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Sample records for active cutaneous vasodilation

  1. Muscle metaboreceptor modulation of cutaneous active vasodilation

    NASA Technical Reports Server (NTRS)

    Crandall, C. G.; Stephens, D. P.; Johnson, J. M.

    1998-01-01

    PURPOSE: Isometric handgrip exercise in hyperthermia has been shown to reduce cutaneous vascular conductance (CVC) by inhibiting the cutaneous active vasodilator system. METHODS: To identify whether this response was initiated by muscle metaboreceptors, in seven subjects two 3-min bouts of isometric handgrip exercise in hyperthermia were performed, followed by 2 min of postexercise ischemia (PEI). An index of forearm skin blood flow (laser-Doppler flowmetry) was measured on the contralateral arm at an unblocked site and at a site at which adrenergic vasoconstrictor function was blocked via bretylium iontophoresis to reveal active cutaneous vasodilator function unambiguously. Sweat rate was measured via capacitance hygrometry, CVC was indexed from the ratio of skin blood flow to mean arterial pressure and was expressed as a percentage of maximal CVC at that site. In normothermia, neither isometric exercise nor PEI affected CVC (P > 0.05). RESULTS: The first bout of isometric handgrip exercise in hyperthermia reduced CVC at control sites and this reduction persisted through PEI (pre-exercise: 59.8 +/- 5.4, exercise: 49.8 +/- 4.9, PEI: 49.7 +/- 5.3% of maximum; both P < 0.05), whereas there were no significant changes in CVC at the bretylium treated sites. The succeeding bout of isometric exercise in hyperthermia significantly reduced CVC at both untreated (pre-exercise: 59.0 +/- 4.8, exercise: 47.3 +/- 4.0, PEI: 50.1 +/- 4.1% of maximum; both P < 0.05) and bretylium treated sites (pre-exercise: 61.4 +/- 7.3, exercise: 50.6 +/- 5.1, PEI: 53.9 +/- 6.0% of maximum, both P < 0.05). At both sites, CVC during PEI was lower than during the pre-exercise period (P < 0.05). Sweat rate rose significantly during both bouts of isometric exercise and remained elevated during PEI. CONCLUSIONS: These data suggest that the reduction in CVC during isometric exercise in hyperthermia, including the inhibition of the active vasodilator system, is primarily mediated by muscle

  2. Nitric oxide and receptors for VIP and PACAP in cutaneous active vasodilation during heat stress in humans.

    PubMed

    Kellogg, Dean L; Zhao, Joan L; Wu, Yubo; Johnson, John M

    2012-11-01

    VPAC2 receptors sensitive to vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), PAC1 receptors sensitive to PACAP, and nitric oxide (NO) generation by NO synthase (NOS) are all implicated in cutaneous active vasodilation (AVD) through incompletely defined mechanisms. We hypothesized that VPAC2/PAC1 receptor activation and NO are synergistic and interdependent in AVD and tested our hypothesis by examining the effects of VPAC2/PAC1 receptor blockade with and without NOS inhibition during heat stress. The VPAC2/PAC1 antagonist, pituitary adenylate cyclase activating peptide 6-38 (PACAP6-38) and the NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME) were administered by intradermal microdialysis. PACAP6-38, l-NAME, a combination of PACAP6-38 and l-NAME, or Ringer's solution alone were perfused at four separate sites. Skin blood flow was monitored by laser-Doppler flowmetry at each site. Body temperature was controlled with water-perfused suits. Blood pressure was monitored by Finapres, and cutaneous vascular conductance (CVC) calculated (CVC = laser-Doppler flowmetry/mean arterial pressure). The protocol began with a 5- to 10-min baseline period without antagonist perfusion, followed by perfusion of PACAP6-38, l-NAME, or combined PACAP6-38 and l-NAME at the different sites in normothermia (45 min), followed by 3 min of whole body cooling. Whole body heating was then performed to induce heat stress and activate AVD. Finally, 58 mM sodium nitroprusside were perfused at all sites to effect maximal vasodilation for normalization of blood flow data. No significant differences in CVC (normalized to maximum) were found among Ringer's PACAP6-38, l-NAME, or combined antagonist sites during normothermia (P > 0.05 among sites) or cold stress (P > 0.05 among sites). CVC responses at all treated sites were attenuated during AVD (P < 0.05 vs. Ringer's). Attenuation was greater at l-NAME and combined PACAP6-38- and l

  3. Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans

    PubMed Central

    2010-01-01

    Human skin blood flow responses to body heating and cooling are essential to the normal processes of physiological thermoregulation. Large increases in skin blood flow provide the necessary augmentation of convective heat loss during environmental heat exposure and/or exercise, just as reflex cutaneous vasoconstriction is key to preventing excessive heat dissipation during cold exposure. In humans, reflex sympathetic innervation of the cutaneous circulation has two branches: a sympathetic noradrenergic vasoconstrictor system, and a non-noradrenergic active vasodilator system. Noradrenergic vasoconstrictor nerves are tonically active in normothermic environments and increase their activity during cold exposure, releasing both norepinephrine and cotransmitters (including neuropeptide Y) to decrease skin blood flow. The active vasodilator system in human skin does not exhibit resting tone and is only activated during increases in body temperature, such as those brought about by heat exposure or exercise. Active cutaneous vasodilation occurs via cholinergic nerve cotransmission and has been shown to include potential roles for nitric oxide, vasoactive intestinal peptide, prostaglandins, and substance P (and/or neurokinin-1 receptors). It has proven both interesting and challenging that no one substance has been identified as the sole mediator of active cutaneous vasodilation. The processes of reflex cutaneous vasodilation and vasoconstriction are both modified by acute factors, such as exercise and hydration, and more long-term factors, such as aging, reproductive hormones, and disease. This review will highlight some of the recent findings in these areas, as well as interesting areas of ongoing and future work. PMID:20448028

  4. Sex differences in postsynaptic sweating and cutaneous vasodilation.

    PubMed

    Gagnon, Daniel; Crandall, Craig G; Kenny, Glen P

    2013-02-01

    The current study aimed to determine whether a peripheral modulation of sweating contributes to the lower sudomotor thermosensitivity previously observed in females during exercise. We examined dose-response relationships in 12 males and 12 females to incremental doses of acetylcholine (ACh) and methylcholine (MCh) for sweating (ventilated capsule), as well as to ACh and sodium nitroprusside (SNP) for cutaneous vasodilation (laser-Doppler). All drugs were infused using intradermal microdialysis. On a separate day, potential sex differences in the onset threshold and/or thermosensitivity of heat loss responses were assessed during progressive increases in mean body temperature elicited by passive heating. Increases in sweating as a function of increasing concentration of ACh (P = 0.008) and MCh (P = 0.046) significantly differed between males and females. Although the concentration eliciting 50% of the maximal sweating response did not differ between sexes for either agonist (P > 0.1), maximum values were lower in females in response to ACh (0.34 ± 0.12 vs. 0.59 ± 0.19 mg·min(-1)·cm(-2), P = 0.04) and MCh (0.48 ± 0.12 vs. 0.78 ± 0.26 mg·min(-1)·cm(-2), P = 0.05). This observation was paralleled by a lower thermosensitivity of sudomotor activity in females during passive heating (1.29 ± 0.34 vs. 1.83 ± 0.33 mg·min(-1)·cm(-2)·°C(-1), P = 0.03), with no significant differences in the change in mean body temperature at which onset of sweating occurred (0.85 ± 0.19 vs. 0.67 ± 0.13°C, P = 0.10). No sex differences in cutaneous vasodilation were observed in response to ACh and SNP, as well as during passive heating (all P > 0.1). These findings provide direct evidence for a peripheral modulation of sudomotor activity in females. In contrast, sex does not modulate cutaneous vasodilation.

  5. Sex differences in postsynaptic sweating and cutaneous vasodilation

    PubMed Central

    Gagnon, Daniel; Crandall, Craig G.

    2013-01-01

    The current study aimed to determine whether a peripheral modulation of sweating contributes to the lower sudomotor thermosensitivity previously observed in females during exercise. We examined dose-response relationships in 12 males and 12 females to incremental doses of acetylcholine (ACh) and methylcholine (MCh) for sweating (ventilated capsule), as well as to ACh and sodium nitroprusside (SNP) for cutaneous vasodilation (laser-Doppler). All drugs were infused using intradermal microdialysis. On a separate day, potential sex differences in the onset threshold and/or thermosensitivity of heat loss responses were assessed during progressive increases in mean body temperature elicited by passive heating. Increases in sweating as a function of increasing concentration of ACh (P = 0.008) and MCh (P = 0.046) significantly differed between males and females. Although the concentration eliciting 50% of the maximal sweating response did not differ between sexes for either agonist (P > 0.1), maximum values were lower in females in response to ACh (0.34 ± 0.12 vs. 0.59 ± 0.19 mg·min−1·cm−2, P = 0.04) and MCh (0.48 ± 0.12 vs. 0.78 ± 0.26 mg·min−1·cm−2, P = 0.05). This observation was paralleled by a lower thermosensitivity of sudomotor activity in females during passive heating (1.29 ± 0.34 vs. 1.83 ± 0.33 mg·min−1·cm−2·°C−1, P = 0.03), with no significant differences in the change in mean body temperature at which onset of sweating occurred (0.85 ± 0.19 vs. 0.67 ± 0.13°C, P = 0.10). No sex differences in cutaneous vasodilation were observed in response to ACh and SNP, as well as during passive heating (all P > 0.1). These findings provide direct evidence for a peripheral modulation of sudomotor activity in females. In contrast, sex does not modulate cutaneous vasodilation. PMID:23154992

  6. Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress

    NASA Technical Reports Server (NTRS)

    Shibasaki, Manabu; Wilson, Thad E.; Cui, Jian; Crandall, Craig G.

    2002-01-01

    Nitric oxide (NO) contributes to active cutaneous vasodilation during a heat stress in humans. Given that acetylcholine is released from cholinergic nerves during whole body heating, coupled with evidence that acetylcholine causes vasodilation via NO mechanisms, it is possible that release of acetylcholine in the dermal space contributes to cutaneous vasodilation during a heat stress. To test this hypothesis, in seven subjects skin blood flow (SkBF) and sweat rate were simultaneously monitored over three microdialysis membranes placed in the dermal space of dorsal forearm skin. One membrane was perfused with the acetylcholinesterase inhibitor neostigmine (10 microM), the second membrane was perfused with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 10 mM) dissolved in the aforementioned neostigmine solution (l-NAME(Neo)), and the third membrane was perfused with Ringer solution as a control site. Each subject was exposed to approximately 20 min of whole body heating via a water-perfused suit, which increased mean body temperature from 36.4 +/- 0.1 to 37.5 +/- 0.1 degrees C (P < 0.05). After the heat stress, SkBF at each site was normalized to its maximum value, identified by administration of 28 mM sodium nitroprusside. Mean body temperature threshold for cutaneous vasodilation was significantly lower at the neostigmine-treated site relative to the other sites (neostigmine: 36.6 +/- 0.1 degrees C, l-NAME(Neo): 37.1 +/- 0.1 degrees C, control: 36.9 +/- 0.1 degrees C), whereas no significant threshold difference was observed between the l-NAME(Neo)-treated and control sites. At the end of the heat stress, SkBF was not different between the neostigmine-treated and control sites, whereas SkBF at the l-NAME(Neo)-treated site was significantly lower than the other sites. These results suggest that acetylcholine released from cholinergic nerves is capable of modulating cutaneous vasodilation via NO synthase mechanisms early in the heat stress but

  7. Sensory nerves contribute to cutaneous vasodilator response to cathodal stimulation in healthy rats.

    PubMed

    Gohin, Stéphanie; Decorps, Johanna; Sigaudo-Roussel, Dominique; Fromy, Bérengère

    2015-09-01

    Cutaneous current-induced vasodilation (CIV) in response to galvanic current application is an integrative model of neurovascular interaction that relies on capsaicin-sensitive fiber activation. The upstream and downstream mechanisms related to the activation of the capsaicin-sensitive fibers involved in CIV are not elucidated. In particular, the activation of cutaneous transient receptor potential vanilloid type-1 (TRPV1) channels and/or acid-sensing ion channels (ASIC) (activators mechanisms) and the release of calcitonin gene-related peptide (CGRP) and substance P (SP) (effector mechanisms) have been tested. To assess cathodal CIV, we measured cutaneous blood flow using laser Doppler flowmetry for 20min following cathodal current application (240s, 100μA) on the skin of the thigh in anesthetized healthy rats for 20min. CIV was studied in rats treated with capsazepine and amiloride to inhibit TRPV1 and ASIC channels, respectively; CGRP8-37 and SR140333 to antagonize CGRP and neurokinin-1 (NK1) receptors, respectively; compared to their respective controls. Cathodal CIV was attenuated by capsazepine (12±2% vs 54±6%, P<0.001), amiloride (19±8% vs 61±6%, P<0.01), CGRP8-37 (15±6% vs 61±6%, P<0.001) and SR140333 (9±5% vs 54±6%, P<0.001) without changing local acidification. This is the first integrative study performed in healthy rats showing that cutaneous vasodilation in response to cathodal stimulation is initiated by activation of cutaneous TRPV1 and ASIC channels likely through local acidification. The involvement of CGRP and NK1 receptors suggests that cathodal CIV is the result of CGRP and SP released through activated capsaicin-sensitive fibers. Therefore cathodal CIV could be a valuable method to assess sensory neurovascular function in the skin, which would be particularly relevant to evaluate the presence of small nerve fiber disorders and the effectiveness of treatments.

  8. TRPV1 channels are involved in niacin-induced cutaneous vasodilation in mice.

    PubMed

    Clifton, Heather L; Inceoglu, Bora; Ma, Linlin; Zheng, Jie; Schaefer, Saul

    2015-02-01

    Niacin is effective in treating dyslipidemias but causes cutaneous vasodilation or flushing, a side effect that limits its clinical use. Blocking prostaglandins in humans reduces but does not consistently eliminate flushing, indicating additional mechanisms may contribute to flushing. The transient receptor potential vanilloid 1 (TRPV1) channel, when activated, causes cutaneous vasodilation and undergoes tachyphylaxis similar to that seen with niacin. Using a murine model, early phase niacin-induced flushing was examined and TRPV1 channel involvement demonstrated using pharmacologic blockade, desensitization, and genetic knockouts (TRPV1 KO). The TRPV1 antagonist AMG9810 reduced the magnitude of the initial and secondary peaks and the rapidity of the vasodilatory response (slope). TRPV1 desensitization by chronic capsaicin reduced the initial peak and slope. TRPV1 KO mice had a lower initial peak, secondary peak, and slope compared with wild-type mice. Chronic niacin reduced the initial peak, secondary peak, and slope in wild-type mice but had no effect in knockout mice. Furthermore, chronic niacin diminished the response to capsaicin in wild-type mice. Overall, these data demonstrate an important role for TRPV1 channels in niacin-induced flushing, both in the acute response and with chronic administration. That niacin-induced flushing is a complex cascade of events, which should inform pharmacological intervention against this side effect.

  9. iNOS-dependent sweating and eNOS-dependent cutaneous vasodilation are evident in younger adults, but are diminished in older adults exercising in the heat.

    PubMed

    Fujii, Naoto; Meade, Robert D; Alexander, Lacy M; Akbari, Pegah; Foudil-Bey, Imane; Louie, Jeffrey C; Boulay, Pierre; Kenny, Glen P

    2016-02-01

    Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS-dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger (n = 12, 23 ± 4 yr) and older (n = 12, 60 ± 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35°C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults.

  10. Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans.

    PubMed

    Wong, Brett J

    2013-04-15

    We tested the hypothesis that inhibition of cutaneous sensory nerves would attenuate reflex cutaneous vasodilation in response to an increase in core temperature. Nine subjects were equipped with four microdialysis fibers on the forearm. Two sites were treated with topical anesthetic EMLA cream for 120 min. Sensory nerve inhibition was verified by lack of sensation to a pinprick. Microdialysis fibers were randomly assigned as 1) lactated Ringer (control); 2) 10 mM nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthase; 3) EMLA + lactated Ringer; and 4) EMLA + L-NAME. Laser-Doppler flowmetry was used as an index of skin blood flow, and blood pressure was measured via brachial auscultation. Subjects wore a water-perfused suit, and oral temperature was monitored as an index of core temperature. The suit was perfused with 50°C water to initiate whole body heat stress to raise oral temperature 0.8°C above baseline. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVC(max)). There was no difference in CVC between control and EMLA sites (67 ± 5 vs. 69 ± 6% CVC(max)), but the onset of vasodilation was delayed at EMLA compared with control sites. The L-NAME site was significantly attenuated compared with control and EMLA sites (45 ± 5% CVC(max); P < 0.01). Combined EMLA + L-NAME site (25 ± 6% CVC(max)) was attenuated compared with control and EMLA (P < 0.001) and L-NAME only (P < 0.01). These data suggest cutaneous sensory nerves contribute to reflex cutaneous vasodilation during the early, but not latter, stages of heat stress, and full expression of reflex cutaneous vasodilation requires functional sensory nerves and NOS.

  11. K+ channel mechanisms underlying cholinergic cutaneous vasodilation and sweating in young humans: roles of KCa, KATP, and KV channels?

    PubMed

    Fujii, Naoto; Louie, Jeffrey C; McNeely, Brendan D; Zhang, Sarah Yan; Tran, My-An; Kenny, Glen P

    2016-09-01

    Acetylcholine released from cholinergic nerves is involved in heat loss responses of cutaneous vasodilation and sweating. K(+) channels are thought to play a role in regulating cholinergic cutaneous vasodilation and sweating, though which K(+) channels are involved in their regulation remains unclear. We evaluated the hypotheses that 1) Ca(2+)-activated K(+) (KCa), ATP-sensitive K(+) (KATP), and voltage-gated K(+) (KV) channels all contribute to cholinergic cutaneous vasodilation; and 2) KV channels, but not KCa and KATP channels, contribute to cholinergic sweating. In 13 young adults (24 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at intradermal microdialysis sites that were continuously perfused with: 1) lactated Ringer (Control), 2) 50 mM tetraethylammonium (KCa channel blocker), 3) 5 mM glybenclamide (KATP channel blocker), and 4) 10 mM 4-aminopyridine (KV channel blocker). At all sites, cholinergic cutaneous vasodilation and sweating were induced by coadministration of methacholine (0.0125, 0.25, 5, 100, and 2,000 mM, each for 25 min). The methacholine-induced increase in CVC was lower with the KCa channel blocker relative to Control at 0.0125 (1 ± 1 vs. 9 ± 6%max) and 5 (2 ± 5 vs. 17 ± 14%max) mM methacholine, whereas it was lower in the presence of KATP (69 ± 7%max) and KV (57 ± 14%max) channel blocker compared with Control (79 ± 6%max) at 100 mM methacholine. Furthermore, methacholine-induced sweating was lower at the KV channel blocker site (0.42 ± 0.17 mg·min(-1)·cm(-2)) compared with Control (0.58 ± 0.15 mg·min(-1)·cm(-2)) at 2,000 mM methacholine. In conclusion, we show that KCa, KATP, and KV channels play a role in cholinergic cutaneous vasodilation, whereas only KV channels contribute to cholinergic sweating in normothermic resting humans. PMID:27440718

  12. Relationship between mean body temperature calculated by two- or three-compartment models and active cutaneous vasodilation in humans: a comparison between cool and warm environments during leg exercise.

    PubMed

    Demachi, Koichi; Yoshida, Tetsuya; Tsuneoka, Hideyuki

    2012-03-01

    The aim of this study was to assess whether the three-compartment model of mean body temperature (Tb3) calculated from the esophageal temperature (Tes), temperature in deep tissue of exercising muscle (Tdt), and mean skin temperature (Tsk) has the potential to provide a better match with the thermoregulatory responses than the two-component model of mean body temperature (Tb2) calculated from Tes and Tsk. Seven male subjects performed 40 min of a prolonged cycling exercise at 30% maximal oxygen uptake at 21°C or 31°C (50% relative humidity). Throughout the experiment, Tsk, Tb2, Tb3, and Tdt were significantly (P < 0.01) lower at 21°C than at 31°C temperature conditions, while Tes was similar under both conditions. During exercise, an increase in cutaneous vascular conductance (skin blood flow / mean arterial pressure) over the chest (%CVCc) was observed at both 21°C and 31°C, while no increase was observed at the forearm at 21°C. Furthermore, the Tb3 and Tdt threshold for the onset of the increase in %CVCc was similar, but the Tes and Tb2 threshold differed significantly (P < 0.05) between the conditions tested. These results suggest that active cutaneous vasodilation at the chest is related more closely to Tb3 or Tdt than that measured by Tes or Tb2 calculated by Tes and Tsk during exercise at both 21°C and 31°C.

  13. Acute dairy milk ingestion does not improve nitric oxide-dependent vasodilation in the cutaneous microcirculation.

    PubMed

    Alba, Billie K; Stanhewicz, Anna E; Kenney, W Larry; Alexander, Lacy M

    2016-07-01

    In epidemiological studies, chronic dairy milk consumption is associated with improved vascular health and reduced age-related increases in blood pressure. Although milk protein supplementation augments conduit artery flow-mediated dilation, whether or not acute dairy milk intake may improve microvascular function remains unclear. We hypothesised that dairy milk would increase direct measurement of endothelial nitric oxide (NO)-dependent cutaneous vasodilation in response to local skin heating. Eleven men and women (61 (sem 2) years) ingested two or four servings (473 and 946 ml) of 1 % dairy milk or a rice beverage on each of 4 separate study days. In a subset of five subjects, an additional protocol was completed after 473 ml of water ingestion. Once a stable blood flow occurred, 15 mm-N G -nitro-l-arginine methyl ester was perfused (intradermal microdialysis) to quantify NO-dependent vasodilation. Red-blood-cell flux (RBF) was measured by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC=RBF/mean arterial pressure) was calculated and normalised to maximum (%CVCmax; 28 mm-sodium nitroprusside). Full expression of cutaneous vasodilation was not different among dairy milk, rice beverage and water, and there was no effect of serving size on the total vasodilatory response. Contrary to our hypothesis, NO-dependent vasodilation was lower for dairy milk than rice beverage (D: 49 (sem 5), R: 55 (sem 5) %CVCmax; P<0·01). Acute dairy milk ingestion does not augment NO-dependent vasodilation in the cutaneous microcirculation compared with a rice beverage control.

  14. Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans.

    PubMed

    Shibasaki, Manabu; Aoki, Ken; Morimoto, Keiko; Johnson, John M; Takamata, Akira

    2009-12-01

    Plasma hyperosmolality delays the response in skin blood flow to heat stress by elevating the internal temperature threshold for cutaneous vasodilation. This elevation could be because of a delayed onset of cutaneous active vasodilation and/or to persistent cutaneous active vasoconstriction. Seven healthy men were infused with either hypertonic (3% NaCl) or isotonic (0.9% NaCl) saline and passively heated by immersing their lower legs in 42 degrees C water for 60 min (room temperature, 28 degrees C; relative humidity, 40%). Skin blood flow was monitored via laser-Doppler flowmetry at sites pretreated with bretylium tosylate (BT) to block sympathetic vasoconstriction selectively and at adjacent control sites. Plasma osmolality was increased by approximately 13 mosmol/kgH(2)O following hypertonic saline infusion and was unchanged following isotonic saline infusion. The esophageal temperature (T(es)) threshold for cutaneous vasodilation at untreated sites was significantly elevated in the hyperosmotic state (37.73 +/- 0.11 degrees C) relative to the isosmotic state (36.63 +/- 0.12 degrees C, P < 0.001). A similar elevation of the T(es) threshold for cutaneous vasodilation was observed between osmotic conditions at the BT-treated sites (37.74 +/- 0.18 vs. 36.67 +/- 0.07 degrees C, P < 0.001) as well as sweating. These results suggest that the hyperosmotically induced elevation of the internal temperature threshold for cutaneous vasodilation is due primarily to an elevation in the internal temperature threshold for the onset of active vasodilation, and not to an enhancement of vasoconstrictor activity.

  15. Mechanisms of cutaneous vasodilation during the postmenopausal hot flash

    PubMed Central

    Low, David A.; Hubing, Kimberley A.; Del Coso, Juan; Crandall, Craig G.

    2010-01-01

    Objective Menopausal hot flashes can seriously disrupt the lives of symptomatic women. The physiological mechanisms of the hot flash efferent responses, particularly in the cutaneous circulation, are not completely understood. The aim of this study was to examine the mechanisms of increases in skin blood flow during the postmenopausal hot flash in symptomatic women. Methods Healthy postmenopausal women rested in a temperature controlled laboratory while responses prior to and during hot flashes were recorded for three unique protocols. Protocols 1 and 2: Women were locally pretreated with an intradermal injection of botulinum toxin A (BTX; blocks the release of neurotransmitters from sympathetic cholinergic nerves) in the forearm (protocol 1) and in the glabellar region (protocol 2). Protocol 3: Skin sympathetic nerve activity from the peroneal nerve was recorded, along with skin blood flow and sweating within the region innervated by that neural signal. Skin blood flow was indexed using laser-Doppler flowmetry at BTX-treated and adjacent untreated control sites. The onset of a hot flash was objectively identified as a transient and pronounced elevation of sternal sweat rate. Results The elevation in forearm (protocol 1) and glabellar skin blood flow (protocol 2) during hot flashes were attenuated at BTX sites relative to adjacent untreated sites (P<0.05 for both protocols). In protocol 3, skin sympathetic nerve activity significantly increased during hot flashes and returned to pre-flash levels following the hot flashes. Conclusion Elevations in skin blood flow during the postmenopausal hot flash are neurally mediated primarily through BTX sensitive nerves; presumably sympathetic cholinergic. PMID:21107299

  16. Prolonged head-down tilt exposure reduces maximal cutaneous vasodilator and sweating capacity in humans

    NASA Technical Reports Server (NTRS)

    Crandall, C. G.; Shibasaki, M.; Wilson, T. E.; Cui, J.; Levine, B. D.

    2003-01-01

    Cutaneous vasodilation and sweat rate are reduced during a thermal challenge after simulated and actual microgravity exposure. The effects of microgravity exposure on cutaneous vasodilator capacity and on sweat gland function are unknown. The purpose of this study was to test the hypothesis that simulated microgravity exposure, using the 6 degrees head-down tilt (HDT) bed rest model, reduces maximal forearm cutaneous vascular conductance (FVC) and sweat gland function and that exercise during HDT preserves these responses. To test these hypotheses, 20 subjects were exposed to 14 days of strict HDT bed rest. Twelve of those subjects exercised (supine cycle ergometry) at 75% of pre-bed rest heart rate maximum for 90 min/day throughout HDT bed rest. Before and after HDT bed rest, maximal FVC was measured, via plethysmography, by heating the entire forearm to 42 degrees C for 45 min. Sweat gland function was assessed by administering 1 x 10(-6) to 2 M acetylcholine (9 doses) via intradermal microdialysis while simultaneously monitoring sweat rate over the microdialysis membranes. In the nonexercise group, maximal FVC and maximal stimulated sweat rate were significantly reduced after HDT bed rest. In contrast, these responses were unchanged in the exercise group. These data suggest that 14 days of simulated microgravity exposure, using the HDT bed rest model, reduces cutaneous vasodilator and sweating capacity, whereas aerobic exercise training during HDT bed rest preserves these responses.

  17. Impaired endothelium independent vasodilation in the cutaneous microvasculature of young obese adults.

    PubMed

    Patik, Jordan C; Christmas, Kevin M; Hurr, Chansol; Brothers, R Matthew

    2016-03-01

    Microvascular dysfunction contributes to the development of cardiovascular and metabolic disease. This study tested the hypothesis that young obese (BMI>30 kg m(-2)), otherwise healthy, adults (N=15) have impaired microvascular function relative to age and sex matched, lean (BMI<25 kg m(-2)) individuals (N=14). Participants were instrumented with two microdialysis probes in the cutaneous vasculature of one forearm; one for a wide dose range of infusions of the endothelium-dependent vasodilator methacholine (MCh) and the other for the endothelium-independent vasodilator sodium nitroprusside (SNP). Local temperature at each site was clamped at 33 °C and cutaneous blood flow was indexed by laser Doppler flowmetry (LDF). LDF was recorded while 7 doses of each drug (MCh: 10(-6)-1M; SNP: 5 × 10(-8)-5 × 10(-2)M) were infused at a rate of 2 μl/min for 8 min per dose. Both sites finished with heating to 43 °C and 5 × 10(-2)M SNP to achieve site specific maximal vasodilation. Mean arterial blood pressure (MAP) was assessed in the last minute of each dose and was used for subsequent calculation of cutaneous vascular conductance (CVC; LDF/MAP) and responses were normalized to each individual site's maximal response (%CVCmax). Group four-parameter dose response curves were compared with an extra sum of squares F-test. SNP EC50 was greater in obese relative to lean (-2.931 ± 0.10 vs -3.746 ± 0.18 Log[SNP]M, P<0.001); however, there was no difference in MCh EC50 between groups (-3.796 ± 0.23 vs -3.852 ± 0.25 Log[MCh]M, P=0.81). Additionally, baseline and maximal CVC in both sites were similar between groups (all P>0.05). These results suggest attenuated endothelium-independent response to nitric oxide while endothelium-dependent vasodilation function is maintained.

  18. Nitric oxide synthase inhibition attenuates cutaneous vasodilation during the post-menopausal hot flash

    PubMed Central

    Hubing, Kimberly A.; Wingo, Jonathan E.; Brothers, R. Matthew; Coso, Juan Del; Low, David A.; Crandall, Craig G.

    2010-01-01

    Objective The purpose of this study was to test the hypothesis that local inhibition of nitric oxide and prostaglandin synthesis attenuates cutaneous vasodilator responses during post-menopausal hot flashes. Methods Four microdialysis membranes were inserted into forearm skin (dorsal surface) of 8 post-menopausal women (mean ± SD, 51±7 y). Ringers solution (control), 10mM Ketorolac (Keto) to inhibit prostaglandin synthesis, 10mM NG-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthase, and a combination of 10mM Keto + 10mM L-NAME were each infused at the separate sites. Skin blood flow at each site was indexed using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure and was expressed as a percentage of the maximal calculated CVC (CVCmax) obtained following infusion of 50mM sodium nitropruside at all sites at the end of the study. Data from 13 hot flashes were analyzed. Results At the control site, the mean ± SD peak increase in CVC was 15.5±6% CVCmax units. This value was not different relative to the peak increase in CVC at the Keto site (13.0±5 % CVCmax units, P = 0.09). However, the peak increase in CVC during the flash was attenuated at the L-NAME and L-NAME + Keto sites (7.4±4 % CVCmax units and 8.7±7 % CVCmax units, respectively) relative to both the control and the Keto sites (P<0.05 for both comparisons). There were no significant differences in the peak increases in sweat rate between any of the sites (P = 0.24). Conclusions These data demonstrate that cutaneous vasodilation during a hot flash has a nitric oxide component. Increases in CVC despite the inhibition of prostaglandin synthesis suggest prostaglandins do not contribute to cutaneous vasodilation during a hot flash. PMID:20505548

  19. Sex- and limb-specific differences in the nitric oxide-dependent cutaneous vasodilation in response to local heating.

    PubMed

    Stanhewicz, Anna E; Greaney, Jody L; Kenney, W Larry; Alexander, Lacy M

    2014-10-01

    Local heating of the skin is commonly used to assess cutaneous microvasculature function. Controversy exists as to whether there are limb or sex differences in the nitric oxide (NO)-dependent contribution to this vasodilation, as well as the NO synthase (NOS) isoform mediating the responses. We tested the hypotheses that 1) NO-dependent vasodilation would be greater in the calf compared with the forearm; 2) total NO-dependent dilation would not be different between sexes within limb; and 3) women would exhibit greater neuronal NOS (nNOS)-dependent vasodilation in the calf. Two microdialysis fibers were placed in the skin of the ventral forearm and the calf of 19 (10 male and 9 female) young (23 ± 1 yr) adults for the local delivery of Ringer solution (control) or 5 mM N(ω)-propyl-l-arginine (NPLA; nNOS inhibition). Vasodilation was induced by local heating (42°C) at each site, after which 20 mM N(G)-nitro-l-arginine methyl ester (l-NAME) was perfused for within-site assessment of NO-dependent vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial pressure and normalized to maximum (28 mM sodium nitroprusside, 43°C). Total NO-dependent vasodilation in the calf was lower compared with the forearm in both sexes (Ringer: 42 ± 5 vs. 62 ± 4%; P < 0.05; NPLA: 37 ± 3 vs. 59 ± 5%; P < 0.05) and total NO-dependent vasodilation was lower in the forearm for women (Ringer: 52 ± 6 vs. 71 ± 4%; P < 0.05; NPLA: 47 ± 6 vs. 68 ± 5%; P < 0.05). NPLA did not affect total or NO-dependent vasodilation across limbs in either sex (P > 0.05). These data suggest that the NO-dependent component of local heating-induced cutaneous vasodilation is lower in the calf compared with the forearm. Contrary to our original hypothesis, there was no contribution of nNOS to NO-dependent vasodilation in either limb during local heating.

  20. Sensory and sympathetic nerve contributions to the cutaneous vasodilator response from a noxious heat stimulus.

    PubMed

    Carter, Stephen J; Hodges, Gary J

    2011-11-01

    We investigated the roles of sensory and noradrenergic sympathetic nerves on the cutaneous vasodilator response to a localized noxious heating stimulus. In two separate studies, four forearm skin sites were instrumented with microdialysis fibres, local heaters and laser-Doppler probes. Skin sites were locally heated from 33 to 42 °C or rapidly to 44 °C (noxious). In the first study, we tested sensory nerve involvement using EMLA cream. Treatments were as follows: (1) control 42 °C; (2) EMLA 42 °C; (3) control 44°C; and (4) EMLA 44 °C. At the EMLA-treated sites, the axon reflex was reduced compared with the control sites during heating to 42 °C (P < 0.05). There were no differences during the plateau phase (P > 0.05). At both the sites heated to 44 °C, the initial peak and nadir became indistinguishable, and the EMLA-treated sites were lower compared with the control sites during the plateau phase (P < 0.05). In the second study, we tested the involvement of noradrenergic sympathetic nerves in response to the noxious heating using bretylium tosylate (BT). Treatments were as follows: (1) control 42 °C; (2) BT 42 °C; (3) control 44 °C; and (4) BT 44 °C. Treatment with BT at the 42 °C sites resulted in a marked reduction in both the axon reflex and the secondary plateau (P < 0.05). At the 44 °C sites, there was no apparent initial peak or nadir, but the plateau phase was reduced at the BT-treated sites (P < 0.05). These data suggest that both sympathetic nerves and sensory nerves are involved during the vasodilator response to a noxious heat stimulus.

  1. Intradermal administration of ATP augments methacholine-induced cutaneous vasodilation but not sweating in young males and females.

