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Biomedical subjects

B A Hamilton

Publications and source records attributed to B A Hamilton.

At least 19 recordsLinked to original sources
PubMed2004

The relation of insulin, leptin and IGF-1 to birthweight in offspring of women with type 1 diabetes.

OBJECTIVE: Maternal diabetes is associated with excess foetal growth. We have assessed the influence of maternal diabetes on hormones associated with foetal growth and the relationship of these hormones to birthweight. DESIGN: Case-control study. PATIENTS: Singleton offspring of mothers with type 1 diabetes (ODM, n = 140) and control mothers (Control, n = 49). MEASUREMENTS: Birthweight, cord blood insulin, proinsulin, 32-33 split proinsulin, leptin, IGF-1, IGFBP-3, cortisol. RESULTS: Maternal diabetes was associated with higher birthweight (ODM 3.80 +/- 0.69 kg; Control; 3.56 +/- 0.52 kg, P = 0.02) and marked increases in insulin (median [interquartile range]: ODM 110 [60-217] pmol/l; Control 22 [15-37] pmol/l; P < 0.0001) and leptin (ODM 32 [15-60] ng/ml; Control 9 [4-17] ng/ml; P < 0.0001) but no absolute difference in IGF-1 (ODM 7.9 [6.2-9.8] nmol/l, Control 7.5 [6.2-9.8] nmol/l, P = 0.24) or its principle binding protein IGFBP-3 (ODM 1.63 +/- 0.38 micro g/ml, Control 1.63 +/- 0.28 micro g/ml; P = 0.12). Individually, insulin, insulin propeptides, leptin, IGF-1 and IGFBP-3 were significantly (P < 0.05) correlated with birthweight (in ODM and Control). IGF-1 and leptin were positively related to birthweight independently of each other and insulin in both ODM and Control. By contrast, insulin showed independent relationships to birthweight in ODM (P < 0.0001) but not in Control (P = 0.4). CONCLUSIONS: Maternal diabetes is associated with marked elevation of insulin and leptin in cord blood of their offspring. Hormonal correlates of birthweight differ between ODM and Control with an independent relationship of insulin to birthweight observed only in ODM.

Adult↗
PubMed2004

Type 1 diabetes-related antibodies in the fetal circulation: prevalence and influence on cord insulin and birth weight in offspring of mothers with type 1 diabetes.

During pregnancy, maternal type 1 diabetes-associated autoantibodies may cross the placenta. It is proposed that insulin antibodies (IA) allow transfer of insulin across the placenta, contributing to fetal hyperinsulinemia and macrosomia. We assessed the prevalence of IA, the tyrosine phosphatase IA-2, and glutamic acid decarboxylase (GADA) in cord blood from offspring of mothers with type 1 diabetes (ODM, n = 138) and control mothers (control, n = 47) and further assessed cross-sectional relationships of antibody titers to birth weight and fetal insulin. In ODM, antibodies were frequently present in cord blood; 124 ODM (95%) were positive for IA, 82 (59%) were positive for GADA antibodies, and 61 (44%) were positive for IA-2 antibodies. In controls, GADA and IA-2 antibodies were absent, whereas seven controls (15%) were positive for IA at low titers (P < 0.0001 ODM vs. controls for all).ODM with IA (IA positive) or without IA (IA negative) had similar birth weights (mean +/- sd: IA positive, 3.8 +/- 0.7 kg; IA negative, 4.0 +/- 0.6 kg; P = 0.31) and cord insulin concentrations (IA positive: median, 112 pmol/liter; interquartile range, 62-219 pmol/liter; IA negative: median, 114 pmol/liter; interquartile range, 59-194 pmol/liter; P = 0.96). Similarly, the presence of GADA and/or IA-2 autoantibodies (n = 103) was not associated with differences in birth weight or insulin concentrations. Antibody titers were not associated with birth weight or insulin as continuous variables in either controls or ODM. Islet autoantibodies and IA are a common finding in cord blood of ODM, but we found no evidence that they influence offspring insulin concentrations or weight at birth.

Autoantibodies↗
PubMed2003

Insulin and insulin propeptides at birth in offspring of diabetic mothers.

