controls and a similar trend was observed in the urinary calcium/creatinine ratio, but these variables did not differ between the study infants with and without nephrocalcinosis. Ultrasonic resolution of nephrocalcinosis was observed in 3 of the 5 infants at 12 months, but in the other 2 the condition still persisted at 24 months. CONCLUSIONS: Long-term furosemide treatment in full-term infants with congestive heart failure entails a considerable risk of developing nephrocalcinosis. Renal ultrasonography is warranted in these patients within a few months after initiation of the treatment and in the case of nephrocalcinosis alteration of the diuretic regimen is to be considered.

Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low birthweight infants.

This longitudinal study was undertaken in order to elucidate the incidence and natural course of nephrocalcinosis in preterm infants and to evaluate whether the ultrasonic classification for nephrocalcinosis used here is suitable for predicting subsequent resolution of the condition. A total of 129 very low birthweight infants were screened for nephrocalcinosis by renal ultrasonography at 2 wk, 6 wk and 3 mo. The pyramidal changes were classified as peripheral, scattered or extensive. Follow-up renal ultrasonography was performed on the infants with nephrocalcinosis at 6, 12, 18 and 24 mo, and thereafter annually up to 6 y of age, or until ultrasonic resolution. The overall incidence of nephrocalcinosis was 20% (26/129). Nephrocalcinotic changes were peripheral in 14 out of the 26 infants (54%), scattered in 7 (27%) and extensive in 5 (19%). Ultrasonic resolution had taken place in all the cases with peripheral nephrocalcinosis by 12 mo, but 3 of the 7 infants with the scattered pattern and 3 of the 4 with the extensive pattern (1 died) were still affected at 24 mo. In two cases with extensive nephrocalcinosis the condition still persisted at 5-6 y of age. We conclude that about 20% of very low birthweight infants develop nephrocalcinosis during the first 3 mo of life. In about half of the affected infants renal changes are restricted and transient, but more extensive forms may last several years. The classification of nephrocalcinosis used here is appropriate for predicting later ultrasonic resolution.

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

The effects of valproate, carbamazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy.

OBJECTIVE: Antiepileptic drugs (AEDs) have endocrine effects that may interfere with growth and sexual maturation in children. The aim of this study was to evaluate the effects of AEDs on growth and pubertal development in girls with epilepsy. STUDY DESIGN: Forty girls taking valproate (VPA), 19 girls taking carbamazepine (CBZ), and 18 girls taking oxcarbazepine (OXC) for epilepsy and 49 healthy control girls participated in the study, which included a cross-sectional clinical examination when the girls were 8 to 18 years old and a longitudinal growth analysis from the age of 1 year. RESULTS: VPA, CBZ, or OXC did not affect linear growth or pubertal development in girls with epilepsy. However, the patients taking VPA gained weight, and an increase in relative weight was seen in girls who started their medication before as well as during puberty. The body mass index of the VPA-treated girls (19.8 +/- 4.8 kg/m2) was higher than that of the control girls (18.0 +/- 2.5 kg/m2) at clinical examination. The weight of the girls taking CBZ or OXC for epilepsy was similar to that of the control girls. Plasma insulin-like growth factor-I (IGF-I) levels were higher in girls treated with CBZ and OXC than in the control girls, but AEDs did not affect fasting serum insulin, IGF-binding protein-1, or IGF-binding protein-3 concentrations in girls on VPA, CBZ, or OXC medication during the period of exposure (average 2.8, 4.1, and 1.9 years, respectively) in this study. CONCLUSIONS: AEDs do not seem to have any adverse effects on linear growth or sexual maturation in girls with epilepsy. VPA-related weight gain can be seen already in prepuberty and it is not associated with hyperinsulinemia in these young patients. The clinical significance of high circulating concentrations of IGF-I in patients taking CBZ or OXC remains to be defined.

Molecular diagnosis of multiple endocrine neoplasia type 2A.

OBJECTIVE: To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia. SUBJECTS: A three-generation kindred with clinically and biochemically diagnosed medullary thyroid cancer. METHOD: Identification of a heterozygote mutation by nucleic acid sequencing and restriction analyses. RESULTS: A heterozygote T-->C (Cys-->Arg) mutation at codon 618 in exon 10 of the RET proto-oncogene was identified in 4 family members who had previously been diagnosed with medullary thyroid cancer. The same mutation was also found in one of the proband's presymptomatic children who subsequently underwent a pre-emptive thyroidectomy. The genetic diagnosis was confirmed by histology. No mutations were detected in any other family members. CONCLUSION: Identification of heterozygote germline mutations in multiple endocrine neoplasia is direct, highly accurate and cost-effective. This study demonstrates that, appropriately used, molecular diagnosis can supersede conventional biochemical methods in the management of patients with inherited cancers.

Pituitary function in children with hydrocephalus before and after the first shunting operation.

