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Biomedical subjects

L Ward

Publications and source records attributed to L Ward.

At least 55 records · Page 3Linked to original sources
PubMed1997

Comparative studies of the pathogenesis, antibody immune responses, and homologous protection to porcine and human rotaviruses in gnotobiotic piglets.

Gnotobiotic piglets serve as a useful animal model for studies of rotavirus pathogenesis and immunity. An advantage over laboratory animal models is the prolonged susceptibility of piglets to rotavirus-induced disease, permitting an analysis of cross-protection and active immunity. Studies from our laboratory of the pathogenesis of human rotavirus infections in gnotobiotic piglets have confirmed that villous atrophy is induced in piglets given virulent but not attenuated human rotavirus (Wa strain) and have revealed that factors other than villous atrophy may contribute to the early diarrhea induced. To facilitate and improve rotavirus vaccination strategies, it is important to identify correlates of protective immunity. Comparison of antibody immune responses induced by infection with virulent porcine and human rotaviruses (mimic host response to natural infection) with those induced by live attenuated human rotavirus (mimic attenuated oral vaccines) in the context of homotypic protection has permitted an analysis of correlates of protective immunity. Our results indicate that the magnitude of the immune response is greatest in lymphoid tissues adjacent to the site of viral replication (small intestine). Secondly there was a direct association between the degree of protection induced and the level of the intestinal immune response, with primary exposure to virulent rotaviruses inducing significantly higher numbers of IgA ASC and complete protection against challenge. These studies thus have established basic parameters related to immune protection in the piglet model of rotavirus-induced disease, verifying the usefulness of this model to apply new strategies for the design and improvement of rotavirus vaccines.

Animals↗
PubMed1997

Multiple frequency bioimpedance: a bed-side technique for assessment of fluid shift patterns in a patient with severe dehydration.

This report describes the use of multiple frequency bioimpedance analysis (MFBIA) to monitor fluid changes in a patient who developed severe dehydration and recovered. Initially, the patient weighed 53.2 kg, his total body water (TBW; D(2)0 dilution) was 33.5 L, his extracellular water (ECW; Br dilution) was 19.5 L, and hydration of the fat-free mass (FFM; dual-energy X-ray absorptiometry) was normal (73%). The resistances at infinite and 0 frequency were R(inf) = 454 and R(0) = 580 ohm respectively, which predicted TBW = 33.1 L and ECW = 16.6 L. On day 7, when the weight loss was 7.2 kg, FFM had decreased by 7.4 kg, and R(inf) and R(0) had increased to 662 and 902 ohm respectively, predicting decreases of 5.8 L in TBW and 3.7 L in ECW. On recovery (day 14), all parameters had returned to baseline values. This study encourages the use of MFBIA as a bed-side technique for the serial assessment of body water compartments in patients with disturbances in fluid balance.

Journal Article↗
PubMed1997

Studies of water and electrolyte movement for oral rehydration solutions (rice- and glucose-based) across a normal and secreting gut using a dual isotope tracer technique in a rat perfusion model.

AIMS: To establish a model to measure bidirectional flow of water from a glucose oral rehydration to solution (G-ORS) and a newly developed rice-based oral rehydration solution (R-ORS) using a dual isotope tracer technique in a rat perfusion model. To measure net water, sodium and potassium absorption from the ORS. METHOD: In vivo steady-state perfusion studies were carried out in normal and secreting (induced by cholera toxin) rat small intestine (n = 11 in each group). To determine bidirectional flow of water from the ORS the animals were initially with tritium, and deuterium was added to the perfusion solution. Sequential perfusate and blood samples were collected after attainment of steady-state conditions and analysed for water and electrolyte content. RESULTS: There was significant increase in net water absorption from the R-ORS compared to the G-ORS in both the normal (P < 0.02) and secreting intestine (P < 0.05). Water efflux was significantly reduced in the R-ORS group compared to the G-ORS group in both the normal (P < 0.01) and the secreting intestine (P < 0.01). There was an increase in sodium absorption in the R-ORS group compared to the G-ORS. The G-ORS produced a significantly greater blood glucose level at 75 min compared to the R-ORS (P < 0.03) in the secreting intestine. CONCLUSIONS: This study demonstrates the improved water absorption from a rice-based ORS in both the normal and secreting intestine. Evidence that the absorption of water may be influenced by the osmolality of the ORS was also demonstrated.

