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Biomedical subjects

P Clark

Publications and source records attributed to P Clark.

At least 37 records · Page 2Linked to original sources
PubMed2003

Microscopic analysis of the cellular events during scatter factor/hepatocyte growth factor-induced epithelial tubulogenesis.

Scatter factor/hepatocyte growth factor (SF/HGF), a large multifunctional polypeptide growth and motility factor, is known to play important roles during embryonic development, adult tissue growth and repair. In an established three-dimensional type I collagen model, SF/HGF induces Madin-Darby canine kidney (MDCK) epithelial cysts to form long, branching tubules (tubulogenesis). In addition, the composition of the surrounding extracellular matrix (ECM) has been shown to modulate SF/HGF-induced morphogenesis, where tubulogenesis was completely abrogated in Matrigel basement membrane. Many cellular events that occur during SF/HGF-mediated remodelling, and its modulation by the ECM, remain unclear. We have investigated these mechanisms through microscopic examination of the time-course of SF/HGF-induced responses in MDCK cysts cultured in type I collagen or Matrigel. We found that early responses to SF/HGF were matrix-independent. Changes included increased paracellular spacing between normally closely apposed lateral membranes, and the formation of filopodial processes, indicating a partial motile response. Cell-cell contact was maintained, with the persistence of cell junctions. Therefore, while one or a number of ECM components are preventing SF/HGF-primed cells from undergoing an invasive and/or migratory programme, non-permissive matrices are not preventing SF/HGF signalling to the cell. Later matrix-dependent responses, which occurred in type I collagen but not Matrigel, included the formation of basal protrusions that comprise two or more neighbouring cells, which extend to form nascent tubules. Modified polarity of cells comprising the basal protrusions was evident, with a marker for the apical membrane being found in the same region as adherens junctions and desmosomes, typically localized at lateral membranes. We propose a model for SF/HGF-induced tubulogenesis in which tubules form from basal protrusions of adjacent cells. This mechanism of in vitro tubule formation has many similarities to reported in vivo epithelial tubulogenesis.

Animals↗
PubMed2003

An outbreak no longer: factors contributing to the return of syphilis in Greater Manchester.

BACKGROUND: In the past few years, increased diagnoses of syphilis have been reported in cities around Britain and Europe. Enhanced surveillance of cases began in 1999 to identify the epidemiology of this increase in Greater Manchester. METHODS: Information was collected on all cases of syphilis newly diagnosed in genitourinary medicine (GUM) clinics in Greater Manchester between January 1999 and November 2002. The data collected included demographic information and information about other sexually transmitted infections, sexual behaviour, perception of risk of infection, and awareness of syphilis transmission. RESULTS: The majority of cases identified were white homosexual men resident in Greater Manchester. Of the 414 cases diagnosed, 74% had either a primary or secondary stage of syphilis infection and 37% of cases were HIV positive. High numbers of individuals practised unprotected oral sex despite good awareness of the risk of infection with syphilis. There is evidence that the way people are meeting sexual contacts is changing, with increasing numbers meeting most of their partners through the internet. CONCLUSIONS: These findings have implications for targeting interventions. The provision of rapid diagnostic and treatment services is likely to be key for the control of syphilis and potentially of subsequent increases in HIV in the region.

Adult↗
PubMed2003

Procalcitonin: a marker of bacteraemia in SIRS.

A number of European studies have documented the ability of procalcitonin (PCT), a novel inflammatory marker, to discriminate patients with sepsis from those with other causes of systemic inflammatory response syndrome (SIRS). The aim of this study was to assess procalcitonin's performance in an Australian intensive care unit (ICU) setting to examine whether it could discriminate between these two conditions. One hundred and twenty-three consecutive adult ICU patients fulfilling criteria for SIRS were enlisted in the study. Over a period of five days, daily serum PCT and C-reactive protein (CRP) levels were measured. At least two sets of cultures were taken of blood, sputum/broncho-alveolar lavage (BAL) and urine. Other cultures were taken as clinically indicated. Questionnaires to ascertain clinical suspicion of sepsis were prospectively answered by the ICU senior registrars. PCT values were ten times higher in patients with positive blood cultures; CRP values were also significantly higher in the bacteraemic patients. Both PCT and CRP had a good ability to discriminate bacteraemia from non-infectious SIRS, with the area under receiver operating characteristics (ROC) curves for PCT being 0.8 and for CRP being 0.82. However neither PCT or CRP was able to discriminate patients with localized sepsis from those without. Utilizing both tests resulted in a more sensitive screen than either one alone, while PCT was a more accurate diagnostic test for bacteraemia than CRP. The PCT value also differed between those who died in hospital and those who survived. Measurement of PCT alone or in combination with CRP can aid discrimination of septicaemia/bacteriemia with associated SIRS from non-infectious SIRS in an Australian ICU setting.

