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Biomedical subjects

J K Wales

Publications and source records attributed to J K Wales.

At least 19 recordsLinked to original sources
PubMed2005

Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.

Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Proton magnetic resonance spectroscopy of brain lesions in children with neurofibromatosis type 1.

Two of the recognized cranial MRI findings in children with neurofibromatosis type 1 (NF1) are neurofibromatosis bright objects (NBO) and brain glioma. Their differential diagnosis can be problematic. This study aimed to determine the features of these abnormalities on short echo-time in-vivo proton magnetic resonance spectroscopy. Twenty children under the age of 16 with NF1 were studied. A single voxel, short echo-time technique (TE = 20 ms; TR = 5000 ms) was used to obtain proton spectra of typical NBO and any regions suggestive of atypical bright objects or tumor. Nine children without neurofibromatosis with no structural brain abnormality acted as aged-matched comparisons. A semi-quantitative analysis indicated significant increase in choline and myo-inisitol in tumors compared to typical NBO (p < 0.05) and compared to controls (p < 0.05); reduction in the levels of N-acetyl moieties in NBO compared to controls (p < 0.05); reduction in N-acetyl in tumors compared to controls (p < 0.001); and reduction in glutamate/glutamine in tumors compared to controls (p < 0.05). This cross-sectional data suggests that proton spectroscopy can aid differentiating between NBO and brain (non-optic/hypothalamic) glioma. Typical NBO have different short echo-time spectroscopic appearances compared to normal brain.

Adolescent↗
PubMed2001

Risk factors for coronary heart disease in obese non-diabetic subjects.

OBJECTIVE: To examine relationships between body mass index (BMI) and coronary risk factors in obese subjects presenting to a dedicated obesity clinic. STUDY DESIGN: Cross-sectional population survey from a single centre. SUBJECTS: Three hundred and eighty-six consecutive non-diabetic obese subjects (301 women, 85 men) attending an obesity clinic for the first time (mean BMI 43.3 kg/m(2); range 30.6-71.5), aged 17-69 y (mean 40.1). MEASUREMENTS: Height, weight, resting blood pressure, fasting plasma cholesterol, triglyceride, glucose and uric acid concentrations. RESULTS: All variables measured showed an increase with higher BMI (triglycerides, P=0.04; glucose, P=0.007; urate, P<0.001; systolic BP, P<0.001; diastolic BP, P<0.001) as measured by one-way ANOVA, except cholesterol concentration which showed no relationship with BMI. In comparison with the group of subjects with BMI 30-35 kg/m(2) mean values for all variables were higher in the more obese subjects. CONCLUSIONS: Non-diabetic subjects with BMI>35 kg/m(2) carry a burden of common coronary risk factors which appears to increase with greater obesity. The risk factor pattern observed echoes that described in insulin resistance syndromes. Plasma cholesterol concentration appears not to be related to BMI.

Adolescent↗
PubMed2001

Symptomatic adrenal insufficiency during inhaled corticosteroid treatment.

Symptomatic adrenal insufficiency, presenting as hypoglycaemia or poor weight gain, may occur on withdrawal of corticosteroid treatment but has not previously been reported during inhaled corticosteroid treatment. This case series illustrates the occurrence of clinically significant adrenal insufficiency in asthmatic children while patients were on inhaled corticosteroid treatment and the unexpected modes of presentation. General practitioners and paediatricians need to be aware that this unusual but acute serious complication may occur in patients treated with inhaled corticosteroids.

Administration, Inhalation↗
PubMed2000

Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth.

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS: The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.

Adolescent↗
PubMed2000

Molecular genetics of septo-optic dysplasia.

Septo-optic dysplasia (SOD) is a highly variable condition characterized by midline neurological abnormalities associated with pituitary hypoplasia and optic nerve hypoplasia. The aetiology is unknown. Mutant mice, in which a novel homeobox gene, Hesx1, has been disrupted, exhibit a phenotype that resembles the phenotype of SOD. We therefore wished to explore the possibility that this gene is implicated in SOD. We cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis, followed by cloning and sequencing of any exons which showed a band shift. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain, leading to a loss of in vitro DNA binding. Subsequently, we have identified heterozygous mutations in HESX1 that are associated with milder pituitary phenotypes. Our studies indicate a vital role for Hesx1/HESX1 in forebrain and pituitary development in mouse and man, and hence in some cases of SOD.