OBJECTIVE: Children with shunted hydrocephalus experience slow linear growth in prepuberty, accelerated pubertal maturation and a reduced final height. A substantial proportion of these patients have a poor growth hormone (GH) response to stimulation and reduced pituitary volume. The basic mechanisms behind these phenomena are still unknown, but one can hypothesize that an unphysiological intracranial pressure (ICP) may be involved. This study was undertaken to investigate the effect of increased ICP on pituitary function. DESIGN: Twenty-one children (nine males) aged 4 months to 15 years were evaluated for pituitary function before and after their first shunting operation. METHODS: A clinical examination was performed, bone age was determined and a combined pituitary stimulation test was performed to evaluate GH, luteinizing hormone, follicle-stimulating hormone, cortisol, thyrotropin and prolactin secretion. RESULTS: GH concentrations were significantly higher 10 and 15 min before the operation (P=0.04 and P=0.03 respectively) than after it. The basal levels of insulin-like growth factor-I (IGF-I) tended to be higher before the operation than afterwards and those of its binding protein-3 (IGFBP-3) were significantly so (P<0.01). CONCLUSIONS: The higher GH response to GH releasing hormone and circulating IGFBP-3 levels in children with hydrocephalus before compared with after their first shunting operation raise the possibility that the reduced GH secretion and retarded linear growth observed in children with shunted hydrocephalus may be a consequence of decreased ICP and/or the lack of physiological pressure variations.

Iopentol (Imagopaque 300) compared with iohexol (Omnipaque 300) and diatrizoate (Urografin 292) in pediatric urography. A clinical trial assessing adverse events and diagnostic information.

A double-blind, parallel-group trial was performed in 96 children in order to evaluate and compare the safety and efficacy of iopentol (Imagopaque, Nycomed imaging AS, Oslo, Norway) with those of routinely used contrast media. Ten children below 1 year of age received iopentol and eight received iohexol (Omnipaque, Nycomed Imaging AS, Oslo, Norway) (both 300 mg I/ml) in a random manner. Seventy-eight children (39 in each group), between one and 10 years of age, received iopentol 300 or diatrizoate (Urografin, Schering AG, Berlin, Germany) 292 mg I/ml for urography. No adverse events were observed among the children below 1 year of age. In the group between one and 10 years there was a statistically and clinically significant difference (p = 0.007) in the incidence of adverse events between the iopentol (2.6%) and diatrizoate (25.6%) groups. All adverse events were of mild or moderate intensity. No serious reactions were encountered. The overall quality of visualization was judged to be diagnostic for all patients. This study supports the use of non-ionic contrast media in pediatric patients and confirms that iopentol is a safe and effective contrast medium well suited for children from 0-10 years of age.

Axial radiography or CT in the measurement of patellofemoral malalignment indices in children and adolescents?

The present study compares the repeatability of patellofemoral malalignment (PFM) indices obtained by 20 degree flexion axial radiography (AR) and computerized tomography (CT) with 0 degree and 20 degree flexion of the knees in children and adolescents. Thirty-one patients with a mean age of 14.2 years (range 8 to 19.2 years) suffering from PFM were examined using these two radiographic techniques. The lateral patellofemoral angle (LPA), the lateral patellar tilt (LPT), and the lateral patellar displacement (LPD) were measured by by two different investigators on different occasions, and the agreement of these indices between CT and AR was evaluated according to Bland and Altman's statistical method. LPT and LPD obtained by AR were more reliable and repeatable than those obtained by CT. The quadriceps muscle contraction exacerbates PFM indices significantly with the knees in full extension (P = 0.0001). LPT and LPD measured at 20 degrees AR show reliably the two pathological components (the patellar tilt and the lateral patellar displacement) of PFM which are necessary for diagnosis and treatment planning. CT with quadriceps contractions is better in qualitative screening of more subtle cases of PFM.

Variations in c-erbB-2 proto-oncogene status in breast cancer tumors as detected by two different cDNA probes.

We examined 232 breast carcinomas for c-erbB-2 amplification by Southern analysis using two different cDNA probes. Using these same probes, 95 of these tumors were also examined for mRNA expression by Northern analysis. Amplification was detected in 20 and 17% of the tumors with the probes pHER 2 and pCER 204, respectively, but only 10% showed amplification with both probes. A significantly higher incidence (p < 0.01) of mRNA overexpression was detected with the pHER 2 probe (34%) compared with the pCER 204 probe (16%), with only 11% of tumors demonstrating overexpression with both probes. A total of 10 tumors (11%) exhibited amplification as well as overexpression with pHER 2, whereas significantly fewer (3%) manifested both abnormalities with the larger pCER 204 probe (p < 0.05). Amplification of c-erbB-2, as detected with the pHER 2 probe but not with the pCER 204 probe, was significantly associated with the absence of both estrogen and progesterone receptors (p < 0.05 and p < 0.01, respectively). No relationship was found with other clinical prognostic indicators, such as nodal involvement and metastases. As determined by either probe, overexpression was not associated with prognostic indicators. There was no significant difference in the c-erbB-2 status of tumors from different racial groups.