Australia↗
PubMed2002

Alignment of myoblasts on ultrafine gratings inhibits fusion in vitro.

During development, skeletal muscle precursor cells fuse to form multi-nucleated myotubes. However, it is unclear how this fusion is regulated such that linear myotubes are produced. In a previous study, we found that linear arrays of myoblasts cultured on micropatterns of laminin fused to form linear myotubes of a constant diameter, independent of the width of the laminin track. This suggested that a mechanism exists to prevent myoblasts from fusing laterally [Exp. Cell Res. 230 (1997) 275]. In this study, we have investigated this further by culturing myoblasts on ultrafine grooved surfaces previously shown to align fibroblasts and epithelial cells. We found that all the individual myoblasts were highly aligned along the groove axis, and time-lapse recordings showed that motility was mostly restricted to a direction parallel to the grooves. In contrast to the previous study, however, there was a strong tendency for early differentiating cells to form aggregates either at an angle of approximately 45 degrees or perpendicular to the groove axis. Nevertheless, we rarely saw myotubes formed at those angles, supporting our earlier idea that the ability of cells to fuse laterally is prohibited. Our data strongly suggest that myoblasts are most likely to fuse in an end-to-end configuration, and it is this that enables them to form linear, rather than irregular myotubes.

Animals↗
PubMed2002

Cytology of haematological cells of otariid seals indigenous to Australasian waters.

OBJECTIVE: To characterise the morphology of cells from the blood of otariid seals. METHODS: Examination of blood by light and scanning electron microscopy. RESULTS: Erythrocytes were typically discocytes. Leukocytes that were recognised included neutrophils, lymphocytes, monocytes, eosinophils and basophils. The morphology varied little between species for neutrophils, lymphocytes and monocytes. Some variation between species was observed for eosinophils and basophils. Platelets were generally aggregated. CONCLUSION: This study provides a guide for the identification of cells from the blood of otariid seals.

Animals↗
PubMed2001

Biochemical characterization of a virus isolate, recovered from a patient with herpes keratitis, that was clinically resistant to acyclovir.

In vitro susceptibility assays of herpes simplex virus (HSV) do not necessarily correlate with treatment outcome. An HSV type 1 (HSV-1) isolate, N4, recovered from a patient who presented with herpes keratitis with localized immunosuppression, was characterized for susceptibility. Although the 50% inhibitory concentration (IC(50)) for this isolate was less than the accepted breakpoint for defining resistance to acyclovir (>2.0 microg/mL), the following lines of evidence suggest that the isolate was acyclovir resistant: (1) the clinical history confirmed that the infection was nonresponsive to acyclovir; (2) the in vitro susceptibility was similar to that of a thymidine kinase (TK)-negative, acyclovir-resistant virus SLU360; (3) the IC(50) of acyclovir was more than 10 times the IC(50) for an acyclovir-susceptible control strain; (4) plaque-purified clonal isolates were resistant to acyclovir (IC(50)s, >2.0 microg/mL); and (5) biochemical studies indicated that the HSV-1 N4 TK was partially impaired for acyclovir phosphorylation. Although residue changes were found in both the viral tk and pol coding regions of HSV-1 N4, characterization of a recombinant virus expressing the HSV-1 N4 polymerase suggested that the TK and Pol together conferred the acyclovir-resistance phenotype.

Acyclovir↗
PubMed2001

Quality improvement report: Effect of a formal education programme on safety of transfusions.

PROBLEM: Failure of correct identification and insufficient monitoring of patients receiving transfusions continue to be appreciable and avoidable causes of morbidity and mortality. DESIGN: A study by a regional transfusion service and a transfusion nurse specialist of the effects of an education programme based on the current national guidelines on identification and monitoring of patients receiving transfusions. SETTING: A large United Kingdom teaching hospital which houses the headquarters of the regional transfusion service. KEY MEASURES FOR IMPROVEMENT: Improvement in compliance with published national guidelines on the prescription and administration of blood transfusions. STRATEGY FOR CHANGE: An audit of current compliance followed by dissemination by a transfusion nurse specialist of a clinical skills package (based on the best practice for transfusion) to all staff involved in giving transfusions. This was supported by trained instructors and the display of standard operating procedures for transfusion in all clinical areas. EFFECT OF CHANGE: An improvement in compliance with the national guidelines to over 95% in six out of seven of the recommendations on best practice was seen 18 months after the initial intervention. LESSONS LEARNT: The study shows that education of those who prescribe and administer transfusions, as recommended by bodies concerned with the hazards of transfusion, can improve the safety of transfusions.