Absorption↗
PubMed1996

Salm-Net facilitates collaborative investigation of an outbreak of Salmonella tosamanga infection in Europe.

Twenty-eight cases of Salmonella tosamanga infection were identified in six western European countries during the first half of 1995. Salm-Net, a European system for collaborative surveillance of gastrointestinal infection, detected the outbreak and coordinated its investigation. There were 28 cases, 14 of each sex, with a broad age distribution. Interviews with cases to identify common food and other exposures failed to generate a working hypothesis. The initial cluster occurred in a period of eight weeks and, since only one further case occurred in June, the investigation was closed. This incident shows that Salm-Net is effective in identifying international outbreaks of human salmonellosis. Practical difficulties in the field investigation of the outbreak are discussed.

Adult↗
PubMed1996

Comparison of biochemical markers of bone turnover in Paget disease treated with pamidronate and a proposed model for the relationships between measurements of the different forms of pyridinoline cross-links.

We have compared the use of new markers of bone turnover in the assessment and treatment of Paget disease and made observations on the mechanisms of bone resorption. Urine hydroxyproline (Hyp) as a bone resorption marker and serum alkaline phosphatase (ALP) as a bone formation marker have traditionally been used to biochemically assess and monitor treatment of Paget disease. Hyp and total ALP were compared with total urine pyridinoline (Pyd) and deoxypyridinoline (Dpd), free urine Pyd and Dpd, urine type I collagen N-terminal cross-linked telopeptide (NTX), type I collagen C-terminal propeptide (PICP), serum osteocalcin, and bone ALP in Paget patients treated with pamidronate. Patients were divided into three biochemical severity-based treatment groups by their fasting urine hydroxyprolline excretion (HypE) levels (Le., group 1, HypE < 5.0 mumol/l of glomerular filtrate [GF]; group 2, HypE of 5.0-9.9 mumol/l of GF; group 3, HypE > 10 mumol/l of GF). Group 1 received one 60 mg intravenous infusion of pamidronate, and groups 2 and 3 received four and six 60 mg infusions at weekly intervals, respectively. Fasting serum and morning urine specimens were taken before and at 2, 6, 13, and 26 weeks after starting treatment. Baseline Z scores were used to compare separation of patient results from normal, and the difference in Z scores from baseline to 13 weeks was used to compare response to treatment. Baseline discrimination and response to treatment at all disease activity levels was greatest for NTX and was poor for osteocalcin, PICP, and C-terminal cross-linked telopeptide of type I collagen (ICTP). The other markers showed good discrimination and response at medium and high levels of disease activity. NTX, total Pyd and Dpd, free Pyd and Dpd, and ICTP are all pyridinoline cross-link-based markers, but discrimination and response by NTX was generally much greater than for the others. Determination of the mechanism of the difference between NTX and other cross-link measures is necessary for appropriate use of the markers and may also lead to a better understanding of the bone resorption process. It has been proposed that the greater sensitivity and discrimination of NTX is because it is more bone-specific than the other cross-link markers with significant amounts of free Pyd and Dpd coming from nonbone sources. We propose another model where the proportion of peptide-bound cross-links such as NTX may be increased in high bone turnover states partly due to a rate-limiting step in their degradation to free cross-links. Conditions with high bone resorption rates would have high levels of NTX that would decline rapidly when resorption rates fall to a level where the capacity to degrade NTX matches the rate of production.

Aged↗
PubMed1996

Cloning and characterization of a novel human gene related to vascular endothelial growth factor.