    PubMed

    Fujii, Naoto; Halili, Lyra; Singh, Maya Sarah; Meade, Robert D; Kenny, Glen P

    2015-10-15

    Acetylcholine released from cholinergic nerves is a key neurotransmitter contributing to heat stress-induced cutaneous vasodilation and sweating. Given that sympathetic cholinergic nerves also release ATP, ATP may play an important role in modulating cholinergic cutaneous vasodilation and sweating. However, the pattern of response may differ between males and females given reports of sex-related differences in the peripheral mechanisms governing these heat loss responses. Cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated in 17 young adults (8 males, 9 females) at four intradermal microdialysis skin sites continuously perfused with: 1) lactated Ringer (Control), 2) 0.3 mM ATP, 3) 3 mM ATP, or 4) 30 mM ATP. At all skin sites, methacholine was coadministered in a concentration-dependent manner (0.0125, 0.25, 5, 100, 2,000 mM, each for 25 min). In both males and females, CVC was elevated with the lone infusion of 30 mM ATP (both P < 0.05), but not with 0.3 and 3 mM ATP compared with control (all P >0.27). However, 0.3 mM ATP induced a greater increase in CVC compared with control in response to 100 mM methacholine infusion in males (P < 0.05). In females, 0.3 mM ATP infusion resulted in a lower concentration of methacholine required to elicit a half-maximal response (EC50) (P < 0.05). In both males and females, methacholine-induced sweating was unaffected by any concentration of ATP (all P > 0.44). We demonstrate that ATP enhances cholinergic cutaneous vasodilation albeit the pattern of response differs between males and females. Furthermore, we show that ATP does not modulate cholinergic sweating. PMID:26290105

  2. Hypoxic cutaneous vasodilation is sustained during brief cold stress and is not affected by changes in CO2.

    PubMed

    Simmons, Grant H; Fieger, Sarah M; Minson, Christopher T; Halliwill, John R

    2010-04-01

    Hypoxia decreases core body temperature in animals and humans during cold exposure. In addition, hypoxia increases skin blood flow in thermoneutral conditions, but the impact of hypoxic vasodilation on vasoconstriction during cold exposure is unknown. In this study, skin blood flow was assessed using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure and normalized to baseline (n = 7). Subjects were exposed to four different conditions in the steady state (normoxia and poikilocapnic, isocapnic, and hypercapnic hypoxia) and were cooled for 10 min using a water-perfused suit in each condition. CVC increased during all three hypoxic exposures (all P < 0.05 vs. baseline), and the magnitude of these steady-state responses was not affected by changes in end-tidal CO(2) levels. During poikilocapnic and hypercapnic hypoxia, cold exposure reduced CVC to the same levels observed during normoxic cooling (P > 0.05 vs. normoxia), whereas CVC remained elevated throughout cold exposure during isocapnic hypoxia (P < 0.05 vs. normoxia). The magnitude of vasoconstriction during cold stress was similar in all conditions (P > 0.05). Thus the magnitude of cutaneous vasodilation during steady-state hypoxia is not affected by CO(2) responses. In addition, the magnitude of reflex vasoconstriction is not altered by hypoxia, such that the upward shift in skin blood flow (hypoxic vasodilation) is maintained during whole body cooling.

  3. Endothelial nitric oxide synthase mediates cutaneous vasodilation during local heating and is attenuated in middle-aged human skin.

    PubMed

    Bruning, Rebecca S; Santhanam, Lakshmi; Stanhewicz, Anna E; Smith, Caroline J; Berkowitz, Dan E; Kenney, W Larry; Holowatz, Lacy A

    2012-06-01

    Local skin heating is used to assess microvascular function in clinical populations because NO is required for full expression of the response; however, controversy exists as to the precise NO synthase (NOS) isoform producing NO. Human aging is associated with attenuated cutaneous vasodilation but little is known about the middle aged, an age cohort used for comparison with clinical populations. We hypothesized that endothelial NOS (eNOS) is the primary isoform mediating NO production during local heating, and eNOS-dependent vasodilation would be reduced in middle-aged skin. Vasodilation was induced by local heating (42°C) and during acetylcholine dose-response (ACh-DR: 0.01, 0.1, 1.0, 5.0, 10.0, 50.0, 100.0 mmol/l) protocols. Four microdialysis fibers were placed in the skin of 24 men and women; age cohorts were 12 middle-aged (53 ± 1 yr) and 12 young (23 ± 1 yr). Sites served as control, nonselective NOS inhibited [N(G)-nitro-l-arginine methyl ester (l-NAME)], inducible NOS (iNOS) inhibited (1400W), and neuronal NOS (nNOS) inhibited (N(ω)-propyl-l-arginine). After full expression of the local heating response, l-NAME was perfused at all sites. Cutaneous vascular conductance was measured and normalized to maximum (%CVC(max): Nitropress). l-NAME reduced %CVCmax at baseline, all phases of the local heating response, and at all ACh concentrations compared with all other sites. iNOS inhibition reduced the initial peak (53 ± 2 vs. 60 ± 2%CVC(max); P < 0.001); however, there were no other differences between control, nNOS-, and iNOS-inhibited sites during the phases of local heating or ACh-DR. When age cohorts were compared, NO-dependent vasodilation during local heating (52 ± 6 vs. 68 ± 4%CVC(max); P = 0.013) and ACh perfusion (50 mmol/l: 83 ± 3 vs. 93 ± 2%CVC(max); 100 mmol/l: 83 ± 4 vs. 92 ± 3%CVC(max); both P = 0.03) were reduced in middle-aged skin. There were no differences in NOS isoform expression obtained from skin biopsy samples between groups (all

  4. The effect of 48 weeks of aerobic exercise training on cutaneous vasodilator function in post-menopausal females.

    PubMed

    Hodges, Gary J; Sharp, Lisa; Stephenson, Claire; Patwala, Ashish Y; George, Keith P; Goldspink, David F; Tim Cable, N

    2010-04-01

    Skin blood flow (SkBF) and endothelial-dependent vasodilatation decline with ageing and can be reversed with exercise training. We tested whether 48 weeks of training could improve SkBF and endothelial function in post-menopausal females; 20 post-menopausal subjects completed the study. SkBF was measured by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. Resting CVC was measured at 32 degrees C and peak CVC at 42 degrees C. Cutaneous endothelial-dependent and -independent vasodilatations were determined by the iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. All assessments described were performed at entry (week 0), and after 6, 12, 24, 36, and 48 weeks of training. Resting CVC measures did not change (P > 0.05) throughout the study. Peak CVC increased (P < 0.05) after 24 weeks (7.2 +/- 1.2 vs. 11.6 +/- 1.4 AU mmHg(-1)) and at the 36- and 48-week assessments (13.0 +/- 1.7 and 14.9 +/- 2.1 AU mmHg(-1), respectively). Responses to ACh also increased (P < 0.05) at the 24-week assessment (5.1 +/- 2.1 vs. 8.55 +/- 2.3 AU mmHg(-1)) and increased further at the 36 and 48-week assessments (11.6 +/- 3.7 and 13.2 +/- 3.9 AU mmHg(-1), respectively). Cutaneous responses to SNP increased (P < 0.05) after 36 weeks (8.7 +/- 2.1 vs. 13.02 +/- 2.23 AU mmHg(-1) at 36 weeks). VO(2max) increased after 12 weeks (23.5 +/- 0.7 vs. 25.4 +/- 0.9 ml kg(-1) min(-1)) and improved (P < 0.05) further throughout the study (31.6 +/- 1.8 ml kg(-1) min(-1) at week 48). Aerobic exercise produces positive adaptations in the cutaneous vasodilator function to local heating as well as in cutaneous endothelial and endothelial-independent vasodilator mechanisms. Aerobic capacity was also significantly improved. These adaptations were further enhanced with progressive increases in exercise intensity.

  5. Derivatives of benzimidazole: vasodilator activity of 2-(p-chloro-alpha-hydroxybenzyl)-benzimidazole hydrochloride. Preliminary study.

    PubMed

    Demenge, P; Carraz, G; Luu Duc, C; Silice, C

    1979-01-01

    The effects of 2-(p-chloro-alpha-hydroxybenzyl)-benzimidazole hydrochloride (HBBPC) have been studied in the rabbit and rat. Most of these studies were performed comparatively with reference vasodilators and papaverine. HBBPC vasodilator activity is nearly the same as that of papaverine in the isolated rabbit ear. The characteristic of the vasoactive action of HBBPC seems to reside in its duration. The mechanism of action of HBBPC seems of peripheral type, that is to say it acts on the vascular smooth muscle.

  6. Serum adenosine deaminase activity in cutaneous anthrax

    PubMed Central

    Sunnetcioglu, Mahmut; Karadas, Sevdegul; Aslan, Mehmet; Ceylan, Mehmet Resat; Demir, Halit; Oncu, Mehmet Resit; Karahocagil, Mustafa Kasım; Sunnetcioglu, Aysel; Aypak, Cenk

    2014-01-01

    Background Adenosine deaminase (ADA) activity has been discovered in several inflammatory conditions; however, there are no data associated with cutaneous anthrax. The aim of this study was to investigate serum ADA activity in patients with cutaneous anthrax. Material/Methods Sixteen patients with cutaneous anthrax and 17 healthy controls were enrolled. We measured ADA activity; peripheral blood leukocyte, lymphocyte, neutrophil, and monocyte counts; erythrocyte sedimentation rate; and C reactive protein levels. Results Serum ADA activity was significantly higher in patients with cutaneous anthrax than in the controls (p<0.001). A positive correlation was observed between ADA activity and lymphocyte counts (r=0.589, p=0.021) in the patient group. Conclusions This study suggests that serum ADA could be used as a biochemical marker in cutaneous anthrax. PMID:24997584

  7. Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel.

    PubMed

    Cornfield, D N; Reeve, H L; Tolarova, S; Weir, E K; Archer, S

    1996-07-23

    At birth, pulmonary vasodilation occurs as air-breathing life begins. The mechanism of O2-induced pulmonary vasodilation is unknown. We proposed that O2 causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel (KCa) via a cyclic nucleotide-dependent kinase. We tested this hypothesis in hemodynamic studies in acutely prepared fetal lambs and in patch-clamp studies on resistance fetal pulmonary artery smooth muscle cells. Fetal O2 tension (PaO2) was increased by ventilating the ewe with 100% O2, causing fetal total pulmonary resistance to decrease from 1.18 +/- 0.14 to 0.41 +/- 0.03 mmHg per ml per min. Tetraethylammonium and iberiotoxin, preferential KCa-channel inhibitors, attenuated O2-induced fetal pulmonary vasodilation, while glibenclamide, an ATP-sensitive K+-channel antagonist, had no effect. Treatment with either a guanylate cyclase antagonist (LY83583) or cyclic nucleotide-dependent kinase inhibitors (H-89 and KT 5823) significantly attenuated O2-induced fetal pulmonary vasodilation. Under hypoxic conditions (PaO2 = 25 mmHg), whole-cell K+-channel currents (Ik) were small and were inhibited by 1 mM tetraethylammonium or 100 nM charybdotoxin (CTX; a specific KCa-channel blocker). Normoxia (PaO2 = 120 mmHg) increased Ik by more than 300%, and this was reversed by 100 nM CTX. Nitric oxide also increased Ik. Resting membrane potential was -37.2 +/- 1.9 mV and cells depolarized on exposure to CTX, while hyperpolarizing in normoxia. We conclude that O2 causes fetal pulmonary vasodilation by stimulating a cyclic nucleotide-dependent kinase, resulting in KCa-channel activation, membrane hyperpolarization, and vasodilation. PMID:8755608

  8. Antioxidant and Vasodilator Activity of Ugni molinae Turcz. (Murtilla) and Its Modulatory Mechanism in Hypotensive Response

    PubMed Central

    Jofré, Ignacio; Pezoa, Cesar; Scheuermann, Erick; Rosalen, Pedro Luiz; Romero, Fernando

    2016-01-01

    Hypertension is a systemic condition with high morbidity and mortality rates worldwide, which poses an increased risk for cardiovascular diseases. In this study, we demonstrated the antioxidant and vasodilator activity of Ugni molinae Turcz. (Murtilla) fruit, a berry native to Chile and proposed models to explain its modulatory mechanism in hypotensive response. Murtilla fruits were cultivated in a germplasm bank and submitted to chemical and biological analyses. The phenolic compounds gallic acid, Catechin, Quercetin-3-β-D-glucoside, Myricetin, Quercetin, and Kaempferol were identified. Murtilla extract did not generate toxic effects on human endothelial cells and had significant antioxidant activity against ROS production, lipid peroxidation, and superoxide anion production. Furthermore, it showed dose-dependent vasodilator activity in aortic rings in the presence of endothelium, whose hypotensive mechanism is partially mediated by nitric oxide synthase/guanylate cyclase and large-conductance calcium-dependent potassium channels. Murtilla fruits might potentially have beneficial effects on the management of cardiovascular diseases.

  9. Antioxidant and Vasodilator Activity of Ugni molinae Turcz. (Murtilla) and Its Modulatory Mechanism in Hypotensive Response

    PubMed Central

    Jofré, Ignacio; Pezoa, Cesar; Scheuermann, Erick; Rosalen, Pedro Luiz; Romero, Fernando

    2016-01-01

    Hypertension is a systemic condition with high morbidity and mortality rates worldwide, which poses an increased risk for cardiovascular diseases. In this study, we demonstrated the antioxidant and vasodilator activity of Ugni molinae Turcz. (Murtilla) fruit, a berry native to Chile and proposed models to explain its modulatory mechanism in hypotensive response. Murtilla fruits were cultivated in a germplasm bank and submitted to chemical and biological analyses. The phenolic compounds gallic acid, Catechin, Quercetin-3-β-D-glucoside, Myricetin, Quercetin, and Kaempferol were identified. Murtilla extract did not generate toxic effects on human endothelial cells and had significant antioxidant activity against ROS production, lipid peroxidation, and superoxide anion production. Furthermore, it showed dose-dependent vasodilator activity in aortic rings in the presence of endothelium, whose hypotensive mechanism is partially mediated by nitric oxide synthase/guanylate cyclase and large-conductance calcium-dependent potassium channels. Murtilla fruits might potentially have beneficial effects on the management of cardiovascular diseases. PMID:27688827

  10. Pharmacological evidence that 5-HT1D activation induces renal vasodilation by NO pathway in rats.

    PubMed

    García-Pedraza, José-Ángel; García, Mónica; Martín, María-Luisa; Morán, Asunción

    2015-06-01

    5-HT is a powerful vasoconstrictor substance in renal vasculature (mainly by 5-HT₂ activation). Nevertheless, 5-HT is notable for its dual cardiovascular effects, producing both vasodilator and vasoconstrictor actions. This study aimed to investigate whether, behind the predominant serotonergic vasoconstrictor action, THE 5-HT system may exert renal vasodilator actions, and, if so, characterize the 5-HT receptors and possible indirect pathways. Renal perfusion pressure (PP), systemic blood pressure (SBP) and heart rate (HR) measurement in in situ autoperfused rat kidney was determined in phenylephrine infused rats. Intra arterial (i.a.) bolus administration of 5-HT (0.00000125-0.1 μg/kg) decreased renal PP in the presence of a phenylephrine continuous infusion (phenylephrine-infusion group), without modifying SBP or HR. These vasodilator responses were potentiated by 5-HT₂ antagonism (ritanserin, 1 mg/kg i.v.), whereas the responses were abolished by 5-HT₁ /₇ antagonist (methiothepin, 100 μg/kg i.v.) or 5-HT1D antagonist (LY310762, 1 mg/kg i.v.). The i.a. administration (0.00000125 to 0.1 μg/kg) of 5-CT or L-694,247 (5-HT1D agonist) mimicked 5-HT vasodilator effect, while other agonists (1-PBG, α-methyl-5-HT, AS-19 (5-HT₇), 8-OH-DPAT (5-HT1A) or CGS-12066B (5-HT1B)) did not alter baseline haemodynamic variables. L-694,247 vasodilation was abolished by i.v. bolus of antagonists LY310762 (5-HT1D, 1 mg/kg) or L-NAME (nitric oxide, 10 mg/kg), but not by i.v. bolus of indomethacin (cyclooxygenase, 2 mg/kg) or glibenclamide (ATP-dependent K(+) channel, 20 mg/kg). These outcomes suggest that 5-HT1D activation produces a vasodilator effect in the in situ autoperfused kidney of phenylephrine-infusion rats mediated by the NO pathway. PMID:25854421

  11. Bronchodilator, vasodilator and spasmolytic activities of Cymbopogon martinii.

    PubMed

    Janbaz, K H; Qayyum, A; Saqib, F; Imran, I; Zia-Ul-Haq, M; de Feo, V

    2014-12-01

    Cymbopogon martinii (Cm.Cr) is traditionally used in south Asian communities for the management of multiple ailments including gastrointestinal, respiratory and vascular disorders and the present study was undertaken to validate these folkloric uses. The application of a methanol extract of the plant (Cm.Cr) to isolated rabbit jejunum preparation exhibited relaxation through decrease in magnitude and frequency of spontaneous contractions. The Cm.Cr also exerted relaxant effect on high K(+) (80 mM) induced contractions in isolated rabbit jejunum preparations. The Cm.Cr and its dichloromethane (Cm.Dcm) and aqueous (Cm.Aq) fractions also caused concentration-dependent relaxation in spontaneous and K(+) (80 mM) induced contractions which are comparables to effects produced by verapamil. Cm.Cr caused shifting of the Ca(2+)-curves toward right, suggesting the presence of a Ca(2+) channel blocking activity. Subsequently, Cm.Cr, Cm.Dcm and Cm.Aq caused relaxation of CCh (1 μM) and K(+) (80 mM) induced contractions in isolated rabbit tracheal preparations, suggesting that the observed relaxant effect can be mediated through antimuscarinic and/or Ca(2+) channel blocking activities. Cm.Cr tested against phenylephrine (PE; 1 μM) and K(+) (80 mM) induced contractions exhibited partial relaxation of isolated rabbit aortic preparations. The above-mentioned studies provided a scientific basis for the folkloric use of Cymbopogon martini in the management of multiple ailments in traditional systems of medicines.

  12. Role of sensory nerves in the rapid cutaneous vasodilator response to local heating in young and older endurance-trained and untrained men.

    PubMed

    Tew, Garry A; Klonizakis, Markos; Moss, James; Ruddock, Alan D; Saxton, John M; Hodges, Gary J

    2011-02-01

    The ability to increase skin blood flow (SkBF) rapidly in response to local heating is diminished with advanced age; however, the mechanisms are unclear. The primary aim of this study was to investigate the role of sensory nerves in this age-related change. A secondary aim was to investigate the effect of aerobic fitness on sensory nerve-mediated vasodilatation in young and aged skin. We measured SkBF (using laser Doppler flowmetry) in young and older endurance-trained and untrained men (n= 7 in each group) at baseline and during 35 min of local skin heating to 42°C at two sites on the ventral forearm. One site was pretreated with topical anaesthetic cream to block local sensory nerve function. Cutaneous vascular conductance (CVC) was calculated as SkBF divided by mean arterial pressure and normalized to maximal values (CVC(max)) achieved during local heating to 44°C. At the untreated site, the rapid vasodilatation during the first ~5 min of local heating (initial peak) was lower in the older untrained group (68 ± 3%CVC(max)) compared with all other groups (young trained, 76 ± 4%CVC(max); young untrained, 75 ± 5%CVC(max); and older trained, 81 ± 3%CVC(max); P < 0.05). Sensory nerve blockade abolished these differences among the groups (P > 0.05). The contribution of sensory nerve-mediated vasodilatation was lower in the older untrained group compared with all other groups (P< 0.05). Our results suggest that the age-related decline in the rapid vasodilator response to local heating in human skin is explained by diminished sensory nerve-mediated vasodilatation. These findings also indicate that this age-related change can be prevented through participation in regular aerobic exercise.

  13. Hypothalamic orexin's role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model.

    PubMed

    Federici, Lauren M; Caliman, Izabela Facco; Molosh, Andrei I; Fitz, Stephanie D; Truitt, William A; Bonaventure, Pascal; Carpenter, Janet S; Shekhar, Anantha; Johnson, Philip L

    2016-03-01

    Distressing symptoms such as hot flashes and sleep disturbances affect over 70% of women approaching menopause for an average of 4-7 years, and recent large cohort studies have shown that anxiety and stress are strongly associated with more severe and persistent hot flashes and can induce hot flashes. Although high estrogen doses alleviate symptoms, extended use increases health risks, and current non-hormonal therapies are marginally better than placebo. The lack of effective non-hormonal treatments is largely due to the limited understanding of the mechanisms that underlie menopausal symptoms. One mechanistic pathway that has not been explored is the wake-promoting orexin neuropeptide system. Orexin is exclusively synthesized in the estrogen receptor rich perifornical hypothalamic region, and has an emerging role in anxiety and thermoregulation. In female rodents, estrogens tonically inhibit expression of orexin, and estrogen replacement normalizes severely elevated central orexin levels in postmenopausal women. Using an ovariectomy menopause model, we demonstrated that an anxiogenic compound elicited exacerbated hot flash-associated increases in tail skin temperature (TST, that is blocked with estrogen), and cellular responses in orexin neurons and efferent targets. Furthermore, systemic administration of centrally active, selective orexin 1 or 2 and dual receptor antagonists attenuated or blocked TST responses, respectively. This included the reformulated Suvorexant, which was recently FDA-approved for treating insomnia. Collectively, our data support the hypothesis that dramatic loss of estrogen tone during menopausal states leads to a hyperactive orexin system that contributes to symptoms such as anxiety, insomnia, and more severe hot flashes. Additionally, orexin receptor antagonists may represent a novel non-hormonal therapy for treating menopausal symptoms, with minimal side effects. PMID:26765933

  14. NO donors, part 8 [1]: synthesis and vasodilating activities of substituted benzylnitrates compared to cyclohexylmethylnitrate and GTN.

    PubMed

    Wessler, Christoph; Homann, Alexander; Fricke, Uwe; Lehmann, Jochen

    2003-06-01

    A series of substituted benzylnitrates (1) and the formally but not chemically similar cyclohexylmethylnitrate (CHMN) have been synthesised. Vasodilating activities were measured on endothelium-intact and N(G)-nitro-L-arginine (L-NNA)-blocked porcine right coronary arteries, precontracted with prostaglandin F(2alpha) (PGF(2alpha)). Glyceroltrinitrate (GTN) was used as reference. In intact coronary arteries the vasodilating activities of all benzylnitrates are lower compared with GTN, but higher compared with CHMN. However, blocking the function of the endothelium by L-NNA, the activity of all benzylnitrates increased, whereas that of CHMN and GTN remained nearly unaffected. Under these conditions, the mononitrates 4-nitro-benzylnitrate (1c) and 4-nitrooxymethyl-benzonitrile (1h) even showed higher vasodilator activities than the trinitrate GTN and in general, vasorelaxation by the benzylnitrates as defined by the concentrations for half maximal effects (EC(50) values) was found to be 2-3 orders of magnitude higher than that induced by CHMN. The study demonstrates that the in vitro activities of organic nitrates do not correlate with the number of nitrate groups within the molecule nor to the lipophilicity of the molecules. Instead, vasodilator activity is highly sensitive to the structure and the type of the substituents in the molecular carrier of the nitrate group.

  15. Modulation of muscle metaboreceptor activation upon sweating and cutaneous vascular responses to rising core temperature in humans.

    PubMed

    Amano, Tatsuro; Ichinose, Masashi; Inoue, Yoshimitsu; Nishiyasu, Takeshi; Koga, Shunsaku; Kondo, Narihiko

    2015-06-15

    The present study investigated the role of muscle metaboreceptor activation on human thermoregulation by measuring core temperature thresholds and slopes for sweating and cutaneous vascular responses during passive heating associated with central and peripheral mechanisms. Six male and eight female subjects inserted their lower legs into hot water (43°C) while wearing a water perfusion suit on the upper body (34°C). One minute after immersion, an isometric handgrip exercise--40% of maximum voluntary contraction-was conducted for 1.5 min in both control and experimental conditions, while postexercise occlusion was performed in the experimental condition only for 9 min. The postexercise forearm occlusion during passive heating consistently stimulated muscle metaboreceptors, as implicated by significantly elevated mean arterial blood pressure throughout the experimental period (P <0.05). Stimulation of the forearm muscle metaboreceptors increased sweating and cutaneous vascular responses during passive heating, and was associated with significant reductions in esophageal temperature threshold of sweating and cutaneous vasodilation (Δ threshold, sweating: 0.33 ± 0.05 and 0.16 ± 0.04°C, cutaneous vascular conductance: 0.38 ± 0.08 and 0.16 ± 0.05°C for control and experimental groups, respectively, P < 0.05). The slopes of these responses were not different between the conditions. These results suggest that muscle metaboreceptor activation in the forearm accelerates sweating and cutaneous vasodilation during passive heating associated with a reduction in core temperature thresholds and may be related to central mechanisms controlling heat loss responses.

  16. In vivo antioxidant and vasodilating activities of Gmelina arborea (Verberaceae) leaves hexane extract.

    PubMed

    Wansi, Sylvie L; Nyadjeu, Paulin; Nguelefack, Télesphore Benoît; Fodouop, Siaka F K; Donatien, Atsamo Albert; Kamanyi, Albert

    2012-01-01

    The present study investigated the effects of Gmelina arborea hexane leaves extract on markers of oxidative stress and its vasorelaxant effects on isolated rat aorta, in order to postulate the possible mechanisms involved in the antihypertensive properties of the plant. To evaluate the antioxidant effects of the extract, rats were randomly divided into four groups of five rats each. With the exception to the group receiving Tween (2.5%), the other groups were treated either with NaCl (900mg/kg/day) alone, NaCl (900mg/kg/day) combined with vitamin C (5mg/kg/day) or Gmelina arborea extract (150mg/kg/day). At the end of eight weeks of treatment, animals were sacrificed and some organs as well as blood samples were collected for biochemical analysis. The in vitro vasodilating effects of the extract (0.5-1.5mg/ml) were evaluated using intact and denuded rat thoracic aortic rings or aorta pre-incubated in L-NAME (2µM), indomethacin (2µM) or glibenclamide (2µM) and contracted with phenylephrine (1µM). The in vivo effects of G. arborea hexane extract prevented both left ventricular and vascular hypertrophy, it also modulated lipid metabolism. Moreover, the extract prevented lipid peroxidation, increased superoxide dismutase and catalase activity as well as NO level. On isolated rat aortic rings, the extract induced concentration-dependent vasorelaxant effects. Extract-induced vasodilation was reduced by mechanical denudation of the endothelium as well as pre-treatment with L-NAME, indomethacin or glibenclamide. These results indicate that Gmelina arborea hexane extract possesses bioactive compounds with antioxidant and vasorelaxant properties. PMID:23045387

  17. Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats.

    PubMed

    Maruyama, Kana; Kagota, Satomi; McGuire, John J; Wakuda, Hirokazu; Yoshikawa, Noriko; Nakamura, Kazuki; Shinozuka, Kazumasa

    2015-01-01

    Endothelium-dependent vasodilation via protease-activated receptor 2 (PAR2) is preserved in mesenteric arteries from SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome even though nitric oxide (NO)-mediated vasodilation is attenuated. Therefore, we examined the PAR2 mechanisms underlying metabolic syndrome-resistant vasodilation in SHRSP.ZF aortas with ageing. In isolated aortas, the PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) caused vasodilation that was sustained in male SHRSP.ZF until 18 weeks of age, but was attenuated afterwards compared with age-matched Wistar-Kyoto rats (controls) at 23 weeks. In contrast, acetylcholine-induced vasodilation was impaired in SHRSP.ZF already at 18 weeks of age. Treatments of aortas with inhibitors of NO synthase and soluble guanylate cyclase abolished the sustained 2fly- and residual acetylcholine-induced vasodilation in SHRSP.ZF at 18 weeks of age. In the aortas of SHRSP.ZF, 8-bromo-cGMP-induced vasodilation, NO production and cGMP accumulation elicited by 2fly were not different from in the controls. PAR2 agonist increased phospho-Ser1177-eNOS protein content only in SHRSP.ZF aortas. These results indicate that vasodilation mediated by PAR2 is sustained even though NO-dependent relaxation is attenuated with ageing/exposure to metabolic disorders in large-caliber arteries from SHRSP.ZF. PAR2 stimulation of NO production via an additional pathway that targets phosphorylation of Ser1177-eNOS suggests a regulatory mechanism for sustaining agonist-mediated vasodilation in metabolic syndrome.

  18. Vasodilator-Stimulated Phosphoprotein Activity Is Required for Coxiella burnetii Growth in Human Macrophages

    PubMed Central

    Colonne, Punsiri M.; Winchell, Caylin G.; Graham, Joseph G.; Onyilagha, Frances I.; MacDonald, Laura J.; Doeppler, Heike R.; Storz, Peter; Kurten, Richard C.; Beare, Paul A.; Voth, Daniel E.

    2016-01-01

    Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, an acute flu-like illness that can progress to chronic endocarditis and liver and bone infections. Humans are typically infected by aerosol-mediated transmission, and C. burnetii initially targets alveolar macrophages wherein the pathogen replicates in a phagolysosome-like niche known as the parasitophorous vacuole (PV). C. burnetii manipulates host cAMP-dependent protein kinase (PKA) signaling to promote PV formation, cell survival, and bacterial replication. In this study, we identified the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP) as a PKA substrate that is increasingly phosphorylated at S157 and S239 during C. burnetii infection. Avirulent and virulent C. burnetii triggered increased levels of phosphorylated VASP in macrophage-like THP-1 cells and primary human alveolar macrophages, and this event required the Cα subunit of PKA. VASP phosphorylation also required bacterial protein synthesis and secretion of effector proteins via a type IV secretion system, indicating the pathogen actively triggers prolonged VASP phosphorylation. Optimal PV formation and intracellular bacterial replication required VASP activity, as siRNA-mediated depletion of VASP reduced PV size and bacterial growth. Interestingly, ectopic expression of a phospho-mimetic VASP (S239E) mutant protein prevented optimal PV formation, whereas VASP (S157E) mutant expression had no effect. VASP (S239E) expression also prevented trafficking of bead-containing phagosomes to the PV, indicating proper VASP activity is critical for heterotypic fusion events that control PV expansion in macrophages. Finally, expression of dominant negative VASP (S157A) in C. burnetii-infected cells impaired PV formation, confirming importance of the protein for proper infection. This study provides the first evidence of VASP manipulation by an intravacuolar bacterial pathogen via activation of PKA in human

  19. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation.

    PubMed

    Aamand, Rasmus; Dalsgaard, Thomas; Jensen, Frank B; Simonsen, Ulf; Roepstorff, Andreas; Fago, Angela

    2009-12-01

    In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the CO2 hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that CO2 and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (CO2/H+) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain. PMID:19820197

  20. Vasodilator activity of 2-(p-chloro-alpha-hydroxybenzyl)benzimidazole (HBBPC) on femoral vascular bed of the rabbit.

    PubMed

    Demenge, P; Silice, C; Luu Duc, C; Carraz, G

    1979-01-01

    The effects of 2-(p-chloro-alpha-hydroxybenzyl) benzimidazole HCl (HBBPC) have been studied on the femoral peripheral resistance (i.v. route) and only femoral blood flow (local i.a. injection), in comparison with other vasodilators, i.e., sodium nitroprusside, dihydralazine and piribedil. The vasomotor activity of HBBPC, namely, decreased peripheral resistance and increased femoral blood flow, seems interesting because it begins after pressure has returned to normal. This substance is likely to induce a vasoconstriction in other areas (increased femoral blood flow with decreased peripheral resistance without a fall of blood pressure).

  1. Acute cyclooxygenase inhibition does not alter muscle sympathetic nerve activity or forearm vasodilator responsiveness in lean and obese adults

    PubMed Central

    Barnes, Jill N.; Charkoudian, Nisha; Matzek, Luke J.; Johnson, Christopher P.; Joyner, Michael J.; Curry, Timothy B.

    2014-01-01

    Abstract Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation and decreased vasodilator responsiveness. We hypothesized that obese individuals would have greater indices of inflammation compared with lean controls, and that cyclooxygenase inhibition using ibuprofen would reduce muscle sympathetic nerve activity (MSNA) and increase forearm blood flow in these subjects. We measured MSNA, inflammatory biomarkers (C‐reactive protein [CRP] and Interleukin‐6 [IL‐6]), and forearm vasodilator responses to brachial artery acetylcholine and sodium nitroprusside in 13 men and women (7 lean; 6 obese) on two separate study days: control (CON) and after 800 mg ibuprofen (IBU). CRP (1.7 ± 0.4 vs. 0.6 ± 0.3 mg/L; P < 0.05) and IL‐6 (4.1 ± 1.5 vs. 1.0 ± 0.1pg/mL; P < 0.05) were higher in the obese group during CON and tended to decrease with IBU (IL‐6: P < 0.05; CRP: P = 0.14). MSNA was not different between groups during CON (26 ± 4 bursts/100 heart beats (lean) versus 26 ± 4 bursts/100 heart beats (obese); P = 0.50) or IBU (25 ± 4 bursts/100 heart beats (lean) versus 30 ± 5 bursts/100 heart beats (obese); P = 0.25), and was not altered by IBU. Forearm vasodilator responses were unaffected by IBU in both groups. In summary, an acute dose of ibuprofen did not alter sympathetic nerve activity or forearm blood flow responses in healthy obese individuals, suggesting that the cyclooxygenase pathway is not a major contributor to these variables in this group. PMID:25347862

  2. Influence of forearm muscle metaboreceptor activation on sweating and cutaneous vascular responses during dynamic exercise.

    PubMed

    Amano, Tatsuro; Ichinose, Masashi; Inoue, Yoshimitsu; Nishiyasu, Takeshi; Koga, Shunsaku; Kenny, Glen P; Kondo, Narihiko

    2016-06-01

    We examined whether the sustained activation of metaboreceptor in forearm during cycling exercise can modulate sweating and cutaneous vasodilation. On separate days, 12 young participants performed a 1.5-min isometric handgrip exercise at 40% maximal voluntary contraction followed by 1) 9-min forearm ischemia (Occlusion, to activate metaboreceptor) or 2) no ischemia (Control) in thermoneutral conditions (27°C, 50%) with mean skin temperature clamped at 34°C. Thirty seconds after the handgrip exercise, participants cycled for 13.5 min at 40% V̇o2 max For Occlusion, forearm ischemia was maintained for 9 min followed by no ischemia thereafter. Local sweat rate (SR, ventilated capsule) and cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) on the contralateral nonischemic arm as well as esophageal and skin temperatures were measured continuously. The period of ischemia in the early stages of exercise increased SR (+0.03 mg·cm(-2)·min(-1), P < 0.05) but not CVC (P > 0.05) above Control levels. No differences were measured in the esophageal temperature at which onset of sweating (Control 37.19 ± 0.09 vs. Occlusion 37.07 ± 0.09°C) or CVC (Control 37.21 ± 0.08 vs. Occlusion 37.08 ± 0.10°C) as well as slopes for these responses (all P > 0.05). However, a greater elevation in SR occurred thereafter such that SR was significantly elevated at the end of the ischemic period relative to Control (0.37 ± 0.05 vs. 0.23 ± 0.05 mg·cm(-2)·min(-1), respectively, P < 0.05) despite no differences in esophageal temperature. We conclude that the activation of forearm muscle metaboreceptor can modulate sweating, but not CVC, during cycling exercise without affecting the core temperature-SR relationship. PMID:27053652

  3. Dynamic characteristics of the cutaneous vasodilator response to a local external pressure application detected by the laser Doppler flowmetry technique on anesthetized rats

    NASA Astrophysics Data System (ADS)

    Humeau, Anne; Koitka, Audrey; Saumet, Jean-Louis; L'Huillier, Jean-Pierre

    2003-10-01

    The laser Doppler flowmetry technique has recently been used to report a significant transient increase of the cutaneous blood flow signal when a local non-noxious pressure is applied progressively on the skin (11.1 Pa/s). The present work analyses the dynamic characteristics of this vasodilatory reflex response on anaesthetised rats. A de-noising algorithm using wavelets is proposed to obtain accurate values of these dynamic characteristics. The blood flow peak and the time to reach this peak are computed on the de-noised recordings. The results show that the mean time to reach the peak of perfusion is 85.3 s (time t = 0 at the beginning of the pressure application). The mean peak value is 188.3 arbitrary units (a.u.), whereas the mean value of the perfusion before the pressure application is 113.4 a.u. The mean minimum value obtained at the end of the experiment is 60.7 a.u. This latter value is, on the average, reached 841.3 s after the beginning of the pressure application. The comparison of the dynamic characteristics, computed with the de-noising algorithm on signals obtained in other situations, will give a better understanding on some cutaneous lesions such as those present on diabetic people.