Animals↗
PubMed2000

Neonatal and post-natal growth.

Growth velocity is higher in late intra-uterine and early post-natal life than at any time thereafter, and accurate measurements are essential for appropriate monitoring. The accuracy with which such measurements are made and recorded is frequently questionable, however, and short- and medium-term changes in growth may be difficult to interpret in the light of normal variations in the pattern of growth. Infants who are small at birth must be accurately classified because intra-uterine growth retardation and small for gestational age have different implications for both causation and outcome. Prediction of expected growth on the basis of mid-parental height is essential but frequently omitted. Post-natal growth impairment is common in pre-term infants and is often rapid in onset. Poor growth may continue for many months, and catch-up may be incomplete. Early growth failure may have a significant influence on subsequent morbidity and mortality.

Aging↗
PubMed2000

Comparison of high-fat and high-carbohydrate foods in a meal or snack on short-term fat and energy intakes in obese women.

The present study aimed to compare the action of high-fat and high-carbohydrate (CHO) foods on meal size (satiation) and post-meal satiety in obese women. A within-subjects design was used; each participant received all four nutritional challenges. Fifteen healthy obese women (age 21-56 years, BMI 35-48 kg/m2) participated; thirteen completed all four test days. On two test days, participants were exposed to a nutritional challenge comprising an ad libitum high-fat or high-CHO lunch. On the other two test days they were exposed to a challenge comprising an ad libitum sweet high-fat or high-CHO mid-afternoon snack. Energy and macronutrient intakes were measured at each eating episode. Visual analogue rating scales were completed periodically to record subjective feelings of appetite. When offered a high-CHO selection of foods at lunch and mid-afternoon participants consumed less energy than when offered a high-fat selection. However, post-meal satiety was similar. Total test-day energy intake was significantly higher when high-fat foods were consumed at lunch, but not as a snack. Consumption of high-fat foods at a lunch and snack increased the amount of fat consumed over the whole test day. In conclusion, energy intake of an eating episode was influenced by nutrient composition in this group of obese women. Consumption of high-fat foods at lunch or as a snack led to overconsumption relative to high-CHO foods. However, high-fat foods at meals may have greater potential to influence daily intake than at snacks, probably because meals are larger eating episodes and therefore give greater opportunity to overconsume.

Adult↗
PubMed1999

HESX1: a novel gene implicated in a familial form of septo-optic dysplasia.

The homeobox gene Hesx1, which encodes a pituitary transcription factor, is first expressed at gastrulation in the mouse embryo. Hesx1 expression begins in prospective forebrain tissue but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Transgenic mice lacking Hesx1 exhibit a phenotype comprising variable anterior CNS defects, such as a reduced prosencephalon, abnormalities in the corpus callosum and septum pellucidum, anophthalmia or microphthalmia, defective olfactory development and bifurcations in Rathke's pouch with pituitary dysplasia. A comparable and highly variable phenotype in humans is septo-optic dysplasia. We have cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis. Two siblings with septo-optic dysplasia were homozygous for a missense mutation within the HESX1 homeobox. This mutation resulted in the substitution of a highly conserved arginine residue (Arg53) by cysteine and led to a loss of in vitro DNA binding. Hence, a vital role for Hesx1/HESX1 in forebrain and pituitary development in mice and humans is suggested.

Animals↗
PubMed1998

Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.

During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.

Abnormalities, Multiple↗
PubMed1998

A comparison of ultrasonic and mechanical stadiometry.

AIM: To compare an ultrasonic height measuring device (Gulliver) with mechanical stadiometry and the classical "book and tape measure" method. METHODS: Blinded duplicate measurements of height were made on each of 14 children by a pair of observers using a stadiometer (H) and Gulliver (G). Height was measured on a further 18 children by parents and an auxologist using Gulliver and the book and tape method (TM), and the results were compared with those obtained with a single stadiometry measurement. Finally, measurement of a rigid metal box was made on 10 occasions by the three methods. RESULTS: In the group of 14 children, the mean difference (range) in height (H minus G) was +2.8 cm (+0.5 to +4.55 cm), with H giving a systematically higher value in 276 of 280 individual measurements. In the group of 18 children, height by H was greater than by G or TM in 47 of 52 individual measurements. The mean (SD) height of the box by H (61.60 (0.07) cm) was greater than by G (60.96 (0.15) cm; p < 0.001) but not TM (61.4 (0.16) cm; p > 0.05). G and TM produced three times less reliable estimations of height than H, but with a large difference in cost, and there was evidence of systematic underrecording of height by 0.5 cm with G. CONCLUSIONS: Stadiometry is precise and reproducible, and can detect true changes in height over one month periods in mid-childhood, and should remain the standard way of observing growth. The book and tape method can produce clinically acceptable quarterly estimations of height that can be performed in the home.

