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Biomedical subjects

John Dowling

Publications and source records attributed to John Dowling.

17 recordsLinked to original sources
PubMed2007

Prenatal corticosterone exposure results in altered AT1/AT2, nephron deficit and hypertension in the rat offspring.

Maternal treatment with the synthetic glucocorticoid, dexamethasone has been reported to result in a nephron deficit and development of hypertension in the offspring of rats. However, it is not known whether elevated maternal corticosterone (CORT), the natural glucocorticoid, has similar effects on blood pressure and nephron endowment. The present study investigated the effects of CORT (0.8 mg kg(-1) day(-1)) administration on embryonic day 14 (E14) and E15 of pregnancy on: (1) nephron number at postnatal day 30 (PN30); (2) blood pressure at PN120; and (3) receptors of the renal renin-angiotensin system (RRAS) (AT(1)Ra, AT(1)Rb and AT(2)Ra) during both embryonic (E16, E20) and adolescent (PN30) life. Plasma CORT concentrations were approximately doubled 30 min after injection. Unbiased stereological analysis revealed that maternal CORT treatment resulted in a nephron deficit of 21 and 19% in male and female offspring, respectively. Mean arterial pressures were significantly elevated in offspring of both sexes from the CORT group. Real-time PCR revealed that CORT treatment increased expression of AT(1)Ra and AT(2)R at E16, and at PN30. Expression of AT(1)Rb was downregulated in embryonic life but upregulated at PN30. We believe that these results are the first to demonstrate that maternal CORT treatment results in a nephron deficit and development of hypertension in the rat offspring. Changes in the RRAS may be contributing to these phenotypes. Critically, this study suggests that increased but physiological levels of the natural glucocorticoid can programme similar changes to those seen with pharmacological doses of the synthetic glucocorticoid. This may have important implications for women experiencing significant stress during pregnancy.

Animals↗
PubMed2006

Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure.

The effects of prenatal protein restriction on adult renal and cardiovascular function have been studied in considerable detail. However, little is known about the effects of life-long protein restriction, a common condition in the developing world. Therefore, we determined in rats the effects of combined pre- and postnatal protein restriction on adult arterial pressure and renal function and responses to increased dietary sodium. Nephron number was also determined. Male Sprague-Dawley rats were born to mothers fed a low [8% (wt/wt), LP] or normal [20% (wt/wt), NP] isocaloric protein diet throughout pregnancy and maintained on these diets after birth. At postnatal day 135, nephron number, mean arterial pressure (MAP), and renal function were determined. A high-NaCl [8.0% (wt/wt), high-salt] diet was fed to a subset of rats from weaning. MAP was less in LP than in NP rats (120 +/- 2 vs. 128 +/- 2 mmHg, P < 0.05) and was not significantly altered by increased salt intake. Nephron number was 31% less in LP than in NP rats (P < 0.001). The volume of individual glomeruli was also less in LP than in NP rats, as were calculated effective renal plasma flow and glomerular filtration rate. Glomerular filtration rate, but not effective renal plasma flow, appeared to be increased by high salt intake, particularly in LP rats. In conclusion, protein restriction induced a severe nephron deficit, but MAP was lower, rather than higher, in protein-restricted than in control rats in adulthood. These findings indicate that the postnatal environment plays a key role in determining the outcomes of developmental programming.

Algorithms↗
PubMed2004

The potential use of prehospital thrombolysis in a rural community.