  4. Cilostazol induces vasodilation through the activation of Ca(2+)-activated K(+) channels in aortic smooth muscle.

    PubMed

    Li, Hongliang; Hong, Da Hye; Son, Youn Kyoung; Na, Sung Hun; Jung, Won-Kyo; Bae, Young Min; Seo, Eun Young; Kim, Sung Joon; Choi, Il-Whan; Park, Won Sun

    2015-07-01

    We investigated the vasorelaxant effect of cilostazol and related signaling pathways in phenylephrine (Phe)-induced pre-contracted aortic rings. Cilostazol induced vasorelaxation in a concentration-dependent manner when aortic rings were pre-contracted with Phe. Application of the voltage-dependent K(+) (Kv) channel inhibitor 4-AP, the ATP-sensitive K(+) (K(ATP)) channel inhibitor glibenclamide, and the inwardly rectifying K(+) (Kir) channel inhibitor Ba(2+) did not alter the vasorelaxant effect of cilostazol; however, pre- and post-treatment with the big-conductance Ca(2+)-activated K(+) (BK(Ca)) channel inhibitor paxilline inhibited the vasorelaxant effect of cilostazol. This vasorelaxant effect of cilostazol was reduced in the presence of an adenylyl cyclase or a protein kinase A (PKA) inhibitor, but not a protein kinase G inhibitor. Inside-out single channel recordings revealed that cilostazol induced the activation of BK(Ca) channel activity. The vasorelaxant effect of cilostazol was not affected by removal of the endothelium. In addition, application of a nitric oxide synthase inhibitor and a small-conductance Ca(2+)-activated K(+) (SK(Ca)) channel inhibitor did not affect cilostazol-induced vasorelaxation. We conclude that cilostazol induced vasorelaxation of the aorta through activation of BK(Ca) channel via a PKA-dependent signaling mechanism independent of endothelium.

  5. PI3K/Akt-independent NOS/HO activation accounts for the facilitatory effect of nicotine on acetylcholine renal vasodilations: modulation by ovarian hormones.

    PubMed

    Gohar, Eman Y; El-gowilly, Sahar M; El-Gowelli, Hanan M; El-Demellawy, Maha A; El-Mas, Mahmoud M

    2014-01-01

    We investigated the effect of chronic nicotine on cholinergically-mediated renal vasodilations in female rats and its modulation by the nitric oxide synthase (NOS)/heme oxygenase (HO) pathways. Dose-vasodilatory response curves of acetylcholine (0.01-2.43 nmol) were established in isolated phenylephrine-preconstricted perfused kidneys obtained from rats treated with or without nicotine (0.5-4.0 mg/kg/day, 2 weeks). Acetylcholine vasodilations were potentiated by low nicotine doses (0.5 and 1 mg/kg/day) in contrast to no effect for higher doses (2 and 4 mg/kg/day). The facilitatory effect of nicotine was acetylcholine specific because it was not observed with other vasodilators such as 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) or papaverine. Increases in NOS and HO-1 activities appear to mediate the nicotine-evoked enhancement of acetylcholine vasodilation because the latter was compromised after pharmacologic inhibition of NOS (L-NAME) or HO-1 (zinc protoporphyrin, ZnPP). The renal protein expression of phosphorylated Akt was not affected by nicotine. We also show that the presence of the two ovarian hormones is necessary for the nicotine augmentation of acetylcholine vasodilations to manifest because nicotine facilitation was lost in kidneys of ovariectomized (OVX) and restored after combined, but not individual, supplementation with medroxyprogesterone acetate (MPA) and estrogen (E2). Together, the data suggests that chronic nicotine potentiates acetylcholine renal vasodilation in female rats via, at least partly, Akt-independent HO-1 upregulation. The facilitatory effect of nicotine is dose dependent and requires the presence of the two ovarian hormones.

  6. Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

    PubMed Central

    Escuin-Ordinas, Helena; Li, Shuoran; Xie, Michael W.; Sun, Lu; Hugo, Willy; Huang, Rong Rong; Jiao, Jing; de-Faria, Felipe Meira; Realegeno, Susan; Krystofinski, Paige; Azhdam, Ariel; Komenan, Sara Marie D.; Atefi, Mohammad; Comin-Anduix, Begoña; Pellegrini, Matteo; Cochran, Alistair J.; Modlin, Robert L.; Herschman, Harvey R.; Lo, Roger S.; McBride, William H.; Segura, Tatiana; Ribas, Antoni

    2016-01-01

    BRAF inhibitors are highly effective therapies for the treatment of BRAFV600-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. PMID:27476449

  7. Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors.

    PubMed

    Escuin-Ordinas, Helena; Li, Shuoran; Xie, Michael W; Sun, Lu; Hugo, Willy; Huang, Rong Rong; Jiao, Jing; de-Faria, Felipe Meira; Realegeno, Susan; Krystofinski, Paige; Azhdam, Ariel; Komenan, Sara Marie D; Atefi, Mohammad; Comin-Anduix, Begoña; Pellegrini, Matteo; Cochran, Alistair J; Modlin, Robert L; Herschman, Harvey R; Lo, Roger S; McBride, William H; Segura, Tatiana; Ribas, Antoni

    2016-08-01

    BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.

  8. Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy.

    PubMed

    Mata, Karina M; Li, Wei; Reslan, Ossama M; Siddiqui, Waleed T; Opsasnick, Lauren A; Khalil, Raouf A

    2015-11-15

    Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E2) may promote vasodilation during pregnancy; however, the specific E2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ERα, ERβ, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E2 (all ERs) and the specific ER agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ERα), diarylpropionitrile (DPN; ERβ), and G1 (GPER). BP was slightly lower and plasma E2 was higher in pregnant versus virgin rats. Western blots revealed increased ERα and ERβ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrine-precontracted vessels, E2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN- and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N(ω)-nitro-l-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E2-, PPT

  9. Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy.

    PubMed

    Mata, Karina M; Li, Wei; Reslan, Ossama M; Siddiqui, Waleed T; Opsasnick, Lauren A; Khalil, Raouf A

    2015-11-15

    Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E2) may promote vasodilation during pregnancy; however, the specific E2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ERα, ERβ, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E2 (all ERs) and the specific ER agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ERα), diarylpropionitrile (DPN; ERβ), and G1 (GPER). BP was slightly lower and plasma E2 was higher in pregnant versus virgin rats. Western blots revealed increased ERα and ERβ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrine-precontracted vessels, E2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN- and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N(ω)-nitro-l-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E2-, PPT

  10. In vitro relation between preganglionic sympathetic stimulation and activity of cutaneous glands in the bullfrog.

    PubMed Central

    Jobling, P; Horn, J P

    1996-01-01

    1. Activation of cutaneous glands was studied by measuring changes in transepithelial potentiation (TEP) after pre- and postganglionic sympathetic stimulation in the bullfrog, Rana catesbeiana. 2. In normal Ringer solution, TEP was 20-90 mV with the basolateral (inside) surface positive. Single shocks to the preganglionic B pathway decreased TEP by up to 3 mV. Cutaneous depolarizations had a latency of 1.2 s, a rise time of 2.5 s, and decayed with an exponential time constant of 15 s. Similar depolarizations were evoked by postganglionic stimulation. 3. Cutaneous depolarizations summed during repetitive stimulation and > 0.05 Hz. For trains of three stimuli, peak amplitude increased with frequency and saturated at 2 Hz. In some preparations, longer trains evoked polyphasic changes in TEP. Preganglionically evoked cutaneous responses were abolished by (+)-tubocurarine. Postganglionically evoked cutaneous depolarizations were antagonized by phentolamine, but not propranolol. 4. Repetitive preganglionic stimulation of the C pathway (> 100 at 20 Hz) evoked little change in TEP and did not modulate depolarizations evoked through the B pathway. In nicotine, peptidergic cotransmission was enhanced in the ganglia, and repetitive C pathway stimulation evoked cutaneous depolarizations whose time course mirrored that of the postganglionic peptidergic after-discharge. The after-discharge and associated cutaneous depolarization were blocked by a luteinizing hormone-releasing hormone antagonist. 5. The results show cutaneous glands are selectively innervated by B neurones and respond to low levels of neural activity. Asynchronous postganglionic firing mediated by peptidergic cotransmission can provide a basis for heterosynaptic interactions between the B and C pathways. PMID:8814622

  11. Activation of autophagic pathways is related to growth inhibition and senescence in cutaneous squamous cell carcinoma.

    PubMed

    Choi, So Ra; Chung, Bo Young; Kim, Seong Who; Kim, Chang Deok; Yun, Woo Jin; Lee, Mi Woo; Choi, Jee Ho; Chang, Sung Eun

    2014-10-01

    Cutaneous squamous cell carcinoma (SCC) is a very common resectable cancer; however, cutaneous SCC is highly resistant to chemotherapy if metastasis develops. Activating transcription factor 3 (ATF3) has been suggested as a marker of advanced or metastatic cutaneous SCC. Autophagy is one of the most important mechanisms in cancer biology and commonly induced by in vitro serum starvation. To investigate the role of autophagy activation in cutaneous SCC, we activated autophagic pathways by serum starvation in SCC13 and ATF3-overexpressing SCC13 (ATF3-SCC13) cell lines. ATF3-SCC13 cells demonstrated high proliferative capacity and low p53 and autophagy levels in comparison with control SCC13 cells under basal conditions. Intriguingly, autophagic stimulation via serum starvation resulted in growth inhibition and senescence in both cells, while ATF3-SCC13 cells further demonstrated growth inhibition and senescence. Apoptosis was not significantly induced by autophagy activation. Taken together, autophagy activation may be a promising antitumor approach for advanced cutaneous SCC. PMID:25046976

  12. Use-dependent loss of active sympathetic neurogenic vasodilation after nitric oxide synthase inhibition in conscious rats. Evidence for the presence of preformed stores of nitric oxide-containing factors

    NASA Technical Reports Server (NTRS)

    Davisson, R. L.; Shaffer, R. A.; Johnson, A. K.; Lewis, S. J.

    1996-01-01

    In this study, we examined whether air-jet stress-induced active sympathetic hindlimb vasodilation in conscious rats involves the release of preformed stores of nitric oxide-containing factors. We determined the effects of repeated episodes of air-jet stress (six episodes given 5 minutes apart) on mean arterial pressure and vascular resistances in the mesenteric bed and intact and sympathetically denervated hindlimb beds of conscious rats treated with saline or the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mumol/kg IV). In saline-treated rats, air-jet stress produced alerting behavior, minor changes in blood pressure, pronounced mesenteric vaso-constriction, and immediate and marked vasodilation in the sympathetically intact hindlimb but a minor vasodilation in the sympathetically denervated hindlimb. Each air-jet stress produced virtually identical responses. In L-NAME-treated rats, the first air-jet stress produced vasodilator responses in the sympathetically intact and sympathetically denervated hindlimbs that were similar to those in the saline-treated rats. However, each subsequent air-jet stress produced progressively smaller vasodilator responses in the sympathetically intact but not the sympathetically denervated hindlimb. There was no loss of air-jet stress-induced alerting behavior or mesenteric vasoconstriction, suggesting that L-NAME did not interfere with the central processing of the air-jet or the resultant changes in autonomic nerve activity. The progressive diminution of air-jet stress-induced vasodilation in the intact hindlimb of L-NAME-treated rats may be due to the use-dependent depletion of preformed stores of nitric oxide-containing factors that cannot be replenished in the absence of nitric oxide synthesis.

  13. Oral clopidogrel improves cutaneous microvascular function through EDHF-dependent mechanisms in middle-aged humans.

    PubMed

    Dahmus, Jessica D; Bruning, Rebecca S; Kenney, W Larry; Alexander, Lacy M

    2013-08-15

    Platelet P₂Y₁₂-ADP and COX-1 receptor inhibition with oral clopidogrel (CLO) and low-dose aspirin (ASA), respectively, attenuates reflex-mediated cutaneous vasodilation, but little is known about how these medications affect local vasodilatory signaling. Reactive hyperemia (RH) results in vasodilation that is mediated by sensory nerves and endothelium-derived hyperpolarization factors (EDHF) through large-conductance calcium-activated potassium channels, whereas slow local heating (LH) elicits vasodilation largely through the production of nitric oxide (NO). We hypothesized that CLO and ASA would attenuate locally mediated cutaneous vasodilation assessed by RH and LH (0.5°C/min). In a randomized, cross-over, double-blind placebo-controlled study, nine healthy men and women (56 ± 1 yr) took CLO (75 mg), ASA (81 mg), and placebo for 7 days. Skin blood flow was measured (laser-Doppler flowmetry, LDF) and cutaneous vascular conductance (CVC) was calculated (LDF/mean arterial pressure) and normalized to maximal CVC (%CVCmax: 43°C and 28 mM sodium nitroprusside). RH response parameters, including area under the curve (AUC), total hyperemic response (THR), and the decay constant tau (λ) were calculated. NO-dependent vasodilation during LH was assessed by calculating the difference in %CVCmax between a control site and an NO synthase-inhibited site (10 mM l-NAME: intradermal microdialysis). CLO augmented the AUC and THR (AUCclo = 3,783 ± 342; THRclo = 2,306 ± 266% CVCmax/s) of the RH response compared with ASA (AUCASA = 3,101 ± 325; THRASA = 1,695 ± 197% CVCmax/s) and placebo (AUCPlacebo = 3,000 ± 283; THRPlacebo = 1,675 ± 170% CVCmax/s; all P < 0.0001 vs. CLO). There was no difference in the LH response or calculated NO-dependent vasodilation among treatments (all P > 0.05). Oral CLO treatment augments vasodilation during RH but not LH, suggesting that CLO may improve cutaneous microvascular function.

  14. Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases

    PubMed Central

    Zhuang, Xiao-dong; Liao, Li-zhen; Dong, Xiao-bian; Hu, Xun; Guo, Yue; Du, Zhi-min; Liao, Xin-xue; Wang, Li-chun

    2016-01-01

    This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice. PMID:26792980

  15. Selective bilateral activation of leg muscles after cutaneous nerve stimulation during backward walking

    PubMed Central

    Massaad, Firas; Jansen, Karen; Bruijn, Sjoerd M.; Duysens, Jacques

    2012-01-01

    During human locomotion, cutaneous reflexes have been suggested to function to preserve balance. Specifically, cutaneous reflexes in the contralateral leg's muscles (with respect to the stimulus) were suggested to play an important role in maintaining stability during locomotor tasks where stability is threatened. We used backward walking (BW) as a paradigm to induce unstable gait and analyzed the cutaneous reflex activity in both ipsilateral and contralateral lower limb muscles after stimulation of the sural nerve at different phases of the gait cycle. In BW, the tibialis anterior (TA) reflex activity in the contralateral leg was markedly higher than TA background EMG activity during its stance phase. In addition, in BW a substantial reflex suppression was observed in the ipsilateral biceps femoris during the stance-swing transition in some participants, while for medial gastrocnemius the reflex activity was equal to background activity in both legs. To test whether the pronounced crossed responses in TA could be related to instability, the responses were correlated with measures of stability (short-term maximum Lyapunov exponents and step width). These measures were higher for BW compared with forward walking, indicating that BW is less stable. However, there was no significant correlation between these measures and the amplitude of the crossed TA responses in BW. It is therefore proposed that these crossed responses are related to an attempt to briefly slow down (TA decelerates the center of mass in the single-stance period) in the light of unexpected perturbations, such as provided by the sural nerve stimulation. PMID:22773779

  16. Hexyl-nicotinate-induced vasodilation in normal human skin.

    PubMed

    Dowd, P M; Whitefield, M; Greaves, M W

    1987-01-01

    Hexyl nicotinate in a lotion formulation was applied topically to the skin of 10 healthy volunteers with clinically normal skin. Erythematous responses were assessed visually and skin blood flow determined by means of a laser Doppler flow meter which measures the blood cell flux (Pf2 Perimed, Sweden). Mean erythematous responses and increased blood cell flux were dose-related but in several subjects increases in blood flow occurred in the presence of barely detectable erythematous responses. In some subjects, hexyl nicotinate may be an effective cutaneous vasodilator even in the presence of minimal erythema.

  17. Recombinant interferon alfa-2a, an active agent in advanced cutaneous T-cell lymphomas.

    PubMed

    Bunn, P A; Ihde, D C; Foon, K A

    1987-01-01

    The cutaneous T-cell lymphomas including mycosis fungoides and the Sézary syndrome, are indolent lymphomas with early systemic dissemination. Like the indolent B-cell lymphomas, they cannot be cured by currently available systemic chemotherapy so new systemic therapies need to be developed. A study of very high-dose recombinant interferon alfa-2a was, therefore, initiated in 20 patients with advanced cutaneous T-cell lymphoma (5 in stage II, 2 in stage III and 13 in stage IV). All patients were refractory to at least 2 standard therapies, including topical nitrogen mustard (18 patients), psoralens and ultraviolet A light (12 patients), total skin electron irradiation (14 patients) and systemic chemotherapy (16 patients). Nine out of 20 patients (45%; 95% confidence interval 25-69%) had either objective partial or complete responses within 3 months of starting treatment. Maximal response, however, often did not occur for at least one year. The median duration of response was 5.5 months and all complete responses lasted more than 2 years. Response frequencies were equal at both cutaneous and extracutaneous sites and in patients with or without prior chemotherapy. Toxicity was exhibited primarily as a flu-like syndrome consisting of fever, malaise, fatigue, anorexia and weight loss which necessitated dose reductions in all patients. Transient elevations in liver function and decreases in renal function and granulocyte counts occurred in some patients. It is concluded that interferon alfa-2a is highly active against advanced cutaneous T-cell lymphomas and that it should be studied in its early stages. It should also be evaluated in combination with other biological agents and with chemotherapy.

  18. Sensitization of rat facial cutaneous mechanoreceptors by activation of peripheral N-methyl-d-aspartate receptors.

    PubMed

    Gazerani, Parisa; Dong, Xudong; Wang, Mianwei; Kumar, Ujendra; Cairns, Brian E

    2010-03-10

    The effect of subcutaneous injection of glutamate on the mechanical sensitivity of rat facial cutaneous mechanoreceptors was examined. Individual facial mechanoreceptors were recorded in the trigeminal ganglion of anesthetized Sprague-Dawley rats. An electronic von Frey hair was used to measure the mechanical threshold (MT) of the afferent fibers at baseline and following subcutaneous injection of glutamate (0, 0.01, 0.1, 1M; 10microl) or glutamate (0, 0.1M) plus the competitive N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV; 0.01M). Subcutaneous injections were randomized and the investigator was unaware of their content. Changes in MT were assessed with a repeated measure ANOVA with time, sex and treatment as factors. Immunohistochemistry was used to confirm NMDA receptor expression by cutaneous nerve fibers. A total of 100 (50 per sex) facial mechanoreceptors were recorded from 61 (32 females, 29 males) rats in two separate experiments. Subcutaneous injections of higher concentrations of glutamate (1, 0.1M) induced a significant mechanical sensitization of skin afferent fibers (compared to 0 and 0.01M). Females (EC(50)=16.2mM) were more sensitive to glutamate than males (EC(50)=73.0mM). Facial cutaneous nerve fibers in both sexes expressed NMDA receptors. APV blocked the mechanical sensitization of the afferent fibers treated by glutamate 0.1M in both sexes with a lower effect in females at a 10-20minute post-injection. Subcutaneous injection of glutamate mechanically sensitizes rat facial cutaneous mechanoreceptors through activation of peripheral NMDA receptors. Peripheral NMDA receptor antagonists may be considered for craniofacial pain.

  19. Blockade of mast cell activation reduces cutaneous scar formation.

    PubMed

    Chen, Lin; Schrementi, Megan E; Ranzer, Matthew J; Wilgus, Traci A; DiPietro, Luisa A

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound.

  20. Vasodilator Therapy: Nitrates and Nicorandil.

    PubMed

    Tarkin, Jason M; Kaski, Juan Carlos

    2016-08-01

    Nitrates have been used to treat symptoms of chronic stable angina for over 135 years. These drugs are known to activate nitric oxide (NO)-cyclic guanosine-3',-5'-monophasphate (cGMP) signaling pathways underlying vascular smooth muscle cell relaxation, albeit many questions relating to how nitrates work at the cellular level remain unanswered. Physiologically, the anti-angina effects of nitrates are mostly due to peripheral venous dilatation leading to reduction in preload and therefore left ventricular wall stress, and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. By counteracting ischemic mechanisms, short-acting nitrates offer rapid relief following an angina attack. Long-acting nitrates, used commonly for angina prophylaxis are recommended second-line, after beta-blockers and calcium channel antagonists. Nicorandil is a balanced vasodilator that acts as both NO donor and arterial K(+) ATP channel opener. Nicorandil might also exhibit cardioprotective properties via mitochondrial ischemic preconditioning. While nitrates and nicorandil are effective pharmacological agents for prevention of angina symptoms, when prescribing these drugs it is important to consider that unwanted and poorly tolerated hemodynamic side-effects such as headache and orthostatic hypotension can often occur owing to systemic vasodilatation. It is also necessary to ensure that a dosing regime is followed that avoids nitrate tolerance, which not only results in loss of drug efficacy, but might also cause endothelial dysfunction and increase long-term cardiovascular risk. Here we provide an update on the pharmacological management of chronic stable angina using nitrates and nicorandil.

  1. In vitro activities of eight antifungal drugs against 106 waterborne and cutaneous exophiala species.

    PubMed

    Najafzadeh, M J; Saradeghi Keisari, M; Vicente, V A; Feng, P; Shamsian, S A A; Rezaei-Matehkolaei, A; de Hoog, G S; Curfs-Breuker, I; Meis, J F

    2013-12-01

    The in vitro activities of eight antifungal drugs against 106 clinical and environmental isolates of waterborne and cutaneous Exophiala species were tested. The MICs and minimum effective concentrations for 90% of the strains tested (n = 106) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.25 μg/ml; micafungin, 1 μg/ml; voriconazole, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 8 μg/ml; amphotericin B, 16 μg/ml; fluconazole, 64 μg/ml. PMID:24100491

  2. In Vitro Activities of Eight Antifungal Drugs against 106 Waterborne and Cutaneous Exophiala Species

    PubMed Central

    Najafzadeh, M. J.; Saradeghi Keisari, M.; Vicente, V. A.; Feng, P.; Shamsian, S. A. A.; Rezaei-Matehkolaei, A.; de Hoog, G. S.; Curfs-Breuker, I.

    2013-01-01

    The in vitro activities of eight antifungal drugs against 106 clinical and environmental isolates of waterborne and cutaneous Exophiala species were tested. The MICs and minimum effective concentrations for 90% of the strains tested (n = 106) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.25 μg/ml; micafungin, 1 μg/ml; voriconazole, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 8 μg/ml; amphotericin B, 16 μg/ml; fluconazole, 64 μg/ml. PMID:24100491

  3. Nocturnal activity of phlebotomine sandflies (Diptera: Psychodidae) in a cutaneous leishmaniasis focus in Chichaoua, Morocco.

    PubMed

    Guernaoui, S; Boussaa, S; Pesson, B; Boumezzough, A

    2006-02-01

    The nocturnal activity of phlebotomine sandflies (Diptera: Psychodidae) was studied "at an epidemic focus" on human cutaneous leishmaniasis due to Leishmania tropica Wright in Chichaoua province, in Morocco. Sandflies were collected using light and sticky-paper traps changed at 2-h intervals, inside and around houses, in August and October 2004. Overall, 633 sandflies, belonging to six species of Phlebotomus and three of Sergentomyia, were collected. Sandfly activity was nocturnal and higher at twilight. Several activity patterns were observed according to the species. Phlebotomus (Paraphlebotomus) sergenti Parrot, 1917, the suspected vector of L. tropica in this focus, was caught during each collection performed from 1900 to 0500 hours, the numbers of species caught peaked at 1900-2100 hours. There were seasonal variations of the nocturnal activity, which could be related to the variations in temperature and relative humidity.

  4. Characterization of platelet-activating factor-induced cutaneous edema and erythema in dogs.

    PubMed

    Watanabe, Miwa; Osada, Hironari; Shimizu, Sunao; Goto, Shun; Nagai, Makoto; Shirai, Junsuke; Sasaki, Kazuaki; Shimoda, Minoru; Itoh, Hiroshi; Ohmori, Keitaro

    2016-09-01

    OBJECTIVE To characterize platelet-activating factor (PAF)-induced edema and erythema in the skin of dogs and compare those reactions with histamine-induced cutaneous reactions. ANIMALS 6 healthy Beagles. PROCEDURES Experiments were performed at ≥ 2-week intervals. Each dog received ID injections (5 μg/site) of PAF C16, PAF C18, lyso-PAF, and histamine. Edema (mean diameter) and erythema scores (none, mild, moderate, or severe) were assessed 30 minutes after the injections. Dogs received ID injections of PAF and histamine each with various concentrations of WEB 2086 (PAF receptor antagonist) or underwent ID testing with PAF and histamine before and 3 hours after oral administration of cetirizine hydrochloride or prednisolone (at 2 doses each). RESULTS ID injections of PAF C16 and PAF C18, but not lyso-PAF, induced comparable levels of edema and erythema. The PAF-induced edema and erythema peaked at 30 minutes and lasted for 6 hours after the injection; histamine-induced edema and erythema peaked at 30 minutes and lasted for 3 hours after the injection. Edema sizes and erythema scores were significantly smaller and lower, respectively, for PAF than for histamine. The WEB 2086 inhibited PAF-induced but not histamine-induced edema and erythema. Cetirizine slightly, but significantly, repressed PAF-induced edema and erythema as well as histamine-induced cutaneous reactions. Prednisolone suppressed both PAF-induced and histamine-induced edema and erythema. CONCLUSIONS AND CLINICAL RELEVANCE In canine skin, the duration of PAF-induced inflammation was longer than that of histamine-induced inflammation. The PAF- and histamine-induced cutaneous reactions were effectively suppressed by oral administration of prednisolone. The importance of PAF in dogs with anaphylaxis and allergic disorders warrants further investigation. PMID:27580108

  5. Direct Vasodilators and Sympatholytic Agents.

    PubMed

    McComb, Meghan N; Chao, James Y; Ng, Tien M H

    2016-01-01

    Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of α-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications. PMID:26033778

  6. [A causative role of vasodilation in migraine? Yes].

    PubMed

    Lucas, C

    2014-01-01

    The role of vasodilatation in migraine pathophysiology is still debated with three hypotheses. The first is that vasodilatation of meningeal or intracranial arteries are the primary cause of pain. The second is that vasodilatation is secondary to neuronal activation, but can sustain or increase pain through sensitized perivascular nociceptors. The third is that vasodilatation is an epiphenomenon neither sufficient nor necessary for pain. We review in this part the arguments in favor of the old hypothesis that vasodilation is the primary cause of pain. Finally we show that there is a mild vasodilation during the attacks provoked by CGRP infusion.

  7. Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling.

    PubMed

    Johnson, John M; Yen, Tony C; Zhao, Kun; Kosiba, Wojciech A

    2005-04-01

    Previous work indicates that sympathetic nerves participate in the vascular responses to direct cooling of the skin in humans. We evaluated this hypothesis further in a four-part series by measuring changes in cutaneous vascular conductance (CVC) from forearm skin locally cooled from 34 to 29 degrees C for 30 min. In part 1, bretylium tosylate reversed the initial vasoconstriction (-14 +/- 6.6% control CVC, first 5 min) to one of vasodilation (+19.7 +/- 7.7%) but did not affect the response at 30 min (-30.6 +/- 9% control, -38.9 +/- 6.9% bretylium; both P < 0.05, P > 0.05 between treatments). In part 2, yohimbine and propranolol (YP) also reversed the initial vasoconstriction (-14.3 +/- 4.2% control) to vasodilation (+26.3 +/- 12.1% YP), without a significant effect on the 30-min response (-26.7 +/- 6.1% YP, -43.2 +/- 6.5% control; both P < 0.05, P > 0.05 between sites). In part 3, the NPY Y1 receptor antagonist BIBP 3226 had no significant effect on either phase of vasoconstriction (P > 0.05 between sites both times). In part 4, sensory nerve blockade by anesthetic cream (Emla) also reversed the initial vasoconstriction (-20.1 +/- 6.4% control) to one of vasodilation (+213.4 +/- 87.0% Emla), whereas the final levels did not differ significantly (-37.7 +/- 10.1% control, -37.2 +/- 8.7% Emla; both P < 0.05, P > 0.05 between treatments). These results indicate that local cooling causes cold-sensitive afferents to activate sympathetic nerves to release norepinephrine, leading to a local cutaneous vasoconstriction that masks a nonneurogenic vasodilation. Later, a vasoconstriction develops with or without functional sensory or sympathetic nerves.

  8. Amauromine, a new vasodilator. Taxonomy, isolation and characterization.

    PubMed

    Takase, S; Iwami, M; Ando, T; Okamoto, M; Yoshida, K; Horiai, H; Kohsaka, M; Aoki, H; Imanaka, H

    1984-11-01

    Amauromine is a new alkaloid with vasodilating activity obtained from the culture broth of Amauroascus sp. No. 6237. Its molecular formula was determined to be C32H36N4O2 on the basis of elementary analysis and high resolution mass spectroscopic measurement. It has low toxicity in mice. PMID:6511659

  9. Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma

    PubMed Central

    Lauenborg, Britt; Christensen, Louise; Ralfkiaer, Ulrik; Kopp, Katharina L.; Jønson, Lars; Dabelsteen, Sally; Bonefeld, Charlotte M.; Geisler, Carsten; Gjerdrum, Lise Mette R.; Zhang, Qian; Wasik, Mariusz A.; Ralfkiaer, Elisabeth; Ødum, Niels; Woetmann, Anders

    2015-01-01

    Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease. PMID:25915535

  10. Mechanisms of nitric oxide-mediated, neurogenic vasodilation in mesenteric resistance arteries of toad Bufo marinus.

    PubMed

    Jennings, Brett L; Donald, John A

    2010-03-01

    This study determined the role of nitric oxide (NO) in neurogenic vasodilation in mesenteric resistance arteries of the toad Bufo marinus. NO synthase (NOS) was anatomically demonstrated in perivascular nerves, but not in the endothelium. ACh and nicotine caused TTX-sensitive neurogenic vasodilation of mesenteric arteries. The ACh-induced vasodilation was endothelium-independent and was mediated by the NO/soluble guanylyl cyclase signaling pathway, inasmuch as the vasodilation was blocked by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and the NOS inhibitors N(omega)-nitro-l-arginine methyl ester and N(omega)-nitro-l-arginine. Furthermore, the ACh-induced vasodilation was significantly decreased by the more selective neural NOS inhibitor N(5)-(1-imino-3-butenyl)-l-ornithine. The nicotine-induced vasodilation was endothelium-independent and mediated by NO and calcitonin gene-related peptide (CGRP), inasmuch as pretreatment of mesenteric arteries with a combination of N(omega)-nitro-l-arginine and the CGRP receptor antagonist CGRP-(8-37) blocked the vasodilation. Clotrimazole significantly decreased the ACh-induced response, providing evidence that a component of the NO vasodilation involved Ca(2+)-activated K(+) or voltage-gated K(+) channels. These data show that NO control of mesenteric resistance arteries of toad is provided by nitrergic nerves, rather than the endothelium, and implicate NO as a potentially important regulator of gut blood flow and peripheral blood pressure. PMID:20071617

  11. Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients

    PubMed Central

    Harradine, Kelly A.; Ridd, Katie; Saunier, Elise F.; Clermont, Frederic F.; Perez-Losada, Jesus; Moore, Dan H.; Epstein, Ervin H.; Bastian, Boris C.; Akhurst, Rosemary J.

    2010-01-01

    Purpose Non-melanoma skin cancer incidence is enhanced over fifty fold in patients taking anti-rejection drugs (ARDs) following organ transplantation. Pre-clinical studies suggest that ARD treatment increases transforming growth factor β1 (TGF-β1) levels, which contribute to enhanced tumor susceptibility independent of the immune suppressive effects of ARDs. This study investigates whether TGF-β signaling is elevated in transplant patients. Experimental Design Immunohistochemical tissue microarray analysis was used to determine levels of TGF-β1, TGF-β2, TGF-β3, TβRII, and activated P-Smad2/3 and P-Smad1/5/8 which are phosphorylated directly by distinct TGF-β/BMP receptor complexes. We analyzed over 200 cutaneous lesions and adjacent non-lesional skin samples from 87 organ transplant recipients, and 184 cutaneous lesions and adjacent skin samples from 184 individuals who had never received ARDs. Results We found significantly higher levels of P-Smad2 in both non-lesional and lesional tissue from transplant recipients compared to those not exposed to ARDs (P ≤ 0.001). In contrast, P-Smad1/5/8, a marker of activation of the bone morphogenetic protein signaling pathway, was generally not expressed at higher levels in patients taking ARDs, including analysis of non-lesional skin, actinic keratoses, carcinoma in situ or squamous cell carcinoma, but was differentially expressed between keratoacanthoma from transplant recipients compared to those from non-transplant recipients (P ≤0.005). Conclusions Observation of elevated P-Smad2 levels in transplant recipients is consistent with the notion that elevated TGF-β signaling may contribute to malignancy in organ transplant recipients. Disparate P-Smad1/5/8 expression levels between keratoacanthoma from the two patients groups might reflect the distinct BMP-responsive cell of origin for this hair follicle-derived lesion. PMID:19671862

  12. Salivary vasodilators of Aedes triseriatus and Anopheles gambiae (Diptera: Culicidae).

    PubMed

    Ribeiro, J M; Nussenzveig, R H; Tortorella, G

    1994-09-01

    Salivary vasodilators of Aedes aegypti (L.) and Anopheles albimanus (Wiedemann) were characterized previously as a tachykinin peptide and a catechol oxidase/peroxidase activity, respectively. To verify whether these two different vasodilators also were found in other distantly related members of each mosquito genus, we characterized the vasodilators from A. triseriatus and A. gambiae. A. triseriatus salivary gland homogenates produced a reversible, endothelium dependent vasorelaxation of rabbit aortic rings constricted with norepinephrine, and contracted an isolated guinea pig ileum preparation. Additionally, the homogenate had no activity on both smooth muscle preparations when both tissues were desensitized previously by a large dose of substance P. Taken together, these assays suggest the presence of a salivary tachykinin in A. triseriatus. A. gambiae salivary gland homogenates induced a slow vasodilation on both endothelium intact and endotheliumless preparations of aortic rings. A. gambiae homogenates also displayed catechol oxidase and peroxidase activity against o-dianisidine but not against serotonin, indicating the presence of an enzyme system slightly different from A. albimanus. We conclude that the presence of salivary tachykinins or catechol/oxidase is not unique to A. aegypti or A. albimanus. PMID:7966179

  13. In vivo standardization of cutaneous bactericidal activity of antiseptics by using monoxenic hairless mice.

    PubMed Central

    Barc, M C; Tekaia, F; Bourlioux, P

    1989-01-01

    This study was designed to investigate the bactericidal activities of antiseptics on the cutaneous flora of hairless mice monoxenic to Staphylococcus epidermidis, Staphylococcus aureus, or Pseudomonas aeruginosa in vivo. A standardized method for testing such antiseptics to compare their bactericidal effectiveness in humans in described. Seven antiseptics belonging to seven different chemical groups (iodine derivatives, alcohols, mercury compounds, quaternary ammonium salts, biguanides, phenols, and carbanilides) were used as recommended by the manufacturers (conditions of contact or prolonged contact time followed by washing with distilled water). Germfree hairless mice were infected with various bacterial strains by gastric intubation, producing levels of about 10(3) CFU/cm2 of skin. The antiseptic under test was placed on the right or left side of the ventral region. The contralateral side served as a control. In order to standardize the method, a number of crucial parameters were carefully controlled: the amount of antiseptic applied, the area of skin treated, the duration of treatment, and the washing procedure. Skin samples were obtained by cutaneous biopsy, which effectively removed all the bacteria along with the sample. The bacterial populations were counted before and after application of the antiseptic. Reductions of between 0.5 and 1.9 log units were obtained; these are comparable to those observed in humans. The standardization of our procedure and the use of animals with a strictly controlled flora eliminated much of the variability and sources of error inherent in human studies. This model could be of value for the study of resistant bacterial strains responsible for nosocomial infections and for investigations of damaged skin. PMID:2506808

  14. Cerebral, subcortical, and cerebellar activation evoked by selective stimulation of muscle and cutaneous afferents: an fMRI study

    PubMed Central

    Wardman, Daniel L.; Gandevia, Simon C.; Colebatch, James G.