Blood Transfusion↗
PubMed2001

Cerebral activation during a simple force production task: changes in the time course of the haemodynamic response.

An event-related paradigm was used to investigate the fMRI signal from the primary motor cortex (M1) and the supplementary motor area (SMA) during isolated isometric wrist extension at five different force levels. There was only a weak trend towards increased area of activation with increased force output, but there was a force-related increase in percentage change of signal within voxels in M1 (Kendall Tc = 0.48, p < 0.01), which may indicate control of force output by variation of neural firing rate. In SMA there was a correlation between peak force output and time-to-peak of the haemodynamic response in SMA (Kendall Tc = 0.74, p < 0.0001). This unexpected finding of a task-related change in the shape of the haemodynamic response within a single brain area requires further investigation. It may indicate a slower rise time at lower perfusion rates, or may be the result of inhibitory processes in motor control.

Adult↗
PubMed2001

Corn pollen deposition on milkweeds in and near cornfields.

The density of corn pollen on leaves of milkweed plants inside and outside of cornfields was measured in several studies from different localities. The purpose was to obtain a representative picture of naturally occurring pollen densities to provide a perspective for laboratory and field studies of monarch larvae feeding on milkweed leaves with Bt corn pollen. Pollen density was highest (average 170.6 grains per cm(2)) inside the cornfield and was progressively lower from the field edge outward, falling to 14.2 grains per cm(2) at 2 m. Inside the cornfield, and for each distance from the field edge, a frequency distribution is presented showing the proportion of leaf samples with different pollen densities. Inside cornfields, 95% of leaf samples had pollen densities below 600 grains per cm(2) and the highest pollen density observed was 1400 grains per cm(2), which occurred in a study with a rainless anthesis period. All other studies had rainfall events during the anthesis period. A single rain event can remove 54-86% of the pollen on leaves. Leaves on the upper portion of milkweed plants, where young monarch larvae tend to feed, had only 30-50% of the pollen density levels of middle leaves.

Animals↗
PubMed2001

Level of maternal antibody required to protect neonates against early-onset disease caused by group B Streptococcus type Ia: a multicenter, seroepidemiology study.

Because of the difficulty of conducting efficacy trials of vaccines against group B streptococcus (GBS), the licensure of these vaccines may have to rely on studies that measure vaccine-induced antibody levels that correlate with protection. This study estimates the level of maternal antibody required to protect neonates against early-onset disease (EOD) caused by GBS type Ia. Levels of maternal serum IgG GBS Ia antibodies, measured by ELISAs in 45 case patients (neonates with EOD caused by GBS Ia) and in 319 control subjects (neonates colonized by GBS Ia but without EOD) born at > or =34 weeks gestation were compared. The probability of developing EOD declined with increasing maternal levels of IgG GBS Ia antibody (P = .03). Neonates whose mothers had levels of IgG GBS Ia antibody > or =5 microg/mL had an 88% lower risk (95% confidence interval, 7%-98%) of developing type-specific EOD, compared with those whose mothers had levels < 0.5 microg/mL. A vaccine that induces IgG GBS Ia antibody levels > or =5 microg/mL in mothers can be predicted to confer a high degree of type-specific immunity to EOD to their infants.

Age of Onset↗
PubMed2001

Cyclic AMP and acidic fibroblast growth factor have opposing effects on tight and adherens junctions in microvascular endothelial cells in vitro.