BACKGROUND: It is recommended that eligible patients receive thrombolytic treatment within 90 min of alerting medical or ambulance services. The Donegal Area Rapid Treatment Study (DARTS) showed that pre-hospital thrombolysis reduces "call to needle" times for patients living remote from the hospital base [Donegal Area Rapid Treatment Study (DARTS): Final Report. North Western Health Board]. AIM: To review DARTS data to describe the potential impact of pre-hospital thrombolysis on a defined population. METHOD: Data from the DARTS project was reviewed to describe cases where thrombolysis was not administered, cases where thrombolysis was administered in hospital but not in the community, and to extrapolate these findings to other rural regions in the area to identify the potential for additional pre-hospital thrombolysis. RESULTS: Eighty-four patients from DARTS practices presented to the district hospital with AMI during the study period with 35% (29/84) receiving thrombolysis. Of the 29 who received thrombolysis, 87% (25) were referred from the general practitioner. Of these, 32% (8/25) were administered thrombolysis by the general practitioner. Of the general practitioner referrals that did not receive pre-hospital thrombolysis (n = 17), 65% (11/17) were not thrombolysed in the community for appropriate clinical reasons and 35% (6/17) could have been potentially eligible for pre-hospital thrombolysis. Inclusion of these patients suggests a potential pre-hospital thrombolysis rate in the region of 56%. For the rural Donegal areas this would result in a potential 17 cases per year being eligible for pre-hospital thrombolysis. CONCLUSIONS: Currently, 35% of the 240 AMIs that occur annually in the region receive thrombolysis. Broad implementation of DARTS in the region would provide pre-hospital thrombolysis to approximately an additional 25 patients each year, with a potential for further gains. For this to become a reality, support and encouragement must be provided to all rural general practitioners, the ambulance services, receiving hospitals and policy makers to implement a pre-hospital thrombolysis policy.

Adult↗
PubMed2004

p38 Mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: correlation with renal injury.

Activation of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway plays an important role in the inflammatory response. It was postulated that p38 MAPK is important in the pathogenesis of human glomerulonephritis and contributes to the development of renal injury. p38 MAPK activation was examined by immunodetection for dual phosphorylated p38 (p-p38) in normal human kidney and 77 renal biopsy specimens encompassing a wide spectrum of glomerulonephritides. In normal kidney, p-p38 immunostaining was restricted to the nuclei of a small number of podocytes, parietal epithelial cells, and tubular cells. There was a dramatic increase in the number of p-p38-positive cells in glomeruli and tubules in nonproliferative and proliferative glomerulonephritis and a substantial increase in the number of interstitial p-p38-positive cells in proliferative glomerulonephritis. Double immunostaining identified p38 activation in intrinsic renal cells (podocytes and endothelial and tubular cells), infiltrating macrophage and neutrophils, and myofibroblasts. Renal failure correlated with the number of p-p38-positive glomerular, tubular, and interstitial cells. Proteinuria correlated with the number of p-p38-positive tubular and interstitial cells and the number of p-p38-positive podocytes in nonproliferative glomerulonephritis. Furthermore, glomerular p38 activation correlated with segmental proliferative and necrotic lesions, and interstitial p38 activation correlated with the degree of interstitial inflammation. In conclusion, activation of p38 MAPK in intrinsic renal cells and infiltrating leukocytes correlated with renal dysfunction and histopathology, suggesting an important pathogenic role for p38 MAPK activation in human glomerulonephritis.

Enzyme Activation↗
PubMed2004

Activation of the extracellular-signal regulated protein kinase pathway in human glomerulopathies.

Examined was extracellular-signal regulated kinase (ERK) activation in normal human kidney (n = 2) and a cohort of glomerulopathies by immunohistochemistry staining for the dual-phosphorylated form of ERK (p-ERK). Cell proliferation was determined by expression of the proliferating cell nuclear antigen (PCNA). In normal human kidney, p-ERK was largely restricted to the cytoplasm of cells of the collecting duct (CD). In glomerulopathies, glomerular ERK activation was highly variable. However, there was colocalization of cell proliferation and ERK activation in the glomerular tuft and crescents. Tubular ERK activation in the different glomerulopathies was confined to the CD in areas with normal architecture. In contrast, ERK activation was prominent in tubules and interstitial cells in areas of tubulointerstitial damage. ERK activation was observed in glomerular and interstitial alpha-smooth muscle actin-positive myofibroblasts, but few macrophages or T cells showed ERK activation. There was a significant correlation between glomerular p-ERK+ and PCNA+ cells and between tubular p-ERK+ and PCNA+ cells. Glomerular p-ERK+ cells correlated with glomerular cellularity and the percentage of glomeruli with segmental lesions. Tubular p-ERK+ cells correlated with renal dysfunction and interstitial fibrosis and tubular atrophy. In conclusion, activation of the ERK pathway in human glomerulopathies correlates with cell proliferation, histologic lesions, and renal dysfunction. ERK activation may promote renal repair through tubular proliferation while promoting renal fibrosis via proliferation of glomerular and interstitial myofibroblasts.