    2014-01-01

    Abstract We compared the brain areas that showed significant flow changes induced by selective stimulation of muscle and cutaneous afferents using fMRI BOLD imaging. Afferents arising from the right hand were studied in eight volunteers with electrical stimulation of the digital nerve of the index finger and over the motor point of the FDI muscle. Both methods evoked areas of significant activation cortically, subcortically, and in the cerebellum. Selective muscle afferent stimulation caused significant activation in motor‐related areas. It also caused significantly greater activation within the contralateral precentral gyrus, insula, and within the ipsilateral cerebellum as well as greater areas of reduced blood flow when compared to the cutaneous stimuli. We demonstrated separate precentral and postcentral foci of excitation with muscle afferent stimulation. We conclude, contrary to the findings with evoked potentials, that muscle afferents evoke more widespread cortical, subcortical, and cerebellar activation than do cutaneous afferents. This emphasizes the importance, for studies of movement, of matching the kinematic aspects in order to avoid the results being confounded by alterations in muscle afferent activation. The findings are consistent with clinical observations of the movement consequences of sensory loss and may also be the basis for the contribution of disturbed sensorimotor processing to disorders of movement. PMID:24771687

  15. No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis.

    PubMed

    Hettema, Martha E; Zhang, Dan; Stienstra, Ymkje; Smit, Andries J; Bootsma, Hendrika; Kallenberg, Cees G M

    2009-07-01

    The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud's phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc. PMID:19350343

  16. Integrins mediate mechanical compression-induced endothelium-dependent vasodilation through endothelial nitric oxide pathway.

    PubMed

    Lu, Xiao; Kassab, Ghassan S

    2015-09-01

    Cardiac and skeletal muscle contraction lead to compression of intramuscular arterioles, which, in turn, leads to their vasodilation (a process that may enhance blood flow during muscle activity). Although endothelium-derived nitric oxide (NO) has been implicated in compression-induced vasodilation, the mechanism whereby arterial compression elicits NO production is unclear. We cannulated isolated swine (n = 39) myocardial (n = 69) and skeletal muscle (n = 60) arteriole segments and exposed them to cyclic transmural pressure generated by either intraluminal or extraluminal pressure pulses to simulate compression in contracting muscle. We found that the vasodilation elicited by internal or external pressure pulses was equivalent; moreover, vasodilation in response to pressure depended on changes in arteriole diameter. Agonist-induced endothelium-dependent and -independent vasodilation was used to verify endothelial and vascular smooth muscle cell viability. Vasodilation in response to cyclic changes in transmural pressure was smaller than that elicited by pharmacological activation of the NO signaling pathway. It was attenuated by inhibition of NO synthase and by mechanical removal of the endothelium. Stemming from previous observations that endothelial integrin is implicated in vasodilation in response to shear stress, we found that function-blocking integrin α5β1 or αvβ3 antibodies attenuated cyclic compression-induced vasodilation and NOx (NO(-)2 and NO(-)3) production, as did an RGD peptide that competitively inhibits ligand binding to some integrins. We therefore conclude that integrin plays a role in cyclic compression-induced endothelial NO production and thereby in the vasodilation of small arteries during cyclic transmural pressure loading.

  17. Subthreshold vestibular reflex effects in seated humans can contribute to soleus activation when combined with cutaneous inputs.

    PubMed

    Thomas, Kristen E; Bent, Leah R

    2013-01-01

    The integration of vestibular and somatosensory information for the control of lower limb musculature remains elusive. To determine whether a subthreshold vestibular input influences the cutaneous evoked response, the isometric EMG activity in the posturally inactive soleus muscles of 13 healthy, seated subjects was collected. Vestibular afferents were activated using galvanic vestibular stimulation (GVS; 1.8-2.5mA, 500ms), while percutaneous electrical stimulation was delivered to the distal tibial nerve (11ms train of 3 × 1.0 ms pulses, 200Hz) to activate foot sole skin afferents. GVS elicited responses in soleus both independently and when combined with cutaneous stimulation. The responses to the combined sensory input showed an interaction between the two sensory modalities to influence muscle activation. Of note is the presence of significant muscle modulation in the combined condition, where subthreshold vestibular inputs altered the outcome of the cutaneous reflex response. This finding has implications for individuals with sensory deficiency. In the case of an absent or deficient sensory modality, balance protective reflexes to maintain postural equilibrium may be enhanced with targeted sensory augmentation.

  18. Inhibition of midbrain-evoked tonic and rhythmic motor activity by cutaneous stimulation in decerebrate cats.

    PubMed

    Beyaert, C A; Haouzi, P; Marchal, F

    2003-03-01

    The effect of mechanical and electrical stimulation of cervical cutaneous afferents was analysed on both the centrally induced tonic and rhythmic activities in hindlimb antagonist muscle nerves of 16 decerebrate paralysed cats. Electrical stimulation of dorsal midbrain evoked in the nerve to the tibialis anterior muscle (TAn) either rhythmic discharges (n=14), associated with tonic discharges in ten cats, or only tonic discharges (n=4). Centrally induced activity in the ipsilateral nerve to gastrocnemius medialis (GMn) occurred in fewer cats (n=12) and displayed similar patterns as in TAn. Manual traction of the scruff of the neck reduced the TAn tonic and rhythmic discharges (n=6) by 73% (P<0.05) and 71% (P<0.05), respectively, and reduced only the tonic component of GMn discharges (by 41%, n=3). Electrical stimulation (impulses 0.1-0.5 ms, 50 Hz) of cervical nerves belonging to C5 or C6 dermatomes, the intensity (0.4-4 mA) of which induced minimal inhibition of both TAn and GMn discharges, reduced significantly the tonic component of TAn discharges (by 39%, n=4). At higher intensities of electrical cervical nerve stimulation (2-6 mA) inducing maximal inhibitory effect, both tonic and rhythmic activities in TAn and GMn were both significantly reduced by, respectively, 81% and 94% in TAn (n=7), and by 49% and 43% in GMn (n=7). Electrical cervical nerve stimulation consistently reduced the isolated tonic discharge in TAn by 66% (n=4, P<0.05) and in GMn by 23% (n=3) when present. Thus the tonic component was more sensitive to inhibition than the rhythmic component of hindlimb muscle nerve activity.

  19. Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing.

    PubMed

    Jackson, Christopher J; Xue, Meilang; Thompson, Patrick; Davey, Ross A; Whitmont, Kaley; Smith, Susan; Buisson-Legendre, Nathalie; Sztynda, Tamara; Furphy, Louise J; Cooper, Alan; Sambrook, Philip; March, Lyn

    2005-01-01

    Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds. PMID:15953048

  20. Outbreak of Cutaneous Leishmaniasis in Peruvian Military Personnel Undertaking Training Activities in the Amazon Basin, 2010.

    PubMed

    Oré, Marianela; Sáenz, Eliana; Cabrera, Rufino; Sanchez, Juan F; De Los Santos, Maxy B; Lucas, Carmen M; Núñez, Jorge H; Edgel, Kimberly A; Sopan, Justino; Fernández, Jorge; Carnero, Andres M; Baldeviano, G Christian; Arrasco, Juan C; Graf, Paul C F; Lescano, Andres G

    2015-08-01

    Military personnel deployed to the Amazon Basin are at high risk for cutaneous leishmaniasis (CL). We responded to an outbreak among Peruvian Army personnel returning from short-term training in the Amazon, conducting active case detection, lesion sample collection, and risk factor assessment. The attack rate was 25% (76/303); the incubation period was 2-36 weeks (median = 8). Most cases had one lesion (66%), primarily ulcerative (49%), and in the legs (57%). Real-time polymerase chain reaction (PCR) identified Leishmania (Viannia) braziliensis (59/61 = 97%) and L. (V.) guyanensis (2/61 = 3%). Being male (risk ratio [RR] = 4.01; P = 0.034), not wearing long-sleeve clothes (RR = 1.71; P = 0.005), and sleeping in open rooms (RR = 1.80; P = 0.009) were associated with CL. Sodium stibogluconate therapy had a 41% cure rate, less than previously reported in Peru (~70%; P < 0.001). After emphasizing pre-deployment education and other basic prevention measures, trainees in the following year had lower incidence (1/278 = 0.4%; P < 0.001). Basic prevention can reduce CL risk in deployed militaries.

  1. Outbreak of Cutaneous Leishmaniasis in Peruvian Military Personnel Undertaking Training Activities in the Amazon Basin, 2010

    PubMed Central

    Oré, Marianela; Sáenz, Eliana; Cabrera, Rufino; Sanchez, Juan F.; De Los Santos, Maxy B.; Lucas, Carmen M.; Núñez, Jorge H.; Edgel, Kimberly A.; Sopan, Justino; Fernández, Jorge; Carnero, Andres M.; Baldeviano, G. Christian; Arrasco, Juan C.; Graf, Paul C. F.; Lescano, Andres G.

    2015-01-01

    Military personnel deployed to the Amazon Basin are at high risk for cutaneous leishmaniasis (CL). We responded to an outbreak among Peruvian Army personnel returning from short-term training in the Amazon, conducting active case detection, lesion sample collection, and risk factor assessment. The attack rate was 25% (76/303); the incubation period was 2–36 weeks (median = 8). Most cases had one lesion (66%), primarily ulcerative (49%), and in the legs (57%). Real-time polymerase chain reaction (PCR) identified Leishmania (Viannia) braziliensis (59/61 = 97%) and L. (V.) guyanensis (2/61 = 3%). Being male (risk ratio [RR] = 4.01; P = 0.034), not wearing long-sleeve clothes (RR = 1.71; P = 0.005), and sleeping in open rooms (RR = 1.80; P = 0.009) were associated with CL. Sodium stibogluconate therapy had a 41% cure rate, less than previously reported in Peru (∼ 70%; P < 0.001). After emphasizing pre-deployment education and other basic prevention measures, trainees in the following year had lower incidence (1/278 = 0.4%; P < 0.001). Basic prevention can reduce CL risk in deployed militaries. PMID:26078320

  2. Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation

    PubMed Central

    Allen, Barry W.; Stamler, Jonathan S.; Piantadosi, Claude A.

    2009-01-01

    The protected transport of nitric oxide (NO) by hemoglobin (Hb) links the metabolic activity of working tissue to the regulation of its local blood supply through hypoxic vasodilation. This physiologic mechanism is allosterically coupled to the O2 saturation of Hb and involves the covalent binding of NO to a cysteine residue in the β-chain of Hb (Cys β93) to form S-nitrosohemoglobin (SNO-Hb). Subsequent S-transnitrosation, the transfer of NO groups to thiols on the RBC membrane and then in the plasma, preserves NO vasodilator activity for delivery to the vascular endothelium. This SNO-Hb paradigm provides insight into the respiratory cycle and a new therapeutic focus for diseases involving abnormal microcirculatory perfusion. In addition, the formation of S-nitrosothiols in other proteins may regulate an array of physiological functions. PMID:19781996

  3. Impaired increases in skin sympathetic nerve activity contribute to age-related decrements in reflex cutaneous vasoconstriction

    PubMed Central

    Greaney, Jody L; Stanhewicz, Anna E; Kenney, W Larry; Alexander, Lacy M

    2015-01-01

    Abstract Reflex cutaneous vasoconstriction is impaired in older adults; however, the relative roles of altered skin sympathetic nerve activity (SSNA) and end-organ peripheral vascular responsiveness are unclear. We hypothesized that in older adults whole-body cooling would elicit a blunted SSNA response and cutaneous adrenergic responsiveness would be reduced. Twelve young adults (Y; 24 ± 1 years) and 12 older adults (O; 57 ± 2 years) participated in two protocols. In Protocol 1, SSNA (peroneal microneurography) and red cell flux in the affected dermatome (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (mean skin temperature (Tsk) 30.5°C; water-perfused suit). Mental stress was performed at mean Tsk 34.0°C (thermoneutral) and at 30.5°C. In Protocol 2, an intradermal microdialysis fibre was placed in the skin of the lateral calf for graded infusions of noradrenaline (norepinephrine) (NA; 10−12 to 10−2 m). Cutaneous vascular conductance (CVC = flux/mean arterial pressure) was expressed as a change from baseline (ΔCVCbase). Vasoconstriction was attenuated in O. SSNA increased significantly during cooling in Y (+184 ± 37%; P < 0.05) but not O (+51 ± 12%; P > 0.05). Mental stress at Tsk 30.5°C further increased SSNA in both groups. There was no age-related difference in adrenergic responsiveness to exogenous NA (logEC50: −6.41 ± 0.24 in Y, −6.37 ± 0.25 in O; P > 0.05). While the SSNA response to whole-body cooling is impaired with ageing, SSNA can be further increased by a non-thermoregulatory stimulus. Cutaneous adrenergic sensitivity is not reduced in O. These findings suggest that alterations in afferent signalling or central processing likely contribute to blunted SSNA responses to cooling and subsequent impairments in reflex cutaneous vasoconstriction in ageing. Key points The reduction in skin blood flow during whole-body cooling is impaired in healthy older adults. However, the

  4. Chronic nerve growth factor administration increases the peripheral exocytotic activity of capsaicin-sensitive cutaneous neurons.

    PubMed

    Bowles, Walter R; Sabino, Ma'lou; Harding-Rose, Catherine; Hargreaves, Kenneth M

    2006-08-01

    Nerve growth factor (NGF) plays an important role in inflammation and pain and has been suggested to regulate the responsiveness and sensitivity of nociceptive fibers. However, no study has evaluated whether chronic NGF alters the exocytotic capacity of peripheral terminals of peptidergic fibers. To test this hypothesis, rats were injected subcutaneously every other day with either murine recombinant NGF (mNGF; 1.0 mg/kg) or vehicle for 7 days; or mNGF (0.1 mg/kg), mNGF (1 mg/kg) or vehicle every other day for 13 days. Treatment of rats with NGF over a 13-day period produced a significant increase in capsaicin-evoked iCGRP release from isolated biopsies of hindpaw skin, as assessed by in vitro superfusion and RIA. This effect was dose-dependent and exhibited a temporal requirement, because the enhancement was only observed after 13 days of treatment and was not evident after 7 days of treatment. This NGF enhancement of capsaicin-evoked iCGRP release was not due solely to increases in peripheral iCGRP content since only the 1mg/kg dose of NGF elevated cutaneous pools of iCGRP, whereas both doses significantly increased capsaicin-evoked peptide release. Moreover, NGF also enhanced capsaicin-evoked thermal hyperalgesia under similar dose- and time-related conditions. Collectively, the chronic administration of NGF not only increases capsaicin-evoked hyperalgesia, but also significantly primes peripheral fibers to enhanced peptidergic exocytosis following activation of the capsaicin receptor. Collectively, these data are consistent with the hypothesis that persistently elevated NGF levels may contribute to enhanced neurogenic regulation of inflammatory and wound healing processes in injured tissue.

  5. Pregnancy-induced remodelling and enhanced endothelium-derived hyperpolarization-type vasodilator activity in rat uterine radial artery: transient receptor potential vanilloid type 4 channels, caveolae and myoendothelial gap junctions

    PubMed Central

    Senadheera, Sevvandi; Bertrand, Paul P; Grayson, T Hilton; Leader, Leo; Murphy, Timothy V; Sandow, Shaun L

    2013-01-01

    In pregnancy, the vasculature of the uterus undergoes rapid remodelling to increase blood flow and maintain perfusion to the fetus. The present study determines the distribution and density of caveolae, transient receptor potential vanilloid type 4 channels (TRPV4) and myoendothelial gap junctions, and the relative contribution of related endothelium-dependent vasodilator components in uterine radial arteries of control virgin non-pregnant and 20-day late-pregnant rats. The hypothesis examined is that specific components of endothelium-dependent vasodilator mechanisms are altered in pregnancy-related uterine radial artery remodelling. Conventional and serial section electron microscopy were used to determine the morphological characteristics of uterine radial arteries from control and pregnant rats. TRPV4 distribution and expression was examined using conventional confocal immunohistochemistry, and the contribution of endothelial TRPV4, nitric oxide (NO) and endothelium-derived hyperpolarization (EDH)-type activity determined using pressure myography with pharmacological intervention. Data show outward hypertrophic remodelling occurs in uterine radial arteries in pregnancy. Further, caveolae density in radial artery endothelium and smooth muscle from pregnant rats was significantly increased by ∼94% and ∼31%, respectively, compared with control, whereas caveolae density did not differ in endothelium compared with smooth muscle from control. Caveolae density was significantly higher by ∼59% on the abluminal compared with the luminal surface of the endothelium in uterine radial artery of pregnant rats but did not differ at those surfaces in control. TRPV4 was present in endothelium and smooth muscle, but not associated with internal elastic lamina hole sites in radial arteries. TRPV4 fluorescence intensity was significantly increased in the endothelium and smooth muscle of radial artery of pregnant compared with control rats by ∼2.6- and 5.5-fold

  6. Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms.

    PubMed

    Stanhewicz, Anna E; Alexander, Lacy M; Kenney, W Larry

    2013-10-01

    Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 ± 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer's solution, 2) 10 mM BH4, and 3) 20 mM N(G)-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1°C rise in oral temperature, mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (%CVCmax 28 mM sodium nitroprusside and local heat 43°C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 ± 2 pmol/ml vs. 3 h: 43.8 ± 3 pmol/ml; P < 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 ± 1 %CVCmax vs. sapropterin: 25 ± 4 %CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 ± 1 %CVCmax vs. BH4-treated: 24 ± 3 %CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to

  7. Hemoglobin Effects on Nitric Oxide Mediated Hypoxic Vasodilation.

    PubMed

    Rong, Zimei; Cooper, Chris E

    2016-01-01

    The brain responds to hypoxia with an increase in cerebral blood flow (CBF). However, such an increase is generally believed to start only after the oxygen tension decreases to a certain threshold level. Although many mechanisms (different vasodilator and different generation and metabolism mechanisms of the vasodilator) have been proposed at the molecular level, none of them has gained universal acceptance. Nitric oxide (NO) has been proposed to play a central role in the regulation of oxygen supply since it is a vasodilator whose production and metabolism are both oxygen dependent. We have used a computational model that simulates blood flow and oxygen metabolism in the brain (BRAINSIGNALS) to test mechanism by which NO may elucidate hypoxic vasodilation. The first model proposed that NO was produced by the enzyme nitric oxide synthase (NOS) and metabolized by the mitochondrial enzyme cytochrome c oxidase (CCO). NO production declined with decreasing oxygen concentration given that oxygen is a substrate for nitric oxide synthase (NOS). However, this was balanced by NO metabolism by CCO, which also declined with decreasing oxygen concentration. However, the NOS effect was dominant; the resulting model profiles of hypoxic vasodilation only approximated the experimental curves when an unfeasibly low K m for oxygen for NOS was input into the model. We therefore modified the model such that NO generation was via the nitrite reductase activity of deoxyhemoglobin instead of NOS, whilst keeping the metabolism of NO by CCO the same. NO production increased with decreasing oxygen concentration, leading to an improved reproduction of the experimental CBF versus PaO2 curve. However, the threshold phenomenon was not perfectly reproduced. In this present work, we incorporated a wider variety of oxygen dependent and independent NO production and removal mechanisms. We found that the addition of NO removal via oxidation to nitrate mediated by oxyhemoglobin resulted in the

  8. Cutaneous zygomycosis.

    PubMed

    Bonifaz, Alexandro; Vázquez-González, Denisse; Tirado-Sánchez, Andrés; Ponce-Olivera, Rosa María

    2012-01-01

    Cutaneous zygomycosis is a fungal infection caused by zygomycetes that affects the skin. It occurs in uncontrolled diabetic patients and immunosuppressed individuals. It has 2 clinical forms: primary cutaneous zygomycosis and secondary cutaneous zygomycosis. The first is characterized by necrotic lesions and the fungus is usually inoculated by trauma. If diagnosed early, it generally has a good prognosis. Secondary zygomycosis is usually a complication and extension of the rhinocerebral variety that starts as a palpebral fistula and progresses to a necrotic lesion with a poor prognosis. The diagnosis is made by identification of the fungus by direct KOH examination, culture, and biopsy. Treatment for the primary disease is surgical debridement plus amphotericin B. The secondary type is treated with amphotericin B and/or posaconazole.

  9. Cutaneous sarcoidosis.

    PubMed

    Wilson, N J; King, C M

    1998-11-01

    Sarcoidosis is a multi-organ granulomatous disorder of unknown cause. Skin sarcoidosis occurs in about 25% of patients with systemic disease and may also arise in isolation. A wide range of clinical presentations of cutaneous sarcoidosis is recognised. The diagnosis rests on the presence of non-caseating granulomas on skin biopsy and the exclusion of other granulomatous skin disease. The treatment and overall prognosis of cutaneous sarcoidosis is primarily dependent on the degree of systemic involvement. In patients with aggressive disease limited to the skin immunosuppressive therapy may be indicated.

  10. Vasodilator effects of adenosine on retinal arterioles in streptozotocin-induced diabetic rats.

    PubMed

    Nakazawa, Taisuke; Mori, Asami; Saito, Maki; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2008-02-01

    Adenosine is a potent vasodilator of retinal blood vessels and is implicated to be a major regulator of retinal blood flow during metabolic stress, but little is known about the impact of diabetes on the role of adenosine in regulation of retinal hemodynamics. Therefore, we examined how diabetes affects adenosine-induced vasodilation of retinal arterioles. Male Wistar rats were treated with streptozotocin (80 mg/kg, intraperitoneally), and experiments were performed 6-8 weeks later. Rats were treated with tetrodotoxin (50 microg/kg, intravenously [i.v.]) to eliminate any nerve activity and prevent movement of the eye and infused with methoxamine continuously to maintain adequate systemic circulation. Fundus images were captured with a digital camera that was equipped with a special objective lens, and diameters of retinal arterioles were measured. Adenosine increased diameters of retinal arterioles and decreased systemic blood pressure. These responses were significantly attenuated by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (30 mg/kg, i.v.) and the adenosine triphosphate-dependent K+ (K(ATP)) channel blocker glibenclamide (20 mg/kg, i.v.). The depressor responses to adenosine were reduced in diabetic rats, whereas diabetes did not alter vasodilation of retinal arterioles to adenosine. In contrast, both depressor response and vasodilation of retinal arteriole to acetylcholine were reduced in diabetic rats. The retinal vasodilator responses to adenosine and acetylcholine observed in diabetic rats were diminished by N(G)-nitro-L-arginine methyl ester. There were no differences in the responses to pinacidil, a K(ATP) channel opener, between the diabetic and nondiabetic rats. These results suggest that both the activation of nitric oxide synthase and opening of K(ATP) channels contribute to the vasodilator effects of adenosine in rats in vivo. However, diabetes has no significant impact on the vasodilation mediated by these mechanisms in

  11. [Niacin deficiency and cutaneous immunity].

    PubMed

    Ikenouchi-Sugita, Atsuko; Sugita, Kazunari

    2015-01-01

    Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity. PMID:25765687

  12. [Niacin deficiency and cutaneous immunity].

    PubMed

    Ikenouchi-Sugita, Atsuko; Sugita, Kazunari

    2015-01-01

    Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

  13. Rapid and Slow Nitric Oxide Responses During Conducted Vasodilation in the In Vivo Intestine and Brain Cortex Microvasculatures

    PubMed Central

    Bohlen, H. Glenn

    2011-01-01

    Conduction of arteriolar vasodilation is initiated by activation of nitric oxide (NO) mechanisms, but dependent on conduction of hyperpolarization. Most studies have used brief (<1 sec) activation of the initial vasodilation to evaluate the fast conduction processes. However, most arteriolar mechanisms involving NO production persist for minutes. In this study, fast and slower components of arteriolar conduction in the in vivo rat brain and small intestine were compared using 3 minute stimulation of NO dependent vasodilation and measurement of [NO] at the distal sites. Within 10-15 seconds, both vasculatures had a rapidly conducted vasodilation and dilation at distance had a fast but small [NO] component. A slower but larger distal vasodilation occurred after 60-90 seconds in the intestine, but not the brain, and was associated with a substantial increase in [NO]. This slowly developed dilation appeared to be caused by flow mediated responses of larger arterioles as smaller arterioles dilated to lower downstream resistance. These results indicate while the intestinal and cerebral arterioles have a fast conducted vasodilation system, the intestinal arterioles also have a slower but larger dilation of major arterioles that is NO related and dependent on the conduction of vasodilation between small arterioles. PMID:22098301

  14. Maternal vasodilation in pregnancy: the emerging role of relaxin

    PubMed Central

    2011-01-01

    Pregnancy is a unique physiological condition of profound maternal renal and systemic vasodilation. Our goal has been to unveil the reproductive hormones mediating this remarkable vasodilatory state and the underlying molecular mechanisms. In addition to advancing our knowledge of pregnancy physiology, reaching this goal may translate into therapeutics for pregnancy pathologies such as preeclampsia and for diseases associated with vasoconstriction and arterial stiffness in nonpregnant women and men. An emerging player is the 6 kDa corpus luteal hormone relaxin, which circulates during pregnancy. Relaxin administration to rats and humans induces systemic and renal vasodilation regardless of sex, thus mimicking the pregnant condition. Immunoneutralization or elimination of the source of circulating relaxin prevents renal and systemic vasodilation in midterm pregnant rats. Infertile women who become pregnant by donor eggs (IVF with embryo transfer) lack a corpus luteum and circulating relaxin, and they show a markedly subdued gestational increase in glomerular filtration rate. These data implicate relaxin as one of the vasodilatory reproductive hormones of pregnancy. There are different molecular mechanisms underlying the so-called rapid and sustained vasodilatory actions of relaxin. The former is mediated by Gαi/o protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase, the latter by vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. The gelatinases, in turn, hydrolyze big endothelin (ET) at a gly-leu bond to form ET1–32, which activates the endothelial ETB receptor/nitric oxide vasodilatory pathway. PMID:21613576

  15. Cutaneous Horn

    MedlinePlus

    ... fair-skinned individuals with a history of significant sun exposure. Signs and Symptoms A cutaneous horn most often ... radiation therapy. Trusted Links MedlinePlus: Skin Conditions MedlinePlus: Sun Exposure References Bolognia, Jean L., ed. Dermatology , pp.1715. ...

  16. Sex and vasodilator responses to hypoxia at rest and during exercise.

    PubMed

    Casey, Darren P; Shepherd, John R A; Joyner, Michael J

    2014-04-01

    In humans, β-adrenergic receptor activation causes a substantial portion of hypoxic vasodilation in skeletal muscle at rest and during forearm exercise. Recent evidence suggests that β-adrenergic receptors are either more sensitive or upregulated in young women vs. men. Therefore, we examined whether sex influences hypoxic vasodilation in 31 young subjects (15 women/16 men; 26 ± 1 yr). We also examined whether potential sex-related differences existed in a group of older adults (6 women/5 men; 61 ± 2 yr). All subjects performed forearm exercise at 10 and 20% of maximum under normoxic and hypoxic [80% arterial O2 saturation (So2)] conditions. Forearm vascular conductance (FVC; ml · min(-1) · 100 mmHg(-1)) was calculated from blood flow (ml/min) and blood pressure (mmHg). At rest, young women demonstrated a greater vasodilator response to hypoxia compared with men (39 ± 12 vs. 13 ± 6%, P < 0.05). The absolute compensatory vasodilator response (hypoxic FVC-normoxic FVC) during exercise was similar between sexes, but the relative change was greater in young women at 10% (28 ± 5 vs. 17 ± 3%, P < 0.05) and 20% exercise (29 ± 4% vs. 15 ± 3%, P < 0.01). Additionally, the absolute changes in vasodilation after normalizing the response to forearm volume or workload were greater in young women during exercise (P < 0.05). Interestingly, the compensatory vasodilator responses between older women and men were similar at 10 and 20% exercise, regardless of whether the response is expressed as absolute, relative, or absolute change normalized for forearm volume or workload (P = 0.054-0.97). Our data suggest that the compensatory vasodilator response to hypoxic exercise is greater in young women compared with men. However, sex-specific differences appear to be lost with aging.

  17. Influence of the Plantar Cutaneous Information in Postural Regulation Depending on the Age and the Physical Activity Status

    PubMed Central

    Maitre, Julien; Paillard, Thierry P.

    2016-01-01

    The aim was to compare the balance control adaptation to different supporting surfaces depending on the age and the physical activity status. The balance control of two groups of young (n = 17) and old (n = 17) participants who practiced regular physical activity (active groups) and two groups of young (n = 17) and old (n = 17) participants who did not practice physical activity (non-active groups) was compared on a firm surface and on a foam surface. The parameters of the center of foot pressure (COP) displacement were compared between the groups. The two older groups were more disturbed than the two younger groups when they stood on a foam surface and there was no difference between active and non-active groups. This result may be linked to the structural and functional involutions of the plantar cutaneous sole and foot that occur with age advancement. The participants’ physical activity practice might be not specific enough to generate a more efficient postural adaption to the foam condition for the active groups than the non-active groups within their respective age groups. PMID:27582699

  18. Influence of the Plantar Cutaneous Information in Postural Regulation Depending on the Age and the Physical Activity Status.

    PubMed

    Maitre, Julien; Paillard, Thierry P

    2016-01-01

    The aim was to compare the balance control adaptation to different supporting surfaces depending on the age and the physical activity status. The balance control of two groups of young (n = 17) and old (n = 17) participants who practiced regular physical activity (active groups) and two groups of young (n = 17) and old (n = 17) participants who did not practice physical activity (non-active groups) was compared on a firm surface and on a foam surface. The parameters of the center of foot pressure (COP) displacement were compared between the groups. The two older groups were more disturbed than the two younger groups when they stood on a foam surface and there was no difference between active and non-active groups. This result may be linked to the structural and functional involutions of the plantar cutaneous sole and foot that occur with age advancement. The participants' physical activity practice might be not specific enough to generate a more efficient postural adaption to the foam condition for the active groups than the non-active groups within their respective age groups. PMID:27582699

  19. Role of Vasodilator Testing in Pulmonary Hypertension.

    PubMed

    Sharma, Abhishek; Obiagwu, Chukwudi; Mezue, Kenechukwu; Garg, Aakash; Mukherjee, Debabrata; Haythe, Jennifer; Shetty, Vijay; Einstein, Andrew J

    2016-01-01

    Pulmonary hypertension is clinically defined by a mean pulmonary artery (PA) pressure of 25mm Hg or more at rest, as measured by right heart catheterization. To identify patients who are likely to have a beneficial response to calcium channel blockers (CCBs) and therefore a better prognosis, acute vasodilator testing should be performed in patients in certain subsets of pulmonary arterial hypertension (PAH). A near normalization of pulmonary hemodynamics is needed before patients can be considered for therapy with CCBs. Intravenous adenosine, intravenous epoprostenol, inhaled nitric oxide, or inhaled iloprost are the standard agents used for vasoreactivity testing in patients with idiopathic PAH. In this review we describe the various aspects of vasodilator testing including the rationale, pathophysiology and agents used in the procedure.

  20. The Gatekeepers in the Mouse Ophthalmic Artery: Endothelium-Dependent Mechanisms of Cholinergic Vasodilation

    PubMed Central

    Manicam, Caroline; Staubitz, Julia; Brochhausen, Christoph; Grus, Franz H.; Pfeiffer, Norbert; Gericke, Adrian

    2016-01-01

    Cholinergic regulation of arterial luminal diameter involves intricate network of intercellular communication between the endothelial and smooth muscle cells that is highly dependent on the molecular mediators released by the endothelium. Albeit the well-recognized contribution of nitric oxide (NO) towards vasodilation, the identity of compensatory mechanisms that maintain vasomotor tone when NO synthesis is deranged remain largely unknown in the ophthalmic artery. This is the first study to identify the vasodilatory signalling mechanisms of the ophthalmic artery employing wild type mice. Acetylcholine (ACh)-induced vasodilation was only partially attenuated when NO synthesis was inhibited. Intriguingly, the combined blocking of cytochrome P450 oxygenase (CYP450) and lipoxygenase (LOX), as well as CYP450 and gap junctions, abolished vasodilation; demonstrating that the key compensatory mechanisms comprise arachidonic acid metabolites which, work in concert with gap junctions for downstream signal transmission. Furthermore, the voltage-gated potassium ion channel, Kv1.6, was functionally relevant in mediating vasodilation. Its localization was found exclusively in the smooth muscle. In conclusion, ACh-induced vasodilation of mouse ophthalmic artery is mediated in part by NO and predominantly via arachidonic acid metabolites, with active involvement of gap junctions. Particularly, the Kv1.6 channel represents an attractive therapeutic target in ophthalmopathologies when NO synthesis is compromised. PMID:26831940

  1. Cutaneous Myiasis.

    PubMed

    Solomon, Michal; Lachish, Tamar; Schwartz, Eli

    2016-09-01

    Myiasis is defined as the infestation of live vertebrates, either humans or animals, with dipterous larvae. Many organs can be infested by these larvae with cutaneous myiasis being the most common form. Cutaneous myiasis can be divided into three categories: localized furuncular myiasis, migratory myiaisis and wound myiasis, which occurs when fly larvae infest the open wounds of the host. Human myiasis has worldwide distribution, with more species and a heavier burden in tropical and subtropical countries. In recent years with increased travel to the tropics, myiasis has become common in returning travelers from these regions, Furuncular myiasis, mainly Dermatobia homonis becomes the most common form seen among them. Treatment is based on full extraction of the larva and no antibiotic treatment is needed. Understanding the mode of transmission of each type of myiasis may help to prevent the infestation. PMID:27443558

  2. Cutaneous sarcoidosis.

    PubMed Central

    Wilson, N. J.; King, C. M.

    1998-01-01

    Sarcoidosis is a multi-organ granulomatous disorder of unknown cause. Skin sarcoidosis occurs in about 25% of patients with systemic disease and may also arise in isolation. A wide range of clinical presentations of cutaneous sarcoidosis is recognised. The diagnosis rests on the presence of non-caseating granulomas on skin biopsy and the exclusion of other granulomatous skin disease. The treatment and overall prognosis of cutaneous sarcoidosis is primarily dependent on the degree of systemic involvement. In patients with aggressive disease limited to the skin immunosuppressive therapy may be indicated. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:10197194

  3. Cutaneous ectoparasites.

    PubMed

    Nordlund, James J

    2009-01-01

    Parasites inhabit many places in the world. Some of these can inhabit the human skin or body. Many of these have been eradicated in the developed countries but persist in some tropical environments that are fun places to visit. Visitors can bring such parasites home with them such as scabies, cutaneous larva migrans, tungiasis and myiasis. Their clinical manifestations and treatment are presented for physicians evaluating and treating travelers from exotic places. PMID:19889135

  4. Improvement of Acetylcholine-Induced Vasodilation by Acute Exercise in Ovariectomized Hypertensive Rats.

    PubMed

    Cheng, Tsung-Lin; Lin, Yi-Yuan; Su, Chia-Ting; Hu, Chun-Che; Yang, Ai-Lun

    2016-06-30

    Postmenopause is associated with the development of cardiovascular disease, such as hypertension. However, limited information is available regarding effects of exercise on cardiovascular responses and its underlying mechanisms in the simultaneous postmenopausal and hypertensive status. We aimed to investigate whether acute exercise could enhance vasodilation mediated by acetylcholine (ACh) and sodium nitroprusside (SNP) in ovariectomized hypertensive rats. The fifteen-week-old female spontaneously hypertensive rats (SHR) were bilaterally ovariectomized, at the age of twenty-four weeks, and randomly divided into sedentary (SHR-O) and acute exercise (SHR-OE) groups. Age-matched WKY rats were used as the normotensive control group. The SHR-OE group ran on a motor-driven treadmill at a speed of 24 m/min for one hour in a moderate-intensity program. Following a single bout of exercise, rat aortas were isolated for the evaluation of the endothelium-dependent (ACh-induced) and endothelium-independent (SNP-induced) vasodilation by the organ bath system. Also, the serum levels of oxidative stress and antioxidant activities, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase, were measured after acute exercise among the three groups. We found that acute exercise significantly enhanced the ACh-induced vasodilation, but not the SNP-induced vasodilation, in ovariectomized hypertensive rats. This increased vasodilation was eliminated after the inhibition of nitric oxide synthase (NOS). Also, the activities of SOD and catalase were significantly increased after acute exercise, whereas the level of MDA was comparable among the three groups. These results indicated that acute exercise improved the endothelium-dependent vasodilating response to ACh through the NOS-related pathway in ovariectomized hypertensive rats, which might be associated with increased serum antioxidant activities.

  5. [The use of arteriography in the pharmacological study of a vasodilator substance].

