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Biomedical subjects

P Holland

Publications and source records attributed to P Holland.

At least 19 recordsLinked to original sources
PubMed2001

Blood support for pediatric surgery.

Increasingly complicated surgeries are being performed on neonatal and pediatric patients. Provision of a safe and adequate blood supply is essential for the success of many of these surgeries. Depending on the clinical situation, autologous and/or allogeneic blood may be used. However, in all cases, every attempt should be made to minimize the number of donor exposures to reduce the risk of transfusion transmitted infections. Transfusion of neonatal and pediatric patients requires additional considerations too, such as the risk of graft vs host disease, cytomegalovirus infection, the effects of various preservative anticoagulant solutions, electrolyte levels during blood storage, and wheather or not leukoreduced components are indicated.

Blood Donors↗
PubMed2000

Modulation of Starling forces and muscle fiber maturity permits adenovirus-mediated gene transfer to adult dystrophic (mdx) mice by the intravascular route.

Duchenne muscular dystrophy (DMD) and other inherited myopathies lead to progressive destruction of most skeletal muscles in the body, including those responsible for maintaining respiration. DMD is a fatal disorder caused by defects in the dystrophin gene. Recombinant adenovirus vectors (AdV) are considered a promising means for therapeutic delivery of a functional dystrophin gene to DMD muscles. If AdV-mediated dystrophin gene replacement in DMD is to be successful, development of a systemic delivery method for targeting the large number of diseased muscles will be required. In this study we investigated two major factors preventing efficient AdV-mediated gene transfer to skeletal muscles of adult animals after intravascular AdV administration: (1) an inability of AdV particles to breach the endothelial barrier and enter into contact with myofibers, and (2) a relatively nonpermissive myofiber population for AdV infection due at least in part to insufficient levels of the coxsackie/adenovirus attachment receptor (CAR). On the basis of established principles governing the transendothelial flux of macromolecules, we further hypothesized that an alteration in Starling forces (increased hydrostatic and decreased osmotic pressures) within the intravascular compartment would facilitate AdV transendothelial flux via convective transport. In addition, experimental muscle regeneration was employed to increase the prevalence of immature myofibers in which CAR expression is upregulated. Here we report that by employing the above-described strategy, high-level heterologous reporter gene expression was achievable in hindlimb muscles of normal rats as well as dystrophic (mdx) mice (genetic homolog of DMD) after a single intraarterial injection of AdV. Microsphere studies confirmed enhanced transport into muscle of fluorescent tracer particles in the size range of AdV, and there was a high concordance between CAR upregulation and myofiber transduction after intraarterial AdV delivery. Furthermore, in mdx mice examined 10 days after intraarterial AdV delivery, the aforementioned procedures had no adverse effects on the force-generating capacity of targeted muscles. These findings have implications for eventual AdV-mediated gene therapy of generalized skeletal muscle diseases such as DMD using a systemic intraarterial delivery approach.

Adenoviridae↗
PubMed2000

Life course accumulation of disadvantage: childhood health and hazard exposure during adulthood.

The present paper examines the association between physical and social disadvantage during childhood and lifetime exposure to health-damaging environments. Study members were participants of Boyd Orr's clinical, social and dietary survey conducted between 1937 and 1939 and were aged between 5 and 14 years at clinical examination. Study participants were traced and between 1997 and 1998 a random sample of 294 were interviewed. The lifegrid interview method was used to collect full occupational, residential and household histories, from which accumulated lifetime exposures to a range of environmental hazards were estimated. Age-adjusted height during childhood was found to be inversely related to subsequent exposure to all hazards combined (males p = 0.002; females p = 0.001). This relationship was found in males with manual fathers (p = 0.044) and females with non-manual fathers (p = 0.035). Chronic disease during childhood was also associated with greater subsequent hazard exposure in males with manual fathers (p = 0.008). Among females with non-manual fathers, in contrast, chronic disease during childhood was associated with reduced subsequent hazard exposure (p = 0.05). These findings suggest that exposure to health-damaging environments during adulthood may accumulate on top of health disadvantage during childhood and that this process of life course accumulation of disadvantage may vary by gender and childhood social class.

Adolescent↗
PubMed2000

Comparative proteome analysis of Helicobacter pylori.

