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Biomedical subjects

C R White

Publications and source records attributed to C R White.

At least 37 records · Page 2Linked to original sources
PubMed2000

Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats.

Zucker rats are a useful model in which to define the mechanisms that link obesity to diabetes and associated cardiovascular disease. The present study tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker rats are hypertensive and display a further increase in arterial pressure when fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were chronically instrumented with telemetry probes and fed a basal salt diet for 3 weeks followed by exposure to a high salt diet for 11 days. On the basal diet, obese (vs lean) rats had significantly higher arterial pressures ( approximately 13 mm Hg), and the high salt diet significantly elevated mean arterial pressure (MAP) in obese (but not lean) Zucker rats ( approximately 12 mm Hg). Blockade of the sympathetic nervous system with hexamethonium caused a significantly larger decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm Hg), but the high salt diet did not increase the hexamethonium-induced reduction in arterial pressure in obese rats. Acute blockade of angiotensin receptors with losartan resulted in similar decreases in MAP in both groups on either diet. Acetylcholine-induced vasodilatory capacity of the carotid artery was significantly less in the obese (vs lean) Zucker rats. Together these data indicate that increased sympathetic nervous system activity and decreased vascular reactivity may contribute to elevated arterial pressure in type 2 diabetic, obese Zucker rats, but the sympathetic nervous system does not appear to contribute to the dietary salt-sensitive hypertension in this model.

Angiotensin II↗
PubMed2000

Maturational differences in soluble guanylate cyclase activity in ovine carotid and cerebral arteries.

Basal cGMP concentrations are greater in immature than in mature cranial arteries, which may help explain why cerebrovascular resistance is lower in neonates than in adults. The present studies explore the hypothesis that this difference derives from age-related differences in soluble guanylate cyclase (sGC) activity. Maturation depressed (p < 0.01) maximal sGC activity (pmol cGMP/mg/min) in both carotid (from 11.10 +/- 0.50 to 3.60 +/- 0.20) and cerebral (from 3.10 +/- 0.31 to 1.45 +/- 0.08) arteries. Western blot analysis of relative sGC abundance (relative to sGC expression in adult kidney) found that sGC abundance was significantly greater (p < 0.05) in newborn carotid (0.38 +/- 0.04) and cerebral arteries (0.37 +/- 0.06) than in adult arteries (0.25 +/- 0.05 and 0.17 +/- 0.03, respectively). Basal Km values in carotid and cerebral arteries did not differ significantly between newborns (3- to 7-d old) and adults. Activation of sGC with nitrosylated heme significantly reduced Km values 3- to 5-fold in both types of artery and in both age groups. Within artery type, maturation had no significant effect on activated Km. Between artery types, activated Km values were greater (p < 0.05) in cerebral (200 +/- 40 microM) than in carotid (80 +/- 10 microM) arteries. Together, these data suggest that variations in sGC substrate affinity contribute to observed differences in sGC activity between artery types but not those between age groups. In contrast, variations in enzyme abundance, and possibly also enzyme-specific activity, appear responsible for differences in sGC activity associated with both age and artery type.

Animals↗
PubMed2000

False-positive "poral" cobalt patch test reactions reside in the eccrine acrosyringium.

Seventy (32%) of 222 patients patch tested in our contact dermatitis clinic from 1993 to 1995 had irritant reactions to cobalt. These reactions were "poral" and seemed to reflect a unique and probably toxic effect of cobalt on the acrosyringium. The reactions are neither follicular nor petechial and we believe they are not allergic. The histopathology of the reactions is described in detail.

Cobalt↗
PubMed1999

Chemiluminescent detection of oxidants in vascular tissue. Lucigenin but not coelenterazine enhances superoxide formation.

