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Biomedical subjects

S A Brown

Publications and source records attributed to S A Brown.

At least 19 recordsLinked to original sources
PubMed2003

Short-term calcitriol administration improves calcium homeostasis in adults with cystic fibrosis.

Osteoporosis is a well-defined health risk in cystic fibrosis (CF) patients due to many factors. Vitamin D insufficiency, despite routine cholecalciferol supplementation in CF patients, may contribute to a relative secondary hyperparathyroidism and possibly deficient bone mineralization. An alternate form of vitamin D, calcitriol, was studied to determine short-term effects on fractional calcium absorption and other calciotropic markers in 10 adult CF subjects and in 10 age-, sex- and body mass index (BMI)-matched controls. Serum fractional absorption of (45)Ca was determined after a calcium-containing meal prior to calcitriol intervention. Other measurements included serum parathyroid hormone (PTH), ionized calcium, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and urinary calcium:creatinine and N-telopeptide (NTx) concentrations. Both groups were then given calcitriol (0.5 micro g p.o. b.i.d. for 14 days) and restudied following the same protocol. Both groups increased their fractional absorption of (45)Ca after calcitriol ( p=0.015 CF subjects, p=0.001 controls), although calcitriol tended to be less effective in the CF group compared with the controls ( p=0.055). Post-prandial serum PTH concentrations were suppressed compared with baseline in both groups ( p=0.03 CF subjects, p=0.006 controls). Urinary NTx concentrations, a marker for bone resorption, decreased significantly in CF subjects after calcitriol (96.0+/-16.0 vs 63.9+/-12.7 nmol BCE/mmol Cr, p=0.01) and remained unchanged in the control group. The controls had an increase in serum 1,25(OH)(2)D concentrations (69.9+/-4.2 vs 90.7+/-9.6 pmol/l, p=0.02) while there was no significant change in the CF group. Oral calcitriol administration appears to improve markers of calcium balance in adults with CF by increasing fractional absorption of (45)Ca and lowering PTH concentrations, similar to its known effects in healthy subjects, while also suppressing urinary NTx, a marker of bone turnover.

Administration, Oral↗
PubMed2003

The role of the platelet function analyser (PFA-100) in the characterization of patients with von Willebrand's disease and its relationships with von Willebrand factor and the ABO blood group.

Determination of the closure time (CT) with the platelet function analyser (PFA-100) is a useful screening test for von Willebrand's disease (VWD) but its role in the characterization of VWD is not well established. We studied the relationship between the prolongation of the CT with adenosine diphosphate (ADP) (CT-ADP) and epinephrine (CT-EPI) cartridges and the von Willebrand factor (VWF) in 53 patients with VWD. We found that a relatively small percentage of the prolongation of the CT-ADR and CT-ADP (16 and 29%, respectively) was determined by a reduction in VWF levels. The CT-ADP was significantly more prolonged in the presence of qualitative defects in VWF but could not discriminate between the VWD subtypes. The ABO blood group had no effect on the prolongation of the CT or the bleeding time. In conclusion, the PFA-100 appears of little use in the characterization of severity and subtype of VWD.

ABO Blood-Group System↗
PubMed2003

Increased clearance of von Willebrand factor antigen post-DDAVP in Type 1 von Willebrand disease: is it a potential pathogenic process?

The mechanism of von Willebrand factor (VWF) clearance is not fully understood. The factors that affect VWF clearance, and the normal in vivo mechanism of clearance, may be relevant to the pathogenesis of Type 1 von Willebrand disease (VWD), in which there is a partial deficiency of VWF. In order to investigate the clearance of VWF in Type 1 VWD, the current study assessed the half-life of VWF antigen (t(1/2) VWF:Ag) in Type 1 VWD patients and individuals with mild hemophilia A following the administration of 1-deamino-8-d-arginine vasopressin (DDAVP; desmopressin). To date 20 individuals have been assessed, 13 with Type 1 VWD and seven with mild hemophilia A. The median t(1/2) VWF:Ag in the Type 1 VWD and mild hemophilia A groups were 4.6 h and 9.5 h, respectively. The difference between the t(1/2) VWF:Ag for the two groups was significant, P < 0.02. Analysis of the data showed a correlation between the t(1/2) VWF:Ag and the baseline VWF:Ag level prior to administration of DDAVP: lower baseline VWF:Ag levels were associated with a shorter t(1/2) VWF:Ag. These data suggest that increased clearance of VWF may be the pathogenic mechanism in some cases of Type 1 VWD.