Maternal diabetes during pregnancy is associated with excess fetal growth and increased fetal insulin production. We hypothesized that insulin propeptides (proinsulin and 32-33 split proinsulin) might be more robust indicators of chronic fetal overproduction of insulin. We examined insulin-like molecules in cord blood (ILM) (insulin, proinsulin, and 32-33 split proinsulin) in relation to birth weight, maternal glycemia, and cord glucose in 140 offspring of mothers with type 1 diabetes (ODM) and 49 offspring of mothers who did not have diabetes (CONTROL) as well as degradation of ILM in response to sampling conditions at birth. Insulin propeptides were abundant in cord blood, comprising 50% of ILM in CONTROL and 36% in ODM (P < 0.0001) and more resistant to degradation than insulin (P < 0.05). Concentrations of all three ILM were highly intercorrelated with median values 2- to 5-fold higher in ODM than CONTROL [e.g. median (range): insulin ODM 110 (60-217) pmol/liter; CONTROL 22 (15-37) pmol/liter; P < 0.0001]. In ODM, 32-33 split proinsulin and proinsulin were more closely related to birth weight (Spearman r for ILM: r(32-33 split)= 0.54; r(PROINSULIN): r = 0.54; r(INSULIN) = 0.40: r(32-33 split) and r(PROINSULIN) > r(INSULIN)P < 0.05) and fetal leptin (r(32-33 split)= 0.55; r(PROINSULIN); r = 0.54; r(INSULIN) = 0.22: r(32-33 split) and r(PROINSULIN) > r(INSULIN)P < 0.05) than insulin). By contrast, insulin was more closely related to cord glucose (r(32-33 split) = 0.15; r(PROINSULIN): r = 0.10; r(INSULIN) = 0.42: r(INSULIN) > r(32-33 split) and r(PROINSULIN)P < 0.05). In CONTROL, 32-33 split proinsulin was also more closely related to fetal leptin r(32-33 split)= 0.61; r(PROINSULIN): r = 0.29; r(INSULIN) = 0.33: r(32-33 split) > r(INSULIN)P < 0.05). In ODM, 32-33 split proinsulin and proinsulin have closer relationships to fetal growth and leptin concentrations at birth than insulin. Measurement of insulin propeptides may be advantageous in assessment of the influence of maternal hyperglycemia on the newborn.

Birth Weight↗
PubMed2001

Of mice and genome sequence.

Availability of the mouse genome sequence will have a major impact on the study of vertebrate evolution, mammalian biology, and animal models of human disease. Resources to explore genome biology in mice will maximize the effect of this watershed event.

Animals↗
PubMed2000

The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a.

Exon shuffling is thought to be an important mechanism for evolution of new genes. Here we show that the mouse neurological mutation flailer (flr) expresses a novel gene that combines the promoter and first two exons of guanine nucleotide binding protein beta 5 (Gnb5) with the C-terminal exons of the closely linked Myosin 5A (MyoVA) gene (Myo5a). The flailer protein, which is expressed predominantly in brain, contains the N-terminal 83 amino acids of Gnb5 fused in-frame with the C-terminal 711 amino acids of MyoVA, including the globular tail domain that binds organelles for intracellular transport. Biochemical and genetic studies indicate that the flailer protein competes with wild-type MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkinje cells. The flailer protein thus has a dominant-negative mechanism of action with a recessive mode of inheritance due to the dependence of competitive binding on the ratio between mutant and wild-type proteins. The chromosomal arrangement of Myo5a upstream of Gnb5 is consistent with non-homologous recombination as the mutational mechanism. To our knowledge, flailer is the first example of a mammalian mutation caused by germ line exon shuffling between unrelated genes.

Amino Acid Sequence↗
PubMed2000

Heredity and the autonomic nervous system in human hypertension.

Because the complex phenotype of human hypertension is at least in part genetically determined, how individual genes ultimately contribute to the disease is not well understood. By contrast, intermediate phenotypes are traits associated with complex disease, but which may display simpler genetic properties such as greater heritability, more consistent and earlier penetrance and bimodality, and may suggest particular candidate susceptibility genes. Because autonomic nervous system activity is altered in hypertension, we examined biochemical, physiologic, and pharmacologic autonomic traits that fulfill at least some of these properties. Such biochemical, physiologic, or pharmacologic autonomic traits may be especially valuable as phenotypic anchor points in linkage or association studies probing the genetic basis of human hypertension.

Autonomic Nervous System↗
PubMed2000

Care management in three practices--scope for improvement?