Lucigenin-amplified chemiluminescence has frequently been used to assess the formation of superoxide in vascular tissues. However, the ability of lucigenin to undergo redox cycling in purified enzyme-substrate mixtures has raised questions concerning the use of lucigenin as an appropriate probe for the measurement of superoxide production. Addition of lucigenin to reaction mixtures of xanthine oxidase plus NADH resulted in increased oxygen consumption, as well as superoxide dismutase-inhibitable reduction of cytochrome c, indicative of enhanced rates of superoxide formation. Additionally, it was revealed that lucigenin stimulated oxidant formation by both cultured bovine aortic endothelial cells and isolated rings from rat aorta. Lucigenin treatment resulted in enhanced hydrogen peroxide release from endothelial cells, whereas exposure to lucigenin resulted in inhibition of endothelium-dependent relaxation in isolated aortic rings that was superoxide dismutase inhibitable. In contrast, the chemiluminescent probe coelenterazine had no significant effect on xanthine oxidase-dependent oxygen consumption, endothelial cell hydrogen peroxide release, or endothelium-dependent relaxation. Study of enzyme and vascular systems indicated that coelenterazine chemiluminescence is a sensitive marker for detecting both superoxide and peroxynitrite.

Acetylcholine↗
PubMed1999

Biological aspects of reactive nitrogen species.

Nitric oxide (NO) plays an important role as a cell-signalling molecule, anti-infective agent and, as most recently recognised, an antioxidant. The metabolic fate of NO gives rise to a further series of compounds, collectively known as the reactive nitrogen species (RNS), which possess their own unique characteristics. In this review we discuss this emerging aspect of the NO field in the context of the formation of the RNS and what is known about their effects on biological systems. While much of the insight into the RNS has been gained from the extensive chemical characterisation of these species, to reveal biological consequences this approach must be complemented by direct measures of physiological function. Although we do not know the consequences of many of the dominant chemical reactions of RNS an intriguing aspect is now emerging. This review will illustrate how, when specificity and amplification through cell signalling mechanisms are taken into account, the less significant reactions, in terms of yield or rates, can explain many of the biological responses of exposure of cells or physiological systems to RNS.

Animals↗
PubMed1999

Diagnosis: atypical fibroxanthoma or not? Evaluating spindle cell malignancies on sun damaged skin: a practical approach.

Poorly differentiated spindle cell malignancies on sun damaged skin frequently pose a diagnostic challenge for dermatopathologists. The vast majority of these neoplasms ultimately are diagnosed as either atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC), or spindle cell melanoma (SCM), and rarely leiomyosarcoma or angiosarcoma. Light microscopic clues may suggest one of these neoplasms, but subtle and overlapping characteristics often render precise diagnosis impossible based on morphological features alone. Immunohistochemistry therefore is necessary to firmly and accurately diagnose the majority of spindle cell malignancies on sun damaged skin. We summarize typical clinical and histological findings associated with this group of malignancies and offer a practical immunohistochemical approach to use in their diagnosis.

Carcinoma, Squamous Cell↗
PubMed1999

Cutaneous malignant epithelioid neoplasms.

In summary, cutaneous malignancies with an epithelioid appearance form a diverse group of neoplasms that may be difficult to diagnose by utilizing routine microscopy alone. Cutaneous malignancies, including malignant melanoma and metastatic carcinoma, certain benign neoplasms such as mixed tumor of the skin and angiolymphoid hyperplasia with eosinophils (epithelioid hemangioma), and infectious conditions such as bacillary (epithelioid) angiomatosis can be considered in this differential. However, through recognition of the characteristic histologic, immunocytochemical, and ultrastructural findings outlined above, definitive diagnosis of these challenging neoplasms is usually possible.

Diagnosis, Differential↗
PubMed1998

Nitrosation of uric acid by peroxynitrite. Formation of a vasoactive nitric oxide donor.

Peroxynitrite (ONOO-), formed by the reaction between nitric oxide (. NO) and superoxide, has been implicated in the etiology of numerous disease processes. Low molecular weight antioxidants, including uric acid, may minimize ONOO---mediated damage to tissues. The tissue-sparing effects of uric acid are typically attributed to oxidant scavenging; however, little attention has been paid to the biology of the reaction products. In this study, a previously unidentified uric acid derivative was detected in ONOO--treated human plasma. The product of the uric acid/ONOO- reaction resulted in endothelium-independent vasorelaxation of rat thoracic aorta, with an EC50 value in the range of 0.03-0.3 microM. Oxyhemoglobin, a .NO scavenger, completely attenuated detectable .NO release and vascular relaxation. Uric acid plus decomposed ONOO- neither released .NO nor altered vascular reactivity. Electrochemical quantification of .NO confirmed that the uric acid/ONOO- reaction resulted in spontaneous (thiol-independent) and protracted (t1/2 approximately 125 min) release of .NO. Mass spectroscopic analysis indicated that the product was a nitrated uric acid derivative. The uric acid nitration/nitrosation product may play a pivotal role in human pathophysiology by releasing .NO, which could decrease vascular tone, increase tissue blood flow, and thereby constitute a role for uric acid not previously described.

