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P Harding

Publications and source records attributed to P Harding.

At least 19 recordsLinked to original sources
PubMed2006

Transforming growth factor beta regulates cyclooxygenase-2 in glomerular mesangial cells.

This study examines the hypothesis that transforming growth factor beta (TGFbeta) regulates cyclooxygenase-2 (COX-2) and induces prostaglandin E synthase (mPGES-1) in rat mesangial cells. COX-2 expression was determined by Northern blot analysis after treatment with either TGFbeta1 or the selective COX-2 inhibitor, NS398. mPGES-1 expression was determined by real-time polymerase chain reaction. The effect of TGFbeta1 on COX-2 gene transcription was assessed using a luciferase reporter assay, and mRNA stability was also determined. To determine whether TGFbeta1 activates elements of the COX-2 promoter, we performed gel shift analyses to examine activation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB). Prostaglandin E(2) (PGE(2)) and thromboxane B2 (TxB2) production was assayed by enzyme immunoassay. Finally, the pathophysiological relevance of COX-2 inhibition on the downstream effects of TGFbeta was assessed by examining collagen type I mRNA and net collagen production. COX-2 mRNA and mPGES-1 were induced after treatment with TGFbeta1 for 4 h, and this rise was accompanied by a three-fold increase in PGE(2) production that could be antagonized by selective inhibition of COX-2 with NS398. TGFbeta1 increased transcription by approximately 50% and activated both AP-1 and NF-kappaB. These effects were antagonized by co-treatment with NS398. Treatment with TGFbeta1 also doubled the half-life of COX-2 mRNA. Neither collagen type I mRNA nor net collagen production were altered by co-treatment with NS398. In conclusion, these results indicate that TGFbeta stimulates COX-2 and mPGES-1, with additional effects on transcription and stability of COX-2 mRNA.

Animals↗
PubMed2005

Distribution of Ixodes ricinus in the British Isles: investigation of historical records.

Ixodes ricinus Linnaeus (Acari: Ixodidae) is the most abundant and widely distributed tick in the British Isles, and is a vector for a number of bacterial, viral and protozoal pathogens of both medical and veterinary importance. This report provides an update to the historical distribution data of I. ricinus, published by the Biological Records Centre (BRC), Monks Wood in The Provisional Atlas of the Ticks (Ixodidae) of the British Isles by K. P. Martyn (1988), and is supplemented with additional BRC records since 1988, additional data from published scientific literature and unpublished field studies, and enhanced with spatial and temporal information on tick stages collected and their host associations. Records have been mapped at 10 km resolution and enhanced to 5 km, 1 km and 0.1 km. Differentiation between records representing one-off collections from those representing populations of I. ricinus has been achieved through the classification of the records into either reported or established populations. Detailed seasonality and host associations of records are investigated, highlighting the value in obtaining additional detailed contemporary data to aid risk assessments and research within this field.

Animals↗
PubMed2002

Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss.

The objective of this work was to determine the effect of androgen deprivation therapy (ADT) on rates of bone mineral density (BMD) loss in men with prostate cancer. It was a prospective study comparing men receiving ADT to age matched controls for 2 y. Subjects received a history, physical exam, bone mineral density measurement, and laboratory evaluation every 6 months. Thirty-nine subjects receiving continuous ADT for prostate cancer (subjects) were compared to 39 age-matched controls not receiving ADT (controls). Twenty-three subjects and 30 controls completed the study through 24 months. Men in the ADT group demonstrated greater rates of bone mineral density loss than men in the control group at every site except the lumbar spine. Twenty-four month per cent of bone mineral density loss is presented as mean+/-standard error (s.e.). At the distal forearm, the ADT group value was -9.4%+/-1.0% and -4.4%+/-0.3% for controls (P<0.0005). The ADT group femoral neck values were -1.9%+/-0.7% and 0.6%+/-0.5% in the control group (P=0.0016). The ADT group total hip value was -1.5%+/-1.0% and 0.8%+/-0.5% in the control group (P=0.0018). The ADT group trochanter value was -2.0%+/-1.3% and -0.1%+/-0.5% in the control group (P=0.0019). The ADT group lumbar spine value was -0.2%+/-0.8 % and 1.1%+/-0.6% in the control group (P=0.079). Our data demonstrate greater rates of bone mineral density loss in men receiving androgen deprivation therapy for prostate cancer.

Absorptiometry, Photon↗
PubMed2001

Rapid responses of British butterflies to opposing forces of climate and habitat change.