    PubMed

    Bonnin, A; d'Izarn, J J; Collard, M; Viallet, J F; Viallet, P; Cluzan, R; Ledoux-Lebard, G

    1977-03-01

    The administration of a vasodilator substance is followed by the development of a higher contrast gradient in a given film in comparison with a reference X-ray carried out in the same subject under comparable technical conditions. Comparative densitometric measurement of the contrast gradient in the two successive arteriographic series, one with and one without the injection, arterial or venous, of a vasodilator substance (Couramine-Rutine) represents a valuable method for the study in man of the action of the substance in a visceral territory. The present study was limited to the kedney (79 cases), ans the territory of the superior mesenteric (46 cases). The absence of any densitometric difference between the two renal series at too low doses of vasodilator substance leads to the supposition of the possibility of a threshold dose of pharmacological activity.

  6. Chronic Compression of the Dorsal Root Ganglion Enhances Mechanically Evoked Pain Behavior and the Activity of Cutaneous Nociceptors in Mice

    PubMed Central

    Wang, Tao; Hurwitz, Olivia; Shimada, Steven G.; Qu, Lintao; Fu, Kai; Zhang, Pu; Ma, Chao; LaMotte, Robert H.

    2015-01-01

    Radicular pain in humans is usually caused by intraforaminal stenosis and other diseases affecting the spinal nerve, root, or dorsal root ganglion (DRG). Previous studies discovered that a chronic compression of the DRG (CCD) induced mechanical allodynia in rats and mice, with enhanced excitability of DRG neurons. We investigated whether CCD altered the pain-like behavior and also the responses of cutaneous nociceptors with unmyelinated axons (C-fibers) to a normally aversive punctate mechanical stimulus delivered to the hairy skin of the hind limb of the mouse. The incidence of a foot shaking evoked by indentation of the dorsum of foot with an aversive von Frey filament (tip diameter 200 μm, bending force 20 mN) was significantly higher in the foot ipsilateral to the CCD surgery as compared to the contralateral side on post-operative days 2 to 8. Mechanically-evoked action potentials were electrophysiologically recorded from the L3 DRG, in vivo, from cell bodies visually identified as expressing a transgenically labeled fluorescent marker (neurons expressing either the receptor MrgprA3 or MrgprD). After CCD, 26.7% of MrgprA3+ and 32.1% MrgprD+ neurons exhibited spontaneous activity (SA), while none of the unoperated control neurons had SA. MrgprA3+ and MrgprD+ neurons in the compressed DRG exhibited, in comparison with neurons from unoperated control mice, an increased response to the punctate mechanical stimuli for each force applied (6, 20, 40, and 80 mN). We conclude that CCD produced both a behavioral hyperalgesia and an enhanced response of cutaneous C-nociceptors to aversive punctate mechanical stimuli. PMID:26356638

  7. Sodium humate accelerates cutaneous wound healing by activating TGF-β/Smads signaling pathway in rats

    PubMed Central

    Ji, Yuanyuan; Zhang, Aijun; Chen, Xiaobin; Che, Xiaoxia; Zhou, Kai; Wang, Zhidong

    2016-01-01

    Sodium humate (HA-Na) has been topically used as a wound healing and anti-inflammatory agent in folk medicine. In the present study, HA-Na was investigated for cutaneous wound healing in Sprague–Dawley rats. HA-Na solution (1.0%, w/v) was topically administered to rats undergoing excision wound models. Healing was assessed with a recombinant bovine basic fibroblast growth factor for external use as positive control. Wound healing rates were calculated on Day 3, 6, 9, 14 and 21 after injury, and tissues were also harvested after the same intervals for histological analysis. In addition, tissue hydroxyproline levels were measured. Furthermore, mRNA levels and protein expressions of transforming growth factor-β1, 2, 3 (TGF-β1, 2, 3) were determined by RT-PCR and western blot. Protein expression levels of Smad-2, -3, -4 and -7 were also detected by western blot. Our study demonstrates that HA-Na has the capacity to promote wound healing in rats via accelerated wound contraction and increased hydroxyproline content. More importantly, these wound healing effects of HA-Na might be mediated through the TGF-β/Smad signaling pathway. HA-Na may be an effective agent for enhanced wound healing. PMID:27006897

  8. Evaluation of cutaneous wound healing activity of Malva sylvestris aqueous extract in BALB/c mice

    PubMed Central

    Afshar, Mohammad; Ravarian, Behdad; Zardast, Mahmoud; Moallem, Seyed Adel; Fard, Mohammad Hasanpour; Valavi, Masoomeh

    2015-01-01

    Objective(s): The aim of this study was to evaluate the effects of Malva sylvestris aqueous extract on cutaneous wound healing in BALB/c mice. Materials and Methods: Twenty seven male BALB/c mice (2.5 months of age) were used. A cut wound (superficial fascia depth) was made locally. The mice were then divided into three groups: the first, second and third groups received topical administration of M. sylvestris 1% aqueous extract, silver sulfadiazine topical cream and cold cream (positive and negative control groups), respectively. On days 4, 7 and 10 excisional biopsies were performed and wound healing was evaluated histopathologically. The data were analyzed by the ANOVA and Tukey statistical tests. Results: On days 4 and 7, the numbers of inflammatory cells in the silver sulfadiazine and M. sylvestris-treated groups were significantly lower than the control group and keratinization at the edges of the wound in both groups was significantly higher than the control group. On the tenth day of the study, the Malva-treated mice showed better healing features and less fibrosis and scar formation, and also fewer hair follicles were damaged in this group. On the tenth day of the study, the numbers of inflammatory cells in M. sylvestris and silver sulfadiazine-treated groups were significantly lower than the control group. Conclusion: The present study supports the beneficial effects of M. sylvestris on the wound healing process and suggests a potential clinical application. PMID:26221487

  9. Selected Cutaneous Disorders in Athletes

    PubMed Central

    Walker, James D.

    1988-01-01

    The author discusses selected cutaneous diseases seen in the athlete. These diseases may be caused by interaction with the elements, the playing surface, other athletes, or the clothing or equipment worn during sport. All of these dermatological conditions are relatively common, but the physically active individual can suffer from these maladies and their complications more often than the inactive person. The emphasis in caring for the participant is on prevention, early recognition and practical aspects of management of cutaneous diseases. PMID:21264034

  10. Nitrite Regulates Hypoxic Vasodilation via Myoglobin–Dependent Nitric Oxide Generation

    PubMed Central

    Totzeck, Matthias; Hendgen-Cotta, Ulrike B.; Luedike, Peter; Berenbrink, Michael; Klare, Johann P.; Steinhoff, Heinz-Juergen; Semmler, Dominik; Shiva, Sruti; Williams, Daryl; Kipar, Anja; Gladwin, Mark T.; Schrader, Juergen; Kelm, Malte; Cossins, Andrew R.; Rassaf, Tienush

    2012-01-01

    Background Hypoxic vasodilation is a physiological response to low oxygen (O2) tension that increases blood supply to match metabolic demands. While this response has been characterized for more than 100 years, the underlying hypoxic sensing and effector signaling mechanisms remain uncertain. We have shown that deoxygenated myoglobin (deoxyMb) in the heart can reduce nitrite to nitric oxide (NO˙) and thereby contribute to cardiomyocyte NO˙ signaling during ischemia. Based on recent observations that Mb is expressed in the vasculature of hypoxia-tolerant fish, we hypothesized that endogenous nitrite may contribute to physiological hypoxic vasodilation via reactions with vascular Mb to form NO˙. Methods and Results We here show that Mb is expressed in vascular smooth muscle and contributes significantly to nitrite-dependent hypoxic vasodilation in vivo and ex vivo. The generation of NO˙ from nitrite reduction by deoxyMb activates canonical soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathways. In vivo and ex vivo vasodilation responses, the reduction of nitrite to NO˙ and the subsequent signal transduction mechanisms were all significantly impaired in mice without myoglobin (Mb−/−). Hypoxic vasodilation studies in Mb, endothelial and inducible NO synthase knockout models (eNOS−/−, iNOS−/−) suggest that only Mb contributes to systemic hypoxic vasodilatory responses in mice. Conclusions Endogenous nitrite is a physiological effector of hypoxic vasodilation. Its reduction to NO˙ via the heme globin Mb enhances blood flow and matches O2 supply to increased metabolic demands under hypoxic conditions. PMID:22685116

  11. Cytotoxic cell involvement in human cutaneous leishmaniasis: assessments in active disease, under therapy and after clinical cure.

    PubMed

    Cunha, C F; Ferraz, R; Pimentel, M I F; Lyra, M R; Schubach, A O; Da-Cruz, A M; Bertho, A L

    2016-04-01

    Cutaneous leishmaniasis (CL) is an important public health issue worldwide. The control of Leishmania infection depends on cellular immune mechanisms, and the inflammatory response may contribute to pathogenesis. A beneficial role of CD8(+) T lymphocytes has been proposed; nevertheless, other studies suggest a cytotoxic role of CD8(+) T lymphocytes involved in tissue damage, showing controversial role of these cells. The goal of the current study was to understand the immunopathology of CL and determine the profile of cytotoxic cells--such as CD4(+) T, natural killer and natural killer T cells--that might be involved in triggering immunological mechanisms, and may lead to cure or disease progression. The frequencies of cytotoxic cell populations in peripheral blood, obtained from patients with active disease, during treatment and after clinical healing, were assessed by flow cytometry. Cytotoxicity could not be related to a deleterious role in Leishmania braziliensis infection, as patients with active CL showed similar percentages of degranulation to healthy individuals (HI). Cured patients exhibited a lower percentage of degranulating cells, which may be due to a downregulation of the immune response. The understanding of the immunopathological mechanisms involved in CL and the commitment of cytotoxic cells enables improvements in therapeutic strategies.

  12. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

    PubMed Central

    Willerslev-Olsen, Andreas; Krejsgaard, Thorbjørn; Lindahl, Lise M.; Litvinov, Ivan V.; Fredholm, Simon; Petersen, David L.; Nastasi, Claudia; Gniadecki, Robert; Mongan, Nigel P.; Sasseville, Denis; Wasik, Mariusz A.; Bonefeld, Charlotte M.; Geisler, Carsten; Woetmann, Anders; Iversen, Lars; Kilian, Mogens; Koralov, Sergei B.

    2016-01-01

    Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient–derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk–dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis. PMID:26738536

  13. Cutaneous angiomyolipoma.

    PubMed

    Val-Bernal, J F; Mira, C

    1996-08-01

    Extrarenal angiomyolipomas are rare lesions. An angiomyolipoma located on the right ear lobe in a 49-year-old man is reported. Pathologic examination showed a well-circumscribed subcutaneous nodule, 2 cm in diameter. The components of the tumor were confirmed by immunohistochemistry. Reactivity for HMB-45 was negative. A review of the twelve published cases, including the present, reveals that the patients age ranged from 33 to 77 years (mean 53.6), the male/female ratio was 11.1. The tumors were solitary, asymptomatic, noninvasive, located most commonly in acral skin or on the ear. The clinical impression is that of a cyst, a lipoma or a vascular tumor. Signs of tuberous sclerosis were absent in all cases. In contrast to the renal form, the cutaneous angiomyolipoma is a tumor differing in sex predominance, clinical associations, circumscription, solitariness, and HMB-45 immunoreactivity. Distinction from other mesenchymal lesions depends on recognition of traditional histologic criteria.

  14. Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

    PubMed Central

    Crecelius, Anne R.; Kirby, Brett S.; Richards, Jennifer C.; Garcia, Leora J.; Voyles, Wyatt F.; Larson, Dennis G.; Luckasen, Gary J.

    2011-01-01

    ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n = 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthase [NG-monomethyl-l-arginine (l-NMMA)] and cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P = 0.22–0.99). In protocol 2 (n = 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n = 8)- and high-dose (n = 8) ATP for 5 min evoked a significant increase in FVC above baseline (low = 198 ± 24%; high = 706 ± 79%). Infusion of l-NMMA and ketorolac together reduced steady-state FVC during both low- and high-dose ATP (P < 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (ΔFVC = −31 ± 11%)- and high-dose ATP (ΔFVC −25 ± 11%; P = 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular

  15. Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries.

    PubMed

    Chen, Mei-Fang; Lai, Su-Yu; Kung, Po-Cheng; Lin, Yo-Cheng; Yang, Hui-I; Chen, Po-Yi; Liu, Ingrid Y; Lua, Ahai Chang; Lee, Tony Jer-Fu

    2016-08-15

    The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O2 demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp, and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine>methamphetamine>hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation

  16. Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles

    PubMed Central

    Hein, Travis W.; Xu, Wenjuan; Xu, Xin; Kuo, Lih

    2016-01-01

    Purpose Hyperglycemia, a hallmark of diabetes mellitus, is associated with retinal inflammation and impairment of endothelium-dependent nitric oxide (NO)–mediated dilation of retinal arterioles. However, molecular mechanisms involved in this diminished endothelial vasodilator function remain unclear. We examined whether inflammatory stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38, contribute to retinal arteriolar dysfunction during exposure to acute and chronic hyperglycemia. Methods Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks; chronic hyperglycemia, 471 ± 23 mg/dL) or age-matched control pigs (euglycemia, 79 ± 5 mg/dL), and then cannulated and pressurized for vasoreactivity study. For acute hyperglycemia study, vessels from nondiabetic pigs were exposed intraluminally to high glucose (25 mM ≈ 450 mg/dL) for 2 hours, and normal glucose (5 mM ≈ 90 mg/dL) served as the control. Results Endothelium-dependent vasodilation to bradykinin was reduced in a similar manner after exposure to acute or chronic hyperglycemia. Administration of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) nearly abolished vasodilations either in control (euglycemia and normal glucose) or hyperglycemic (acute and chronic) vessels. Treatment of either acute or chronic hyperglycemic vessels with JNK inhibitor SP600125 or JNK-interacting protein-1 (JIP1) inhibitor BI-78D3, but not p38 inhibitor SB203580, preserved bradykinin-induced dilation in an L-NAME–sensitive manner. By contrast, endothelium-independent vasodilation to sodium nitroprusside was unaffected by acute or chronic hyperglycemia. Conclusions Activation of JIP1/JNK signaling in retinal arterioles during exposure to acute or chronic hyperglycemia leads to selective impairment of endothelium-dependent NO-mediated dilation. Therapeutic targeting of the vascular JNK pathway may improve retinal endothelial vasodilator function during early diabetes. PMID

  17. pGlcNAc Nanofiber Treatment of Cutaneous Wounds Stimulate Increased Tensile Strength and Reduced Scarring via Activation of Akt1

    PubMed Central

    Lindner, Haley Buff; Felmly, Lloyd McPherson; Demcheva, Marina; Seth, Arun; Norris, Russell; Bradshaw, Amy D.; Vournakis, John; Muise-Helmericks, Robin C.

    2015-01-01

    Treatment of cutaneous wounds with poly-N-acetyl-glucosamine containing nanofibers (pGlcNAc), a novel polysaccharide material derived from a marine diatom, results in increased wound closure, antibacterial activities and innate immune responses. We have shown that Akt1 plays a central role in the regulation of these activities. Here, we show that pGlcNAc treatment of cutaneous wounds results in a smaller scar that has increased tensile strength and elasticity. pGlcNAc treated wounds exhibit decreased collagen content, increased collagen organization and decreased myofibroblast content. A fibrin gel assay was used to assess the regulation of fibroblast alignment in vitro. In this assay, fibrin lattice is formed with two pins that provide focal points upon which the gel can exert force as the cells align from pole to pole. pGlcNAc stimulation of embedded fibroblasts results in cellular alignment as compared to untreated controls, by a process that is Akt1 dependent. We show that Akt1 is required in vivo for the pGlcNAc-induced increased tensile strength and elasticity. Taken together, our findings suggest that pGlcNAc nanofibers stimulate an Akt1 dependent pathway that results in the proper alignment of fibroblasts, decreased scarring, and increased tensile strength during cutaneous wound healing. PMID:25955155

  18. Topical menthol increases cutaneous blood flow.

    PubMed

    Craighead, Daniel H; Alexander, Lacy M

    2016-09-01

    Menthol, the active ingredient in several topically applied analgesics, activates transient receptor potential melastatin 8 (TRPM8) receptors on sensory nerves and on the vasculature inducing a cooling sensation on the skin. Ilex paraguariensis is also a common ingredient in topical analgesics that has potential vasoactive properties and may alter the mechanisms of action of menthol. We sought to characterize the microvascular effects of topical menthol and ilex application and to determine the mechanism(s) through which these compounds may independently and combined alter cutaneous blood flow. We hypothesized that menthol would induce vasoconstriction and that ilex would not alter skin blood flow (SkBF). Three separate protocols were conducted to examine menthol and ilex-mediated changes in SkBF. In protocol 1, placebo, 4% menthol, 0.7% ilex, and combination menthol+ilex gels were applied separately to the skin and red cell flux was continuously measured utilizing laser speckle contrast imaging (LSCI). In protocol 2, seven concentrations of menthol gel (0.04%, 0.4%, 1%, 2%, 4%, 7%, 8%) were applied to the skin to model the dose-response curve. In protocol 3, placebo, menthol, ilex, and menthol+ilex gels were applied to skin under local thermal control (34°C) both with and without sensory nerve blockage (topical lidocaine 4%). Post-occlusive reactive hyperemia (PORH) and local heating (42°C) protocols were conducted to determine the relative contribution of endothelium derived hyperpolarizing factors (EDHFs)/sensory nerves and nitric oxide (NO), respectively. Red cell flux was normalized to mean arterial pressure expressed as cutaneous vascular conductance (CVC: flux·mmHg(-1)) in all protocols. Topical menthol application increased SkBF compared to placebo (3.41±0.33 vs 1.1±0.19CVC: p<0.001). During the dose-response, SkBF increased with increasing doses of menthol (main effect, p<0.05) with an ED50 of 1.0%. Similarly, SkBF was increased after menthol

  19. Response and Tolerance to Oral Vasodilator Uptitration after Intravenous Vasodilator Therapy in Advanced Decompensated Heart Failure

    PubMed Central

    Verbrugge, Frederik H.; Dupont, Matthias; Finucan, Michael; Gabi, Alaa; Hawwa, Nael; Mullens, Wilfried; Taylor, David O.; Young, James B.; Starling, Randall C.; Wilson Tang, W.H.

    2015-01-01

    Aims To assess the hemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) uptitration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF). Methods and Results Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared to patients not converted (28 ± 7 versus 25 ± 8 mmHg, respectively; P-value=0.024). Beneficial hemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m² without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value=0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up primarily due to incident hypotension. Conclusion The use of a standardized hemodynamically-guided uptitration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization. PMID:26213182

  20. Convergence in reflex pathways from multiple cutaneous nerves innervating the foot depends upon the number of rhythmically active limbs during locomotion.

    PubMed

    Nakajima, Tsuyoshi; Mezzarane, Rinaldo A; Hundza, Sandra R; Komiyama, Tomoyoshi; Zehr, E Paul

    2014-01-01

    Neural output from the locomotor system for each arm and leg influences the spinal motoneuronal pools directly and indirectly through interneuronal (IN) reflex networks. While well documented in other species, less is known about the functions and features of convergence in common IN reflex system from cutaneous afferents innervating different foot regions during remote arm and leg movement in humans. The purpose of the present study was to use spatial facilitation to examine possible convergence in common reflex pathways during rhythmic locomotor limb movements. Cutaneous reflexes were evoked in ipsilateral tibialis anterior muscle by stimulating (in random order) the sural nerve (SUR), the distal tibial nerve (TIB), and combined simultaneous stimulation of both nerves (TIB&SUR). Reflexes were evoked while participants performed rhythmic stepping and arm swinging movement with both arms and the leg contralateral to stimulation (ARM&LEG), with just arm movement (ARM) and with just contralateral leg movement (LEG). Stimulation intensities were just below threshold for evoking early latency (<80 ms to peak) reflexes. For each stimulus condition, rectified EMG signals were averaged while participants held static contractions in the stationary (stimulated) leg. During ARM&LEG movement, amplitudes of cutaneous reflexes evoked by combined TIB&SUR stimulation were significantly larger than simple mathematical summation of the amplitudes evoked by SUR or TIB alone. Interestingly, this extra facilitation seen during combined nerve stimulation was significantly reduced when performing ARM or LEG compared to ARM&LEG. We conclude that locomotor rhythmic limb movement induces excitation of common IN reflex pathways from cutaneous afferents innervating different foot regions. Importantly, activity in this pathway is most facilitated during ARM&LEG movement. These results suggest that transmission in IN reflex pathways is weighted according to the number of limbs directly engaged

  1. RNase 7 in Cutaneous Defense

    PubMed Central

    Rademacher, Franziska; Simanski, Maren; Harder, Jürgen

    2016-01-01

    RNase 7 belongs to the RNase A superfamily and exhibits a broad spectrum of antimicrobial activity against various microorganisms. RNase 7 is expressed in human skin, and expression in keratinocytes can be induced by cytokines and microbes. These properties suggest that RNase 7 participates in innate cutaneous defense. In this review, we provide an overview about the role of RNase 7 in cutaneous defense with focus on the molecular mechanism of the antimicrobial activity of RNase 7, the regulation of RNase 7 expression, and the role of RNase 7 in skin diseases. PMID:27089327

  2. β-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase.

    PubMed

    Limberg, Jacqueline K; Johansson, Rebecca E; Peltonen, Garrett L; Harrell, John W; Kellawan, J Mikhail; Eldridge, Marlowe W; Sebranek, Joshua J; Schrage, William G

    2016-03-15

    We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P < 0.01), and this effect was not different between men and women (P = 0.41). l-NMMA infusion had no effect on isoproterenol-mediated dilation in men (P > 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P < 0.01) and women (P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). β-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease. PMID:26747505

  3. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors.

    PubMed

    Járai, Z; Wagner, J A; Varga, K; Lake, K D; Compton, D R; Martin, B R; Zimmer, A M; Bonner, T I; Buckley, N E; Mezey, E; Razdan, R K; Zimmer, A; Kunos, G

    1999-11-23

    Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that "abnormal cannabidiol" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 microgram/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 microM) or by cannabidiol (10 microM). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K(+)-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.

  4. Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines.

    PubMed

    Kvandal, Per; Stefanovska, Aneta; Veber, Mitja; Kvernmo, Hebe Désirée; Kvermmo, Hebe Désirée; Kirkebøen, Knut Arvid

    2003-05-01

    Nitric oxide (NO) and prostaglandines (PGs) are important in regulation of vascular tone and blood flow. Their contribution in human cutaneous circulation is still uncertain. We inhibited NO synthesis by infusing N(G)-monomethyl-L-arginine (L-NMMA) in the brachial artery (16 micromol/min for 5 min) and reversed it by intraarterial infusion of L-arginine (40 micromol/min for 7.5 min). PG synthesis was inhibited by the cyclooxygenase inhibitor aspirin (600 mg over 5 min intravenously). Basal cutaneous perfusion and perfusion responses during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were recorded by laser Doppler flowmetry (LDF). We performed wavelet transforms of the measured signals. Mean spectral amplitude within the frequency interval from 0.0095 to 1.6 Hz and mean and normalized amplitudes of five intervals around 1, 0.3, 0.1, 0.04, and 0.01 Hz were analysed. The oscillations with frequencies around 1, 0.3, 0.1, and 0.04 Hz are influenced by the heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, and the neurogenic activity of the vessel wall, respectively. We have previously shown that the oscillation with a frequency around 0.01 Hz is modulated by the vascular endothelium. L-NMMA reduced mean value of the LDF signal by approximately 20% (P = 0.0067). This reduction was reversed by L-arginine. Mean value of the LDF signals during ACh and SNP iontophoresis did not change after infusion of L-NMMA. Aspirin did not affect mean value of the LDF signal or the LDF signal during ACh or SNP iontophoresis. Before interventions the only significant difference between the effects of ACh and SNP was observed in the frequency around 0.01 Hz, where ACh increased normalized amplitude to a greater extent than SNP. L-NMMA abolished this difference, whereas it reappeared after infusion of L-arginine (P = 0.0084). Aspirin did not affect this

  5. Activated inflammatory T cells correlate with lesion size in human cutaneous leishmaniasis.

    PubMed

    Antonelli, Lis R V; Dutra, Walderez O; Almeida, Roque P; Bacellar, Olivia; Carvalho, Edgar M; Gollob, Kenneth J

    2005-11-15

    Leishmaniasis is an important parasitic disease affecting millions worldwide. In attempts to understand the clinical relevance of immunological measurements as determined using flow cytometry, several immunological phenotypes were determined for a group of well defined human leishmaniasis patients and correlated with clinical measurements of the disease (Montenegro skin test (MST) and lesion area). The analysis demonstrated a positive correlation between the MST size and the frequency of ex vivo recent activated CD4(+) T cells. In contrast, higher frequencies of recent activated CD8(+) T cells were correlated with a smaller MST size. Moreover, a positive correlation was observed between the lesion total area and the frequency of activated CD69(+) (ex vivo) and CD40L(+) (cultured with Leishmania soluble antigen (SLA)) T lymphocytes. Finally, larger lesions were also correlated with a higher frequency of SLA specific inflammatory cytokine (IFN-gamma or TNF-alpha) producing lymphocytes. These studies demonstrate that immunological markers are correlated with clinical indicators of human leishmaniasis and serve to better understand the evolution of this important parasitic disease.

  6. Discovery of small molecules with vasodilating characteristics and adjustable hydrolytic behavior.

    PubMed

    Brunhofer-Bolzer, Gerda; Gabriel, Mario; Studenik, Christian R; Erker, Thomas

    2015-08-01

    In this contribution the development of a new class of vasodilating compounds obtained by lead structure optimization is described. Three groups of compounds were synthesized and tested for their activity on various smooth muscle preparations of the guinea pig. Beside the lead compound 3a, the most interesting derivative was 1H-imidazole-1-carbothioic acid O-cyclohexyl ester hydrochloride (5b) with a good selective vasodilating potential on aorta and pulmonary artery rings (EC50 14 μM and 24 μM, respectively). Due to the properties of small molecules the hydrolysis behavior of the compounds can be easily adapted hence opening a new route in terms of duration of the agent's effect. With the aid of structure-activity relationship studies, structural motifs influencing the biological activity on isolated smooth muscle cell preparations of the synthesized compounds were proposed. The presented compounds offer good tools in identifying promising molecules as emergency therapy in myocardial infarction. PMID:26072172

  7. Treatment of Cutaneous Lupus Erythematosus

    PubMed Central

    Kim, Grace K.; Del Rosso, James Q.

    2013-01-01

    The treatment of cutaneous lupus erythematosus is centered upon formulating a regimen of topical and systemic therapies designed to reduce disease activity and minimize cosmetic damage. Sun avoidance and sunscreen are important preventative measures proven to minimize cutaneous lupus erythematosus exacerbations. Limited disease is typically managed with topical corticosteroids or calcineurin inhibitors. Antimalarial therapy is the gold standard of systemic therapy. Many other treatments have been studied in patients with recalcitrant cutaneous lupus erythematosus, and their use must be evaluated based on individual risk-benefit concerns. R-salbutamol and pulsed dye laser therapy have proven to be effective topical alternatives. Additional systemic agents include retinoids, immunosuppressants, immunomodulators, biologics, and other experimental therapies with novel modes of action. According to the Oxford Centre for Evidence-based Medicine criteria for evaluating the strength of evidence supporting an individual treatment measure, no therapy for cutaneous lupus erythematosus has achieved Level 1 status. This demonstrates the need for randomized, controlled trials and systematic reviews of all cutaneous lupus erythematosus interventions in order to meet increasing standards and demand for evidence-based practice. PMID:23320123

  8. Multiple Cutaneous Reticulohistiocytoma

    PubMed Central

    Hemmady, Karishma D; Someshwar, Shylaja S; Jerajani, Hemangi R

    2016-01-01

    Multicentric reticulohistiocytosis is a rare non-Langerhans cell histiocytosis characterized in its full form by severe destructive arthritis, cutaneous nodules, and systemic manifestations. Cutaneous lesions may precede, accompany, or more commonly develop later than other features in this disease. We describe a case of multiple cutaneous reticulohistiocytoma without any systemic associations after thorough investigations. PMID:26955136

  9. Beta-adrenoceptor-mediated vasodilation of retinal blood vessels is reduced in streptozotocin-induced diabetic rats.

    PubMed

    Nakazawa, Taisuke; Sato, Ayumi; Mori, Asami; Saito, Maki; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2008-01-01

    We investigated the effects of epinephrine and dopamine on retinal blood vessels in streptozotocin (STZ, 80 mg/kg, i.p.)-treated rats and age-matched control rats to determine whether diabetes mellitus alters the retinal vascular responses to circulating catecholamines. Experiments were performed 6-8 weeks after treatment with STZ or the vehicle. The fundus images were captured with the digital fundus camera system for small animals we developed and diameters of retinal blood vessels contained in the digital images were measured. Epinephrine increased the diameters of retinal blood vessels, but the vasodilator responses were reduced in diabetic rats. Dopamine produced a biphasic retinal vascular response with an initial vasoconstriction followed by a vasodilation. The vasoconstrictor effects of dopamine on retinal arterioles were enhanced in diabetic rats, whereas the difference between the two groups was abolished by treatment with propranolol. The vasodilator effect of isoproterenol, but not of the activator of adenylyl cyclase colforsin, on retinal blood vessels was reduced in diabetic rats. No difference in vasoconstriction of retinal blood vessels to phenylephrine between non-diabetic and diabetic rats was observed. The vasodilator responses of retinal blood vessels to 1,1-dimethyl-4-phenylpiperazinium, a ganglionic nicotinic receptor agonist, were also attenuated in diabetic rats. These results suggest that diabetes mellitus alters the retinal vascular responses to circulating catecholamines and the impairment of vasodilator responses mediated by beta-adrenoceptors contributes to the alteration.

  10. Cutaneous and colonic rat DRG neurons differ with respect to both baseline and PGE2-induced changes in passive and active electrophysiological properties.

    PubMed

    Gold, Michael S; Traub, Richard J

    2004-06-01

    This study was designed to test the hypotheses that pain syndromes associated with specific body regions reflect unique properties of sensory neurons innervating these regions and/or unique responses of these afferents to tissue damage. Acutely dissociated adult rat dorsal root ganglia (DRG) neurons retrogradely labeled from either the colon or the glabrous skin of the hindpaw were studied by whole cell patch-clamp recording in current-clamp mode. Two populations of colonic afferent neurons were studied: pelvic afferents (arising from L(6), S(1), and S(2) DRG = LS DRG) and hypogastric/lumbar colonic afferents (arising from T(13), L(1), and L(2) DRG = TL DRG). Passive and active electrophysiological properties were studied before and after application prostaglandin E(2) (PGE(2)). We observed marked differences between cutaneous and colonic sensory neurons with respect to baseline passive and active electrophysiological properties as well as both the magnitude and pattern of PGE(2)-induced changes in excitability, passive, and active properties. There were also significant differences between TL and LS neurons with respect to baseline and PGE(2)-induced changes in several passive and active electrophysiological properties. Our results suggest that differences between cutaneous and colonic neurons reflect differences in pattern and/or density of ionic currents present in the plasma membrane. More interestingly, the ionic currents underlying the PGE(2)-induced sensitization of cutaneous neurons appeared to differ from those underlying the sensitization of colonic neurons. The implication of this observation is that it may be possible, in fact necessary, to treat pain arising from specific body regions with unique therapeutic interventions. PMID:14736864

  11. Cholinergic vasodilator mechanism in human fingers

    SciTech Connect

    Coffman, J.D.; Cohen, R.A.

    1987-03-01

    The effect of a cholinergic agonist and antagonist on finger blood flow (FBF) was studied in 10 normal subjects. Total finger blood flow was measured by venous occlusion, air plethysmography, and capillary blood flow (FCF) by the disappearance rate of a radio-isotope from a fingertip injection. Methacholine in doses of 10-80 ..mu..g/min was given by constant infusion via a brachial artery catheter. Average FBF and vascular resistance were not significantly affected. However, the half time (t/sub 1/2/) of the disappearance rate decreased from 50.8 +/- 13.4 to 11.1 +/- 1.5 min; a decrease occurred in all subjects. In seven subjects, atropine (0.2 mg) had no affect alone but inhibited the effect of methacholine on FCF and prevented the redness and sweating of the forearm and hand that occurs with this agent. This study demonstrates a muscarinic cholinergic vasodilator mechanism in the fingertip that uniquely increase capillary blood flow.

  12. Solar radiation and cutaneous melanoma.

    PubMed

    Viola, M V; Houghton, A N

    1982-09-01

    Exposure to solar radiation has been widely implicated in the dramatic rise in the incidence of cutaneous melanoma throughout the world. The association may be more complex than originally suspected, involving such factors as sunspot-activity cycles and changes in the ozone layer affecting ultraviolet flux at the earth's surface. The evidence for these relationships is examined.

  13. Vasodilator interactions in skeletal muscle blood flow regulation

    PubMed Central

    Hellsten, Y; Nyberg, M; Jensen, L G; Mortensen, S P

    2012-01-01

    During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or on the extraluminal side of the blood vessels. A number of vasodilators have been shown to bring about this increase in blood flow and, importantly, interactions between these compounds seem to be essential for the precise regulation of blood flow. Two compounds stand out as central in these vasodilator interactions: nitric oxide (NO) and prostacyclin. These two vasodilators are both stimulated by several compounds, e.g. adenosine, ATP, acetylcholine and bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other is compromised. Although numerous studies have examined the role of single and multiple pharmacological inhibition of different vasodilator systems, and important vasodilators and interactions have been identified, a large part of the exercise hyperaemic response remains unexplained. It is plausible that this remaining hyperaemia may be explained by cAMP- and cGMP-independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow regulation remain to be further explored to fully elucidate the regulation of exercise hyperaemia. PMID:22988140

  14. Synthesis of Silicon and Germanium Containing Heteroaromatic Sulfides as Cholesterol Level Lowering and Vasodilating Agents

    PubMed Central

    Rubina, Kira; Abele, Edgars; Arsenyan, Pavel; Abele, Ramona; Veveris, Maris

    2001-01-01

    Silicon and germanium containing heteroaromatic sulfides have been prepared using phase transfer catalytic (PTC) system thiol / Si or Ge containing alkyl halide / solid KOH / 18- crown-6 / toluene. The target sulfides were isolated in yields up to 92 %. It has been found that 2-{[dimethyl (β-triethylgermylethyl)-silylmethyl]thio}-1-methylimidazole and 2-{[dimethyl(β-triphenylsilylethyl) silyl-methyl]thio}benzothiazole are the most active cholesterol level lowering and vasodilating agents. PMID:18475980

  15. Free radicals release vasodilator(s) from endothelial and smooth muscle cells

    SciTech Connect

    Chen, X.; Hu, Y.C.; Gillis, C.N. )

    1991-03-15

    Electrolysis-generated free radicals (ES-FR) injure the endothelium (EC) of rabbit lungs perfused in situ. The authors now report that ES-FR release EDRF-like substance(s) from both vascular EC and smooth muscle sources. Rabbit aortic segments with or without endothelium or columns of bovine aortic EC grown on biosilon beads were perfused with Krebs solution containing 6 uM indomethacin and 10 units/ml SOD. Effluent passed over two endothelial-denuded aortic rings precontracted with phenylephrine. Electrolysis of perfusion medium, released a vasodilator substance(s) from both. Vasodilatation was directly related to the current used and had t{sub 1/2} similar to that of EDRF released from EC columns by ADP. Release was attenuated by N-{omega}-nitro-L-arginine or sodium salicylate perfused through the cell column or aortic segments, or by 0.5% hemoglobin passed over the bioassay aortic rings. Finally, prompt transfer of 0.3-0.5 ml of medium, subjected to ES off-line, also relaxed pre-contracted aortic rings. Thus ES-FR can release EDRF-like substance(s) from both aortic EC and EC-denuded aortic smooth muscle. Since release was attenuated by salicylate, a specific trapping agent for hydroxyl radicals, the authors suggest that the latter is related to release of the vasodilator.

  16. Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse.