Animals↗
PubMed1998

Immune complex disease associated with Epstein-Barr virus infectious mononucleosis.

We describe a patient with immune complex-mediated glomerulonephritis and leukocytoclastic vasculitis associated with Epstein-Barr virus (EBV) infectious mononucleosis. The patient required hemodialysis and has residual hypertension. This case implicates acute EBV infection as a cause of immune complex-mediated glomerulonephritis.

Acute Disease↗
PubMed1998

Captopril treatment and its withdrawal prevents impairment of endothelium-dependent responses in the spontaneously hypertensive rat.

Angiotensin converting enzyme inhibitors (ACE-I) have been shown to prevent impairment of endothelial cell function in Spontaneous Hypertensive rats (SHR). The purpose of this study was to examine the effects of early, long-term captopril (ACE-I) treatment and its withdrawal on vascular reactivity in SHR. Three groups of male SHR were studied: 1) untreated SHR; 2) SHR treated with captopril in-utero and maintained on oral treatment post-weaning (SHRCAP); and 3) SHR treated with captopril in-utero followed by withdrawal of drug therapy at two months of age (OFFCAP). All rats were studied at six months of age. Isolated aortic ring segments were suspended in tissue chambers for measurement of isometric force. Ring segments were exposed to cumulative concentrations of serotonin or phenylephrine (3 x 10(-9)-3 x 10(-5) M). SHR demonstrated an enhanced sensitivity to serotonin induced contraction. EC50 value were: SHR 3.6+/-1.4 x 10(-7)M, SHRCAP 9.5+/-0.5 x 10(-7) and OFFCAP 8.1+/-0.9 x 10(-7). Endothelium-dependent relaxation to acetylcholine (ACh) was markedly impaired in the SHR. Maximum relaxation (Rmax) to ACh was 61.1+/-1.6% of serotonin induced contraction versus 91.4 +/- 1.2% and 90.7 + 1.8% relaxation in SHRCAP and OFFCAP, respectfully (p<0.05). These data suggest that early, long-term treatment with captopril can prevent alterations in endothelial function observed in SHR even after ACE-inhibitor therapy has been stopped.

Analysis of Variance↗
PubMed1997

Formation of the NO donors glyceryl mononitrate and glyceryl mononitrite from the reaction of peroxynitrite with glycerol.

Peroxynitrite (ONOO-), formed from the rapid reaction of superoxide (O2-.) with NO, is known to generate stable compounds capable of donating NO on reaction with thiols and molecules containing hydroxy groups. Using glycerol as a model compound for the reactions of ONOO- with biomolecules containing hydroxy groups, we separated the products and identified them by HPLC/MS. It was shown that both glyceryl mononitrate and glyceryl mononitrite were formed and released NO on incubation with copper and l-cysteine. The compounds were stable over a period of 4h when shielded from light and kept on ice. Slow spontaneous decomposition occurred in the buffer used for the bioassay, but this was not sufficient to explain the vasorelaxing properties of these NO donors. It is concluded that the stable organic nitrate and nitrite have the capacity to be metabolized by vascular tissues, resulting in vasorelaxation.

Animals↗
PubMed1997

Estrogen restores endothelial cell function in an experimental model of vascular injury.