Actins↗
PubMed2004

Glomerulosclerosis: a paraneoplastic phenomenon?

Glomerulosclerosis is not classically considered a paraneoplastic glomerular lesion. Focal and segmental glomerulosclerosis (FSGS) has rarely been reported in association with solid tumours. We report three cases of FSGS and an additional case of collapsing glomerulosclerosis in patients presenting with nephrotic syndrome and malignancy.

Adult↗
PubMed2004

Nodular glomerulosclerosis in cystic fibrosis mimics diabetic nephropathy.

BACKGROUND/AIMS: Despite the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator, being widely expressed throughout the kidney, there is no clearly defined renal phenotype in patients with cystic fibrosis. As patients with cystic fibrosis survive longer progressive pancreatic destruction may lead to abnormal glucose tolerance and diabetes mellitus, which in the kidney may be associated with the characteristic changes of nodular glomerulosclerosis. METHODS: The adult cystic fibrosis service at the Alfred hospital consists of a cohort of 200 patients. We describe 3 cystic fibrosis patients with impaired renal function who had renal biopsies performed as part of their diagnostic work-up. All patients had fasting plasma glucose levels, oral glucose tolerance tests and measurements of HbA1c performed to assess for the presence of cystic fibrosis-related diabetes mellitus. RESULTS: The renal biopsies of all 3 patients showed histological changes characteristic of diabetic nephropathy. In all cases described characteristic Kimmelstiel-Wilson nodules were present. However, in all 3 patients the presence of impaired glucose tolerance and diabetes mellitus was excluded using standard biochemical diagnostic criteria. CONCLUSION: We describe 3 adult CF patients, who on renal biopsy had histological evidence of nodular glomerulosclerosis in the absence of abnormal glucose metabolism. We speculate that the pro-inflammatory cytokine profile, typical of cystic fibrosis, predisposes to the lesions described.

Adult↗
PubMed2004

Analysis of Web access logs for surveillance of influenza.

The purpose of this study was to determine whether the level of influenza in a population correlates with the number of times that internet users access information about influenza on health-related Web sites. We obtained Web access logs from the Healthlink Web site. Web access logs contain information about the user and the information the user accessed, and are maintained electronically by most Web sites, including Healthlink. We developed weekly counts of the number of accesses of selected influenza-related articles on the Healthlink Web site and measured their correlation with traditional influenza surveillance data from the Centers for Disease Control and Prevention (CDC) using the cross-correlation function (CCF). We defined timeliness as the time lag at which the correlation was a maximum. There was a moderately strong correlation between the frequency of influenza-related article accesses and the CDC's traditional surveillance data, but the results on timeliness were inconclusive. With improvements in methods for performing spatial analysis of the data and the continuing increase in Web searching behavior among Americans, Web article access has the potential to become a useful data source for public health early warning systems.

Centers for Disease Control and Prevention, U.S.↗
PubMed2003

Nephron number, renal function, and arterial pressure in aged GDNF heterozygous mice.