OBJECTIVE: The process of assessment of older people for residential/nursing home care may take place by hospital based social workers, or by care managers working in the community. We sought to compare the assessment process in each setting. The standards for the audit were that the data collection for both groups was equivalent, that both groups had a multi-disciplinary assessment, and that outcomes in both settings were appropriate. DESIGN: Identification of all older people assessed as requiring residential/nursing home care from 1/7/97-31/12/97, who were registered with the three general practices in Aberdeen participating in this study. Social Work case files and care plans were reviewed. All individuals were visited and dependency scores obtained--Abbreviated Mental Test, Barthel Index, and CAPE (Clifton Assessment Procedures for the elderly--Behaviour Rating Scale component) score. SETTING: Review of hospital social work case files, and community based case files. Interviewing of the older person in their own home, hospital, residential or nursing home to obtain dependency scores. SUBJECTS: Thirty three people were referred-17 from the community, and 16 from hospital. RESULTS: Case files in both groups were well maintained. There were differences in procedures between the assessment processes, but outcomes appeared to be similar. There was no statistical difference in mean dependency scores between each group. However, information on levels of support in the files was limited, particularly for the community group. Dependency scores correlated with residential/nursing home care being appropriate for the 33 individuals, but only 50% of people were identified as wanting such arrangements. Evidence of a recorded medical assessment was absent in 47% of the community referred population. CONCLUSION: Evidence of a multi-disciplinary assessment was not always available, especially for the community referred individuals. A greater emphasis on a multi-disciplinary assessment could highlight a need for rehabilitation, which might allow for the improvement and maintenance of some frail older people in the community, this often being in accordance with their wishes.

Activities of Daily Living↗
PubMed1997

The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression.

The mouse vibrator mutation causes an early-onset progressive action tremor, degeneration of brain stem and spinal cord neurons, and juvenile death. We cloned the vibrator mutation using an in vivo positional complementation approach and complete resequencing of the resulting 76 kb critical region from vibrator and its parental chromosome. The mutation is an intracisternal A particle retroposon insertion in intron 4 of the phosphatidylinositol transfer protein alpha gene, causing a 5-fold reduction in RNA and protein levels. Expression of neurofilament light chain is also reduced in vibrator, suggesting one signaling pathway that may underlie vibrator pathology. The vibrator phenotype is suppressed in one intercross. We performed a complete genome scan and mapped a major suppressor locus (Mvb-1) to proximal chromosome 19.

Alleles↗
PubMed1996

Disruption of the nuclear hormone receptor RORalpha in staggerer mice.

Homozygous staggerer (sg) mice show a characteristic severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells. These cells show immature morphology, synaptic arrangement, biochemical properties and gene expression, and are reduced in numbers. In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss, suggesting that sg has a role in mature Purkinje cells. Effects of this mutation on cerebellar development have been studied for 25 years, but its molecular basis has remained unknown. We have genetically mapped staggerer to an interval of 160 kilobases on mouse chromosome 9 which was found to contain the gene encoding RORalpha, a member of the nuclear hormone-receptor superfamily. Staggerer mice were found to carry a deletion within the RORalpha gene that prevents translation of the ligand-binding homology domain. We propose a model based on these results, in which RORalpha interacts with the thyroid hormone signalling pathway to induce Purkinje-cell maturation.

Amino Acid Sequence↗
PubMed1996

The effect of human immunodeficiency virus infection and drug use on birth characteristics.

OBJECTIVE: To explore the effect of human immunodeficiency virus (HIV) infection and drug use on birth weight, length, and gestational duration at delivery. METHODS: Subjects had a history of injection drug use or a sexual partner who was an injection drug user, were Scottish, and their HIV serostatus during pregnancy was known. Control pregnancies were matched for age, parity, ethnic group, year of delivery, and postal code sector of home address. In addition, some were matched for smoking and housing deprivation score. Birth weights were standardized for gestational age by expressing them as z scores with a mean of zero and a standard deviation of unity. Statistical analysis was by univariate and multiple regression with multilevel modeling. RESULTS: Regression analysis for birth weight, gestational age, and gestation-adjusted birth weights (z score) included 789 pregnancies in 693 women. Human immunodeficiency virus seropositivity was associated with a z score that was 0.27 lower (P = .03), but there was no significant difference in gestational duration at delivery. Current oral or injection drug use were associated with a reduction in standardized birth weight (z score -0.27, P = .06, and z score -0.28, P = .04, respectively), and injection drug use with a reduction in occipitofrontal circumference only (1.8 cm reduction, P = .05). Injection drug use, but not the other factors, had an effect on gestational age at delivery (1.54 weeks earlier, P < .001). CONCLUSION: Although HIV seropositivity is associated with a small reduction in standardized birth weight, this effect is less than that attributable to smoking and may not be of clinical significance. The effect seems to be associated with placental size. Opiate use, regardless of route, had a small association with reduced birth weight, suggesting a specific drug effect. However, only injection drug use had a strong association with early delivery, and this effect was likely to be clinically significant at the population level.

Birth Weight↗
PubMed1995

Plasma glutathione concentration in patients with chronic hepatitis C virus infection.