BACKGROUND: It has been suggested that reendothelialization of damaged blood vessels protects against the vascular injury response. The goal of the present study was to determine whether estrogen restores endothelial cell function in balloon-injured rat carotid arteries. METHODS AND RESULTS: Ten-week-old male and female Sprague-Dawley rats with intact gonads underwent balloon injury to the right common carotid artery. Female rats were randomized to receive either daily subcutaneous injections of 17beta-estradiol (17betaE[2]; 20 microg x kg[-1] x d[-1]) or vehicle over the course of the study. Vessel morphology was assessed 2 weeks after injury. Significant neointima formation was observed in vehicle-treated males. This response was blunted in vehicle-treated and 17beta-E(2)-supplemented females. Intima-to-media ratios were 1.28+/-0.23 (males), 0.72+/-0.07 (vehicle-treated females), and 0.49+/-0.07 (17beta-E[2]supplemented females). To test whether reductions in neointimal lesion formation were related to the functional reendothelialization of the damaged vessel, endothelium-dependent relaxation was tested in isolated ring segments from the three experimental groups. Vessels were precontracted with phenylephrine followed by cumulative administration of acetylcholine, an endothelium-dependent vasodilator. Maximum relaxation to acetylcholine was 8.13+/-1.70% (males), 22.06+/-4.36% (vehicle-treated females), and 46.47+/-3.48% (17beta-E[2]-supplemented females). The enhanced endothelium-dependent relaxation of rings from 17betaE(2)-supplemented females correlated with reduced neointimal proliferation in this group. The concentration of nitric oxide metabolites in plasma correlated positively with plasma 17beta-E(2) concentration. CONCLUSIONS: These results suggest that estrogen protects against neointimal injury in the balloon-injured rat, at least in part, by facilitating the reendothelialization of the damaged vessel.

Acetylcholine↗
PubMed1997

Identification of common polymorphisms in the coding sequence of the human MSH receptor (MCIR) with possible biological effects.

The extension locus has been identified in many mammalian species as a gene that determines the relative amounts of eumelanin and phaeomelanin pigments in hair and skin. In at least three species, this locus has been demonstrated to encode the melanocyte-stimulating hormone receptor (MC1-R), and functionally variant alleles have been demonstrated to cause a broad range of pigmentation phenotypes. To test for MC1-R allelic variation in man, genomic DNA was extracted from skin samples collected from patients with different skin types (I-VI), and eye and hair color. A PCR-based approach was used to amplify the full-length coding sequence of the MC1-R and the resulting products were sequenced. Two polymorphic alleles were identified with single point mutations in the coding sequence: a valine-to-methionine substitution at position 92 (V92M), and an aspartic acid-to-glutamic acid substitution at position 84 (D84E). RFLP analysis demonstrated the presence of the V92M allele in 4 out of 60 (6.6%) of individuals examined, predominantly those with blue eyes and blond hair. This polymorphism was found in both heterozygous and homozygous states in individuals with type I skin. The D84E allele was found in one individual with skin type I; this person also has the V92 M allele and thus is a compound heterozygote.

Amino Acid Sequence↗
PubMed1997

The interplay of nitric oxide and peroxynitrite with signal transduction pathways: implications for disease.

Since the discovery that at least one form of endothelium derived relaxing factor is nitric oxide (NO), numerous studies have uncovered diverse roles for this free radical in a variety of physiological and pathophysiological processes. NO production, a process mediated by a family of enzymes termed NO synthases, has been detected in most cell types. Many of the effects of NO are thought to be mediated through its direct interaction with specific and defined cell signaling pathways. The nature of such interactions are highly dependent on the concentration of NO and cell type. Furthermore, specific NO derived reaction products, such as peroxynitrite, also have the potential to effect cell signal transduction events. As with NO, this can occur through diverse mechanisms and depends on concentration and cell type. It is perhaps not surprising that the reported effects of NO in different disease states are often conflicting. In this brief overview, a framework for placing these apparently disparate properties of NO will be described and will focus on the effects of NO and peroxynitrite on signaling pathways.

Animals↗
PubMed1997

Amelanotic malignant melanoma.

Amelanotic malignant melanoma (AMM) often defies clinical diagnosis because of its wide range of clinical appearances and lack of pigmentation. Biopsy of AMM typically yields the correct diagnosis, although the histological findings, especially in metastatic lesions, occasionally may be confused with other malignancies. In cases histologically challenging, immunohistochemical techniques frequently provide diagnostic information. Multiple mechanisms to explain amelanosis have been suggested, all resulting in a single, common amelanotic phenotype. Appropriate studies to compare outcomes of amelanotic versus pigmented melanomas have not been performed. Treatment recommendations for AMM are identical to those for pigmented melanomas, although accurately defining clinical margins of the neoplasm often is challenging. Overall, a high index of suspicion and a low threshold to biopsy unusual clinical lesions ultimately may allow for earlier diagnosis and treatment of these frequently lethal malignancies.

Biopsy↗