Helicobacter pylori, the causative agent of gastritis, ulcer and stomach carcinoma, infects approximately half of the worlds population. After sequencing the complete genome of two strains, 26695 and J99, we have approached the demanding task of investigating the functional part of the genetic information containing macromolecules, the proteome. The proteins of three strains of H. pylori, 26695 and J99, and a prominent strain used in animal models SS1, were separated by a high-resolution two-dimensional electrophoresis technique with a resolution power of 5000 protein spots. Up to 1800 protein species were separated from H. pylori which had been cultivated for 5 days on agar plates. Using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) peptide mass fingerprinting we have identified 152 proteins, including nine known virulence factors and 28 antigens. The three strains investigated had only a few protein spots in common. We observe that proteins with an amino acid exchange resulting in a net change of only one charge are shifted in the two-dimensional electrophoresis (2-DE) pattern. The expression of 27 predicted conserved hypothetical open reading frames (ORFs) and six unknown ORFs were confirmed. The growth conditions of the bacteria were shown to have an effect on the presence of certain proteins. A preliminary immunoblotting study using human sera revealed that this approach is ideal for identifying proteins of diagnostic or therapeutic value. H. pylori 2-DE patterns with their identified protein species were added to the dynamic 2D-PAGE database (http://www.mpiib-berlin.mpg.de/2D-PAGE/). This basic knowledge of the proteome in the public domain will be an effective instrument for the identification of new virulence or pathogenic factors, and antigens of potentially diagnostic or curative value against H. pylori.

Bacterial Proteins↗
PubMed2000

The three systems: a conceptual way of understanding nocturnal enuresis.

Childhood nocturnal enuresis has traditionally been regarded as a multifaceted problem with a variety of treatment interventions. This paper proposes a model based on the notion that nocturnal enuresis arises through the ill functioning of one or more of the following three systems - a lack of vasopressin release during sleep; bladder instability; and/or an inability to arouse from sleep to bladder sensations. Clinical signs of each system are outlined and the appropriate treatment intervention for each is discussed. It is argued that addressing nocturnal enuresis in this way will enhance overall treatment effectiveness.

Arousal↗
PubMed2000

Standardized limb abduction for bioimpedance measurements using position restraints.

Bioelectrical impedance analysis (BIA) measurements are widely used in the assessment of body hydration. However, there are many variables which can influence the impedance values obtained and their individual significance is not entirely clear. One such variable is limb position and it is possible to standardize this either by invoking subject cooperation or by the use of some form of mechanical constraint. This study evaluates these two approaches. BIA measurements were made on five healthy male volunteers both with the positioners and without. Additional variables including room temperature, prandial status, exercise, alcohol intake, bed surface for the test, and bladder status were controlled. The mean percentage difference between impedance values with and without positioners was (-0.37 +/- 0.69)%. The mean difference between occasions with and without mechanical fixing was (2.02 +/- 2.5)% and (2.58 +/- 3)% respectively. None of these differences is statistically significant. It was concluded that reproducibility of BIA measurements obtained with active subject cooperation in limb position is not significantly improved if mechanical positioners are used. This may not apply where subject cooperation is poor e.g. in very sick or very young people or in repeated measurements in different days.

Adult↗
PubMed2000

How accurately are height, weight and leg length reported by the elderly, and how closely are they related to measurements recorded in childhood?

BACKGROUND: This paper examines (1) the accuracy of self-reported height, leg length and weight in a group of subjects aged 56-78; (2) whether recent measurement of height and weight influences the accuracy of self-reporting and (3) associations between childhood and adult height, leg length and BMI measured in old age. METHODS: All 3182 surviving members of the Boyd Orr cohort were sent postal questionnaires in 1997-1998 and a sub-sample (294) was also clinically examined. RESULTS: Self-reported height was overestimated and body mass index (BMI), based on reported height and weight, underestimated. The mean difference between self-report and measured values were for height: 2.1 cm in males and 1.7 cm in females; for BMI the difference was -1.3 kg/m(2) in males and -1.2 kg/m(2) in females. Shorter individuals and older subjects tended to over-report their height more than others. The overweight under-reported their weight to a greater extent. Recent measurement appeared to decrease over-reporting of height but not weight. Correlations between self-report and measured height and BMI were generally over 0.90, but weaker for leg length (r = 0.70 in males and 0.71 in females). Adult height and leg length were quite closely related to their relative values in childhood (correlation coefficients ranged from 0.66 to 0.84), but associations between adult and childhood BMI were weak (r = 0.19 in males and 0.21 in females). CONCLUSIONS: Self-reported measures of height and weight may be used in studies of the elderly although systematic reporting errors may bias effect estimates. As overweight individuals tend to under-report and the short and underweight tend to over-report, studies investigating associations of disease with height and weight using self-reported measures will underestimate effects. The weak associations between childhood and adult BMI indicate that associations between childhood adiposity and adult cardiovascular disease found in this cohort may reflect the specific effect of childhood overweight, rather than its persistence into adulthood. This suggests that avoidance of adiposity may be as important in childhood as in adulthood.

Aged↗
PubMed1999

The functional microdomain in transmembrane helices 2 and 7 regulates expression, activation, and coupling pathways of the gonadotropin-releasing hormone receptor.