Habitat degradation and climate change are thought to be altering the distributions and abundances of animals and plants throughout the world, but their combined impacts have not been assessed for any species assemblage. Here we evaluated changes in the distribution sizes and abundances of 46 species of butterflies that approach their northern climatic range margins in Britain-where changes in climate and habitat are opposing forces. These insects might be expected to have responded positively to climate warming over the past 30 years, yet three-quarters of them declined: negative responses to habitat loss have outweighed positive responses to climate warming. Half of the species that were mobile and habitat generalists increased their distribution sites over this period (consistent with a climate explanation), whereas the other generalists and 89% of the habitat specialists declined in distribution size (consistent with habitat limitation). Changes in population abundances closely matched changes in distributions. The dual forces of habitat modification and climate change are likely to cause specialists to decline, leaving biological communities with reduced numbers of species and dominated by mobile and widespread habitat generalists.

Adaptation, Physiological↗
PubMed2001

Effect of N-acetyl-seryl-aspartyl-lysyl-proline on DNA and collagen synthesis in rat cardiac fibroblasts.

N:-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell entry into the S phase of the cell cycle and is normally present in human plasma. Ac-SDKP is exclusively hydrolyzed by ACE, and its plasma concentration is increased 5-fold after ACE inhibition in humans. We examined the effect of 0.05 to 100 nmol/L Ac-SDKP on 24-hour (3)H-thymidine incorporation (DNA synthesis) by cardiac fibroblasts both in the absence and presence of 5% FCS. Captopril (1 micromol/L) was added in all cases to prevent the degradation of Ac-SDKP. Treatment of cardiac fibroblasts with 5% FCS increased thymidine incorporation from a control value of 12 469+/-594 to 24 598+/-1051 cpm (P:<0.001). Cotreatment with 1 nmol/L Ac-SDKP reduced stimulation to control levels (10 373+/-200 cpm, P:<0.001). We measured hydroxyproline content and incorporation of (3)H-proline into collagenous fibroblast proteins and found that Ac-SDKP blocked endothelin-1 (10(-8) mol/L)-induced collagen synthesis in a biphasic and dose-dependent manner, causing inhibition at low doses, whereas high doses had little or no effect. It also blunted the activity of p44/p42 mitogen-activated protein kinase in a biphasic and dose-dependent manner in serum-stimulated fibroblasts, suggesting that the inhibitory effect of DNA and collagen synthesis may depend in part on blocking mitogen-activated protein kinase activity. Participation of p44/p42 in collagen synthesis was confirmed, because a specific inhibitor for p44/p42 activation (PD 98059, 25 micromol/L) was able to block endothelin-1-induced collagen synthesis, similar to the effect of Ac-SDKP. The fact that Ac-SDKP inhibits DNA and collagen synthesis in cardiac fibroblasts suggests that it may be an important endogenous regulator of fibroblast proliferation and collagen synthesis in the heart. Ac-SDKP may participate in the cardioprotective effect of ACE inhibitors by limiting fibroblast proliferation (and hence collagen production), and therefore it would reduce fibrosis in patients with hypertension.

Angiotensin II↗
PubMed2000

The effects of clinical case management on hospital service use among ED frequent users.

This study examined the impact of case management on hospital service use, hospital costs, homelessness, substance abuse, and psychosocial problems in frequent users of a public urban emergency department (ED). Subjects were 53 patients who used the ED five times or more in 12 months. Utilization, cost, and psychosocial variables were compared 12 months before and after the intervention. The median number of ED visits decreased from 15 to 9 (P < .01), median ED costs decreased from $4,124 to $2,195 (P < .01) and median medical inpatient costs decreased from $8,330 to $2,786 (P < .01). Homelessness decreased by -57% (P < .01), alcohol use by -22% (P = .05) and drug use by -26% (P = .05). Linkage to primary care increased 74% (P < .01). Fifty-four percent of medically indigent subjects obtained Medicaid (P < .01). There was a net cost savings, with each dollar invested in the program yielding a $1.44 reduction in hospital costs. Thus, case management appears to be a cost-effective means of decreasing acute hospital service use and psychosocial problems among frequent ED users.

Adult↗
PubMed2000

Chronic cyclooxygenase-2 inhibition blunts low sodium-stimulated renin without changing renal haemodynamics.