This paper describes the cloning and characterization of a new member of the vascular endothelial growth factor (VEGF) gene family, which we have designated VRF for VEGF-related-factor. Sequencing of cDNAs from a human fetal brain library and RT-PCR products from normal and tumor tissue cDNA pools indicate two alternatively spliced messages with open reading frames of 621 and 564 bp, respectively. The predicted proteins differ at their carboxyl ends resulting from a shift in the open reading frame. Both isoforms show strong homology to VEGF at their amino termini, but only the shorter isoform maintains homology to VEGF at its carboxyl terminus and conserves all 16 cysteine residues of VEGF165. Similarity comparisons of this isoform revealed overall protein identity of 48% and conservative substitution of 69% with VEGF189. VRF is predicted to contain a signal peptide, suggesting that it may be a secreted factor. The VRF gene maps to the D11S750 locus at chromosome band 11q13, and the protein coding region, spanning approximately 5 kb, is comprised of 8 exons that range in size from 36 to 431 bp. Exons 6 and 7 are contiguous and the two isoforms of VRF arise through alternate splicing of exon 6. VRF appears to be ubiquitously expressed as two transcripts of 2.0 and 5.5 kb; the level of expression is similar among normal and malignant tissues.

Amino Acid Sequence↗
PubMed1996

Effect of oral L-carnitine on serum myoglobin in hemodialysis patients.

Oral L-carnitine has been reported to lower the elevated serum myoglobin of renal failure in chronic peritoneal dialysis patients, and intravenous L-carnitine can improve muscle fatigue and cramps in chronic hemodialysis patients. In this study oral L-carnitine, 1.98 g/day, was administered to 6 chronic hemodialysis patients for 8 weeks. Serum levels of myoglobin, creatine kinase, and aldolase, as well as skeletal muscle symptoms (cramps during dialysis, fatigue, and weakness) were monitored biweekly for 12 weeks. Mean baseline serum myoglobin level was 337 +/- 34 ng/mL. By 6 and 8 weeks mean serum myoglobin was 234 +/- 39 and 233 +/- 40 ng/mL, significantly lower by the Friedman test (p < 0.05). Four weeks after carnitine was discontinued, mean serum myoglobin had risen to 320 +/- 118 ng/mL. Serum creatine kinase and aldolase levels were normal throughout the study. All 6 patients noted improvement in muscular symptoms, with maximal effect at 8 weeks, although 2 patients did not improve until 2 to 4 weeks after carnitine was stopped. We conclude that oral L-carnitine may lower serum myoglobin and improve muscle cramps and weakness in hemodialysis patients. The maximal effect of carnitine on myoglobin occurs 2 weeks before the maximal improvement in muscular symptoms.

Administration, Oral↗
PubMed1995

Effect of TGF-beta on differentiated organoids of the colon carcinoma cell line LIM 1863.

The LIM 1863 colon carcinoma cell line grows in suspension as morphologically and functionally organized organoids in serum-containing medium. Addition of TGF-beta caused the organoids to adhere and inhibited DNA synthesis. A 20 min incubation with TGF-beta was sufficient to induce adherence and this could be inhibited by cycloheximide. The adhesion and DNA synthesis inhibition were demonstrated to be separate events. We were not able to detect any changes in matrix or cell membrane antigens. Similarly there were no changes in synthesized proteins (by two-dimensional gel electrophoresis), and no upregulation of proteoglycan. When adhered organoids were lysed from the tissue culture plastic surface, untreated organoids adhered to this surface. This 'conditioned' surface was destroyed by trypsin but not collagenase or medium from normal LIM 1863 cultures. However, the adherent phenotype was prevented when organoids were treated with transforming growth factor-beta (TGF-beta) in the presence of medium conditioned by normal LIM 1863 cultures rather than in fresh medium. The adhesion process was inhibited by an antibody (QE2E5) against beta 1 integrin although no quantitative changes in integrins were observed (by immunoprecipitation or RNA analysis). A second anti-beta 1 integrin antibody (61.2C4) inhibited LIM 1863 adhesion to collagen but not TGF-beta induced adhesion, implying that TGF-beta induced a specific conformational change or interaction of a beta 1 integrin. In this morphologically structured system TGF-beta induced a number of subtle effects including formation of new extracellular matrix and conformational change of a beta 1 integrin, rather than the major quantitative changes in cell/matrix molecules reported previously.