Structural microdomains of G protein-coupled receptors (GPCRs) consist of spatially related side chains that mediate discrete functions. The conserved helix 2/helix 7 microdomain was identified because the gonadotropin-releasing hormone (GnRH) receptor appears to have interchanged the Asp(2.50) and Asn(7.49) residues which are conserved in transmembrane helices 2 and 7 of rhodopsin-like GPCRs. We now demonstrate that different side chains of this microdomain contribute specifically to receptor expression, heterotrimeric G protein-, and small G protein-mediated signaling. An Asn residue is required in position 2.50(87) for expression of the GnRH receptor at the cell surface, most likely through an interaction with the conserved Asn(1.50(53)) residue, which we also find is required for receptor expression. Most GPCRs require an Asp side chain at either the helix 2 or helix 7 locus of the microdomain for coupling to heterotrimeric G proteins, but the GnRH receptor has transferred the requirement for an acidic residue from helix 2 to 7. However, the presence of Asp at the helix 7 locus precludes small G protein-dependent coupling to phospholipase D. These results implicate specific components of the helix 2/helix 7 microdomain in receptor expression and in determining the ability of the receptor to adopt distinct activated conformations that are optimal for interaction with heterotrimeric and small G proteins.

Animals↗
PubMed1999

The effect of adverse life events on glycaemic control in children with insulin dependent diabetes mellitus.

Forty-five children aged 6 to 14 years with insulin-dependent diabetes mellitus were recruited from a paediatric diabetic clinic. Glycaemic control, child emotional and behavioural problems, and maternal mental state were assessed at recruitment and after 12 months. Life events were measured at 12 months using a standardised semi-structured interview schedule. A between-groups comparison design was used to explore the effect of life events, child emotional and behavioural problems, and maternal mental state on glycaemic control. The children had relatively high rates of emotional and behavioural problems. Overall, the children had a similar number of life events to healthy children in the general population, but proportionally, experienced fewer desirable events. Children who had experienced at least one event in a family setting, or a disappointing event, were more likely to have high glycated haemoglobin levels afterwards than were children who had not experienced such events. Linear regression models showed that only disappointments, family events and glycated haemoglobin at the start of the study made important independent contributions to glycated haemoglobin at 12 months. Child age, emotional and behavioural problems, and maternal mental state, had no effect on glycaemic control.

Anxiety Disorders↗
PubMed1999

Reconstructing the life course: health during early old age in a follow-up study based on the Boyd Orr cohort.

A method is described for investigating life course influences on health in early old age. The lives of some 300 individuals at present aged 65-75 y have been reconstructed from the archived records of a pre-WWII survey, in which they took part as children, and from lifegrid interviews with the same individuals 60 y later. Despite loss to study at several points those interviewed are shown to be representative of the British population socio-demographically, in comparison with the 1931 and 1991 decennial censuses, and physically, in comparison with the Health Survey for England. Bias is conservative because the most disadvantaged were disproportionately affected by loss to follow-up through death and because non-responders to interview were more disadvantaged as children than the interviewees. Representativeness and conservative bias, it is argued, justify the use of these data for investigating life course influences on health in early old age.

Aged↗
PubMed1999

Abnormal surfactant composition and activity in severe bronchiolitis.

A prospective study of infants under 1 y of age, ventilated for severe viral bronchiolitis, was carried out in four paediatric intensive care units in order to study surfactant activity and composition in this condition. Lung lavage fluid from 24 infants with bronchiolitis, 19 with bronchiolitis and sepsis or cardiac failure and 12 controls were analysed by the "click test" for surfactant activity and for phospholipids. Surfactant activity was present in all controls, but in only 2 of the 24 infants with bronchiolitis alone. The presence of phosphatidylglycerol correlated perfectly with the click test, suggesting that reduced activity is due to changes in surfactant lipid composition. In those with bronchiolitis plus coexisting disease, surfactant activity and phosphatidylglycerol were absent in only half. Surfactant activity and phosphatidylglycerol re-appeared by extubation. Severe viral bronchiolitis is associated with an absence of surfactant activity and PG, which resolves by clinical recovery. Infants with coexisting conditions are not always surfactant deficient. Surfactant administration is likely to be beneficial, but requires a selective approach.

Bronchiolitis↗
PubMed1999

Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine- or stress-activated signal transduction pathways.