BACKGROUND: Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is found in the macula densa of the renal cortex and is upregulated by dietary sodium restriction. Because of this discrete cortical localization, we hypothesized that COX-2 plays a role in the chronic stimulation of renin via the macula densa pathway. METHODS: We examined the effect of the selective COX-2 inhibitor NS 398 in male Sprague-Dawley rats. RESULTS: A low sodium diet (0.02% NaCl) for 14 days elevated plasma-renin activity (PRA) nine-fold, from 6.1 +/- 2.0 to 54.9 +/- 6.5 ng angiotensin I (Ang I)/ml per h (P < 0.0001). Selective COX-2 inhibition with NS 398 had no effect on PRA in animals on normal sodium (5.1 +/- 1.3 ng Ang I/ml per h), but decreased PRA by 41% in sodium-restricted rats, to 33.3 +/- 3.6 ng Ang I/ml per h (P < 0.05). Chronic treatment with NS 398 did not decrease renal renin content (31.8 +/- 1.8 versus 33.5 +/- 2.6 ng Ang I/ mg per h, with NS 398 versus controls), nor did it influence systemic blood pressure or renal haemodynamics. Neither urinary sodium excretion nor prostaglandin (PG)E2 excretion was altered in rats given NS 398. Chronic treatment with the non-selective COX inhibitor indomethacin during sodium restriction over 5 days reduced PRA by 35%, from 29.36 +/- 4.81, to 19.13 +/- 2.88 ng Ang I/ml per h (P < 0.05). Indomethacin had no effect on blood pressure or renal blood flow but reduced urinary PGE2 excretion by 70%. CONCLUSIONS: One component of the chronic stimulation of PRA by dietary sodium restriction via the macula densa pathway appears to involve the induction of COX-2.

Animals↗
PubMed1999

Transcatheter closure of secundum atrial septal defects with the new self-centering Amplatzer Septal Occluder.

AIMS: The study was set up to find out whether a new self-centering prosthesis for transcatheter closure of secundum atrial septal defects could overcome the disadvantages of previously described devices. METHODS AND RESULTS: Fifty-two consecutive patients with a significant atrial septal defect were considered for transcatheter closure with the Amplatzer Septal Occluder. The device, made of a Nitinol and polyester fabric mesh, provides a different approach to defect occlusion by stenting the atrial septal defect up to a stretched diameter of 26 mm. Three infants whose large defects were demonstrated on a transthoracic echocardiogram were excluded from transcatheter treatment. On transoesophageal echocardiography, 49 defects ranged from 6-26 mm, in one adult the defect measured 28 mm and this patient was excluded from attempted transcatheter closure. At cardiac catheterization in five further patients, devices were not implanted, in two because the stretched diameter exceeded 26 mm and in three the device was withdrawn because it was unstable or compromised the mitral valve. Thus, device closure was performed in 43 patients. At follow-up after 3 months the complete closure rate was 97%. CONCLUSION: The self-centering Amplatzer Septal Occluder is very efficient and user-friendly and offers interventional closure in 83% of an unselected group of patients presented with an atrial septal defect.

Adolescent↗
PubMed1999

Gross and fine motor development is impaired in children with cyanotic congenital heart disease.

Many factors may intervene with the motor development of children with congenital heart disease (CHD). Children aged 5 to 14 years with various CHD were examined for disturbances of gross and fine motor development using motometric tests and compared with 30 healthy controls. The results of the Körperkoordinationstest für Kinder (KTK) (a body coordination test for children) for gross motor development were significantly lower in patients with uncorrected cyanotic CHD (motor quotient MQ 74.8 +/- 11.7, mean +/- 1 standard deviation, n = 16) and after corrective surgery (MQ 81.2 +/- 16.6, n = 25) than in controls (MQ 102.8 +/- 11.8, n = 30). No relationship between these results and the cardiopulmonary exercise capacity was found. In patients with cyanotic CHD, significant deficits in fine motor development were present before corrective surgery (e.g. Zielpunktiertest [dotting] MQ 87.7 +/- 9.9 vs. 106.5 +/- 10.8), but already two years afterwards the results reached nearly normal values (MQ 97.1 +/- 17.0). In contrast, children with acyanotic CHD demonstrated normal gross and fine motor development. These results indicate that long-standing hypoxemia in infancy must be considered as an important cause of the pronounced motor disturbances. Early neurological evaluation of these children and a specialized motor physiotherapy are recommended.

Adolescent↗
PubMed1997

Cyclooxygenase-2 mediates increased renal renin content induced by low-sodium diet.