Carcinoma↗
PubMed1995

The cortical neuritic pathology of Huntington's disease.

We have studied the brains of 10 patients with clinically and pathologically defined Huntington's disease and graded the degree of striatal pathology according to the Vonsattel grading system. Sections from nine cerebral cortical areas (Brodmann areas 8, 10, 24, 33, 28, 38, 7, 39, 18), the cerebellum, hypothalamus, medulla and caudate nucleus were stained with antibodies to ubiquitin and ubiquitin C-terminal hydrolase (PGP 9.5). Dystrophic neurites, immunoreactive with ubiquitin and PGP 9.5 were detected in all cortical areas, in layers 3, 5 and 6, of all brains studied. No dystrophic neurites were found in subcortical areas or cerebellum. Sections from cortical areas 8 and 24 from the two brains with the most and least ubiquitin-immunoreactive neurites were stained with antibodies to beta-amyloid precursor protein, tau, glial fibrillary acidic protein, neurofilament protein, alpha B crystallin, GABA, cholecystokinin and somatostatin. The dystrophic neurites were found to also react with beta-amyloid precursor protein. Electron microscopy showed the abnormal neurites to contain granulofilamentous material. Granular deposits with a diameter of 40-100 nm were interspersed between randomly orientated 'fuzzy' or coated, straight or slightly curved filaments measuring 10-15 nm in diameter. These structures have not been seen in control brain and differ from age-related neuritic degeneration and neurites associated with amyloid. Immunohistochemically these structures most resemble CA 2/3 neurites seen in Lewy body disease, and, ultrastructurally, the intraneuronal filamentous inclusions in motor neuron disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Analysis of the role of membrane polarity in polycystic kidney disease of transgenic SBM mice.

Altered membrane polarity has been proposed as an important pathogenetic factor in the development of renal cysts in polycystic kidney disease. To determine whether this alteration in epithelial phenotype is a primary or secondary phenomenon, we examined the epithelial membrane polarity of SBM transgenic mice, in which epithelial proliferation mediated by the c-myc oncogene is an established primary event. Kidneys from 32 transgenic mice and 10 age-matched controls from fetal to adult age were immunostained with antibodies to Na,K-ATPase, fodrin, ankyrin, E-cadherin, and tubule segment-specific lectins. In normal control mice, Na,K-ATPase localization was apical in fetal kidneys but became translocated to the basolateral membrane at maturity. Early microcysts in fetal transgenic kidneys displayed similar (95 to 100%) apical Na,K-ATPase. In young and newborn transgenic mice (1 to 8 days of age), Na,K-ATPase localization was extremely heterogeneous. Noncystic tubules demonstrated either apical (mean 23 to 28%), basolateral (mean 48 to 58%), mixed (mean 4 to 15%), or absent (mean 10 to 13%) staining for Na,K-ATPase. Apical Na,K-ATPase was more frequently observed in early cysts (mean 55%) in young transgenic mice but became less prevalent in adult mice (mean 22%), where 30% of cysts had basolateral staining, 39% mixed patterns, and 9% absent staining. Macrocysts typically lost all Na,K-ATPase reactivity. At all ages, Na,K-ATPase colocalized well with cytoskeletal proteins ankyrin and fodrin. These heterogeneous patterns of Na,K-ATPase staining indicate that although altered cell polarity is frequent in early cystic epithelium of SBM mice, it is not a prerequisite to cystogenesis or progressive cyst enlargement. In conclusion, our results support the view that altered cystic membrane polarity is not a primary process, but represents the persistence of an immature epithelial phenotype characteristic of proliferative polycystic kidney disease epithelia.

Animals↗
PubMed1994

Animal research.