    PubMed

    Zhu, Guangshuo; Groneberg, Dieter; Sikka, Gautam; Hori, Daijiro; Ranek, Mark J; Nakamura, Taishi; Takimoto, Eiki; Paolocci, Nazareno; Berkowitz, Dan E; Friebe, Andreas; Kass, David A

    2015-02-01

    Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO·), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. These features have spawned current pharmaceutical development of HNO donors as heart failure therapeutics. HNO interacts with selective redox sensitive cysteines to effect signaling but is also proposed to activate soluble guanylate cyclase (sGC) in vitro to induce vasodilation and potentially enhance contractility. Here, we tested whether sGC stimulation is required for these HNO effects in vivo and if HNO also modifies a redox-sensitive cysteine (C42) in protein kinase G-1α to control vasorelaxation. Intact mice and isolated arteries lacking the sGC-β subunit (sGCKO, results in full sGC deficiency) or expressing solely a redox-dead C42S mutant protein kinase G-1α were exposed to the pure HNO donor, CXL-1020. CXL-1020 induced dose-dependent systemic vasodilation while increasing contractility in controls; however, vasodilator effects were absent in sGCKO mice whereas contractility response remained. The CXL-1020 dose reversing 50% of preconstricted force in aortic rings was ≈400-fold greater in sGCKO than controls. Cyclic-GMP and cAMP levels were unaltered in myocardium exposed to CXL-1020, despite its inotropic-vasodilator activity. In protein kinase G-1α(C42S) mice, CXL-1020 induced identical vasorelaxation in vivo and in isolated aortic and mesenteric vessels as in littermate controls. In both groups, dilation was near fully blocked by pharmacologically inhibiting sGC. Thus, sGC and cGMP-dependent signaling are necessary and sufficient for HNO-induced vasodilation in vivo but are not required for positive inotropic action. Redox modulation of protein kinase G-1α is not a mechanism for HNO-mediated vasodilation.

  17. 5-Hydroxytryptamine-induced vasodilator responses in the hindquarters of the anaesthetized rat, involve beta2-adrenoceptors.

    PubMed

    Calama, E; García, M; Jarque, M J; Morán, A; Martín, M L; San Román, L

    2003-10-01

    These studies were conducted to examine the role of the vasoactive mediators nitric oxide (NO) and adrenaline (epinephrine) in the serotonin (5-hydroxytryptamine; 5-HT)-induced vasodilator response in the hindquarter vascular bed of anaesthetized rats. Intra-arterial administration of doses of 5-HT in the range 0.12-25 ng kg(-1) produced a dose-independent vasodilator effect in the hindquarters. The selective 5-HT(1D/1B) receptor agonist, L-694,247 at intra-arterial doses of 0.0012-1000 ng kg(-1), as well as adrenaline (at doses of 0.05-50 ng kg(-1) i.a.), mimicked the dose-independent vasodilator effect induced by intra-arterial administration of 5-HT. Intravenous pre-treatment with the selective beta2-receptor antagonist ICI 118,551 (0.5 mg kg(-1)) blocked the vasodilator effect of 5-HT, adrenaline and L-694,247. Additionally, the inhibitor of NO synthase NG-nitro-L-arginine (L-NAME) (at a dose of 10 mg kg(-1) i.v.) blocked the vasodilator action of acetylcholine 300-3000 ng kg(-1)) but did not modify 5-HT-induced vasodilatation. The vasodilator effect produced by intra-arterial administration of 5-HT in the hindquarters was significantly inhibited both 30 min after denervation of the lumbar sympathetic chains and 1 h after bilateral adrenalectomy. Our data suggest that in the in-situ autoperfused hindquarters of the rat 5-HT-induced vasodilatation is mediated by a local 5-HT(1D) or 5-HT(1D/1B) activation, which in turn mediates the adrenal release of adrenaline, which then produces beta2-activation and vasodilatation.

  18. GLUCOSE-INDUCED INTESTINAL VASODILATION VIA ADENOSINE A1 RECEPTORS REQUIRES NITRIC OXIDE BUT NOT K+ATP CHANNELS

    PubMed Central

    Matheson, Paul J.; Li, Na; Harris, Patrick D.; Zakaria, El Rasheid; Garrison, R. Neal

    2010-01-01

    INTRODUCTION Both nitric oxide (NO) and adenosine A1 receptor activation mediate microvascular vasodilation during intestinal glucose absorption. Our overall hypothesis is that ATP utilization during glucose absorption would increase adenosine metabolite release, which acts on adenosine A1 receptors to alter endothelial production of NO and/or activate ATP-dependent potassium channels (K+ATP) to dilate intestinal microvessels. METHODS Intravital videomicroscopy of the rat jejunum was used to record the vascular responses of inflow (termed 1A) arterioles and proximal (p3A) and distal (d3A) premucosal arterioles during exposure to isotonic glucose or mannitol solutions alone or in the presence of the selective nitric oxide synthase (NOS) inhibitor (L-NMMA), an adenosine A1 receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine (DPCPX)), or a K+ATP channel inhibitor (glibenclamide). RESULTS As expected, glucose exposure caused rapid dilation of both p3A and d3A arterioles, while mannitol exposure had no effect on microvascular diameters. Adenosine A1 receptor blockade completely prevented glucose-induced dilation of the premucosal arterioles. NOS inhibition significantly blunted the glucose-induced vasodilation of the premucosal arterioles, but had little effect in the mannitol group. Simultaneous application of both the NOS inhibitor and the adenosine A1 receptor antagonist gave the same reduction in glucose-induced dilation of the premucosal arterioles as the adenosine A1 receptor antagonist alone. Blockade of K+ATP channels with glibenclamide did not attenuate glucose-induced vasodilation of the premucosal arterioles. CONCLUSIONS These data suggest that glucose-induced vasodilation of premucosal jejunal arterioles is mediated through adenosine A1 receptors, and NO at least partially mediates the adenosine A1 receptor-induced vasodilation. In addition, K+ATP channels are not involved in premucosal arteriolar vasodilation during intestinal glucose exposure. PMID

  19. Cutaneous vascular and sweating responses to intradermal administration of prostaglandin E1 and E2 in young and older adults: a role for nitric oxide?

    PubMed

    Fujii, Naoto; Singh, Maya Sarah; Halili, Lyra; Boulay, Pierre; Sigal, Ronald J; Kenny, Glen P

    2016-06-01

    Cyclooxygenase (COX) contributes to cutaneous vasodilation and sweating responses; however, the mechanisms underpinning these responses remain unknown. We hypothesized that prostaglandin E1 (PGE1) and E2 (PGE2) (COX-derived vasodilator products) directly mediate cutaneous vasodilation and sweating through nitric oxide synthase (NOS)-dependent mechanisms in young adults. Furthermore, we hypothesized that this response is diminished in older adults, since aging attenuates COX-dependent cutaneous vasodilation and sweating. In 9 young (22 ± 5 yr) and 10 older (61 ± 6 yr) adults, cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites receiving incremental doses (0.05, 0.5, 5, 50, 500 μM each for 25 min) of PGE1 or PGE2 with and without coadministration of 10 mM N(ω)-nitro-l-arginine, a nonspecific NOS inhibitor. N(ω)-nitro-l-arginine attenuated PGE1-mediated increases in CVC at all concentrations in young adults, whereas it reduced PGE2-mediated increases in CVC at lower concentrations (0.05-0.5 μM) in older adults (all P < 0.05). However, the magnitude of the PGE1- and PGE2-mediated increases in CVC did not differ between groups (all P > 0.05). Neither PGE1 nor PGE2 increased sweat rate at any of the administered concentrations for either the young or older adults (all P > 0.05). We show that although cutaneous vascular responsiveness to PGE1 and PGE2 is similar between young and older adults, the cutaneous vasodilator response is partially mediated through NOS albeit via low-to-high concentrations of PGE1 in young adults and low concentrations of PGE2 in older adults, respectively. We also show that in both young and older adults, PGE1 and PGE2 do not increase sweat rate under normothermic conditions.

  20. Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteasomal degradation.

    PubMed

    Meurer, Sabine; Pioch, Sylke; Pabst, Tatjana; Opitz, Nils; Schmidt, Peter M; Beckhaus, Tobias; Wagner, Kristina; Matt, Simone; Gegenbauer, Kristina; Geschka, Sandra; Karas, Michael; Stasch, Johannes-Peter; Schmidt, Harald H H W; Müller-Esterl, Werner

    2009-07-01

    Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its major intracellular receptor, the alphabeta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of the heme of sGC, as well as the responsiveness of sGC to NO. sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here, we show that oxidation-induced downregulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand BAY 58-2667 prevented sGC ubiquitination and stabilized both alpha and beta subunits. Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC. PMID:19478201

  1. Role of opioid receptors in neurogenic dural vasodilation and sensitization of trigeminal neurones in anaesthetized rats

    PubMed Central

    Williamson, D J; Shepheard, S L; Cook, D A; Hargreaves, R J; Hill, R G; Cumberbatch, M J

    2001-01-01

    Migraine headache is thought to be caused by a distension of meningeal blood vessels, the activation of trigeminal sensory neurones and the the development of a central sensitization within the trigeminal nucleus caudalis (TNC). It has been proposed that clinically effective 5-HT1B/1D agonists act peripherally to inhibit the release of calcitonin gene-related peptide (CGRP) and neurogenic dural vasodilation, and to attenuate nociceptive neurotransmission within the TNC. Since opioids are also effective anti-migraine agents the present studies investigated the role of opioids within the trigemino-vascular system in anaesthetised rats. Electrical stimulation of the dura mater evoked neurogenic dural vasodilation which was significantly inhibited by morphine (1 mg kg−1) the selective μ-opioid agonist DAGO (10 μg kg−1) and the mixed agonist/antagonist butorphanol (1 mg kg−1) but not by the κ- and δ-opioid agonists (±) U50488H (100 μg kg−1) and DPDPE (1 mg kg−1). Morphine had no effect on CGRP-evoked dural vasodilation. In electrophysiological studies morphine (1 – 10 mg kg−1) significantly attenuated brainstem neuronal activity in response to electrical stimulation of the dura by 65% at 10 mg kg−1. Morphine (3 mg kg−1) also inhibited the TNC neuronal sensitization following CGRP-evoked dilation. The present studies have demonstrated that opioids block the nociceptive neurotransmission within the trigeminal nucleus caudalis and in addition inhibit neurogenic dural vasodilation via an action on μ-opioid receptors located on trigeminal sensory fibres innervating dural blood vessels. These peripheral and central actions are similar to those of the ‘triptan' 5-HT1B/1D agonists and could account for the anti-migraine actions of opioids. PMID:11454653

  2. Greater Beta-Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives

    PubMed Central

    Limberg, Jacqueline K.; Peltonen, Garrett L.; Johansson, Rebecca E.; Harrell, John W.; Kellawan, Jeremy M.; Eldridge, Marlowe W.; Sebranek, Joshua J.; Walker, Benjamin J.; Schrage, William G.

    2016-01-01

    Background: β-adrenergic receptors play an important role in mitigating the pressor effects of sympathetic nervous system activity in young women. Based on recent data showing oral contraceptive use in women abolishes the relationship between muscle sympathetic nervous system activity and blood pressure, we hypothesized forearm blood flow responses to a β-adrenergic receptor agonist would be greater in young women currently using oral contraceptives (OC+, n = 13) when compared to those not using oral contraceptives (OC–, n = 10). Methods: Women (18–35 years) were studied during the early follicular phase of the menstrual cycle (days 1–5) or placebo phase of oral contraceptive use. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured at baseline and during graded brachial artery infusion of the β-adrenergic receptor agonist, Isoproterenol (ISO), as well as Acetylcholine (ACH, endothelium-dependent vasodilation) and Nitroprusside (NTP, endothelium-independent vasodilation). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100 mmHg) and the rise in FVC from baseline during infusion quantified vasodilation (ΔFVC = FVCinfusion − FVCbaseline). Results: ISO increased FVC in both groups (p < 0.01) and ISO-mediated ΔFVC was greater in OC+ compared to OC– (Main effect of group, p = 0.02). Expressing data as FVC and FBF resulted in similar conclusions. FVC responses to both ACH and NTP were also greater in OC+ compared to OC–. Conclusions: These data are the first to demonstrate greater β-adrenergic receptor-mediated vasodilation in the forearm of women currently using oral contraceptives (placebo phase) when compared to those not using oral contraceptives (early follicular phase), and suggest oral contraceptive use influences neurovascular control. PMID:27375493

  3. Tranilast Increases Vasodilator Response to Acetylcholine in Rat Mesenteric Resistance Arteries through Increased EDHF Participation

    PubMed Central

    Sastre, Esther; Caracuel, Laura; Callejo, María; Balfagón, Gloria

    2014-01-01

    Background and Purpose Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). Experimental Approach Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholine-induced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. Key Results Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilast-incubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. Conclusions and Implications Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels. PMID:24992476

  4. UV-induced cutaneous photobiology.

    PubMed

    Beissert, S; Granstein, R D

    1996-12-01

    Ultraviolet radiation (UVR) present in sunlight is a major environmental factor capable of affecting human health and well being. The organ primarily affected by UVR is the skin, which is composed of a variety of different cell types. Here, UVR is needed for production of active vitamin D as well as producing undesirable effects such as sunburn, premature cutaneous photoaging, and promoting skin cancer development. Depending on the radiation dose, UVR influences virtually every cutaneous cell type investigated differently. Since the end of the nineteenth century, sun exposure has been known to induce skin cancer, which is now the human malignancy with the most rapidly increasing incidence. In several experimental models, mid-range UVR has been demonstrated to be the major cause of UV-induced cutaneous tumors. The stratospheric ozone layer protecting the terrestrial surface from higher quantum energy solar radiation is being damaged by industrial activities resulting in the possibility of increased UVR exposure in the future. Investigations in the field of experimental dermatology have shown that within the skin an immunosurveillance system exists that may be able to detect incipient neoplasms and to elicit a host responses against it. This article reviews the literature on studies designed to investigate the effects of UVR on cutaneous cellular components, with special focus on the immune system within the skin and the development of UV-induced cancer.

  5. Acute Thermotherapy Prevents Impairments in Cutaneous Microvascular Function Induced by a High Fat Meal

    PubMed Central

    Harvey, Jennifer C.; Roseguini, Bruno T.; Goerger, Benjamin M.; Fallon, Elizabeth A.

    2016-01-01

    We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5–10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). HFM had no effect on initial peak (48 ± 4 %CVCmax) compared to control (49 ± 4 %CVCmax) but attenuated the plateau (51 ± 4 %CVCmax) compared to control (63 ± 4 %CVCmax, P < 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %CVCmax) compared to control and HFM (P < 0.05), while plateau (73 ± 3 % CVCmax) was augmented only compared to the HFM trial (P < 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT. PMID:27595112

  6. Acute Thermotherapy Prevents Impairments in Cutaneous Microvascular Function Induced by a High Fat Meal.

    PubMed

    Harvey, Jennifer C; Roseguini, Bruno T; Goerger, Benjamin M; Fallon, Elizabeth A; Wong, Brett J

    2016-01-01

    We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5-10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). HFM had no effect on initial peak (48 ± 4 %CVCmax) compared to control (49 ± 4 %CVCmax) but attenuated the plateau (51 ± 4 %CVCmax) compared to control (63 ± 4 %CVCmax, P < 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %CVCmax) compared to control and HFM (P < 0.05), while plateau (73 ± 3 % CVCmax) was augmented only compared to the HFM trial (P < 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT. PMID:27595112

  7. Acute Thermotherapy Prevents Impairments in Cutaneous Microvascular Function Induced by a High Fat Meal

    PubMed Central

    Harvey, Jennifer C.; Roseguini, Bruno T.; Goerger, Benjamin M.; Fallon, Elizabeth A.

    2016-01-01

    We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5–10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). HFM had no effect on initial peak (48 ± 4 %CVCmax) compared to control (49 ± 4 %CVCmax) but attenuated the plateau (51 ± 4 %CVCmax) compared to control (63 ± 4 %CVCmax, P < 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %CVCmax) compared to control and HFM (P < 0.05), while plateau (73 ± 3 % CVCmax) was augmented only compared to the HFM trial (P < 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT.

  8. Red blood cells stored for increasing periods produce progressive impairments in nitric oxide–mediated vasodilation

    PubMed Central

    Alexander, Jason T.; El-Ali, Alexander M.; Newman, James L.; Karatela, Sulaiman; Predmore, Benjamin L.; Lefer, David J.

    2014-01-01

    BACKGROUND Clinical outcomes in transfused patients may be affected by the duration of blood storage, possibly due to red blood cell (RBC)-mediated disruption of nitric oxide (NO) signaling, a key regulator of vascular tone and blood flow. STUDY DESIGN AND METHODS AS-1 RBC units stored up to 42 days were sampled at selected storage times. Samples were added to aortic rings ex vivo, a system where NO-mediated vasodilation could be experimentally controlled. RESULTS RBC units showed storage-dependent changes in plasma hemoglobin (Hb), RBC 2,3-diphosphoglycerate acid, and RBC adenosine triphosphate conforming to expected profiles. When freshly collected (Day 0) blood was added to rat aortic rings, methacholine (MCh) stimulated substantial NO-mediated vasodilation. In contrast, MCh produced no vasodilation in the presence of blood stored for 42 days. Surprisingly, the vasoinhibitory effects of stored RBCs were almost totally mediated by RBCs themselves: removal of the supernatant did not attenuate the inhibitory effects, while addition of supernatant alone to the aortic rings only minimally inhibited MCh-stimulated relaxation. Stored RBCs did not inhibit vasodilation by a direct NO donor, demonstrating that the RBC-mediated vasoinhibitory mechanism did not work by NO scavenging. CONCLUSIONS These studies have revealed a previously unrecognized vasoinhibitory activity of stored RBCs, which is more potent than the described effects of free Hb and works through a different mechanism that does not involve NO scavenging but may function by reducing endothelial NO production. Through this novel mechanism, transfusion of small volumes of stored blood may be able to disrupt physiologic vasodilatory responses and thereby possibly cause adverse clinical outcomes. PMID:23480490

  9. Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production

    PubMed Central

    2014-01-01

    Background It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S). Methods We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger. Results Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation. Conclusions Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance. PMID:24693878

  10. Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training.

    PubMed

    Newcomer, Sean C; Leuenberger, Urs A; Hogeman, Cynthia S; Proctor, David N

    2005-07-01

    Forearm endothelium-dependent vasodilation is impaired with age in sedentary, but not endurance-trained, men. The purpose of this investigation was to determine whether these age- and physical activity-related differences in endothelium-dependent vasodilation also occur in the leg. Brachial and common femoral arterial blood flow were measured with Doppler ultrasound during increasing doses of acetylcholine (1, 4, and 16 microg.100 ml limb tissue(-1).min(-1)), substance P (8, 31, and 125 pg.100 ml limb tissue(-1).min(-1)), and sodium nitroprusside (0.063, 0.25, and 1 microg.100 ml limb tissue(-1).min(-1)) in 23 healthy men (8 younger sedentary, 8 older sedentary, and 7 older endurance trained). Increases in forearm blood flow to the highest dose of acetylcholine and sodium nitroprusside were smaller (P < 0.05) in older sedentary (841 +/- 142%, 428 +/- 74%) compared with younger sedentary (1,519 +/- 256%, 925 +/- 163%) subjects. Similarly, increases in forearm blood flow to sodium nitroprusside (1 microg.100 ml limb tissue(-1).min(-1)) were smaller (P < 0.05) in older endurance-trained (505 +/- 110%) compared with younger sedentary (925 +/- 163%) subjects. In contrast, no differences in leg blood flow responses to intra-arterial infusions of acetylcholine, substance P, or sodium nitroprusside were noted between subject groups. These results demonstrate that 1) acetylcholine- and sodium nitroprusside-induced vasodilation are attenuated in the forearm vasculature and preserved in the leg vasculature of older sedentary subjects and 2) sodium nitroprusside-induced vasodilation remains attenuated in the forearm vasculature of healthy older endurance-trained men but preserved in the leg vasculature of these men.

  11. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.

    PubMed

    Bernardi, Mauro; Moreau, Richard; Angeli, Paolo; Schnabl, Bernd; Arroyo, Vicente

    2015-11-01

    The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance. PMID:26192220

  12. Antihypertensive and vasodilator effects of methanolic and aqueous extracts of Tribulus terrestris in rats.

    PubMed

    Phillips, Oludotun A; Mathew, Koyippalli T; Oriowo, Mabayoje A

    2006-04-01

    The effects of methanolic and aqueous extracts of Tribulus terrestris on rat blood pressure (BP) and the perfused mesenteric vascular bed were investigated. The extracts dose-dependently reduced BP in spontaneously hypertensive rats (SHRs) with the aqueous fraction being more potent than the methanolic fraction at all doses tested. In vitro, the methanolic but not aqueous extract produced a dose-dependent increase in perfusion pressure of the mesenteric vascular bed. When perfusion pressure was raised with phenylephrine (10(-5) M), the aqueous extract produced a dose-dependent reduction in perfusion pressure at all doses. A low dose of the methanolic extract produced a vasoconstrictor effect while higher doses produced dose-dependent reduction in perfusion pressure. L-NAME (10(-4) M) significantly reduced but did not abolish vasodilation induced by the extracts. Vasodilator responses to aqueous and methanolic fractions were significantly reduced in preparations where perfusion pressure was raised with KCl (60 mM). A combination of KCl and L-NAME abolished the vasodilator responses induced by the extracts. It was concluded that methanolic and aqueous extracts of Tribulus terrestris possess significant antihypertensive activity in spontaneously hypertensive rats. The antihypertensive effects appeared to result from a direct arterial smooth muscle relaxation possibly involving nitric oxide release and membrane hyperpolarization.

  13. Lipid Emulsion Inhibits Vasodilation Induced by a Toxic Dose of Bupivacaine via Attenuated Dephosphorylation of Myosin Phosphatase Target Subunit 1 in Isolated Rat Aorta.

    PubMed

    Ok, Seong-Ho; Byon, Hyo-Jin; Kwon, Seong-Chun; Park, Jungchul; Lee, Youngju; Hwang, Yeran; Baik, Jiseok; Choi, Mun-Jeoung; Sohn, Ju-Tae

    2015-01-01

    Lipid emulsions are widely used for the treatment of systemic toxicity that arises from local anesthetics. The goal of this in vitro study was to examine the cellular mechanism associated with the lipid emulsion-mediated attenuation of vasodilation induced by a toxic dose of bupivacaine in isolated endothelium-denuded rat aorta. The effects of lipid emulsion on vasodilation induced by bupivacaine, mepivacaine, and verapamil were assessed in isolated aorta precontracted with phenylephrine, the Rho kinase stimulant NaF, and the protein kinase C activator phorbol 12,13-dibutyrate (PDBu). The effects of Rho kinase inhibitor Y-27632 on contraction induced by phenylephrine or NaF were assessed. The effects of bupivacaine on intracellular calcium concentrations ([Ca(2+)]i) and tension induced by NaF were simultaneously measured. The effects of bupivacaine alone and lipid emulsion plus bupivacaine on myosin phosphatase target subunit 1 (MYPT1) phosphorylation induced by NaF were examined in rat aortic vascular smooth muscle cells. In precontracted aorta, the lipid emulsion attenuated bupivacaine-induced vasodilation but had no effect on mepivacaine-induced vasodilation. Y-27632 attenuated contraction induced by either phenylephrine or NaF. The lipid emulsion attenuated verapamil-induced vasodilation. Compared with phenylephrine-induced precontracted aorta, bupivacaine-induced vasodilation was slightly attenuated in NaF-induced precontracted aorta. The magnitude of the bupivacaine-induced vasodilation was higher than that of a bupivacaine-induced decrease in [Ca(2+)]i. Bupivacaine attenuated NaF-induced MYPT1 phosphorylation, whereas lipid emulsion pretreatment attenuated the bupivacaine-induced inhibition of MYPT1 phosphorylation induced by NaF. Taken together, these results suggest that lipid emulsions attenuate bupivacaine-induced vasodilation via the attenuation of inhibition of MYPT1 phosphorylation evoked by NaF.

  14. The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin.

    PubMed

    Banki, E; Hajna, Zs; Kemeny, A; Botz, B; Nagy, P; Bolcskei, K; Toth, G; Reglodi, D; Helyes, Zs

    2014-10-01

    We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.

  15. Interferon-β Induces Cellular Senescence in Cutaneous Human Papilloma Virus-Transformed Human Keratinocytes by Affecting p53 Transactivating Activity

    PubMed Central

    Chiantore, Maria V.; Vannucchi, Serena; Accardi, Rosita; Tommasino, Massimo; Percario, Zulema A.; Vaccari, Gabriele; Affabris, Elisabetta; Fiorucci, Gianna; Romeo, Giovanna

    2012-01-01

    Interferon (IFN)-β inhibits cell proliferation and affects cell cycle in keratinocytes transformed by both mucosal high risk Human Papilloma Virus (HPV) and cutaneous HPV E6 and E7 proteins. In particular, upon longer IFN-β treatments, cutaneous HPV38 expressing cells undergo senescence. IFN-β appears to induce senescence by upregulating the expression of the tumor suppressor PML, a well known IFN-induced gene. Indeed, experiments in gene silencing via specific siRNAs have shown that PML is essential in the execution of the senescence programme and that both p53 and p21 pathways are involved. IFN-β treatment leads to a modulation of p53 phosphorylation and acetylation status and a reduction in the expression of the p53 dominant negative ΔNp73. These effects allow the recovery of p53 transactivating activity of target genes involved in the control of cell proliferation. Taken together, these studies suggest that signaling through the IFN pathway might play an important role in cellular senescence. This additional understanding of IFN antitumor action and mechanisms influencing tumor responsiveness or resistance appears useful in aiding further promising development of biomolecular strategies in the IFN therapy of cancer. PMID:22615843

  16. Vasodilator response to histamine: dependence upon the site of administration.

    PubMed

    Galeno, T M; Knuepfer, M M; Brody, M J

    1979-06-15

    Histamine causes vasodilation in part by interacting with histamine H2 receptors. The present study was undertaken to evaluate the difference in vasodilator sensitivity of H2 receptors on the inside compared to the outside of the vessel. In order to induce tone, norepinephrine was administered to an in vitro preparation of rabbit ear artery treated with mepyramine to block H1 receptors. Histamine was then either selectively perfused through the artery or added to the outside of the vessel via the organ bath. The outside of the artery was found to be twice as sensitive to the vasodilator effect of histamine as the inside. These data provide the first evidence for greater extraluminal sensitivity of vascular smooth muscle and suggest that the response to histamine will depend in part on the route the amine takes to reach receptors, e.g., from blood-borne sources or from extraluminal stores.

  17. Exogenous melatonin administration modifies cutaneous vasoconstrictor response to whole body skin cooling in humans.

    PubMed

    Aoki, Ken; Zhao, Kun; Yamazaki, Fumio; Sone, Ryoko; Alvarez, Guy E; Kosiba, Wojciech A; Johnson, John M

    2008-03-01

    Humans and other diurnal species experience a fall in internal temperature (T(int)) at night, accompanied by increased melatonin and altered thermoregulatory control of skin blood flow (SkBF). Also, exogenous melatonin induces a fall in T(int), an increase in distal skin temperatures and altered control of the cutaneous active vasodilator system, suggesting an effect of melatonin on the control of SkBF. To test whether exogenous melatonin also affects the more tonically active vasoconstrictor system in glabrous and nonglabrous skin during cooling, healthy males (n = 9) underwent afternoon sessions of whole body skin temperature (T(sk)) cooling (water-perfused suits) after oral melatonin (Mel; 3 mg) or placebo (Cont). Cutaneous vascular conductance (CVC) was calculated from SkBF (laser Doppler flowmetry) and non-invasive blood pressure. Baseline T(int) was lower in Mel than in Cont (P < 0.01). During progressive reduction of T(sk) from 35 degrees C to 32 degrees C, forearm CVC was first significantly reduced at T(sk) of 34.33 +/- 0.01 degrees C (P < 0.05) in Cont. In contrast, CVC in Mel was not significantly reduced until T(sk) reached 33.33 +/- 0.01 degrees C (P < 0.01). The decrease in forearm CVC in Mel was significantly less than in Cont at T(sk) of 32.66 +/- 0.01 degrees C and lower (P < 0.05). In Mel, palmar CVC was significantly higher than in Cont above T(sk) of 33.33 +/- 0.01 degrees C, but not below. Thus exogenous melatonin blunts reflex vasoconstriction in nonglabrous skin and shifts vasoconstrictor system control to lower T(int). It provokes vasodilation in glabrous skin but does not suppress the sensitivity to falling T(sk). These findings suggest that by affecting the vasoconstrictor system, melatonin has a causal role in the nocturnal changes in body temperature and its control.

  18. Characterization of cutaneous and articular sensory neurons

    PubMed Central

    da Silva Serra, Ines; Husson, Zoé; Bartlett, Jonathan D.

    2016-01-01

    Background A wide range of stimuli can activate sensory neurons and neurons innervating specific tissues often have distinct properties. Here, we used retrograde tracing to identify sensory neurons innervating the hind paw skin (cutaneous) and ankle/knee joints (articular), and combined immunohistochemistry and electrophysiology analysis to determine the neurochemical phenotype of cutaneous and articular neurons, as well as their electrical and chemical excitability. Results Immunohistochemistry analysis using RetroBeads as a retrograde tracer confirmed previous data that cutaneous and articular neurons are a mixture of myelinated and unmyelinated neurons, and the majority of both populations are peptidergic. In whole-cell patch-clamp recordings from cultured dorsal root ganglion neurons, voltage-gated inward currents and action potential parameters were largely similar between articular and cutaneous neurons, although cutaneous neuron action potentials had a longer half-peak duration (HPD). An assessment of chemical sensitivity showed that all neurons responded to a pH 5.0 solution, but that acid-sensing ion channel (ASIC) currents, determined by inhibition with the nonselective acid-sensing ion channel antagonist benzamil, were of a greater magnitude in cutaneous compared to articular neurons. Forty to fifty percent of cutaneous and articular neurons responded to capsaicin, cinnamaldehyde, and menthol, indicating similar expression levels of transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), and transient receptor potential melastatin 8 (TRPM8), respectively. By contrast, significantly more articular neurons responded to ATP than cutaneous neurons. Conclusion This work makes a detailed characterization of cutaneous and articular sensory neurons and highlights the importance of making recordings from identified neuronal populations: sensory neurons innervating different tissues have subtly different properties

  19. Painful cutaneous laser stimuli induce event-related oscillatory EEG activities that are different from those induced by nonpainful electrical stimuli.

    PubMed

    Chien, J H; Liu, C C; Kim, J H; Markman, T M; Lenz, F A

    2014-08-15

    The non-phase-locked EEG response to painful stimuli has usually been characterized as decreased oscillatory activity (event-related desynchronization, ERD) in the alpha band. Increased activity (event-related synchronization, ERS) in the gamma band has been reported more recently. We have now tested the hypothesis that the non-phase-locked responses to nonpainful electric cutaneous stimuli are different from those to painful cutaneous laser stimuli when the baseline salience of the two stimuli is the same and the salience during the protocol is modulated by count laser and count electric tasks. Both of these stimuli were presented in random order in a single train at intensities that produced the same baseline salience in the same somatic location. The response to the laser stimulus was characterized by five windows (designated windows I-V) in the time-frequency domain: early (200-400 ms) and late (600-1,400 ms) delta/theta ERS, 500-900 ms alpha ERD, 1,200-1,600 ms beta ERS (rebound), and 800-1,200 ms gamma ERS. Similar ERS/ERD windows of activity were found for the electric stimulus. Individual participants very commonly had activity in windows consistent with the overall analysis. Linear regression of ERS/ERD for parietal channels was most commonly found for sensory (pain or unpleasantness)- or attention (salience)-related measures. Overall, the main effect for modality was found in window I-delta/theta and window V-gamma, and the Modality with Task interaction was found in all five windows. All significant interaction terms included Modality as a factor. Therefore, Modality was the most common factor explaining our results, which is consistent with our hypothesis. PMID:24848464

  20. Painful cutaneous laser stimuli induce event-related oscillatory EEG activities that are different from those induced by nonpainful electrical stimuli.

    PubMed

    Chien, J H; Liu, C C; Kim, J H; Markman, T M; Lenz, F A

    2014-08-15

    The non-phase-locked EEG response to painful stimuli has usually been characterized as decreased oscillatory activity (event-related desynchronization, ERD) in the alpha band. Increased activity (event-related synchronization, ERS) in the gamma band has been reported more recently. We have now tested the hypothesis that the non-phase-locked responses to nonpainful electric cutaneous stimuli are different from those to painful cutaneous laser stimuli when the baseline salience of the two stimuli is the same and the salience during the protocol is modulated by count laser and count electric tasks. Both of these stimuli were presented in random order in a single train at intensities that produced the same baseline salience in the same somatic location. The response to the laser stimulus was characterized by five windows (designated windows I-V) in the time-frequency domain: early (200-400 ms) and late (600-1,400 ms) delta/theta ERS, 500-900 ms alpha ERD, 1,200-1,600 ms beta ERS (rebound), and 800-1,200 ms gamma ERS. Similar ERS/ERD windows of activity were found for the electric stimulus. Individual participants very commonly had activity in windows consistent with the overall analysis. Linear regression of ERS/ERD for parietal channels was most commonly found for sensory (pain or unpleasantness)- or attention (salience)-related measures. Overall, the main effect for modality was found in window I-delta/theta and window V-gamma, and the Modality with Task interaction was found in all five windows. All significant interaction terms included Modality as a factor. Therefore, Modality was the most common factor explaining our results, which is consistent with our hypothesis.

  1. SOLUBLE GUANYLATE CYCLASE IS REQUIRED FOR SYSTEMIC VASODILATION BUT NOT POSITIVE INOTROPY INDUCED BY NITROXYL (HNO) in the MOUSE

    PubMed Central

    Zhu, Guangshuo; Groneberg, Dieter; Sikka, Gautam; Hori, Daijiro; Ranek, Mark J.; Nakamura, Taishi; Takimoto, Eiki; Paolocci, Nazareno; Berkowitz, Dan E.; Friebe, Andreas; Kass, David A.

