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Biomedical subjects

L Ward

Publications and source records attributed to L Ward.

At least 19 recordsLinked to original sources
PubMed2001

Clinical assessment of HIV-associated lipodystrophy syndrome: bioelectrical impedance analysis, anthropometry and clinical scores.

BACKGROUND: Diagnosis of the HIV-associated lipodystrophy syndrome is based on clinical assessment, in lack of a consensus about case definition and reference methods. Three bedside methods were compared in their diagnostic value for lipodystrophy. PATIENTS AND METHODS: Consecutive HIV-infected outpatients (n=278) were investigated, 128 of which also had data from 1997 available. Segmental bioelectrical impedance analysis (BIA) and waist, hip and thigh circumferences were performed. Changes in seven body regions were rated by physicians and patients using linear analogue scale assessment (LASA). Diagnostic cut-off values were searched by receiver operator characteristics. RESULTS: Lipodystrophy was diagnosed in 85 patients (31%). BIA demonstrated higher fat-free mass in patients with lipodystrophy but not after controlling for body mass index and sex. Segmental BIA was not superior to whole body BIA in detecting lipodystrophy. Fat-free mass increased from 1997 to 1999 independent from lipodystrophy. Waist-hip and waist-thigh ratios were higher in patients with lipodystrophy. BIA, anthropometry and LASA did not provide sufficient diagnostic cut-off values for lipodystrophy. Agreement between methods, and between patient and physician rating, was poor. CONCLUSION: These methods do not fulfil the urgent need for quantitative diagnostic tools for lipodystrophy. BIA estimates of fat free mass may be biased by lipodystrophy, indicating a need for re-calibration in HIV infected populations.

Adult↗
PubMed2000

Neurofibrillary tangles in progressive supranuclear palsy brains exhibit immunoreactivity to frameshift mutant ubiquitin-B protein.

In Alzheimer's disease (AD) neurofibrillary tangles (NFT) are strongly tau and ubiquitin immunopositive, and contain an aberrant form of ubiquitin derived from the ubiquitin-B gene denoted as UBB+1. We explored whether the tau-related NFT seen in another neurodegenerative disease, progressive supranuclear palsy (PSP), also showed an accumulation of UBB+1. Three cases of PSP were examined immunohistochemically for tau protein, ubiquitin-protein conjugates and UBB+1 using single and double labelling. We conclude that UBB+1 is associated with compact globose tangles rather than dispersed accumulations of tau in PSP, showing that its presence is not unique to AD. We propose that aggregation of ubiquitinated proteins into compact inclusions in PSP might be due to inhibition of the degradation of multiubiquitinated proteins by ubiquitin chains containing proximal UBB+1 rather than normal ubiquitin.

Aged↗
PubMed2000

Mechanisms of tubulin modification by phosphatidylcholine hydroperoxides.

The interaction of lipid peroxides with cellular proteins has been postulated to contribute to cellular aging. A potential target for such effects is tubulin, the building block of microtubules. We examined the concentration-dependent effects of phosphatidylcholine hydroperoxides on the ability of tubulin to polymerize into microtubules. The results demonstrated that even very low concentrations of peroxides were sufficient to interfere with the tubulin and, therefore, the microtubule function. Decreased tubulin activity (as measured by tubulin GTPase activity) showed correlation with the modification of methionine and cysteine in tubulin and a change in the tubulin conformational state as indicated by fluorescence and ultraviolet spectroscopic measurements. As no effect on electric conductivity was observed, indicating that modulation of ionic binding was not involved, the interaction mechanism may be a hydrophobic one.

Amino Acids↗
PubMed2000

Molecular epidemiology of an outbreak caused by Salmonella enterica serovar Newport in Finland and the United Kingdom.

Between December 1997 and January 1998 an increase in the number of isolates of Salmonella enterica serovar Newport, a serotype rarely causing indigenous infections in Finland, was detected. This included two clusters of gastroenteritis following funeral meals. An inquiry via Enter-net revealed a concomitant increase in cases of S. Newport in the United Kingdom. To investigate the Finnish outbreak, a total of 56 S. Newport strains (22 from the outbreak period, 27 from pre- and post-outbreak period, and 7 from imported food producing animals) were studied by pulsed-field gel electrophoresis (PFGE); selected isolates were also phage typed. Two retrospective questionnaire studies evaluating food exposures among the funeral attendants were conducted. All isolates from the clusters had an identical PFGE pattern which was also found in 13 infections temporally close to but not associated with the clusters. The Finnish outbreak was caused by the same phage type as the one in the United Kingdom. In both clusters, an epidemiological link between illness and exposure to cured ham was found. In conclusion, the outbreak was not limited to the two clusters but was more widely spread both in and outside Finland. Early alarm systems of food-borne outbreaks and collaboration between European countries are needed for investigating international outbreaks.

Abdominal Pain↗
PubMed2000

Fever and sepsis during neutropenia are associated with expansion of extracellular and loss of intracellular water.