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Animal Welfare↗
PubMed1994

Relationships of Na+ and K+ concentrations to GRP, CGRP, and calcitonin immunoreactivities and Na+,K(+)-ATPase (NKA) inhibitory activity in human breast cyst fluid.

BACKGROUND: Although the etiology of gross cystic disease of the breast is unknown, elevated cyst concentrations of potassium (K+) (> 60 mM/L) may be related to symptoms. The purpose of this study was to clarify the mechanism(s) of K+ accumulation in breast cysts. METHODS: We assayed cyst fluids for factors known to exert effects on K+ transport, namely, endogenous digitalis-like inhibitors of Na+,K(+)-ATPase (NKA) and the neuropeptides gastrin-releasing peptide (GRP), calcitonin (CT), and calcitonin gene-related peptide (CGRP). RESULTS: Cyst fluid K+ was directly correlated with cyst volume, cyst NKA inhibitory activity (in ouabain equivalents), and cyst concentrations of calcitonin, GRP, and CGRP. Cyst fluid Na+ was inversely correlated with cyst fluid K+, cyst NKA inhibitory activity, cyst volume, and cyst fluid concentrations of calcitonin, GRP, and CGRP. NKA inhibitory activity correlated directly with GRP and CGRP. Immunocytochemistry localized GRP to breast cyst lining cells and areas of ductal and lobular epithelial hyperplasia in biopsies of 15 of 15 cysts and in 5 of 5 breast carcinomas, but not in (0 of 5) normal breast biopsies. Specificity of GRP staining was demonstrated by total abolition of reactivity after adsorption with synthetic GRP, but not after adsorption with synthetic substance P, neurokinin A, or neurokinin B. CONCLUSIONS: We conclude that both the concentrations of endogenous digitalis-like factors and the neuropeptides calcitonin, GRP, and CGRP in human breast cyst fluids are related to the concentrations of K+ and Na+ in breast cysts and to cyst volume.

Adult↗
PubMed1994

Effect of follicular fluid supplementation on the in vitro development of human pre-embryos.

OBJECTIVE: To evaluate the value of supplementing a standard culture medium with 10% heat-inactivated mature follicular fluid (FF). DESIGN: Prospective randomized study evaluating the in vitro development of nontransferred, nonfrozen human pre-embryos in three culture conditions from day 3 to day 8 postfertilization. Preliminary evaluation by RIA and electrophoresis of factors responsible for these results. RESULTS: Ten percent mature FF supplementation of Inra Menezo (B2 medium) was associated with a significantly higher proportion of human pre-embryos reaching the morula (95% versus 72% with 10% maternal serum, P = 0.04) and the blastocyst stage (50% versus 11% with B2 alone, P = 0.02). The concentration of insulin-like growth factors I and II did not differ significantly between serum and mature FF-supplemented medium. Protein electrophoresis showed a difference of two bands corresponding to a molecular weight of 17,000 present in the serum and not in the FF-supplemented medium. CONCLUSION: Culture medium supplementation with 10% mature FF is associated with a significantly higher proportion of pre-embryos reaching the morula and blastocyst stage. The observed difference could be explained by the presence of a low molecular weight (17,000) embryotoxic factor contained in the serum-supplemented medium.

Blastocyst↗
PubMed1994

Oncology data management in the UK--BODMA's view. British Oncology Data Managers Association.

Over the past 10 years, the original partnership of clinician and statistician for the running of clinical research projects, especially clinical trials, has come to be supplemented by the data manager and trial coordinator. Increasing numbers of such personnel are now being employed, covering a wide diversity of work areas, including clinical research, medical audit and the cancer registries. The British Oncology Data Managers Association (BODMA) was founded in 1987 and is now in a good position to review the current status of data management in the UK. It is proposed that a national network of data managers and trial coordinators within specialist trials centres, oncology departments and district general hospitals, with a good training programme, plus a recognised career structure, is the way to make the best use of this key resource. BODMA is addressing many of these issues and aims to improve and maintain the quality of data management.

Clinical Trials as Topic↗