We hypothesized that neuronal nitric oxide synthase and cyclooxygenase-2, which both exist in the renal cortex, predominantly in the macula densa, play a role in the control of renal renin tissue content. We studied the possible role of neuronal nitric oxide synthase in regulating renal renin content by using mice in which the neuronal nitric oxide synthase gene has been disrupted (nNOS-/-) compared with its two progenitor strains, the 129/SvEv and the C57BL/6, to determine if the absence of neuronal nitric oxide synthase would result in decreased renal renin content or blunt the increase observed during low sodium intake. Renal renin content from cortical slices was determined in adult mice from all three strains maintained on a normal sodium diet. Renal renin content was significantly reduced in the nNOS-/- mice compared with the 129/SvEv and the C57BL/6 mice (3.11 +/- 0.23 versus 5.66 +/- 0.50 and 7.55 +/- 1.17 micrograms angiotensin l/mg dry weight, respectively; P < .005), suggesting that neuronal nitric oxide synthase may stimulate renal renin content under basal conditions. Neither selective pharmacological inhibition of neuronal nitric oxide synthase using 7-nitroindazole or disruption of the neuronal nitric oxide synthase gene affected the increase in renal content observed during dietary sodium restriction. The influence of cyclooxygenase-2 on renal renin content through a macula densa-mediated pathway was studied using a selective cyclooxygenase-2 inhibitor, NS398, in 129/SvEv mice. A low-sodium diet increased renal renin content from 6.97 +/- 0.52 to 11.59 +/- 0.79 micrograms angiotensin l/mg dry weight (P < .005); but this increase was blocked by NS398. In addition, treatment with NS398 reduced renin mRNA in response to a low-sodium diet. Thus, increased renal renin content in response to dietary sodium restriction appears to require the induction of cyclooxygenase-2, while neuronal nitric oxide synthase appears to affect basal but not stimulated renal renin content.

Animals↗
PubMed1995

Effects of interleukin-1 beta and nitric oxide on cardiac myocytes.

Using cultured neonatal ventricular myocytes, we investigated whether nitric oxide (NO) directly influences myocyte growth. Treatment of myocytes with phenylephrine stimulated growth, as indicated by increases in atrial natriuretic factor, brain natriuretic peptide (BNP) mRNA and BNP secretion, activator protein 1 activity (activation of early-response genes), and total cellular protein content. NO was stimulated by treatment of myocytes with interleukin-1 beta (IL-1 beta) or was generated by the NO donor nitroglycerin, and its effects on total protein content and BNP secretion were measured. Treatment of cardiocytes with 3.4 nmol/L IL-1 beta for 24 hours stimulated NO (nitrite) production by threefold, which resulted from an increase in the inducible isoform of NO synthase mRNA. Dexamethasone inhibited IL-1 beta induction of nitrite production, whereas the protein kinase C inhibitor staurosporine had no effect. IL-1 beta had no effect on either basal or phenylephrine-stimulated protein content but inhibited phenylephrine-stimulated BNP secretion. Nitroglycerin (10(-7) to 10(-3) mol/L) dose-dependently increased NO production; however, only the highest dose (10(-3) mol/L) reduced basal and phenylephrine-stimulated total protein content and BNP secretion. cGMP, a second messenger of NO, had no effect on either basal or phenylephrine-stimulated BNP secretion or total protein content. In conclusion, our data indicate that BNP mRNA is stimulated by phenylephrine as shown previously for atrial natriuretic factor. Although both BNP and total protein content are increased by phenylephrine, these effects are not inhibited by NO. However, IL-1 beta inhibits phenylephrine-stimulated BNP secretion but not total protein content, suggesting that regulation of BNP secretion can be dissociated from total protein synthesis during myocyte growth.

Animals↗
PubMed1994

Morphologic ultrastructure of anchoring fibers in normal vocal fold basement membrane zone.

Anchoring fibers are collagenous structures that help secure basal cells to the superficial layer of the lamina propria (SLLP). Transmission electron microscopy was used to study the morphology and organization of these anchoring fibers at the human vocal fold basement membrane zone. This study shows that anchoring fibers loop from the lamina densa through the lamina propria and reattach to the lamina densa. Collagen fibers from the lamina propria appear to pass through the loops created by the anchoring fibers. This relationship partially explains how the epidermis secures itself to the SLLP during vibration resulting from phonation. The population density of anchoring fibers and genetics is discussed.

Aged↗
PubMed1994

[Onchocerciasis control program in West Africa: socioeconomic development and risk of recrudescence of transmission. 2. Experimental study of the transmission of Onchocerca volvulus strains from Southwestern Sierra Leone by Simulium yahense and Simulium squamosum].