It has recently been proposed that a depletion of glutathione (GSH) may be a contributing factor to viral persistence and resistance to interferon-alpha (IFN-alpha) therapy in chronic hepatitis C virus (HC) infection. The aim of this study was: (1) to compare plasma GSH levels in patients with chronic HCV infection and normal healthy controls; and (2) to correlate GSH levels with liver histology and serum HCV RNA levels. Twenty-four patients with compensated chronic hepatitis C and 27 healthy subjects were studied. Serum and heparinized plasma were prospectively prepared and frozen within 1 h of collection. Plasma glutathione and glutathione peroxidase (GP) levels were measured spectrophotometrically. The serum HCV RNA level was quantitated by the branched chain DNA signal-amplification assay. Plasma GSH levels were not decreased in patients with chronic HCV infection but were actually greater than in controls (control 1.27 +/- 0.12 micrograms ml-1, HCV 1.62 +/- 0.11 micrograms ml-1, P < 0.05). There was also no difference in plasma GP activity between these two groups (control 0.233 +/- 0.007 U ml-1, HCV 0.230 +/- 0.007 U ml-1). Among the patients with chronic HCV infection, there was no correlation between either plasma GSH or GP levels and the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), serum HCV RNA level, or liver histology. This study demonstrates that chronic HCV infection does not decrease the plasma GSH and GP levels.

Adult↗
PubMed1994

The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping.

Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.

Amino Acid Sequence↗
PubMed1994

Human liver plasma membranes contain an enzyme activity that removes membrane anchor from alkaline phosphatase and converts it to a plasma-like form.

Treatment of liver plasma membranes with Triton X-100 allowed an endogenous alkaline phosphatase-converting activity to convert amphiphilic alkaline phosphatase (membrane anchor covalently attached) to hydrophilic dimers that resemble the enzyme found in normal plasma. The Triton-solubilized activity was unaffected by protease inhibitors. Amphiphilic alkaline phosphatase purified from human liver and placenta were both substrates. The Triton-solubilized enzyme would not hydrolyze L-3-phosphatidyl(2-3H)-inositol or p-nitrophenylphosphoryl choline, nor would it cleave endogenous alkaline phosphatase from intact plasma membranes. These observations and the analysis of the protein product of the hydrolysis of placental alkaline phosphatase, following treatment with the converting activity, indicated that the enzyme has the specificity of a glycosyl-phosphatidylinositol phospholipase D. Further characterization of the enzyme activity suggests additional similarities with the glycosyl-phosphatidylinositol phospholipase D found in mammalian plasma. Alkaline phosphatase-converting activity in plasma membranes represented the same percent of total protein as it did in whole liver, whereas serum contained 3- to 10-times this amount. Endogenous converting activity in plasma membranes was not solubilized by salt washes, sonication, or repeated freeze-thaw treatments. We believe it is unlikely that the alkaline phosphatase-converting activity in liver plasma membranes resulted from adsorption of the enzyme present in plasma.

Alkaline Phosphatase↗
PubMed1994

Out-patient medical care in Edinburgh for IDU-related HIV.

Using combined medical and drug clinics, by the end of 1990 we had initiated contact with 511 HIV positive individuals, 75% injection drug use (IDU) related. We have previously reported a significant reduction in the number of missed appointments from 1985-89 following the introduction of methadone and an all day clinic, but between 1989 and 1990 the appointment default rate rose from 17 to 25%. A significant percentage increase in missed appointments was, however, only seen in those not attending the all day clinic (chi 2(3) = 121.3, p < 0.001). An analysis of the patients missing appointments during 1989-90 revealed that 36-45% of patients attending each year missed only 1 or 2 appointments, that the majority of missed appointments each year were accounted for by less than 20% of the patients, around 60% of these patients missed appointments in both years and that only 2% of patients attending both years consistently miss 3 or more appointments per year. Laboratory monitoring of HIV, that is at least one sampling episode in a year, was achieved, however, in 92-95% of the patients attending each year. The annual number of patients lost to follow-up varied between 7 and 11% per year, but did not change significantly over time, whilst the cumulative number of HIV infected individuals lost to follow-up after 5 years was only 14%. Between 1986 and 1990 self-reported reduction in IDU was more likely in HIV positive than negative individuals; the number of HIV positive individuals who reported injecting for more than 50% of the year fell from 40 to 5% (chi 2(4) = 15.23, p < 0.01) whilst the number who reported at least one injection per year fell from 51 to 23% (chi 2(4) = 62.06, p < 0.001). By comparison amongst non-HIV-infected patients the percentage who reported opiate use for more than 50% of the visits during a year rose from 54% in 1986 to a peak of 70% in 1989 (chi 2(4) = 10.22, p < 0.05) and those who reported opiate use at least once during the year rose from 57% in 1986 to a peak of 75% in 1989 (chi 2(4) = 14.3, p = 0.006). Combined medical and drug clinics from 1986 to 1990 together with a multi-disciplinary team approach to medical care was successful in delivering health care to HIV-infected injection drug users.(ABSTRACT TRUNCATED AT 400 WORDS)

Ambulatory Care↗