The loss of one allele for glial cell line-derived neurotrophic factor (GDNF) results in approximately 30% fewer but normal sized glomeruli in young mice. Low nephron number, inherited or acquired, has been linked to increased risk of development of hypertension and renal failure. This study examines whether GDNF heterozygous mice, with an inherent reduction in nephron number, demonstrate a deterioration in renal structure and function and rise in arterial pressure in later life. Fourteen-month-old male GDNF heterozygous (n=7) and wild-type (n=6) mice were anesthetized and prepared for measurement of mean arterial pressure, glomerular filtration rate (GFR), and renal blood flow. After measurement of renal function, kidneys were fixed for stereological determination of total glomerular number and mean glomerular volume. Mean arterial pressure was, on average, 18 mm Hg higher in GDNF heterozygous (98+/-4 mm Hg) than wild-type mice (80+/-2 mm Hg; P<0.01). However, GFR (0.656+/-0.054 versus 0.688+/-0.076 mL/min per g kidney wt) and renal blood flow (5.29+/-0.42 versus 4.70+/-0.34 mL/min per g kidney wt) were not different between groups. Fourteen-month-old GDNF heterozygous mice had approximately 30% fewer glomeruli than wild-type mice (9206+/-934 versus 13440+/-1275; P<0.01) and significantly larger glomeruli (4.51+/-0.39 versus 3.72+/-0.63x10(-4)mm(3); P<0.01). Thus, aged GDNF heterozygous mice maintained a normal GFR and renal blood flow despite reduced nephron numbers. The elevated arterial pressure, glomerular hypertrophy, and hyperfiltration demonstrated in the GDNF heterozygous mice at this age may indicate a compensatory mechanism whereby GFR is maintained in the presence of a reduced nephron endowment.

Aging↗
PubMed2002

Correlation of histopathological features and renal impairment in autosomal dominant Alport syndrome in Bull terriers.

BACKGROUND: Bull terrier hereditary nephritis represents a model for autosomal dominant Alport syndrome, as affected dogs have the characteristically lamellated glomerular basement membrane and demonstrate vertical male-to-male disease transmission. METHODS: This study compared the histopathological features in kidneys from affected Bull terrier neonates, puppies, and adult dogs with normal or impaired renal function, with the histopathological appearance of kidneys from age- and size-matched normal dogs. RESULTS: There were fewer glomeruli per unit area of cortex in kidneys from affected neonatal kidneys (P<0.05), increased numbers of fetal glomeruli in affected puppy kidneys (P<0.05), and a separate population of glomeruli with larger renal corpuscles and glomerular tufts in kidneys from affected adult dogs with normal renal function (both P<0.0001) compared with normal dogs. Other histological features that are characteristic of human X-linked and autosomal recessive Alport syndrome and that were present included hypercellular glomeruli, occasional crescents, segmental and global glomerular sclerosis, periglomerular fibrosis, interstitial fibrosis without significant cellular infiltrates and cystic dilatation of Bowman's capsular space and tubules. In dogs with renal impairment, the tubular index was the best predictor of increased urinary protein:creatinine (r=0.92) compared with glomerular, interstitial and vascular indices (r=0.77, 0.88 and 0.81), and medullary fibrosis correlated best with serum creatinine (r=0.72, P=0.0002). CONCLUSIONS: The demonstration in Bull terrier kidneys of fewer nephrons in neonates increased fetal glomeruli, and a separate population of glomeruli with larger corpuscles and tufts reflects the effects of the underlying genetic mutation that are first manifest antenatally. The major determinant of renal impairment in adult affected Bull terriers is, however, progressive tubulointerstitial damage after birth.

Animals↗
PubMed2002

Karyomegalic nephropathy: an uncommon cause of progressive renal failure.