The movements of human populations towards the mining wealth of the northern parts of Sierra Leone are favorable to a high contact rate between onchocerciasis patients coming from the south-western area of this country and the vector species Simulium yahense and Simulium squamosum which assume the essential of onchocerciasis transmission in the above-mentioned mining area. In fact, the Onchocerca volvulus strains concerned by this contact seem to be more pathogenic than those locally transmitted. In order to assess the danger it could represent for the Onchocerciasis Control Programme in West Africa, we carried out the experimental study of transmission which may result from this contact when more or less infected onchocerciasis patients are involved. The results indicated that this transmission by S. yahense may reach high proportions only when heavily infected onchocerciasis patients are implicated. We took also notice of the low capacity of S. squamosum to transmit the O. volvulus strains from the south-western Sierra Leone, irrespective of the microfilarial load of patients. Thus, in the most favorable conditions of a high parasite-vector contact of the study, involvement of S. yahense and onchocerciasis patients with high skin microfilarial loads is the only occurrence to which a high risk of intensive transmission may be related. The authors consider that the probability of such a risk occurring will be drastically reduced, due to the considerable decrease of skin microfilarial loads in human communities which regularly have the advantage of ivermectin (Mectizan) mass treatments.

Animals↗
PubMed1993

Dose-dependent effects of angiotensin converting enzyme (ACE) inhibitors on glomerular prostanoid production by normotensive rats.

1. This study was designed to investigate whether the angiotensin converting enzyme (ACE) inhibitors, captopril, enalapril and fosinopril have a dose-dependent effect on the production of prostaglandin E2 (PGE2), prostaglandin I2 (prostacyclin, PGI2) and thromboxane A2 (TxA2) by glomeruli isolated from normotensive Wistar-Kyoto rats. 2. Measurements of glomerular prostanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. All three ACE inhibitors demonstrated dose-dependent effects upon glomerular prostanoid production which varied with the individual ACE inhibitor. 4. Enalapril induced a dose-dependent increase in the ratio of (PGE2 + PGI2)/TxA2, from 2.17 +/- 0.20 to 5.35 +/- 0.84 and to 10.0 +/- 1.16 with the low and high doses of enalapril respectively. In contrast, the high dose of captopril tended to reduce the ratio when compared to the low dose. 5. The results obtained in this study suggest that although all three ACE inhibitors appear to induce prostacyclin synthetase and/or modulate phospholipase A2 (PLA2) activity, these effects differ with the ACE inhibitor studied and the dose employed. 6. This study has demonstrated dose-dependent effects of three ACE inhibitors on glomerular prostanoid production which may be significant in modulating glomerular haemodynamics and growth characteristics of glomerular cells.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Measurement of digitalis-glycoside levels in ocular tissues: a way to improve postmortem diagnosis of lethal digitalis-glycoside poisoning? I. Digoxin.

Prompted by animal studies reporting the accumulation of digitalis-glycosides in ocular tissues, we investigated whether measurement of digoxin levels in human ocular tissues can improve the postmortem diagnosis of lethal digoxin intoxication. Digoxin was measured in the vitreous humor and choroid-retina of patients who had received in-patient treatment with digoxin prior to death (therapeutic group) and in a single case of suicidal intoxication. The results were compared with the digoxin levels in the femoral vein blood, myocardium, kidney and liver, and evaluated in light of the medical history of each patient. In the therapeutic group the mean digoxin level was higher in the choroid-retina than in other tissues and body fluids. The range of variation in levels in the choroid-retina following therapeutic doses was comparable to that in the other tissues. An extremely high level of digoxin was present in the choroid-retina in the case of suicidal intoxication. In all cases, levels in the vitreous humor were very low compared to those in the choroid-retina. Hence, it is unlikely that significant distortion of choroid-retinal levels occurs due to postmortem diffusion of digoxin into the vitreous body. Our results indicate that measurement of digoxin levels in the choroid-retina can aid the postmortem diagnosis of lethal digoxin intoxication.

Aged↗
PubMed1992

Measurement of digitalis-glycoside levels in ocular tissues: a way to improve postmortem diagnosis of lethal digitalis-glycoside poisoning? II. Digitoxin.

Postmortem digitoxin levels in the choroid-retina and vitreous humor of patients who had undergone digitoxin therapy (therapeutic group) and in one case of suicidal digitoxin poisoning were measured and compared with levels in femoral vein blood, myocardium, kidney and liver. The results were interpreted in light of the medical history of each patient. The digitoxin level in the choroid-retina of the single case of suicidal poisoning was far higher than the choroid-retinal levels in the therapeutic group. In the latter, variation in choroid-retinal levels was comparable to that in the other tissues. In cases where the choroid-retina of the right and left eyes were examined, digitoxin levels in both eyes were essentially equal. There was no indication of significant changes in choroid-retinal levels due to postmortem diffusion of digitoxin into the vitreous body. Based on these results, determination of digitoxin levels in the choroid-retina could contribute to improving postmortem diagnosis of lethal digitoxin poisoning.

Adult↗