    2014-01-01

    Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO.), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. These features have spawned current pharmaceutical development of HNO donors as heart failure therapeutics. HNO interacts with selective redox sensitive cysteines to effect signaling, but is also proposed to activate soluble guanylate cyclase (sGC) in vitro to induce vasodilation and potentially enhance contractility. Here we tested whether sGC stimulation is required for these HNO effects in vivo and if HNO also modifies a redox-sensitive cysteine (C42) in protein kinase G-1α (PKG1α) to control vasorelaxation. Intact mice and isolated arteries lacking the sGC-β subunit (sGCKO, results in full sGC deficiency) or expressing solely a redox-dead C42S mutant PKG1α were exposed to the pure HNO donor, CXL-1020. CXL-1020 induced dose-dependent systemic vasodilation while increasing contractility in controls; however, vasodilator effects were absent in sGCKO mice whereas contractility response remained. The CXL-1020 dose reversing 50% of pre-constricted force in aortic rings was ~400-fold greater in sGCKO than controls. Cyclic-GMP and cAMP levels were unaltered in myocardium exposed to CXL-1020 despite its inotropicvasodilator activity. In PKG1αC42S mice, CXL-1020 induced identical vasorelaxation in vivo and in isolated aortic and mesenteric vessels as in littermate controls. In both groups, dilation was near fully blocked by pharmacologically inhibiting sGC. Thus, sGC and cGMP-dependent signaling are necessary and sufficient for HNO-induced vasodilation in vivo, but are not required for positive inotropic action. Redox modulation of PKG1α is not a mechanism for HNO-mediated vasodilation. PMID:25452469

  2. AVP-induced pulmonary vasodilation during specific V1 receptor block in conscious dogs.

    PubMed

    Nyhan, D P; Clougherty, P W; Murray, P A

    1987-09-01

    Our objectives were 1) to determine whether exogenously administered arginine vasopressin (AVP) can exert a vasoactive influence on the pulmonary circulation of conscious dogs during specific vasopressinergic-1 (V1) receptor block, and 2) to assess the extent to which the pulmonary vascular response to AVP during V1 receptor block is mediated by either sympathetic beta-adrenergic or cholinergic receptor activation or by cyclooxygenase pathway activation. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by stepwise constriction of the thoracic inferior vena cava to reduce Q. In dogs pretreated with a specific V1 receptor antagonist [d(CH2)5 AVP, 10 micrograms/kg iv], AVP infusion (7.6 ng.kg-1 X min-1 iv) increased (P less than 0.01) Q from 139 +/- 6 to 175 +/- 8 ml.min-1 X kg-1, and decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure: PAP-PCWP) over the entire range of Q studied (140 to 80 ml.min-1 X kg-1). This pulmonary vasodilator response to AVP during V1 block was also observed following sympathetic beta-adrenergic block alone, following combined sympathetic beta-adrenergic and cholinergic block, and following cyclooxygenase pathway inhibition. Thus exogenous administration of AVP during specific V1 receptor block results in active, nonflow-dependent pulmonary vasodilation. This pulmonary vasodilator response is not mediated by reflex activation of sympathetic beta-adrenergic or cholinergic receptors or by metabolites of the cyclooxygenase pathway over a broad range of Q. PMID:2888317

  3. Lipid emulsion inhibits vasodilation induced by a toxic dose of bupivacaine by suppressing bupivacaine-induced PKC and CPI-17 dephosphorylation but has no effect on vasodilation induced by a toxic dose of mepivacaine

    PubMed Central

    Cho, Hyunhoo; Ok, Seong Ho; Kwon, Seong Chun; Lee, Soo Hee; Baik, Jiseok; Kang, Sebin; Oh, Jiah

    2016-01-01

    Background The goal of this in vitro study was to investigate the effect of lipid emulsion on vasodilation caused by toxic doses of bupivacaine and mepivacaine during contraction induced by a protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), in an isolated endothelium-denuded rat aorta. Methods The effects of lipid emulsion on the dose-response curves induced by bupivacaine or mepivacaine in an isolated aorta precontracted with PDBu were assessed. In addition, the effects of bupivacaine on the increased intracellular calcium concentration ([Ca2+]i) and contraction induced by PDBu were investigated using fura-2 loaded aortic strips. Further, the effects of bupivacaine, the PKC inhibitor GF109203X and lipid emulsion, alone or in combination, on PDBu-induced PKC and phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17) phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) was examined by western blotting. Results Lipid emulsion attenuated the vasodilation induced by bupivacaine, whereas it had no effect on that induced by mepivacaine. Lipid emulsion had no effect on PDBu-induced contraction. The magnitude of bupivacaine-induced vasodilation was higher than that of the bupivacaine-induced decrease in [Ca2+]i. PDBu promoted PKC and CPI-17 phosphorylation in aortic VSMCs. Bupivacaine and GF109203X attenuated PDBu-induced PKC and CPI-17 phosphorylation, whereas lipid emulsion attenuated bupivacaine-mediated inhibition of PDBu-induced PKC and CPI-17 phosphorylation. Conclusions These results suggest that lipid emulsion attenuates the vasodilation induced by a toxic dose of bupivacaine via inhibition of bupivacaine-induced PKC and CPI-17 dephosphorylation. This lipid emulsion-mediated inhibition of vasodilation may be partly associated with the lipid solubility of local anesthetics. PMID:27738501

  4. Complement component C3 mediates Th1/Th17 polarization in human T cell activation and cutaneous Graft-versus-Host Disease

    PubMed Central

    Ma, Qing; Li, Dan; Carreño, Roberto; Patenia, Rebecca; Tsai, Kenneth Y.; Xydes-Smith, Marika; Alousi, Amin M.; Champlin, Richard E.; Sale, George E.; Afshar-Kharghan, Vahid

    2015-01-01

    The complement system has been shown to regulate T cell activation and alloimmune responses in graft-versus-host disease (GVHD). Mice deficient in the central component of complement system C3 have significantly lower GVHD-related mortality/morbidity and C3 modulates Th1/Th17 polarization in mouse GVHD. To investigate whether anti-complement therapy has any impact on human T cell activation, a drug candidate Compstatin was used to inhibit C3 activation in this study. We found the frequency of IFN-γ (Th1), IL-4 (Th2), IL-17 (Th17), IL-2 and TNF-α producing cells were significantly reduced among activated CD4+ cells in the presence of Compstatin. Compstatin treatment decreased the proliferation of both CD4+ and CD8+ T cells upon TCR stimulation. However, Compstatin does not affect the production of IL-2 and TNF-α in activated CD8+ T cells, and the differentiation of CD8+ T cells into distinct memory and effector subsets remained intact. Furthermore, we examined complement deposition in the skin and lip biopsy samples of patients diagnosed with cutaneous GVHD. C3 deposition was detected in the squamous epithelium and dermis, blood vessels and damaged sweat glands, and associated with gland damage and regeneration. We conclude that C3 mediates Th1/Th17 polarization in human T cell activation and skin GVHD in patients. PMID:24777193

  5. [Primary cutaneous plasmacytoma].

    PubMed

    Dhouib Sellami, Rym; Sassi, Samia; Mrad, Karima; Abess, Imen; Driss, Maha; Ben Romdhane, Khaled

    2007-04-01

    Primary cutaneous plasmacytoma (PCP) is a rare cutaneous B cell lymphoma. We report a case of PCP in a 64 year old woman presenting with a nodular lesion of the left cheek. Histologically, the lesion was composed predominately of variably maturated plasma cells with monotypic expression of lambda chain. Extracutaneous localizations of the disease had been excluded. The prognosis of PCP is better than that of the metastatic cutaneous lesion of myeloma. The main prognosis factors are the size tumor and clinical presentation (solitary, versus multiple lesions). Solitary lesions of the PCP are treated by surgical excision and sometimes local radiotherapy. PMID:17909472

  6. Cutaneous lymphatic sporotrichosis.

    PubMed

    Anandi, V; Kurien, T; Jacob, M; Koshi, G

    1994-01-01

    The first case of cutaneous lymphatic sporotrichosis from Nagaland and a case of cutaneous sporotrichosis from Kerala who had acquired infection from Assam are reported. The diagnosis in both cases were established by isolating Sporothrix schenckii from multiple cutaneous lesions. The dimorphic nature of fungus was established in vitro by demonstrating the mycelial phase at 25-30 degrees C and yeast phase at 37 degrees C and pathogenicity to white mice. Both the patients were successfully treated with oral administration of potassium iodide for 3 months. PMID:8088907

  7. Cutaneous tuberculosis in children.

    PubMed

    Sethuraman, Gomathy; Ramesh, Venkatesh

    2013-01-01

    Cutaneous tuberculosis is a rare form of extrapulmonary tuberculosis that accounts for 1% to 2% of cases. Childhood skin tuberculosis represents 18% to 82% of all cutaneous tuberculosis cases. Scrofuloderma and lupus vulgaris are the two most common clinical forms in children. An increase in the number of tuberculids, especially lichen scrofulosorum, has been observed in the last several years. Cutaneous tuberculosis in children can be severe and have a protracted course. Multiplicity of lesions and multifocal disseminated involvement in scrofuloderma and lupus vulgaris is common. Scrofuloderma progressing to gummatous lesions (scrofulous gumma) is mostly described in children. Morbidities and deformities are more severe in children.

  8. Inhibition of PPARγ during rat pregnancy causes intrauterine growth restriction and attenuation of uterine vasodilation

    PubMed Central

    Gokina, Natalia I.; Chan, Siu-Lung; Chapman, Abbie C.; Oppenheimer, Karen; Jetton, Thomas L.; Cipolla, Marilyn J.

    2013-01-01

    Decreased peroxisome proliferator-activated receptor gamma (PPARγ) activity is thought to have a major role in preeclampsia through abnormal placental development. However, the role of PPARγ in adaptation of the uteroplacental vasculature that may lead to placental hypoperfusion and fetal growth restriction during pregnancy is not known. Here, pregnant Sprague–Dawley rats (n = 11/group) were treated during the second half of pregnancy with the PPARγ inhibitor GW9662 (10 mg/kg/day in food) or vehicle. Pregnancy outcome and PPARγ mRNA, vasodilation and structural remodeling were determined in maternal uterine and mesenteric arteries. PPARγ was expressed in uterine vascular tissue of both non-pregnant and pregnant rats with ~2-fold greater expression in radial vs. main uterine arteries. PPARγ mRNA levels were significantly higher in uterine compared to mesenteric arteries. GW9662 treatment during pregnancy did not affect maternal physiology (body weight, glucose, blood pressure), mesenteric artery vasodilation or structural remodeling of uterine and mesenteric vessels. Inhibition of PPARγ for the last 10 days of gestation caused decreased fetal weights on both day 20 and 21 of gestation that was associated with impaired vasodilation of radial uterine arteries in response to acetylcholine and sodium nitroprusside. These results define an essential role of PPARγ in the control of uteroplacental vasodilatory function during pregnancy, an important determinant of blood flow to the placenta and fetus. Strategies that target PPARγ activation in the uterine circulation could have important therapeutic potential in treatment of pregnancies complicated by hypertension, diabetes or preeclampsia. PMID:23888144

  9. The sesquiterpene (-)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis.

    PubMed

    Corpas-López, V; Merino-Espinosa, G; Díaz-Sáez, V; Morillas-Márquez, F; Navarro-Moll, M C; Martín-Sánchez, J

    2016-10-01

    Cutaneous leishmaniasis treatment remains challenging due to the absence of a satisfactory treatment. The screening of natural compounds is a valuable strategy in the search of new drugs against leishmaniasis. The sesquiterpene (-)-α-bisabolol is effective in vivo against visceral leishmaniasis due to Leishmania infantum, but its mechanism of action remains elusive. The aim of this study is to validate this promising compound against the causative species of Old World cutaneous leishmaniasis and to get an insight into its antileishmanial mode of action. The compound was evaluated on L. tropica promastigotes and intracellular amastigotes using bone marrow-derived macrophages and its cytotoxicity was evaluated on L929 fibroblasts. The reactive oxygen species generation was evaluated using a sensitive probe. Mitochondrial depolarization was assessed evaluating the fluorescence due to rhodamine 123 in a flow cytometer. Apoptosis was investigated by measuring the fluorescence due to annexin V and propidium iodide in a flow cytometer. The ultrastructure of treated promastigotes and intracellular amastigotes was analysed through transmission electron microscopy. (-)-α-Bisabolol was active against L. tropica intracellular amastigotes displaying an inhibitory concentration 50 % of 25.2 µM and showing low cytotoxicity. This compound induced time and dose-dependent oxidative stress, mitochondrial depolarization and phosphatidilserine externalization (a marker of apoptosis). These effects were noticed at a low concentration and short exposure time. In the ultrastructural analyses, the treated parasites showed mitochondrial disruption, presence of electron-dense structures and chromatin condensation. These results suggest that this natural compound induces oxidative stress and mitochondrial-dependent apoptosis on Leishmania without disturbing the plasma membrane. PMID:27539477

  10. The sesquiterpene (-)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis.

    PubMed

    Corpas-López, V; Merino-Espinosa, G; Díaz-Sáez, V; Morillas-Márquez, F; Navarro-Moll, M C; Martín-Sánchez, J

    2016-10-01

    Cutaneous leishmaniasis treatment remains challenging due to the absence of a satisfactory treatment. The screening of natural compounds is a valuable strategy in the search of new drugs against leishmaniasis. The sesquiterpene (-)-α-bisabolol is effective in vivo against visceral leishmaniasis due to Leishmania infantum, but its mechanism of action remains elusive. The aim of this study is to validate this promising compound against the causative species of Old World cutaneous leishmaniasis and to get an insight into its antileishmanial mode of action. The compound was evaluated on L. tropica promastigotes and intracellular amastigotes using bone marrow-derived macrophages and its cytotoxicity was evaluated on L929 fibroblasts. The reactive oxygen species generation was evaluated using a sensitive probe. Mitochondrial depolarization was assessed evaluating the fluorescence due to rhodamine 123 in a flow cytometer. Apoptosis was investigated by measuring the fluorescence due to annexin V and propidium iodide in a flow cytometer. The ultrastructure of treated promastigotes and intracellular amastigotes was analysed through transmission electron microscopy. (-)-α-Bisabolol was active against L. tropica intracellular amastigotes displaying an inhibitory concentration 50 % of 25.2 µM and showing low cytotoxicity. This compound induced time and dose-dependent oxidative stress, mitochondrial depolarization and phosphatidilserine externalization (a marker of apoptosis). These effects were noticed at a low concentration and short exposure time. In the ultrastructural analyses, the treated parasites showed mitochondrial disruption, presence of electron-dense structures and chromatin condensation. These results suggest that this natural compound induces oxidative stress and mitochondrial-dependent apoptosis on Leishmania without disturbing the plasma membrane.

  11. [Penile sporotrichoid cutaneous leishmaniasis].

    PubMed

    Masmoudi, A; Boudaya, S; Bouzid, L; Frigui, F; Meziou, T J; Akrout, F; Turki, H; Zahaf, A

    2005-12-01

    The localisation of the cutaneous leishmaniasis of L. major at the penis level is rare, we report here a new observation. Mr K. R aged of 41, without known pathological background presented for 20 days a nodular lesion of the anterior face of the neck, 2 juxtaposed ulcerated nodular lesions of the left wrist. He presented also subcutaneous nodules ranged linearly and extended to the root of the penis. Theses lesions were covered by an erythematous or ulcerated skin. The smear made from the genital lesions of the penis confirmed the diagnosis of a cutaneous leishmaniasis. The evolution was favourable after a 21 days treatment by doxycyclin after an interval of one week. Our observation was specific by the localisation of the cutaneous leishmaniasis and by the clinical form. This shows that in our region cutaneous leishmaniasis is characterised by different clinical symptoms. PMID:16425718

  12. Role of angiotensin II and alpha-adrenergic receptors during estrogen-induced vasodilation in ewes.

    PubMed

    Davis, L E; Magness, R R; Rosenfeld, C R

    1992-11-01

    Estradiol-17 beta (E2 beta) produces uterine and systemic vasodilation in nonpregnant ewes without altering mean arterial pressure (MAP). Mechanisms responsible for maintaining MAP and thus uterine blood flow (UBF) may include activation of the renin-angiotensin and/or adrenergic systems. We therefore investigated the effects of systemic blockade of angiotensin II (ANG II) and/or alpha-adrenergic receptors in nonpregnant, castrated ewes, using saralasin (Sar) and/or phentolamine (Phen) in the presence or absence of intravenous E2 beta (1.0 microgram/kg). In nonestrogenized ewes neither antagonist alone had substantial cardiovascular effects; however, Sar + Phen decreased systemic vascular resistance (SVR) 20 +/- 7.4% (SE) and increased heart rate (HR) 50 +/- 19% (P < 0.01); MAP and UBF were unaffected. Following E2 beta treatment SVR fell 17 +/- 2.4% (P < 0.01), UBF increased more than fourfold, and MAP was unchanged. Compared with E2 beta alone, Phen + E2 beta decreased SVR 42 +/- 4.7%, and MAP fell 11 +/- 1.8% (P < 0.05) despite 40-50% increases in HR and cardiac output (P < 0.05). Responses to Sar + E2 beta were similar to E2 beta alone, except for a fall in MAP, whereas responses to Sar + Phen + E2 beta resembled those of Phen + E2 beta. E2 beta-induced uterine vasodilation was unaltered by Sar and/or Phen. During E2 beta-induced vasodilation, MAP is maintained by enhanced activation of the alpha-adrenergic and renin-angiotensin systems; however, uterine vascular responses to E2 beta are independent of both systems and perfusion pressure.

  13. Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance.

    PubMed

    Andrews, Karen L; Lumsden, Natalie G; Farry, Julie; Jefferis, Ann-Maree; Kemp-Harper, Barbara K; Chin-Dusting, Jaye P F

    2015-07-01

    Pre-clinical studies have identified nitroxyl (HNO), the reduced congener of nitric oxide (NO•), as a potent vasodilator which is resistant to tolerance development. The present study explores the efficacy of HNO in human blood vessels and describes, for the first time, a vasodilator for humans that is not susceptible to tolerance. Human radial arteries and saphenous veins were obtained from patients undergoing coronary artery graft surgery and mounted in organ baths. Repeated vasodilator responses to the HNO donor Angeli's salt (AS) and NO• donor glyceryl trinitrate (GTN) were determined. AS- and GTN-induced concentration-dependent vasorelaxation of both human radial arteries (AS pEC50: 6.5 ± 0.2; -log M) and saphenous veins (pEC50: 6.7 ± 0.1) with similar potency. In human radial arteries, GTN-induced relaxation was reduced by the NO• scavenger hydroxocobalamin (HXC; P<0.05) but was unaffected by the HNO scavenger L-cysteine. Alternately, AS was unaffected by HXC but was reduced by L-cysteine (5-fold shift, P<0.05). The sGC (soluble guanylate cyclase) inhibitor ODQ abolished responses to both AS and GTN in arteries and veins (P<0.05). Inhibition of voltage-dependent potassium channels (Kv channels) with 4-AP also significantly reduced responses to AS (pEC50: 5.5) and GTN, suggesting that the relaxation to both redox congeners is cGMP- and Kv channel-dependent. Critically, a concentration-dependent development of tolerance to GTN (1 and 10 μM; P<0.05), but not to AS, was observed in both saphenous veins and radial arteries. Like GTN, the HNO donor AS causes vasorelaxation of human blood vessels via activation of a cGMP-dependent pathway. Unlike GTN, however, it does not develop tolerance in human blood vessels.

  14. Vasodilator factors in the systemic and local adaptations to pregnancy

    PubMed Central

    Valdes, Gloria; Kaufmann, Peter; Corthorn, Jenny; Erices, Rafaela; Brosnihan, K Bridget; Joyner-Grantham, JaNae

    2009-01-01

    We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the

  15. Nebivolol: vasodilator properties and evidence for relevance in treatment of cardiovascular disease.

    PubMed

    Howlett, Jonathan G

    2014-05-01

    β-adrenergic blocking agents, a pharmacologically diverse class of cardiovascular medications, are recommended as first-line treatment for patients with hypertension and concomitant structural heart disease, and for angina and heart failure. Many within-class differences exist, from pharmacokinetics and pharmacodynamics to ancillary effects, such as intrinsic sympathomimetic activity, antiarrhythmic activity, α-1 adrenergic receptor blockade affinity, and direct vasodilation. Nebivolol is a third-generation, β1 selective, long acting β-blocker, which causes direct vasodilation via endothelium-dependent nitric oxide stimulation. The vasodilatory actions of nebivolol might result in clinical effects with some distinct properties. Differences from other β-blockers might include improvement of endothelial function, enhancement of forward flow in muscular resistance arteries, maintenance of exercise tolerance, and overall improved tolerability, side effect profile, and adherence. Nebivolol has been shown to be a clinically effective β-blocker for treatment as initial or add-on therapy for systemic hypertension, as an antianginal agent, and as therapy for patients with heart failure. These properties position nebivolol as a treatment option for patients with hypertension and/or structural heart disease, although its precise role in the therapeutic armamentarium remains to be clarified. PMID:24750980

  16. Activation of κ Opioid Receptors in Cutaneous Nerve Endings by Conorphin-1, a Novel Subtype-Selective Conopeptide, Does Not Mediate Peripheral Analgesia.

    PubMed

    Deuis, Jennifer R; Whately, Ella; Brust, Andreas; Inserra, Marco C; Asvadi, Naghmeh H; Lewis, Richard J; Alewood, Paul F; Cabot, Peter J; Vetter, Irina

    2015-10-21

    Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach. PMID:26225903

  17. c-CBL E3 Ubiquitin Ligase is Over-Expressed in Cutaneous T-Cell Lymphoma: Its Inhibition Promotes Activation Induced Cell Death

    PubMed Central

    Wu, Jianqiang; Salva, Katrin A.; Wood, Gary S.

    2014-01-01

    Mycosis fungoides (MF) and Sezary syndrome (SS) are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death (AICD) which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS-ligand (FASL) and subsequent apoptosis through the FAS death receptor pathway. It has been known for more than a decade that TCR signaling is defective in CTCL; however, the underlying mechanism has not been apparent. In this report, we show that the E3 ubiquitin ligase, c-CBL, is over-expressed in CTCL and that its knockdown overcomes defective TCR signaling resulting in phosphorylation of PLCg1, calcium influx, ROS generation, up-regulation of FASL and extrinsic pathway apoptosis in CTCL cells expressing adequate FAS. In CTCL cells with suboptimal FAS expression, FAS can be upregulated epigenetically by derepression of the FAS promoter using methotrexate (MTX) which we showed previously has activity as a DNA methylation inhibitor. Using these combined strategies, FAS-low as well as FAS-high CTCL cells can be killed effectively. PMID:25140833

  18. Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/AKT/NFκB signaling pathways in SKH-1 hairless mice.

    PubMed

    Pal, Harish Chandra; Athar, Mohammad; Elmets, Craig A; Afaq, Farrukh

    2015-01-01

    Solar ultraviolet B (UVB) radiation has been shown to induce inflammation, DNA damage, p53 mutations and alterations in signaling pathways eventually leading to skin cancer. In this study, we investigated whether fisetin reduces inflammatory responses and modulates PI3K/AKT/NFκB cell survival signaling pathways in UVB-exposed SKH-1 hairless mouse skin. Mice were exposed to 180 mJ cm(-2) of UVB radiation on alternate days for a total of seven exposures, and fisetin (250 and 500 nmol) was applied topically after 15 min of each UVB exposure. Fisetin treatment to UVB-exposed mice resulted in decreased hyperplasia and reduced infiltration of inflammatory cells. Fisetin treatment also reduced inflammatory mediators such as COX-2, PGE2 as well as its receptors (EP1-EP4) and MPO activity. Furthermore, fisetin reduced the level of inflammatory cytokines TNFα, IL-1β and IL-6 in UVB-exposed skin. Fisetin treatment also reduced cell proliferation markers as well as DNA damage as evidenced by increased expression of p53 and p21 proteins. Further studies revealed that fisetin inhibited UVB-induced expression of PI3K, phosphorylation of AKT and activation of the NFκB signaling pathway in mouse skin. Overall, these data suggest that fisetin may be useful against UVB-induced cutaneous inflammation and DNA damage.

  19. Cutaneous histiocytosis syndromes.

    PubMed

    Roper, S S; Spraker, M K

    1985-11-01

    Cutaneous histiocytosis may take two principal forms. It is either a benign proliferative process or a relentless, progressive process with a poor prognosis. In histiocytic medullary reticulosis, histiocytes demonstrate nuclear atypia and the outcome is uniformly fatal. Benign cephalic histiocytosis X causes lesions similar to those of histiocytosis X, but Langerhans' cells are absent. In congenital self-healing histiocytosis X, the Letterer-Siwe-like cutaneous infiltrate contains Langerhans' cells, but the lesions heal spontaneously without treatment. The nodular cutaneous lesions of juvenile xanthogranuloma appear in infancy and resolve without treatment; however, the higher percentage (10%) of associated ocular lesions may lead to glaucoma and blindness. In histiocytosis X, the cutaneous lesions show a marked proliferation of Langerhans' cells, with prognosis dependent on the patient's age and the extent of organ dysfunction. Patients who survive the acute form of the disease may develop diabetes insipidus, growth retardation, pulmonary fibrosis, and biliary cirrhosis. A subtle immunologic defect has been identified in patients with histiocytosis X, yet the pathogenesis of the disease is still speculative. Familial disease occurring in early infancy should be differentiated from complete or partial immunodeficiency syndromes. Guidelines for evaluating patients with cutaneous histiocytosis are reviewed.

  20. Cutaneous metastases of hepatocellular carcinoma.

    PubMed

    Lazaro, M; Serrano, M L; Allende, I; Ratón, J A; Acebo, E; Diaz-Perez, J L

    2009-12-01

    Cutaneous metastases are an unusual finding that may present as the first sign of an internal neoplasia. A case of cutaneous metastases of hepatocellular carcinoma, which may often involve other organs but very rarely metastases to the skin, is reported.

  1. Cutaneous signs of piety.

    PubMed

    Ramesh, V; Al Aboud, Khalid

    2014-07-01

    It is important for dermatologists to be aware of cutaneous changes related to religious practices to help in their recognition and management. The anatomic location of cutaneous lesions associated with friction from praying varies based on religious practice. Allergic contact dermatitis from products and substances commonly used in worshipping also vary by religion. Some religious practices may render individuals prone to infections that manifest on the skin. Tattoos of godly figures also may adorn the body. Religious practices also have been implicated in cases of urticaria, köbnerization, and leukoderma. This article reviews the clinical presentation of some of the most common cutaneous changes that occur in individuals who practice the following religions: Christianity, Islam, Judaism, Hinduism, and Sikhism. PMID:25101349

  2. Primary cutaneous nocardiosis.

    PubMed

    Jiang, Shan; Jiang, Guan; Lei, Tie-Chi

    2014-11-01

    Nocardiosis is a rare human infection due to ubiquitous soil born gram-positive, filametous aerobic bacteria. First signs are frequently cutaneous either as part of systemic infection disseminated to the skin, or as primary cutaneous inoculation. An 88 years old man presented with a 3-day history of red papules and pustules with pain on his forehead. The combination of the unusual clinical presentation, laboratory examinations, and a favorable response to co-trimoxazole therapy were consistent with a diagnosis of primary cuteneous nocardiosis. Early recognition and treatment of the disease will improve the cure rate. PMID:25518763

  3. The cutaneous porphyrias.

    PubMed

    Schulenburg-Brand, Danja; Katugampola, Ruwani; Anstey, Alexander V; Badminton, Michael N

    2014-07-01

    The porphyrias are a group of mainly inherited disorders of heme biosynthesis where accumulation of porphyrins and/or porphyrin precursors gives rise to 2 types of clinical presentation: cutaneous photosensitivity and/or acute neurovisceral attacks. The cutaneous porphyrias present with either bullous skin fragility or nonbullous acute photosensitivity. This review discusses the epidemiology, pathogenesis, clinical presentation, laboratory diagnosis, complications, and current approach to porphyria management. Although focusing mainly on their dermatological aspects, the article also covers the management of acute porphyria, which by virtue of its association with variegate porphyria and hereditary coproporphyria, may become the responsibility of the clinical dermatologist.

  4. Cutaneous histiocytosis in dogs.

    PubMed

    Mays, M B; Bergeron, J A

    1986-02-15

    Multifocal cutaneous histiocytic lesions were recognized in 9 dogs. Clinically, the dogs had multiple erythematous plaques or nodules in the skin (1 to 5 cm diameter). Histologically, the lesions were comprised of dermal or pannicular infiltrates of large histiocytic cells, with varying numbers of other inflammatory cells intermixed. By electron microscopy, the cells resembled those of canine cutaneous histiocytoma. The lesions seemed to wax and wane and appeared in new sites, regardless of treatment. The dogs ranged in age from 2 to 13 years; 7 dogs were under 6 years of age. Both sexes and various breeds were represented. An infectious agent could not be identified.

  5. The cutaneous porphyrias.

    PubMed

    Schulenburg-Brand, Danja; Katugampola, Ruwani; Anstey, Alexander V; Badminton, Michael N

    2014-07-01

    The porphyrias are a group of mainly inherited disorders of heme biosynthesis where accumulation of porphyrins and/or porphyrin precursors gives rise to 2 types of clinical presentation: cutaneous photosensitivity and/or acute neurovisceral attacks. The cutaneous porphyrias present with either bullous skin fragility or nonbullous acute photosensitivity. This review discusses the epidemiology, pathogenesis, clinical presentation, laboratory diagnosis, complications, and current approach to porphyria management. Although focusing mainly on their dermatological aspects, the article also covers the management of acute porphyria, which by virtue of its association with variegate porphyria and hereditary coproporphyria, may become the responsibility of the clinical dermatologist. PMID:24891059

  6. Anti-nucleosome and anti-chromatin antibodies are present in active systemic lupus erythematosus but not in the cutaneous form of the disease.

    PubMed

    Souza, A; da Silva, L M; Oliveira, F R; Roselino, A M F; Louzada-Junior, P

    2009-03-01

    The objective of this study is to investigate the presence of anti-nucleosome (anti-NCS) and anti-chromatin (anti-CRT) antibodies in patients with cutaneous lupus erythematosus (CLE) compared with active and inactive systemic lupus erythematosus (SLE). A total of 154 subjects were evaluated: 54 patients presenting CLE, 66 patients with active SLE and 34 with inactive SLE. Lupus activity was assessed using the disease activity index (SLEDAI). Anti-NCS and anti-CRT antibodies were detected by enzyme-linked immunosorbent assay (ELISA). Only one of 54 patients with CLE tested positive for both anti-NCS and anti-CRT antibodies. The prevalence of anti-CRT antibodies was significantly higher in active SLE (84.8%) when compared with inactive SLE (26.4%) and CLE (1.8%) (P < 0.001). Anti-NCS antibodies were also more prevalent in active SLE patients (74.2%) than inactive SLE (11.7%) and CLE patients (1.8%) (P < 0.001). The presence of anti-CRT and anti-NCS antibodies was correlated to disease activity in patients with SLE (r = 0.4937, r = 0.5621, respectively). Furthermore, the detection of both antibodies was correlated with disease activity in patients with SLE who tested negative for anti-dsDNA antibodies (r = 0.4754 for anti-NCS and r = 0.4281 for anti-CRT). The presence of these two auto-antibodies was strongly associated with renal damage in patients with SLE (OR = 13.1, for anti-CRT antibodies and OR = 25.83, for anti-NCS antibodies). The anti-NCS and anti-CRT antibodies were not found in CLE. In patients with SLE, there is a correlation of these antibodies with disease activity and active nephritis. When compared with anti-dsDNA antibodies, anti-NCS and anti-CRT antibodies were more sensitive in detecting disease activity and kidney damage in lupus patients.

  7. Blood pressure lowering, vasodilator and cardiac-modulatory potential of Carum roxburghianum seed extract.

    PubMed

    Khan, Munasib; Khan, Arif-ullah; Najeeb-ur-Rehman; Gilani, Anwarul-Hassan

    2015-01-01

    In current study, we describe blood pressure (BP)-lowering, endothelium-dependent, and independent vasodilator and cardio-modulatory actions of Carum roxburghianum seed. The crude extract of C. roxburghianum seed (Cr.Cr) induced dose-dependent (10-100 mg/kg) fall in arterial BP of anaesthetized rats. In isolated rabbit aorta, Cr.Cr (0.3-10 mg/mL) inhibited high K+ (80 mM) and phenylephrine (PE, 1 µM)-induced contractions, like verapamil and papaverine. In endothelium-intact rat aortic preparations, Nω-nitro-L-arginine methyl ester hydrochloride-sensitive vasodilator activity was observed with Cr.Cr, which also relaxed endothelium-denuded aorta tissues. In guinea-pig atria, Cr.Cr initially caused mild cardiac stimulation, followed by inhibition, as shown by papaverine. These results reveal that cardiovascular effects of C. roxburghianum seed extract are mediated possibly through combination of Ca++ antagonist, nitric oxide modulating and phosphodiesterase inhibitory mechanisms, though further in-depth studies are required for elucidating precise mode of action.

  8. Blood pressure lowering, vasodilator and cardiac-modulatory potential of Carum roxburghianum seed extract.

    PubMed

    Khan, Munasib; Khan, Arif-ullah; Najeeb-ur-Rehman; Gilani, Anwarul-Hassan

    2015-01-01

    In current study, we describe blood pressure (BP)-lowering, endothelium-dependent, and independent vasodilator and cardio-modulatory actions of Carum roxburghianum seed. The crude extract of C. roxburghianum seed (Cr.Cr) induced dose-dependent (10-100 mg/kg) fall in arterial BP of anaesthetized rats. In isolated rabbit aorta, Cr.Cr (0.3-10 mg/mL) inhibited high K+ (80 mM) and phenylephrine (PE, 1 µM)-induced contractions, like verapamil and papaverine. In endothelium-intact rat aortic preparations, Nω-nitro-L-arginine methyl ester hydrochloride-sensitive vasodilator activity was observed with Cr.Cr, which also relaxed endothelium-denuded aorta tissues. In guinea-pig atria, Cr.Cr initially caused mild cardiac stimulation, followed by inhibition, as shown by papaverine. These results reveal that cardiovascular effects of C. roxburghianum seed extract are mediated possibly through combination of Ca++ antagonist, nitric oxide modulating and phosphodiesterase inhibitory mechanisms, though further in-depth studies are required for elucidating precise mode of action. PMID:24785464

  9. NK Cell Activity Differs between Patients with Localized and Diffuse Cutaneous Leishmaniasis Infected with Leishmania mexicana: A Comparative Study of TLRs and Cytokines

    PubMed Central

    Cañeda-Guzmán, Isabel Cristina; Salaiza-Suazo, Norma; Fernández-Figueroa, Edith A.; Carrada-Figueroa, Georgina; Aguirre-García, Magdalena; Becker, Ingeborg

    2014-01-01

    Leishmania mexicana causes localized (LCL) or diffuse cutaneous leishmaniasis (DCL). The cause of dissemination in DCL remains unknown, yet NK cells possibly play a role in activating leishmanicidal mechanisms during innate and adaptive immune responses. We had previously shown that Leishmania lipophosphoglycan (LPG) is a ligand for TLR2, activating human NK cells. We have now analyzed NK cells in LCL and DCL patients. NK numbers and effector mechanisms differed drastically between both groups of patients: DCL patients showed reduced NK cell numbers; diminished IFN-γ and TNF-α production; and lower TLR2, TLR1, and TLR6 expression as compared to LCL patients. The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients. NK cell response was further analyzed according to gender, age, and disease evolution in LCL patients showing that female patients produced higher IFN-γ levels throughout the disease progression, whereas TLR2 expression diminished in both genders with prolonged disease evolution and age. We furthermore show the activation pathway of LPG binding to TLR2 and demonstrated that TLR2 forms immunocomplexes with TLR1 and TLR6. In addition to the reduced NK cell numbers in peripheral blood, DCL patients also showed reduced NK cell numbers in the lesions. They were randomly scattered within the lesions, showing diminished cytokine production, which contrasts with those of LCL lesions, where NK cells produced IFN-γ and TNF-α and were found within organized granulomas. We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease. Our results provide new information on the contribution of NK cells in Leishmania infections of the human host. PMID:25397678

  10. NK cell activity differs between patients with localized and diffuse cutaneous leishmaniasis infected with Leishmania mexicana: a comparative study of TLRs and cytokines.

    PubMed

    Cañeda-Guzmán, Isabel Cristina; Salaiza-Suazo, Norma; Fernández-Figueroa, Edith A; Carrada-Figueroa, Georgina; Aguirre-García, Magdalena; Becker, Ingeborg

    2014-01-01

    Leishmania mexicana causes localized (LCL) or diffuse cutaneous leishmaniasis (DCL). The cause of dissemination in DCL remains unknown, yet NK cells possibly play a role in activating leishmanicidal mechanisms during innate and adaptive immune responses. We had previously shown that Leishmania lipophosphoglycan (LPG) is a ligand for TLR2, activating human NK cells. We have now analyzed NK cells in LCL and DCL patients. NK numbers and effector mechanisms differed drastically between both groups of patients: DCL patients showed reduced NK cell numbers; diminished IFN-γ and TNF-α production; and lower TLR2, TLR1, and TLR6 expression as compared to LCL patients. The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients. NK cell response was further analyzed according to gender, age, and disease evolution in LCL patients showing that female patients produced higher IFN-γ levels throughout the disease progression, whereas TLR2 expression diminished in both genders with prolonged disease evolution and age. We furthermore show the activation pathway of LPG binding to TLR2 and demonstrated that TLR2 forms immunocomplexes with TLR1 and TLR6. In addition to the reduced NK cell numbers in peripheral blood, DCL patients also showed reduced NK cell numbers in the lesions. They were randomly scattered within the lesions, showing diminished cytokine production, which contrasts with those of LCL lesions, where NK cells produced IFN-γ and TNF-α and were found within organized granulomas. We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease. Our results provide new information on the contribution of NK cells in Leishmania infections of the human host. PMID:25397678

  11. Evaluation of in vitro activity of two topical products against three organisms isolated from canine referral patients with otitis externa and cutaneous pyoderma.