Adult↗
PubMed2003

Cellular origin of ionizing radiation-induced NF-kappaB activation in vivo and role of NF-kappaB in ionizing radiation-induced lymphocyte apoptosis.

PURPOSE: To investigate the cellular origin of ionizing radiation (IR)-induced NF-kappaB activation in vivo and the role of NF-kappaB in IR-induced lymphocyte apoptosis. MATERIALS AND METHODS: NF-kappaB activities were analysed by gel shift/supershift assay in isolated murine T- and B-cells, macrophages (MPhi) and tissues from normal and T- and B-cell-deficient Rag1 mice with or without exposure to IR. IR-induced lymphocyte apoptosis was determined by analysis of 3,3'-dihexyloxacarbocyanine iodide (DiOC(6)) uptake, annexin-V staining and the sub-G0/1 population, or by TUNEL assay. RESULTS: The results showed that IR activated NF-kappaB in lymphocytes, including both T- and B-cells, but failed to do so in MPhi. Furthermore, T- and B-cell-deficient Rag1 mice exposed to IR exhibited a significant reduction in NF-kappaB activation as compared with normal mice. Although NF-kappaB1 (p50) gene knockout or NF-kappaB decoy oligonucleotide treatment specifically inhibited IR-induced lymphocyte NF-kappaB activation, they had no significant effect on IR-induced lymphocyte apoptosis. CONCLUSIONS: This finding suggests that lymphocytes are the main cellular origin of IR-induced NF-kappaB activation in vivo. However, NF-kappaB activation has no significant effect on IR-induced lymphocyte apoptosis.

Animals↗
PubMed2003

Limited breadth of a T-helper cell response to a human immunodeficiency virus envelope protein.

Single-envelope human immunodeficiency virus (HIV) vaccines have been studied for more than a decade, with some successes in homologous challenge experiments in nonhuman primates but with no clear successes in clinical trials. To gain insight into the breadth of the immunity elicited by such vaccines, we have dissected the T-helper cell response of C57BL/6 mice to an individual, molecularly cloned envelope protein. Here, we report that T-helper cells responsive to HIV type 1 1035 envelope are very highly restricted in C57BL/6 animals: seven different hybridomas recovered from five separate mice recognized the same peptide, PKVSFEPIPIHYCAP, located in the C2 region of gp120. Three of these hybridomas were tested on a natural variant of the peptide but failed to respond. A more extensive analysis of whole splenic populations from other C57BL/6 mice immunized with the 1035 envelope reproducibly confirmed that the gp120-specific T-helper response was almost exclusively focused on a single epitope. We conclude that single-envelope vaccines may frequently fail to provoke an immune response sufficiently diverse to recognize variant sequences among circulating HIV. The results encourage the inclusion of more than one envelope in future vaccines to enhance the potential diversity and respective surveillance capacities of responding T-helper cell populations.

AIDS Vaccines↗
PubMed2002

Finite-size effects in the conductivity of cluster assembled nanostructures.

Atomic clusters have been deposited between lithographically defined contacts with nanometer scale separations. The design of the contacts is based on an appropriate application of percolation theory to conduction in cluster deposited devices and allows finite-size effects to be clearly observed. It is demonstrated, both by experiment and by simulation, that for small contact separations the percolation threshold is shifted to extremely low surface coverages. The selected rectangular contact geometry ensures that wirelike structures are formed close to the percolation threshold.

Journal Article↗
PubMed2002

Abnormal bone turnover in cystic fibrosis adults.

Cystic fibrosis (CF) patients often have low bone mineral density (BMD) and may suffer from fractures and kyphosis. The pathogenesis of low BMD in CF is multifactorial. To study bone metabolism, we collected fasting serum and urine from 50 clinically stable CF adults (mean age 28 years) and 53 matched controls to measure markers of bone formation and bone resorption. The CF subjects had moderate lung disease (FEV1: 46.1 +/- 18.6% predicted) and malnutrition (BMI: 20.0 +/- 3.3 kg/m2). Only 3 subjects had normal BMD. CF subjects had higher urinary N-telopeptides of type I collagen (81.0 +/- 60.0 vs 49.0 +/- 24.2 nm BCE/mmol creatinine, p = 0.0006) and free deoxypyridinoline (7.3 +/- 5.0 vs 5.3 +/- 1.9 nM/mM, p = 0.004) levels than controls. Serum osteocalcin levels were similar in the two groups, a result confirmed by two immunoassays that recognize different epitopes on osteocalcin. Serum bone-specific alkaline phosphatase levels were elevated in CF patients (32.0 +/- 11.3 vs 21.8 +/- 7.0 U/l, p < 0.0001), but were much more closely associated with serum total alkaline phosphatase levels (r = 0.51, p = 0.001) than with age or gender. Parathyroid hormone levels were elevated (p = 0.007) and 25-hydroxyvitamin D levels were depressed (p = 0.0002) in the CF patients in comparison with controls. These results indicate that adults with CF have increased bone resorption with little change in bone formation. Medications that decrease bone resorption or improve calcium homeostasis may be effective therapies for CF bone disease.