Anthropometry↗
PubMed1998

Serum insulin-like growth factor-I, IGF binding protein-3 and IGFBP-3 protease activity after cranial irradiation.

The relationship between peak growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3) and IGFBP-3 protease activity was studied in 28 children and adolescents undergoing investigation of pituitary function 0.4-14.2 years after cranial or craniospinal irradiation for the treatment of CNS tumours distant from the hypothalamic-pituitary axis (n = 16) or prophylaxis against CNS leukaemia (n = 12). Seven out of 15 patients with GH deficiency (GHD) (defined as a peak GH concentration <7.5 ng/ml in a stimulation test) had IGF-I <-2 standard deviation score (SDS). None of the 28 patients had serum IGFBP-3 concentrations measured by radioimmunoassay (RIA) <-1.5 SDS with no difference between those with and without GHD. IGFBP-3 concentrations measured by RIA were strongly correlated to IGFBP-3 band density on Western ligand blot (WLB) (r = 0.71; p < 0.0001). IGFBP-3 protease activity was negatively correlated to IGFBP-3 by RIA (r = -0.55; p < 0.01) and to IGFBP-3 by WLB (r = -0.51; p < 0.01). Twenty-two patients had normal IGFBP-3 protease activity (<30% of the activity in pregnancy serum) indicating that serum IGFBP-3 protease activity does not account for the normal levels of IGFBP-3 in RIA. Low serum IGF-I but normal IGFBP-3 concentrations and in the majority normal IGFBP-3 protease activity was found in patients in the years after CNS irradiation. Neither serum IGF-I nor IGFBP-3 can be used as a reliable index of the development of radiation-induced GHD.

Adolescent↗
PubMed1997

The measurement of neonates.

Accurate measurements of both healthy and premature neonates are possible but rarely performed. Routine anthropometry is often not performed at all or with large measurement errors due to inadequate training of personnel or inappropriate equipment. Sick neonates are often considered unsuitable for anthropometry and growth is wrongly equated with weight gain. Gain in length may be disturbed by poor health and permanent extrauterine growth retardation and changes in body proportions induced in some survivors of neonatal intensive care. Drug treatments may have profound effects on length gain and the relationship of length to weight.

Anthropometry↗
PubMed1997

Biochemical tests in the diagnosis of childhood growth hormone deficiency.

GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. We have examined, therefore, the performance of other tests of the GH axis [urinary GH excretion, serum insulin-like growth factor I(IGF-I), and IGF-binding protein-3 (IGFBP-3) levels] compared with GH stimulation tests in identifying children defined clinically as GH deficient. Group I comprised 60 children (mean age, 10.3 +/- 4.8 yr) whose diagnosis of GHD was based on a medical history indicative of pituitary dysfunction (n = 43) or on the typical phenotypic features and appropriate auxological characteristics of isolated GHD (n = 17). Group II comprised 110 short children (mean age, 9.8 +/- 4 yr) in whom GHD was not suspected, but needed exclusion. The best sensitivity for a single GH test was 85% at a peak GH cut-off level of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The sensitivities of IGF-I, IGFBP-3, and urinary GH, using a cut-off of -2 SD score were poor at 34%, 22%, and 25%, respectively, with specificities of 72%, 92%, and 76% respectively. Only 2 of 21 pubertal children in group I and none of the 27 subjects with radiation-induced GHD had an IGFBP-3 SD score less than -1.5. We devised a scoring system based on the positive predictive value of each test, incorporating data from the GH test and the IGF-I and IGFBP-3 levels. A specificity of 94% could be achieved with a score of 10 or more (maximum 17) (sensitivity 34%). The latter could not be improved above 81% with a score of 5 points or more (specificity, 69%). A high score was, therefore, highly indicative of GHD, but was achieved by few patients. A normal IGFBP-3 level, however, did not exclude GHD, particularly in patients with radiation-induced GHD and those in puberty. A GH test with a peak level more than 10 ng/mL was the most useful single investigation to exclude a diagnosis of GHD.

Adolescent↗