A hallmark of inflammation is the burst-like formation of certain proteins, initiated by cellular stress and proinflammatory cytokines like interleukin 1 (IL-1) and tumor necrosis factor, stimuli which simultaneously activate different mitogen-activated protein (MAP) kinases and NF-kappaB. Cooperation of these signaling pathways to induce formation of IL-8, a prototype chemokine which causes leukocyte migration and activation, was investigated by expressing active and inactive forms of protein kinases. Constitutively active MAP kinase kinase 7 (MKK7), an activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathway, induced IL-8 synthesis and transcription from a minimal IL-8 promoter. Furthermore, MKK7 synergized in both effects with NF-kappaB-inducing kinase (NIK). Activation of the IL-8 promoter by either of the kinases required functional NF-kappaB and AP-1 sites. While NIK and MKK7 did not affect degradation of IL-8 mRNA, an active form of MKK6, which selectively activates p38 MAP kinase, induced marked stabilization of the transcript and further increased IL-8 protein formation induced by NIK plus MKK7. Consistently, the MAP kinase kinase kinase MEKK1, which can activate NF-kappaB, SAPK/JNK, and p38 MAP kinases, most potently induced IL-8 formation. These results provide evidence that maximal IL-8 gene expression requires the coordinate action of at least three different signal transduction pathways which cooperate to induce mRNA synthesis and suppress mRNA degradation.

Binding Sites↗
PubMed1999

Plasma vasopressin and response to treatment in primary nocturnal enuresis.

AIMS: To examine the relation between nocturnal vasopressin release and response to treatment with the vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP) in children with primary monosymptomatic nocturnal enuresis. DESIGN: Children were recruited from a specific enuresis clinic and entered into a defined treatment programme. Nocturnal vasopressin concentrations were measured every 15 minutes over a four hour period during overnight admission. RESULTS: Sixty seven children were eligible for entry into the study, 35 of whom agreed to overnight sampling. There was a quadratic relation between mean plasma AVP and response to treatment with DDAVP, with very high or very low concentrations being unresponsive. Plasma AVP profiles ranged from low concentrations with little variability to high concentrations with wide variability. CONCLUSION: The ability to respond to DDAVP is related to endogenous AVP production and is influenced by neuronal patterning in early infancy. The best predictors of success with treatment were a past history of breast feeding, mean nocturnal AVP concentration, and the height of the child. The response was adversely affected by poor weight at birth and poor linear growth. The study suggests differing causes of nocturnal enuresis related to different patterns of AVP release.

Adolescent↗
PubMed1998

Hippocampal lesions enhance configural learning by reducing proactive interference.

Rats were trained on an operant conditional discrimination in which an ambiguous stimulus (X) indicated both the occasions on which responding in the presence of a second cue (A) would be reinforced and the occasions on which responding in the presence of a third cue (B) would not be reinforced (X --> A+, A-, X --> B-, B+). Both rats with neurotoxic lesions of the hippocampus and control rats learned this discrimination more rapidly when the training trials were widely spaced (mean intertrial interval of 8 min) than when they were massed (mean intertrial interval of 1 min). With spaced practice, lesioned and control rats learned this discrimination equally well. But when the training trials were massed, lesioned rats learned more rapidly than controls. At the end of training, performance of all rats was tested at three different intertrial intervals, 0.5 min, 1 min, and 8 min. The control rats trained with 8-min intertrial intervals showed deficits in discrimination performance when the test intertrial interval was 0.5 min or 1 min. An analysis of sequential effects indicated that a major source of this performance deficit was the control rats' failure to withhold responding on nonreinforced trials when those trials were immediately preceded by reinforced trials within 0.5 min or 1 min. In contrast, performance of lesioned rats was not affected by either the test intertrial interval or by the nature of preceding trials. Thus, with short intertrial intervals, hippocampal lesions may have improved learning or performance on a given trial by reducing proactive interference from the previous trial.

Animals↗
PubMed1998

The effectiveness of desmopressin in the treatment of childhood nocturnal enuresis: predicting response using pretreatment variables.

OBJECTIVE: To determine the factors that predict the effectiveness of desmopressin in the treatment of childhood nocturnal enuresis. PATIENTS AND METHOD: Sixty-six children with monosymptomatic nocturnal enuresis were treated with intranasal or oral desmopressin for a 4-week period. starting with a standard dose of 20 microg (0.2 mg oral) and increasing after 2 weeks where no progress was apparent to 40 microg (0.4 mg oral). Before treatment a range of variables (demographic, situational, enuretic history, physiological, parental attitude and child) were recorded. Three parameters of success acted as dependent variables, with stepwise linear regression models used to determine pretreatment predictors of success with desmopressin. RESULT: Each outcome variable produced a very similar model of predictors. Success, as assessed by the most dry nights over a 14-night period, was associated with less severe enuresis before treatment, a parental belief that the child's enuresis was unstable and higher birthweight. CONCLUSION: From the analysis, a model of arginine vasopressin release is proposed and the clinical implications of the findings addressed.

Administration, Intranasal↗