BACKGROUND AND AIMS: Shifts from intracellular to extracellular water are features of a catabolic reaction to sepsis. Bedside assessment of fluid shifts was carried out in neutropenic patients at high risk of systemic infection. METHODS: Multifrequency bioelectrical impedance analysis was performed in 41 patients with leukemia or high-malignant lymphoma and chemotherapy-induced neutropenia. RESULTS: Hydration was stable during afebrile periods except for transient intra- and extracellular dehydration after chemotherapy. The risk of over-hydration and dehydration increased 3-fold during fever. Over-hydration was more severe when occurring during fever. Extracellular water was highly variable and tended to increase, and intracellular water was slowly depleted. During sepsis, these alterations were enhanced. Changes in hydration status did not predict subsequent progression to sepsis because it developed more slowly than other symptoms of infection. CONCLUSIONS: Extracellular over-hydration and intracellular dehydration are observed in febrile infection in neutropenia, similar to severe sepsis. If the technical limits of bioelectrical impedance are taken into account, this method may be useful for non-invasive monitoring of these features of metabolic stress.

Adolescent↗
PubMed2000

Prediction of acute renal failure by "bedside formula" in medical and surgical intensive care patients.

BACKGROUND: Prediction of which intensive care unit (ICU) patients are likely to develop acute renal failure (ARF) would be useful. However, scoring systems such as APACHE have been disappointing in this regard. We previously developed a bedside formula to predict ARF using only 3 parameters: serum albumin, urine osmolality, and presence of sepsis. METHODS: We prospectively evaluated 115 consecutive medical ICU (MICU) patients, comparing the bedside formula to APACHE II AND APACHE III as predictors of ARF or death and looking at nutritional parameters such as iron binding capacity, triceps skin fold, mid-arm circumference, and total lymphocyte count. We then evaluated 123 additional consecutive MICU and 98 consecutive surgical ICU (SICU) patients, comparing the bedside formula to APACHE II. RESULTS: The bedside formula was consistently more accurate than APACHE II in predicting ARF or in-hospital death in MICU patients. However, in SICU neither formula predicted ARF, and APACHE II predicted in-hospital death slightly better. No nutritional parameter other than albumin correlated with ARF. CONCLUSION: The bedside formula appears superior to APACHE II in predicting ARF or death in MICU but not SICU. This suggests that these two ICU populations are different.

APACHE↗
PubMed2000

A novel A10E homozygous mutation in the HSD3B2 gene causing severe salt-wasting 3beta-hydroxysteroid dehydrogenase deficiency in 46,XX and 46,XY French-Canadians: evaluation of gonadal function after puberty.

Severe 3beta-hydroxysteroid dehydrogenase (3betaHSD) deficiency is a rare form of congenital adrenal hyperplasia resulting from mutations in the HSD3B2 gene that impair steroidogenesis in both the adrenals and gonads and cause salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. About two thirds of the reported patients are 46,XY. We describe two French-Canadian patients from two families without a known relationship who presented with severe salt-wasting 3betaHSD deficiency in infancy. Although the diagnosis was considered clinically, plasma steroid profiles were confusing. We have thus directly sequenced DNA fragments generated by PCR amplification of the four exons, exon-intron boundaries, and the 5'-flanking regions of the HSD3B2 gene. Sequencing of exon II revealed the presence of a C to A transversion in both alleles of these two cases, thus converting codon 10 (GCA), which codes for Ala, into GAA, encoding Glu. This Ala is highly conserved in the vertebrate 3betaHSD gene family and is located in the putative NAD-binding domain of the enzyme. The mutant type II 3betaHSD enzyme carrying an A10E substitution exhibited no detectable activity in intact transfected Ad293 cells. Both homozygous patients share the same haplotype, spanning approximately 3.3 centimorgans surrounding the HSD3B2 locus, which is consistent with a founder effect for this missense mutation. The 46,XY patient presented with ambiguous genitalia at birth and underwent normal masculinization at puberty, but was azoospermic at 18.5 yr of age. The 46,XX patient presented progressive breast development, menarche, and evidence of progesterone secretion. The only previously reported cases with pubertal follow-up revealed paternity in one male and hypogonadism in one female. These findings demonstrate the complex relationships between the genotype and the gonadal phenotype in severe 3betaHSD deficiency and the difficulty in predicting fertility.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Type V osteogenesis imperfecta: a new form of brittle bone disease.

Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.

Adolescent↗
PubMed2000

The 3T3-L1 fibroblast to adipocyte conversion is accompanied by increased expression of angiopoietin-1, a ligand for tie2.

The tie2 receptor tyrosine kinase plays a key role in angiogenesis, and the remodeling and maturation of blood vessels. In this study we have used a factor-dependent cell line (Ba/F3) expressing a chimeric receptor containing the extracellular domain of mouse tie2 and the transmembrane and cytoplasmic domain of the erythropoietin receptor to identify specific binding activity associated with an adipogenic sub-line of 3T3 fibroblasts (3T3-L1). 3T3-L1 fibroblasts are capable of undergoing differentiation to adipocytes under specific culture conditions. When compared to 3T3-L1 cells, the adipocyte differentiated cultures, which contain both pre-adipocytes and adipocytes, exhibited a significantly increased ability to support the growth of Ba/F3 cells expressing the chimeric receptor. Using probes specific for two recently described ligands for tie2, Ang-1 and Ang-2, we have shown that mRNA encoding Ang-1 is upregulated when 3T3-L1 fibroblasts are differentiated to adipocytes. These results suggest that the levels of Ang-1 protein and mRNA in 3T3-L1 cells can be regulated by cellular differentiation in adipose development.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Clonal relationship of Salmonella enterica serovar typhimurium phage type DT104 in Germany and Austria.