Endothelial adherens junctions (AJ) and tight junctions (TJ) are important determinants of vascular permeability and cell morphology. Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP. The proliferation of HPMEC was weakly stimulated by ECGS, while cAMP was inhibitory. ECGS had little effect on transendothelial resistance (TER), but increased macromolecular permeability, whereas cAMP induced a twofold increase in TER and reduced macromolecular permeability. Ultrastructurally, ECGS-treated HPMEC exhibited an "activated" phenotype typified by proliferating cells, with poorly organized cell-cell junctions, whereas cAMP-treated cells appeared quiescent and markedly flattened with extended paracellular junctions, resembling endothelium in situ. The expression and localization of junctional molecules, F-actin, and junctional phosphotyrosine were examined by confocal microscopy and immunoblotting. Junctional molecules in ECGS-treated cells were less organized at lateral membranes than in control cells, whereas in cAMP-treated cells, they were highly localized at continuous contacts. These differences correlated with the intensity of junctional phosphotyrosine, being lowest with cAMP treatment. In the AJ of ECGS-treated and control cells, beta-catenin predominated but in cAMP-treated cells, gamma-catenin/plakoglobin was enriched. In addition, cAMP upregulated junctional expression of VE-cadherin and PECAM-1 and increased the levels of the TJ molecules occludin and ZO-1. The expression levels of junctional components, and their tyrosine phosphorylation, play an important role in dynamic regulation of endothelial cell-cell junctions.

Actins↗
PubMed2001

Rescue of the Friedreich's ataxia knockout mouse by human YAC transgenesis.

We have generated and characterised transgenic mice that contain the entire Friedreich's ataxia gene (FRDA) within a human YAC clone of 370 kb. In an effort to overcome the embryonic lethality of homozygous Frda knockout mice and to study the behaviour of human frataxin in a mouse cellular environment, we bred the FRDA YAC transgene onto the null mouse background. Phenotypically normal offspring that express only YAC-derived human frataxin were identified. The human frataxin was expressed in the appropriate tissues at levels comparable to the endogenous mouse frataxin, and it was correctly processed and localised to mitochondria. Biochemical analysis of heart tissue demonstrated preservation of mitochondrial respiratory chain function, together with some increase in citrate synthase and aconitase activities. Thus, we have demonstrated that human frataxin can effectively substitute for endogenous murine frataxin in the null mutant. Our studies are of immediate consequence for the generation of Friedreich's ataxia transgenic mouse models, and further contribute to the accumulating knowledge of human-mouse functional gene replacement systems.

Animals↗
PubMed2001

Antenatal waist circumference and hypertension risk.

OBJECTIVE: To assess whether waist circumference at the first antenatal visit predicts risk of developing hypertension later in pregnancy. METHODS: Pregnant women with singleton pregnancies (n = 1142, median age 29 years, interquartile range 25-32 years, 387 primigravidas) were recruited at their first antenatal visits. Using standardized methods, midwives determined the weights, heights (for calculation of body mass index [BMI]), and waist circumferences of all women. Eighty-two women developed pregnancy-induced hypertension, and 21 developed preeclampsia (hypertension with proteinuria). RESULTS: The median waist circumference between 6 and 16 weeks' gestation was 79 cm (interquartile range 72-84 cm), and there was no significant relationship between waist circumference and gestational age. Greater waist circumference was noted in subjects who subsequently developed pregnancy-induced hypertension (median 81 versus 77 cm, Mann-Whitney U test, P =.002) or preeclampsia (median 80 versus 77 cm, P =.02). The conventional, nonpregnant waist circumference action level of 80 cm gave a Mantel-Haenszel odds ratio (OR) for pregnancy-induced hypertension of 1.8 (95% confidence interval [CI] 1.1, 2.9) and for preeclampsia of 2.7 (95% CI 1.1, 6.8), compared with waists of less than 80 cm. Body mass index values were higher in women who developed pregnancy-induced hypertension (median 26 versus 24, P =.001) or preeclampsia (median 26 versus 24, P =.02). The conventional action limit for a BMI of 25 had an OR for pregnancy-induced hypertension of 2.0 (95% CI 1.2, 3.4) and for preeclampsia of 1.9 (95% CI 0.7, 4.8). Results were similar when the analysis was restricted to data from primigravidas. CONCLUSION: We conclude that waist circumference up to 16 weeks' gestation can predict pregnancy-induced hypertension and preeclampsia. Therefore, waist circumference could form the basis for health promotion involving raising awareness of the importance of or urging weight reduction for women planning pregnancies.

Adult↗
PubMed2001

Tuberculous aneurysm of the aorta presenting with uncontrolled hypertension.

Mycotic aneurysm secondary to tuberculous infection of the aorta is a rare entity with less than 50 cases having been described in the literature. Clinical presentation is usually a consequence of the aneurysm, including pain, palpable mass, or hypovolemia secondary to leak. Definitive treatment is surgical, with nearly 30 documented successful cases. The authors present a case of tuberculous aortitis with mycotic aneurysms that presented with uncontrolled hypertension and occlusion of the right renal artery that underwent successful surgical repair.

Adult↗