Adolescent↗
PubMed2002

Experience of prophylaxis treatment in children with severe haemophilia.

The practice of prophylactic treatment of boys with severe haemophilia has been evaluated in our centre. Prophylaxis was started at the median age of 3.7 years (range 0.4-12.7 years) in 38/41 children (93%) under 17 years of age. Median follow-up was 4.1 years (range 0.4-12.7 years). The criteria of primary prophylaxis according to the definition by the European Paediatric Network of Haemophilia Management was fulfilled by 9/38 (24%). Although a majority [76%, 29/38] of the children started prophylaxis after a median number of joint bleeds of 3.5, 70% of the children in this group had clinical joint scores of 0. Intravenous catheter insertion was required at a median age of 15.5 months (range 5-36 months) in 21% of the children, resulting in a catheter infection rate of 1.74 per 1000 catheter days. None developed an inhibitor on prophylaxis and three patients who had low-titre inhibitors (< 5 Bethesda units) prior to prophylaxis had undetectable inhibitors after prophylaxis. The home-treatment training programme required considerable time and cost. As a result, 87% of the children used peripheral venous access and hospital visits declined as prophylaxis became established. Parents' incentives for prophylaxis were that the children undertook many physical activities and sports previously not recommended, there was less parental anxiety and an overall improvement in the quality of life for the whole family.

Bacterial Infections↗
PubMed2002

Effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of benazepril in cats.

The effect of renal insufficiency was studied on the pharmacokinetics (PK) and pharmacodynamics (PD) of the angiotensin-converting enzyme (ACE) inhibitor benazepril in cats. The active metabolite of benazepril, benazeprilat, is eliminated principally ( approximately 85%) via biliary excretion in cats. A total of 20 control animals and 32 cats with moderate renal insufficiency induced by partial nephrectomy were used. Assessments were made at steady state after treatment with placebo or benazepril (0.25-2 mg/kg) once daily for a minimum of 10 days. The PK endpoint was the AUC (0-->24 h) of total plasma benazeprilat. The PD endpoints were systolic, diastolic and mean blood pressures (respectively SBP, DBP and MBP) measured by telemetry, and plasma ACE activity, assessed by an ex vivo assay. Renal function was assessed by glomerular filtration rate (GFR), measured by inulin clearance, and plasma creatinine concentrations (1/PCr). As compared with control animals, the renal insufficient cats had a 78% reduction in GFR (0.57 +/- 0.41 mL/min kg), increased plasma creatinine (2.7 +/- 1.0 mg/dL), urea (44.0 +/- 11.9 mg/dL) and ACE activity, and moderately increased blood pressure (SBP 171.8 +/- 5.1 mmHg) (all parameters P < 0.05). Renal insufficient cats receiving benazepril had significantly (P < 0.05) lower SBP, DBP, MBP and ACE, and higher GFR values as compared with placebo-treated animals. There were no significant differences in SBP, DBP, MBP, benazeprilat or ACE values according to the degree of renal insufficiency in cats receiving benazepril. It is concluded that no dose adjustment of benazepril is necessary in cats with moderate renal insufficiency.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Overlapping functions of the cell adhesion molecules Nr-CAM and L1 in cerebellar granule cell development.

The structurally related cell adhesion molecules L1 and Nr-CAM have overlapping expression patterns in cerebellar granule cells. Here we analyzed their involvement in granule cell development using mutant mice. Nr-CAM-deficient cerebellar granule cells failed to extend neurites in vitro on contactin, a known ligand for Nr-CAM expressed in the cerebellum, confirming that these mice are functionally null for Nr-CAM. In vivo, Nr-CAM-null cerebella did not exhibit obvious histological defects, although a mild size reduction of several lobes was observed, most notably lobes IV and V in the vermis. Mice deficient for both L1 and Nr-CAM exhibited severe cerebellar folial defects and a reduction in the thickness of the inner granule cell layer. Additionally, anti-L1 antibodies specifically disrupted survival and maintenance of Nr-CAM-deficient granule cells in cerebellar cultures treated with antibodies. The combined results indicate that Nr-CAM and L1 play a role in cerebellar granule cell development, and suggest that closely related molecules in the L1 family have overlapping functions.