BACKGROUND: Karyomegalic nephropathy, first identified in 1974, represents an increasingly recognized, but perhaps underdiagnosed condition associated with interstitial nephritis. It undoubtedly leads to end-stage renal disease requiring renal support. METHODS AND RESULTS: We present a series of six cases of karyomegalic nephropathy. The age at diagnosis was 9-51 years, median 33 years. Impaired renal function, proteinuria, and haematuria were present in the majority of cases. Non-specific elevated liver enzymes were present in three cases. Two patients died soon after transplantation from overwhelming respiratory sepsis. The classical histological features of large, abnormal hyperchromatic nuclei with irregular outlines within epithelial cells were present in renal epithelial cells. Abnormality of DNA ploidy distributions compared with age- and sex-matched controls, and characterized by the presence of significant numbers of cells with high ploidy values was present in cases but not in controls. Mitotic figures were absent. Proliferation markers, Ki-67 and proliferating cell nuclear antigen/cyclin were not significantly elevated in those cases examined. Human leukocyte antigen analysis did not support the clustering of A9 or B35, in the cases or their families. CONCLUSIONS: The presence of significant renal impairment, positive urine sediment, abnormal liver enzymes, and early age of onset should alert one to the presence of karyomegalic nephropathy. It represents an underdiagnosed disorder with a high degree of ploidy indicative of karyotypic abnormality.

Adult↗
PubMed2002

Urine macrophage migration inhibitory factor reflects the severity of renal injury in human glomerulonephritis.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean +/- SD; 191 +/- 132 pg MIF/micromol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 +/- 397 pg MIF/micromol Cr) but was increased 3.4-fold in proliferative nephropathies (645 +/- 527 pg MIF/micromol Cr; P < 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.

Adult↗
PubMed1983

Autonomic measures and behavioral indices of pain sensitivity.

Autonomic measures (skin conductance and heart rate) were obtained from subjects before (warning period), during (immersion period), and after (resting state) the performance of the Cold Pressor task under tolerance instructions. The Autonomic Perception Questionnaire was administered shortly before the Cold Pressor task. Skin conductance and heart rate during the warning period proved to be significant predictors of pain tolerance behaviorally measured. The Autonomic Perception Questionnaire did not reveal any relationship between awareness of autonomic arousal and pain tolerance nor between actual level of arousal and subjective awareness of this arousal.

Arousal↗
PubMed1982

Autonomic indices and reactive pain reports on the McGill Pain Questionnaire.

Skin conductance and heart rate measures obtained from subjects previous to, during, and after their performance of the cold pressor task were correlated with their responses to the McGill Pain Questionnaire administered immediately after the completion of the cold pressor task. A reliable relationship between skin conductance level and responses on the evaluative scale of the MPA was found in the resting state, while anticipating the cold pressor task and during this task. Heart rate was related to these pain reports only during the warning or anticipation period. These findings were interpreted as supporting the use of the McGill Pain Questionnaire in the assessment of the reactive component of pain. They also suggest the utility of further research into autonomic indices as physiological correlates of this reactive aspect of pain.

Arousal↗
PubMed1981

Interview vs. paper-and-pencil administration of the McGill Pain Questionnaire.

In a 2 x 2 design, college student subjects described one of two levels of cold pressor pain (threshold or tolerance) with the McGill Pain Questionnaire administered via one of two modes (interview or paper-and-pencil). Interview administration was associated with higher scores on 5 of the 6 MPQ scores calculated. Data did not support the notion that this effect is entirely attributable to increased probability of interviewed subjects' endorsement of descriptors for which clarification of meaning was sought. Reliable effects of pain intensity and mode of administration significantly interact.

Adult↗
PubMed1981

Sensitivity of the McGill Pain Questionnaire to intensity and quality of laboratory pain.

Subjects completed a modified McGill Pain Questionnaire (MPQ) to describe one of two laboratory stressors (cold pressor or electrical tooth pulp stimulation) at one of two subjective intensities (pain threshold or pain tolerance). Differences in MPQ-derived scores were associated with both type of stressor and intensity level, as were patterns of frequently chosen word groups and specific words. These data support the validity of interpretations drawn from MPQ differences in clinical practice and research. In addition, the fact that the MPQ can be used in both clinical and laboratory settings suggests one way in which relevant dimensions of similarity and difference among "types" of pain may be clarified in later research.

Adult↗