A new epidemic clone of Salmonella enterica serovar Typhimurium designated definitive phage type (DT) 104 has been emerging since 1990 to become most common type among S. Typhimurium isolates in Germany and Austria. Molecular fingerprinting (PFGE-pattern, plasmid profiles, IS200 pattern, ribotype, ERIC-type, OMP and MLE patterns) revealed the majority of the DT104 isolates to have clonal identity; they were designated as type 1 (about 95%). Moreover, clonal type 1 of DT104 was found to occur in sensitive as well as in a range of multiply drug-resistant variants and in a variety of plasmid profile types (in particular with small cryptic plasmids in the range of 1.0 to 5.0 Md). Since the clonal type 1 of DT104 has been identified among isolates from other countries, too, including such from the United Kingdom, the United Arab Emirates, the Philippines, and the Netherlands, its pandemic spread in man indicates that the import/export of this pathogen continues. About 5% of the DT104 isolates have been identified as genetically diverse indicating the independent appearance of the same multiple drug resistance and phage pattern phenotype among different Salmonella ancestor strains.

Animals↗
PubMed1999

Prevention of appendicular bone loss in Paget's disease following treatment with intravenous pamidronate disodium.

It has been shown previously that intravenous pamidronate treatment for severe Paget's disease is associated with appendicular bone loss. This 2 year study was designed to determine whether cotreatment with calcitriol and a calcium supplement would prevent this. Intravenous pamidronate was used to treat 49 patients with symptomatic Paget's disease. Patients were stratified into two groups of differing biochemical severity based on hydroxyproline excretion (HypE) expressed as micromoles per liter of glomerular filtrate (GF): (1) a severe group with HypE > 10 micromol/L GF; and (2) a moderate group with HypE 5-10 micromol/L GF. Within each group, patients were randomly allocated to receive supplements of calcium and calcitriol (supplemented) or no supplements (unsupplemented) after initiation of pamidronate therapy. The severe group received 360 mg of pamidronate as six doses of 60 mg once weekly and the moderate group received 240 mg as four weekly doses of 60 mg. Patients were followed for 24 months following treatment and had serial bone densitometry of the forearm measured as well as urine and plasma biochemistry. When the groups were combined, the unsupplemented patients showed a decrease in bone mineral density (BMD) at the ultradistal forearm site, which persisted to 24 months. Those supplemented with calcium and calcitriol showed an increase in BMD and the difference between the two groups was significant at all times posttreatment (p < 0.03). When the groups were analyzed separately, those with moderate disease again showed significant differences in BMD between supplemented and unsupplemented patients at all timepoints. In the severe group, the differences did not reach statistical significance due to smaller patient numbers. Similar changes in BMD were also observed at the forearm shaft site. When serial parathyroid hormone (PTH) levels (with the moderate and severe groups combined) were plotted against time since treatment the rise in PTH in the supplemented patients was less than the rise in the unsupplemented patients (p < 0.04). These results suggest that forearm bone loss after intravenous pamidronate treatment for moderate-to-severe Paget's disease can largely be prevented by administration of calcium and calcitriol. The mechanism may be a blunting of the secondary hyperparathyroidism that occurs after intravenous pamidronate. These findings may have wider application in moderate-to-severe Paget's disease treated with other bisphosphonates.

Administration, Oral↗
PubMed1999

Multiple frequency bioelectrical impedance analysis: a cross-validation study of the inductor circuit and Cole models.

It has been proposed that multiple frequency bioelectrical impedance models of the human body should include an inductive property for the circulatory system, the inductor circuit model (ICM), and that such a model, when coupled with a new method of data analysis, can improve the predictive power of multiple frequency bioelectrical impedance analysis (MFBIA). This hypothesis was tested using MFBIA measurements and gold standard measures of total body and extracellular water volumes in a cross-validation study in two subject groups (viz. controls and HIV). The MFBIA measurements were analysed using the current, widely accepted Cole model and the alternative ICM model which includes an inductive component. Correlations in the range 0.75 to 0.92 (for TBW) and 0.46 to 0.79 (for ECW) for impedance quotients versus gold standard measures within the subject groups were observed. These decreased, to as low as r = 0.50 for TBW and r = 0.29 for ECW, when the derived algorithms were applied to the alternative subject group. These results suggest that lack of portability of MFBIA algorithms between subject groups is not due to an inadequacy of the analogue circuit model per se but is possibly due more to fundamental flaws in the principles associated with its application. These include assuming a constant proportionality of body segment geometries and tissue fluid resistivities. This study has also demonstrated that this inadequacy cannot be overcome by simply introducing an inductive component into the analogue electrical circuit.

Algorithms↗