Animals↗
PubMed2001

Biomass byproducts for the remediation of wastewaters contaminated with toxic metals.

Pollution of the environment with toxic metals is widespread and often involves large volumes of wastewater. Remediation strategies must be designed to support high throughput while keeping costs to a minimum. Biosorption is presented as an alternative to traditional physicochemical means for removing toxic metals from wastewater. We have investigated the metal binding qualities of two biomass byproducts that are commercially available in quantity and at low cost, namely "spillage", a dried yeast and plant mixture from the production of ethanol from corn, and ground corn cobs used in animal feeds. The biomass materials effectively removed toxic metals, such as Cu, Cs, Mo, Ni, Pb, and Zn, even in the presence of competing metals likely to be found in sulfide mine tailing ponds. The effectiveness of these biosorbents was demonstrated using samples from the Berkeley Pit in Montana. Investigations included column chromatography and slurry systems, and linear distribution coefficients are presented. X-ray spectroscopy was used to identify the binding sites for metals adsorbed to the spillage material. The results of our experiments demonstrate that the biosorption of metals from wastewaters using biomass byproducts is a viable and cost-effective technology that should be included in process evaluations.

Adsorption↗
PubMed2001

Circadian rhythms: mop up the clock!

All circadian clock genes discovered in Drosophila have mammalian counterparts with extensive sequence homology. Similarities and differences have been identified between insect and mammalian oscillators. Recent studies have shed new light on two mammalian clock components: Mop3 and Per2.

ARNTL Transcription Factors↗
PubMed2001

Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination.

We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame deletion of 12 amino acids. The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect (one case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation.

Alanine↗
PubMed2001

Prenatal diagnosis of pyruvate dehydrogenase deficiency using magnetic resonance imaging.

INTRODUCTION: Pyruvate dehydrogenase deficiency is an inherited inborn error of metabolism associated with early neonatal death and long-term neurologic sequelae in survivors. Prenatal diagnosis currently relies on isolation of fetal cells for subsequent genetic and/or biochemical studies. Magnetic resonance imaging and magnetic resonance spectroscopy have been used on occasion for both postnatal diagnosis and management of pyruvate dehydrogenase deficiency. We illustrate a case in which these non-invasive modalities also prove useful for prenatal diagnosis of this condition. CASE: A 31-year-old multipara with a history of two prior infants affected with pyruvate dehydrogenase deficiency presented with a spontaneous dichorionic, diamniotic twin pregnancy. Magnetic resonance imaging and magnetic resonance spectroscopy were performed on both fetuses. Magnetic resonance imaging of the presenting (male) fetus demonstrated mild ventriculomegaly, increased extracerebrospinal fluid, and decreased cortical sulcation and gyration. The non-presenting (female) fetus was structurally normal. Magnetic resonance spectroscopy spectra were obtained for both fetuses, and were normal. The diagnosis of pyruvate dehydrogenase deficiency was made in the presenting fetus after delivery on the basis of subsequent mortality from severe lactic acidosis. CONCLUSION: Prenatal MR imaging of the fetal brain can be used for prenatal diagnosis in fetuses at risk for pyruvate dehydrogenase deficiency. Prenatal MR spectroscopy, although technically feasible, does not appear to have a role in the prenatal diagnosis of this condition.

Acidosis, Lactic↗
PubMed2001

Outcomes of alcohol treatment for adolescents.

The use by adolescents and young adults of alcohol and other drugs continues to be a tremendous problem for this nation. Over 30% of all high school students nationwide report episodes of hazardous drinking (five or more drinks on one occasion), when both moderate and heavy alcohol consumption are associated with a higher risk of alcohol-related medical consequences and accidental injuries for youth. Increased awareness and concern related to adolescent substance use has led to the outgrowth of additional treatment facilities and programs for this age group. The current chapter discusses how developmental factors may impact the assessment process and subsequent treatment for adolescent alcohol use disorders. In addition, outcome research, intervention studies, relapse, and factors that may influence the recovery process are discussed.

Adolescent↗