    PubMed

    Okwumabua, O; Goodman, F; Elfassy, O

    2000-01-01

    Canine otitis externa and cutaneous pyoderma are common problems that are often associated with Staphylococcus intermedius, Pseudomonas aeruginosa, and Malassezia pachydermatis. In vitro activity of two topical products against these organisms isolated from canine referral patients were evaluated. Organisms were grown and diluted to a concentration equivalent to 10(7) colony-forming units (CFU) per mL and exposed to either a 0 or 1/5 dilution of Hexadene Flush with Spherulites (Virbac Animal Health Inc, Fort Worth, TX) or a 1/5 or 1/25 dilution of ResiCHLOR Lotion with Spherulites (Virbac Animal Health Inc, Fort Worth, TX) at time intervals from 1 to 30 minutes. Results showed that all three organisms were killed within 1 minute of contact time at 0 and 1/5 dilution of the flush. The lotion diluted to 1/5 also killed all three organisms. At 1/25 dilution, this lotion killed S. intermedius and P. aeruginosa within 1 minute of contact time, whereas M. pachydermatis was killed after 1 minute. The findings suggest that the two topical products exhibit efficacy against these common skin pathogens in vitro and can be useful in their clinical management.

  12. Anti-herpes simplex virus (HSV-1) activity of oxyresveratrol derived from Thai medicinal plant: mechanism of action and therapeutic efficacy on cutaneous HSV-1 infection in mice.

    PubMed

    Chuanasa, Taksina; Phromjai, Jurairatana; Lipipun, Vimolmas; Likhitwitayawuid, Kittisak; Suzuki, Mikiko; Pramyothin, Pornpen; Hattori, Masao; Shiraki, Kimiyasu

    2008-10-01

    Oxyresveratrol, a major compound purified from Artocarpus lakoocha, a Thai traditional medicinal plant, was evaluated for its mechanism of action and therapeutic efficacy on cutaneous herpes simplex virus (HSV) infection in mice. The inhibitory concentrations for 50% HSV-1 plaque formation of oxyresveratrol, three clinical isolates, thymidine kinase (TK)-deficient and phosphonoacetic acid (PAA)-resistant HSV-1 were 19.8, 23.3, 23.5, 24.8, 25.5 and 21.7microg/ml, respectively. Oxyresveratrol exhibited the inhibitory activity at the early and late phase of viral replication and inhibited the viral replication with pretreatment in one-step growth assay of HSV-1 and HSV-2. Oxyresveratrol inhibited late protein synthesis at 30microg/ml. The combination of oxyresveratrol and acyclovir (ACV) produced synergistic anti-HSV-1 effect, as characterized by the isobologram of plaque inhibition. Mice orally treated with oxyresveratrol (500mg/kg/dose) dose at 8 h before and three times daily had significant delay in herpetic skin lesion development (P<0.05). Topical application of 30% oxyresveratrol ointment five times daily significantly delayed the development of skin lesions and protected mice from death (P<0.0001).

  13. Important cutaneous manifestations of inflammatory bowel disease

    PubMed Central

    Trost, L; McDonnell, J

    2005-01-01

    Inflammatory bowel disease (IBD) has many extraintestinal manifestations. Cutaneous manifestations are usually related to the activity of the bowel disease but may have an independent course. Anyone presenting with IBD should be examined for cutaneous manifestations. Pyoderma gangrenosum is a severe painful ulcerating disease that requires moist wound management and, in the absence of secondary infection, systemic corticosteroids, cyclosporine, or both. Infliximab may also be used. Erythema nodosum is a common cause of tender red nodules of the shins. Management includes leg elevation, NSAIDs, and potassium iodide. Oral manifestations of IBD include aphthous stomatitis, mucosal nodularity (cobblestoning), and pyostomatitis vegetans. Treatment should be directed both at the cutaneous lesions and at the underlying systemic condition. PMID:16143688

  14. Current approach to cutaneous mastocytosis in childhood

    PubMed Central

    Tamay, Zeynep; Özçeker, Deniz

    2016-01-01

    Mastocytosis is a heterogeneous disorder characterized by clonal proliferation and accumulation of mast cells in one of more organs which may lead to different clinical pictures. Pathological increase and activation of mast cells in various tissues can cause different clinical pictures. Cutaneous mastocytosis limited to the skin is the most typical clinical picture observed in children and systemic mastocytosis is very rare in the pediatric age group. The diagnosis of cutaneous mastocytosis is based on clinical findings, but is often delayed due to lack of clinical awareness of the disease and lack of its consideration in the differential diagnosis. This article focuses on the current diagnosis, management and treatment of cutaneous mastocytosis in children in order to increase awareness about this issue.

  15. mRNA Decapping Enzyme 1a (Dcp1a)-induced Translational Arrest through Protein Kinase R (PKR) Activation Requires the N-terminal Enabled Vasodilator-stimulated Protein Homology 1 (EVH1) Domain*

    PubMed Central

    Dougherty, Jonathan D.; Reineke, Lucas C.; Lloyd, Richard E.

    2014-01-01

    We have shown previously that poliovirus infection disrupts cytoplasmic P-bodies in infected mammalian cells. During the infectious cycle, poliovirus causes the directed cleavage of Dcp1a and Pan3, coincident with the dispersion of P-bodies. We now show that expression of Dcp1a prior to infection, surprisingly, restricts poliovirus infection. This inhibition of infection was independent of P-body formation because expression of GFP-Dcp1a mutants that cannot enter P-bodies restricted poliovirus infection similar to wild-type GFP-Dcp1a. Expression of wild-type or mutant GFP-Dcp1a induced phosphorylation of eIF2α through the eIF2α kinase protein kinase R (PKR). Activation of PKR required the amino-terminal EVH1 domain of Dcp1a. This PKR-induced translational inhibition appears to be specific to Dcp1a because the expression of other P-body components, Pan2, Pan3, Ccr4, or Caf1, did not result in the inhibition of poliovirus gene expression or induce eIF2α phosphorylation. The translation blockade induced by Dcp1a expression suggests novel signaling linking RNA degradation/decapping and regulation of translation. PMID:24382890

  16. mRNA decapping enzyme 1a (Dcp1a)-induced translational arrest through protein kinase R (PKR) activation requires the N-terminal enabled vasodilator-stimulated protein homology 1 (EVH1) domain.

    PubMed

    Dougherty, Jonathan D; Reineke, Lucas C; Lloyd, Richard E

    2014-02-14

    We have shown previously that poliovirus infection disrupts cytoplasmic P-bodies in infected mammalian cells. During the infectious cycle, poliovirus causes the directed cleavage of Dcp1a and Pan3, coincident with the dispersion of P-bodies. We now show that expression of Dcp1a prior to infection, surprisingly, restricts poliovirus infection. This inhibition of infection was independent of P-body formation because expression of GFP-Dcp1a mutants that cannot enter P-bodies restricted poliovirus infection similar to wild-type GFP-Dcp1a. Expression of wild-type or mutant GFP-Dcp1a induced phosphorylation of eIF2α through the eIF2α kinase protein kinase R (PKR). Activation of PKR required the amino-terminal EVH1 domain of Dcp1a. This PKR-induced translational inhibition appears to be specific to Dcp1a because the expression of other P-body components, Pan2, Pan3, Ccr4, or Caf1, did not result in the inhibition of poliovirus gene expression or induce eIF2α phosphorylation. The translation blockade induced by Dcp1a expression suggests novel signaling linking RNA degradation/decapping and regulation of translation. PMID:24382890

  17. Maximal vasodilation does not eliminate the vascular waterfall in the canine hindlimb.

    PubMed

    Shrier, I; Magder, S

    1995-11-01

    Previous studies have shown that blood flow through skeletal muscle is regulated by changes in an arteriolar vascular waterfall [critical pressure (Pcrit)] and a proximal (arterial) resistance (Ra) element. To determine whether Pcrit still exists during maximal vasodilation, we pump perfused vascularly isolated canine hindlimbs. We set outflow pressure to zero and measured Pcrit, perfusion pressure (Pper), and regional elastic recoil pressure (Pcl; by a stop-flow technique) and calculated both Ra and venous resistance before and after maximal vasodilation with adenosine and nitroprusside. Pcrit was 56.4 +/- 5.1 mmHg before vasodilation and decreased to 11.0 +/- 0.6 mmHg after vasodilation, which was less than the downstream pressure in the venous compliant region (Pel). Therefore, Pcrit should not have affected flow at normal Pper levels under vasodilated conditions. However, we could still measure Pcrit because our technique allowed Pel to decline and Pcrit becomes apparent once Pel < Pcrit. With vasodilation, Ra decreased to < 8.1 +/- 2.6% and Rv decreased to 41 +/- 6% of control values. In contrast to the nonvasodilated vasculature, increases in venous pressure during maximal vasodilation caused immediate increases in Pper. This also suggests that the vascular waterfall is inactive under conditions of maximal vasodilation. We conclude that a small arteriolar Pcrit is still present in the maximally vasodilated hindlimb but is less than the downstream pressure and does not affect flow under these conditions.

  18. [Cutaneous myxoma (focal dermal mucinosis)].

    PubMed

    Senff, H; Kuhlwein, A; Jänner, M; Schäfer, R

    1988-09-01

    Two cases of cutaneous myxoma are presented. In case 1 the cutaneous myxoma was localized on the left thumb and clinically resembled a pyogenic granuloma. In case 2 it was found at the left nipple. The benign cutaneous tumor may herald a cardiac myxoma and other conditions. Thus, a cutaneous myxoma should be accepted as an indication for thorough investigation of the whole body at regular intervals. As there are neither clinically nor histologically adequate criteria for differentiation, cutaneous myxoma and focal dermal mucinosis can be considered as variants of a single entity.

  19. The Cutaneous Rabbit Revisited

    ERIC Educational Resources Information Center

    Flach, Rudiger; Haggard, Patrick

    2006-01-01

    In the cutaneous rabbit effect (CRE), a tactile event (so-called attractee tap) is mislocalized toward an adjacent attractor tap. The effect depends on the time interval between the taps. The authors delivered sequences of taps to the forearm and asked participants to report the location of one of the taps. The authors replicated the original CRE…

  20. "Malignant Cutaneous Ulcer".

    PubMed

    Sundriyal, Deepak; Kotwal, Sumedha

    2016-09-01

    Renal cell carcinoma (RCC) is an aggressive malignancy and the rich vascular supply enables it to metastasize early via haematogenous route. Skin lesions are a late manifestation of the disease. Clinicians should be aware of cutaneous presentation of RCC while evaluating a case of unknown primary with skin lesions. PMID:27651705

  1. Different vasodilator responses of human arms and legs

    PubMed Central

    Newcomer, Sean C; Leuenberger, Urs A; Hogeman, Cynthia S; Handly, Brian D; Proctor, David N

    2004-01-01

    Forearm vascular responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators have been thoroughly characterized in humans. While the forearm is a well-established experimental model for studying human vascular function, it is of limited consequence to systemic cardiovascular control owing to its small muscle mass and blood flow requirements. In the present study we determined whether these responses could be generalized to the leg. Based upon blood pressure differences between the leg and arm during upright posture, we hypothesized that the responsiveness to endothelium-dependent vasodilators would be greater in the forearm than the leg. Brachial and femoral artery blood flow (Q, ultrasound Doppler) at rest and during intra-arterial infusions of endothelium-dependent (acetylcholine and substance P) and -independent (sodium nitroprusside) vasodilators were measured in eight healthy men (22–27 years old). Resting blood flows in the forearm before infusion of acetylcholine, substance P or sodium nitroprusside were 25 ± 4, 30 ± 7 and 29 ± 5 ml min−1, respectively, and in the leg were 370 ± 32, 409 ± 62 and 330 ± 30 ml min−1, respectively. At the highest infusion rate of acetylcholine (16 μg (100 ml tissue)−1 min−1) there was a greater (P < 0.05) increase in Q to the forearm (1864 ± 476%) than to the leg (569 ± 86%). Similarly, at the highest infusion rate of substance P (125 pg (100 ml tissue)−1 min−1) there was a greater (P < 0.05) increase in Q to the forearm (911 ± 286%) than to the leg (243 ± 58%). The responses to sodium nitroprusside (1 μg (100 ml tissue)−1 min−1) were also greater (P < 0.05) in the forearm (925 ± 164%) than in the leg (326 ± 65%). These data indicate that vascular responses to both endothelium-dependent and -independent vasodilator agents are blunted in the leg compared to the forearm. PMID:14990681

  2. Early experiences of vasodilators and hypotensive anesthesia in children.

    PubMed

    Brown, T C K

    2012-07-01

    The physiological application of OHMS LAW explains the basis of hypotensive anesthesia. V = IR translates into: Pressure = Flow × Resistance or Blood pressure = Cardiac Output × Peripheral Resistance. If peripheral resistance is reduced by a vasodilator such as sodium nitroprusside (a short acting, vascular smooth muscle relaxant) or phenoxybenzamine (a long acting α adrenoreceptor antagonist), blood pressure will fall and vasoconstriction and bleeding will be reduced. A less desirable alternative to lowering blood pressure could be to reduce cardiac output by suppressing myocardial contractility using a ß(1) adrenoceptor antagonist or an inhalational agent such as isoflurane.

  3. Assessment of the effect of vasodilators on the distribution of cardiac output by whole-body Thallium imaging

    SciTech Connect

    Juni, J.E.; Wallis, J.; Diltz, E.; Nicholas, J.; Lahti, D.; Pitt, B.

    1985-05-01

    Vasodilator therapy (tx) of congestive heart failure (CHF) has been shown to be effective in increasing cardiac output (CO) and lowering vascular resistance. Unfortunately, these hemodynamic effects are not usually accompanied by improved peripheral circulation of exercise capacity. To assess the effect of a new vasodilator, Cl-914, on the redistribution of CO to the peripheral circulation, the authors performed testing whole-body thallium scanning (WB-Th) on 6 patients (pts) with severe CHF. Immediately following i.v. injection of 1.5 mCi Th-201, WB scanning was performed from anterior and posterior views. Regions of interest were defined for the peripheral (P) muscles (legs and arms), central torso (C), and splanchnic bed (S). The geometric mean of activity in these regions was calculated from both views. Each pt was studied before tx and again, after 1 week on tx. Invasive measurements revealed that all pts had significant improvements in resting cardiac output (mean increase 49%) and vascular resistance (mean decrease 30%). Unlike other vasodilators, all CI-914 pts had a significant improvement in treadmill exercise capacity (mean increase 54%). WB-Th revealed a significant shift in CO to the peripheral circulation with P:C increased 33.2% (rho= .001) and P:S increased 29% (rho=.01). Vasoactive drugs may significantly alter the relative distribution of cardiac output. WB-Th scanning provides a simple quantitative means of following such changes.

  4. Hepatorenal cutaneous syndrome demonstrated by 99mTc macro aggregated albumin whole-body scintigraphy.

    PubMed

    Padma, S; Palaniswamy, Shanmuga Sundaram; Gandhi, Sunny; Babu K, Sanjay

    2014-09-01

    Hepatopulmonary syndrome, also known as hepatorenal syndrome, is a triad of liver disease, impaired oxygenation, and intrapulmonary vascular abnormalities. Forty-seven percent of patients with end-stage liver disease may have hepatopulmonary syndrome, an independent predictor of poor prognosis. Gross dilatation of pulmonary precapillary and capillary vessels, as well as an absolute increase in the number of dilated vessels, is the classic pathological description. We report a young man with cirrhosis demonstrating extrapulmonary shunting of 99mTc-MAA to kidneys with extensive peripheral arteriovenous (cutaneous) vasodilation, which we prefer to name as the "mosaic sign" in the absence of spider nevi or erythema.

  5. Active subcutaneous calcinosis demonstrated by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in a case of limited cutaneous systemic sclerosis.

    PubMed

    Vadrucci, Manuela; Castellani, Massimo; Benti, Riccardo

    2016-01-01

    Systemic sclerosis (SSc) is a rheumatic autoimmune disease of unknown origin causing fibrosis of the skin and the internal organs. The limited cutaneous variant is the most common subtype of SSc, and it is predominantly characterized by skin and soft-tissues involvement. A 72-year-old woman, who had been diagnosed with the limited cutaneous form of SSc 16 years before, underwent fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) examination due to unexplained weight loss and recent onset of fatigue and joint pain. PET/CT images showed widespread soft-tissue calcinosis characterized by elevated glucose uptake. PMID:27095870

  6. Mechanisms of acute vasodilator response to bacterial lipopolysaccharide in the rat coronary microcirculation.

    PubMed

    Cannon, T R; Mann, G E; Baydoun, A R

    1998-02-01

    1. In this study the mechanisms of the acute vasodilator action of bacterial lipopolysaccharide (LPS) were investigated in the rat Langendorff perfused heart. 2. Infusion of LPS (5 microg ml(-1)) caused a rapid and sustained fall in coronary perfusion pressure (PP) of 59 +/- 4 mmHg (n = 12) and a biphasic increase in NO levels determined in the coronary effluent by chemiluminescent detection. Both the fall in PP and the increase in NO release were completely abolished (n = 3) by pretreatment of hearts with the NO synthase inhibitor L-NAME (50 microM). 3. LPS-induced vasodilatation was markedly attenuated to 5 +/- 4 mmHg (n 3) by pretreatment of hearts with the B2 kinin receptor antagonist Hoe-140 (100 nM). 4. Vasodilator responses to LPS were also blocked by brief pretreatment with mepacrine (0.5 microM, n = 3) or nordihydroguaiaretic acid (0.1 microM, n = 4) and markedly attenuated by WEB 2086 (3 microM, n = 4). 5. Thirty minutes pretreatment of hearts with dexamethasone (1 nM), but not progesterone (1 microM), significantly modified responses to LPS. The action of dexamethasone was time-dependent, having no effect when applied either simultaneously with or pre-perfused for 5 min before the administration of LPS but inhibiting the response to LPS by 91 +/- 1% (n = 4) when pre-perfused for 15 min. The inhibition caused by dexamethasone was blocked by 15 min pretreatment with the glucocorticoid receptor antagonist RU-486 (100 nM) or by 2 min pre-perfusion of a 1:200 dilution of LCPS1, a selective antilipocortin 1 (LC1) neutralizing antibody. 6. Treatment with the protein synthesis inhibitor, cycloheximide (10 microM, for 15 min) selectively blunted LPS-induced vasodilatation, reducing the latter to 3 +/- 5 mmHg (n = 3), while having no effect on vasodilator responses to either bradykinin or sodium nitroprusside. 7. These results indicate that LPS-induced vasodilatation in the rat heart is dependent on activation of kinin B2 receptors and synthesis of NO. In addition

  7. Cyclooxygenase-derived vasoconstriction restrains hypoxia-mediated cerebral vasodilation in young adults with metabolic syndrome

    PubMed Central

    Harrell, John W.

    2013-01-01

    Poor cerebrovascular function in metabolic syndrome (MetSyn) likely contributes to elevated risk of cerebrovascular disease in this growing clinical population. Younger MetSyn adults without clinical evidence of cerebrovascular disease exhibit preserved hypercapnic vasodilation yet markedly impaired hypoxic vasodilation, but the mechanisms behind reduced hypoxic vasodilation are unknown. Based on data from rats, we tested the hypothesis that younger adults with MetSyn exhibit reduced cerebral hypoxic vasodilation due to loss of vasodilating prostaglandins. Middle cerebral artery velocity (MCAv) was measured with transcranial Doppler ultrasound in adults with MetSyn (n = 13, 33 ± 3 yr) and healthy controls (n = 15, 31 ± 2 yr). Isocapnic hypoxia was induced by titrating inspired oxygen to lower arterial saturation to 90% and 80% for 5 min each. Separately, hypercapnia was induced by increasing end-tidal CO2 10 mmHg above baseline levels. Cyclooxygenase inhibition (100 mg indomethacin) was conducted in a randomized double-blind, placebo controlled design. MCAv was normalized for group differences in blood pressure (healthy: 89 ± 2 mmHg vs. MetSyn: 102 ± 2 mmHg) as cerebrovascular conductance index (CVCi), and used to assess cerebral vasodilation. Hypoxia increased CVCi in both groups; however, vasodilation was ∼55% lower in MetSyn at SpO2 = 80% (P < 0.05). Indomethacin tended to decrease hypoxic vasodilation in healthy controls, and unexpectedly increased dilation in MetSyn (P < 0.05). In contrast to hypoxia, hypercapnia-mediated vasodilation was similar between groups, as was the decrease in vasodilation with indomethacin. These data indicate increased production of vasoconstrictor prostaglandins restrains hypoxic cerebral vasodilation in MetSyn, preventing them from responding appropriately to this important physiological stressor. PMID:24213610

  8. Canine gastric mucosal vasodilation with prostaglandins and histamine analogs

    SciTech Connect

    Gerber, J.G.; Nies, A.S.

    1982-10-01

    The effect of direct intragastric artery infusion of prostaglandins E2 and I2, arachidonic acid, dimaprit (histamine H2 agonist), and 2',2'-pyridylethylamine (histamine H1 agonist) on gastric mucosal blood flow was examined in dogs to elucidate the relationship between gastric secretory state and mucosal blood flow in dogs. These compounds were chosen because of their diverse effect on gastric acid secretion. Gastric fundus blood flow was measured both electromagnetically with a flow probe around the left gastric artery which supplies the fundus almost exclusively, and by the radioactive microsphere technique. Intraarterial infusion of all the compounds resulted in gastric mucosal vasodilation even though PGE2, PGI2, and arachidonic acid inhibit gastric acid secretion, dimaprit stimulated gastric acid secretion, and 2',2'-pyridylethylamine does not affect gastric acid secretion. There was total agreement in the blood flow measurements by the two different techniques. Our data suggest that gastric acid secretion and gastric vasodilation are independently regulated. In addition, the validity of the studies in which the aminopyrine clearance indicates that prostaglandins are mucosal vasoconstrictors needs to be questioned because of the reliance of those measurements on the secretory state of the stomach.

  9. Methyl nicotinate-induced vasodilation in generalized social phobia.

    PubMed

    Katzman, Martin; Cornacchi, Sylvie; Coonerty-Femiano, Aimee; Hughes, Bronwen; Vermani, Monica; Struzik, Lukasz; Ross, Brian M

    2003-10-01

    Elevated vasodilatory response (blushing) to social situations is characteristic of social phobia (SP). A relatively unexplored basis for this phenomenon is alteration in underlying vasodilatory mechanisms. To investigate this possibility, we evaluated the vasodilatory response induced by methyl nicotinate (niacin ester derivative) in 31 generalized SP patients and 41 matched healthy volunteers (HV). A patch impregnated with 0, 0.1, 0.5, 1, and 10 mM methyl nicotinate was applied to the forearm or face of subjects for 1 min, followed by 20-min laser Doppler spectroscopy blood flow monitoring. Blood flow stimulation with 1 and 10 mM methyl nicotinate was significantly reduced in SP patients by 35 and 17%, respectively. Induced blood flow was negatively correlated with patients' Leibowitz Social Phobia Scale (LSAS) at 1 and 10 mM doses. Furthermore, the maximal rate of change of vasodilatory reaction was correlated with symptom scores at 1 and 10 mM doses. Induced increases in the arm and face blood flow measurements correlated, supporting the external validity of the former location. Generalized SP patients vasodilate less to topical methyl nicotinate challenges, with effect amplification in severely ill patients. Although the mechanism for this is unclear, we propose desensitization of the prostaglandin-mediated vasodilating system as an explanation. Neuropsychopharmacology (2003) 28, 1846-1851, advance online publication, 23 July 2003; doi:10.1038/sj.npp.1300227

  10. Comparison of vasodilator drug prazosin with digoxin in aortic regurgitation.

    PubMed

    Hockings, B E; Cope, G D; Clarke, G M; Taylor, R R

    1980-05-01

    Intravenous administration of the vasodilator sodium nitroprusside has beneficial haemodynamic effects in subjects with severe aortic regurgitation while acute digitalisation can produce unwanted effects associated with an increase in systemic vascular resistance. This study compares the haemodynamic effects of the vasodilator prazosin and digoxin in eight patients with isolated severe aortic regurgitation. Prazosin 5 mg orally resulted in a 12 +/- 3 (SE) per cent increase in cardiac index (thermodilution), maintained over four to six hours, while digoxin 0.75 mg intravenously did not change the cardiac index. Prazosin reduced mean arterial pressure by 9 +/- 3 mmHg and systemic vascular resistance by 18 +/- 4 per cent while digoxin resulted in a 6 +/- 2 per cent increase in the latter. Mean pulmonary capillary wedge pressure fell 3 mmHg with prazosin. In this group of patients with severe aortic regurgitation but without severe cardiac failure, the changes with either drug, studied in doses conventionally used, were small but those with prazosin were directionally more desirable than those resulting from digoxin. PMID:7378215

  11. [Estimation of activity of bis-netropsin derivatives based on a model of an experimental cutaneous herpes simplex virus disease of guinea pigs].

    PubMed

    andronova, V L; Grokhovskiĭ, S L; Surovaia, A N; Gurskiĭ, G V; Deriabin, P G; L'vov, D K; Galegov, G A

    2013-01-01

    Using the model of an experimental cutaneous infection of guinea pig males caused by herpes simple virus type 1, it is shown that application of dimerico derivatives of netropsin Lys-bis Nt and 15Lys-bis Nt in the form of polietilenglicol-based ointment suppresses viral infection more effectively than acyclovir.

  12. Cutaneous Melanoma in Asians

    PubMed Central

    Kim, Sang Yub

    2016-01-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians. PMID:27689028

  13. Cutaneous Melanoma in Asians.

    PubMed

    Kim, Sang Yub; Yun, Sook Jung

    2016-09-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians. PMID:27689028

  14. Update on cutaneous tuberculosis*

    PubMed Central

    Dias, Maria Fernanda Reis Gavazzoni; Bernardes Filho, Fred; Quaresma, Maria Victória; do Nascimento, Leninha Valério; Nery, José Augusto da Costa; Azulay, David Rubem

    2014-01-01

    Tuberculosis continues to draw special attention from health care professionals and society in general. Cutaneous tuberculosis is an infection caused by M. tuberculosis complex, M. bovis and bacillus Calmette-Guérin. Depending on individual immunity, environmental factors and the type of inoculum, it may present varied clinical and evolutionary aspects. Patients with HIV and those using immunobiological drugs are more prone to infection, which is a great concern in centers where the disease is considered endemic. This paper aims to review the current situation of cutaneous tuberculosis in light of this new scenario, highlighting the emergence of new and more specific methods of diagnosis, and the molecular and cellular mechanisms that regulate the parasite-host interaction. PMID:25387498

  15. Cutaneous Melanoma in Asians

    PubMed Central

    Kim, Sang Yub

    2016-01-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians.

  16. Vasodilator and vasoconstrictor responses induced by 5-hydroxytryptamine in the in situ blood autoperfused hindquarters of the anaesthetized rat.

    PubMed

    Calama, E; Fernández, M M; Morán, A; Martín, M L; San Román, L

    2002-08-01

    In the present study we attempted to characterise the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT, serotonin) in in situ autoperfused rat hindquarters. Intra-arterial administration of the lowest doses of 5-HT used (0.12-12.5 ng/kg) induced vasodilator responses, whereas the highest doses (25-1000 ng/kg) produced vasoconstriction. The vasodilator effect was inhibited by methiothepin (a non-specific 5-HT(1,2,5,6,7) receptor antagonist) and by a 5-HT(1D/1B) receptor antagonist, i.e., 3-[4-(4-chlorophenyl)piperazin-1-yl]-1,1-diphenyl-2-propanolol (BRL 15572), but not by ritanserin (a selective 5-HT(2) receptor antagonist), 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole (SB 206553, a selective 5-HT(2B/2C) receptor antagonist) or mesulergine (a non-specific serotonergic antagonist that shows affinity to the 5-HT(7) receptor). This vasodilator effect was mimicked by administration of a selective 5-HT(1) receptor agonist - 5-carboxamidotryptamine (5-CT) - and by 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-1 H-indol-3-yl]ethanamine (L-694,247, a selective 5-HT(1D/1B) receptor agonist). Methiothepin, but not mesulergine, inhibited 5-CT-induced vasodilatation and the selective 5-HT(1D/1B) receptor antagonist (BRL 15572) inhibited the vasodilator action induced by L-694,247. The vasoconstrictor effect of 5-HT was significantly decreased by methiothepin, ritanserin and SB 206553, and was mimicked by alpha-methyl-5-HT (a selective 5-HT(2) receptor agonist) but not by administration of BW 723C86, a selective 5HT(2B) receptor agonist. Ritanserin, SB 206553 and spiperone (a non-specific 5-HT(1/2A) receptor antagonist) inhibited the alpha-methyl-5HT-induced vasoconstriction.Our data suggest that the vasodilator response induced by 5-HT in autoperfused rat hindquarters is mainly mediated by 5-HT(1D/1B) receptors, whereas the vasoconstrictor effect is mainly due to the activation of 5-HT(2A) receptors.

  17. Primary cutaneous PEComa.

    PubMed

    Chaplin, Anna; Conrad, David M; Tatlidil, Cuneyt; Jollimore, Jason; Walsh, Noreen; Covert, Alan; Pasternak, Sylvia

    2010-05-01

    A 48-year-old woman attended a physician because of a solitary cutaneous nodule on the left lower leg. Microscopic examination of the excisional specimen revealed a dermal tumor composed of nests of epithelioid cells exhibiting clear cytoplasm. They had centrally located vesicular nuclei with distinct nucleoli. A rich network of capillaries was present throughout. The tumor showed an infiltrative border. There was no epidermal involvement. Periodic acid-Shif (PAS) and PAS-Diastase stains demonstrated glycogen deposition within the cytoplasm of the clear cells. Immunohistochemical evaluation revealed that the tumor cells were positive for HMB-45 and microftalmia associated transcription factor (MITF). Focal desmin positivity was also seen. The tumor cells were negative for S-100 protein, alfa smooth muscle actin, HHF-35, and various cytokeratins. The case is one of a primary cutaneous pecoma. Pecomas are rare, recently described mesenchymal tumors composed of perivascular epithelioid cells. They constitute a spectrum of lesions in different organs including angiomyolipoma of the kidney and liver, sugar tumor of the lung, lymphangiomatosis, and lymphangiomyoma. Primary cutaneous PEComas are exceptionally rare and have only recently been recognized. To date, these are approximately 22 cases in the English literature. Follow-up data is limited but they appear to behave in a benign fashion. We report an additional case with the goal of alerting dermatopathologists to this distinctive unusual neoplasm.

  18. Nitric oxide dependent vasodilation in young spontaneously hypertensive rats.

    PubMed

    Radaelli, A; Mircoli, L; Mori, I; Mancia, G; Ferrari, A U

    1998-10-01

    Conflicting evidence exists on the possible impairment of tonic nitric oxide (NO) mediated vasodilation as a causative factor in the genesis of human as well as experimental hypertension. We evaluated the tonic NO-dependent vasodilation from the pressor response to NO synthesis inhibition by NG-monomethyl-L-arginine (L-NMMA) in 9 conscious, chronically instrumented spontaneously hypertensive rats (SHR) at 12 weeks of age, ie, during the early established hypertensive stage. Nine age-matched Wistar-Kyoto rats (WKY) were used as controls. The pressor responses to L-NMMA (100 mg . kg-1 IV bolus plus 1.5 mg . kg-1 . min-1 infusion for 60 minutes) as well as to non NO-dependent pressor stimuli, namely, vasopressin (2, 4, and 8 ng . kg-1) and phenylephrine (0.5, 1, and 2 microg . kg-1) given as IV boluses, were assessed both under control conditions and during suppression of autonomic reflexes by hexamethonium (30 mg . kg-1 IV bolus+1.5 mg . kg-1 . min-1 infusion). Rather than being reduced, the pressor responses to L-NMMA were 39% and 71% larger in the control and areflexic conditions, respectively, than those observed in WKY (both P<0.01). A similar pattern was observed for the pressor responses to vasopressin (+37% and +68% in the control and areflexic conditions, respectively; both P<0.01) and phenylephrine, (+20% and +52%; both P<0.05). Additional groups of 6-week-old prehypertensive SHR (n=11) and age-matched WKY (n=11) were subjected to an identical protocol: in these animals, the pressor responses to L-NMMA were similar in each strain, as were the pressor responses to vasopressin and phenylephrine in both control and areflexic conditions. In conclusion, our observations indicate that during the developmental phase of hypertension in the SHR model, namely, during the prehypertensive as well as the early established hypertensive stage, NO-dependent vasodilation is preserved (if not enhanced) so that a putative impairment of this function provides no significant

  19. Metabolic syndrome reduces the contribution of K+ channels to ischemic coronary vasodilation.

    PubMed

    Borbouse, Léna; Dick, Gregory M; Payne, Gregory A; Berwick, Zachary C; Neeb, Zachary P; Alloosh, Mouhamad; Bratz, Ian N; Sturek, Michael; Tune, Johnathan D

    2010-04-01

    This investigation tested the hypothesis that metabolic syndrome decreases the relative contribution of specific K(+) channels to coronary reactive hyperemia. Ca(2+)-activated (BK(Ca)), voltage-activated (K(V)), and ATP-dependent (K(ATP)) K(+) channels were investigated. Studies were conducted in anesthetized miniature Ossabaw swine fed a normal maintenance diet (11% kcal from fat) or an excess calorie atherogenic diet (43% kcal from fat, 2% cholesterol, 20% kcal from fructose) for 20 wk. The latter diet induces metabolic syndrome, increasing body weight, fasting glucose, total cholesterol, and triglyceride levels. Ischemic vasodilation was determined by the coronary flow response to a 15-s occlusion before and after cumulative administration of antagonists for BK(Ca) (penitrem A; 10 microg/kg iv), K(V) (4-aminopyridine; 0.3 mg/kg iv) and K(ATP) (glibenclamide; 1 mg/kg iv) channels. Coronary reactive hyperemia was diminished by metabolic syndrome as the repayment of flow debt was reduced approximately 30% compared with lean swine. Inhibition of BK(Ca) channels had no effect on reactive hyperemia in either lean or metabolic syndrome swine. Subsequent inhibition of K(V) channels significantly reduced the repayment of flow debt ( approximately 25%) in both lean and metabolic syndrome swine. Additional blockade of K(ATP) channels further diminished ( approximately 45%) the repayment of flow debt in lean but not metabolic syndrome swine. These data indicate that the metabolic syndrome impairs coronary vasodilation in response to cardiac ischemia via reductions in the contribution of K(+) channels to reactive hyperemia. PMID:20118408

  20. Topical anaesthesia does not affect cutaneous vasomotor or sudomotor responses in human skin.

    PubMed

    Metzler-Wilson, K; Wilson, T E

    2013-10-01

    (1) The effects of local sensory blockade (topical anaesthesia) on eccrine sweat glands and cutaneous circulation are not well understood. This study aimed to determine whether topical lidocaine/prilocaine alters eccrine sweat gland and cutaneous blood vessel responses. (2) Sweating (capacitance hygrometry) was induced via forearm intradermal microdialysis of five acetylcholine (ACh) doses (1 × 10(-4) to 1 × 10(0) m, 10-fold increments) in control and treated forearm sites in six healthy subjects. Nitric oxide-mediated vasodilatory (sodium nitroprusside) and adrenergic vasoconstrictor (noradrenaline) agonists were iontophoresed in lidocaine/prilocaine-treated and control forearm skin in nine healthy subjects during blood flow assessment (laser Doppler flowmetry, expressed as% from baseline cutaneous vascular conductance; CVC; flux/mean arterial pressure). (3) Non-linear regression curve fitting identified no change in the ED50 of ACh-induced sweating after sensory blockade (-1.42 ± 0.23 logM) compared to control (-1.27 ± 0.23 logM; P > .05) or in Emax (0.43 ± 0.08 with, 0.53 ± 0.16 mg cm(-2) min(-1) without lidocaine/prilocaine; P > .05). Sensory blockade did not alter the vasodilator response to sodium nitroprusside (1280 ± 548% change from baseline CVC with, 1204 ± 247% without lidocaine/prilocaine) or vasoconstrictor response to noradrenaline (-14 ± 4% change from baseline CVC with, -22 ± 14% without lidocaine/prilocaine; P > 0.05). (4) Cutaneous sensory blockade does not appear to alter nitric oxide-mediated vasodilation, adrenergic vasoconstriction, or cholinergic eccrine sweating dose-response sensitivity or responsiveness to maximal dose. Thus, lidocaine/prilocaine treatment should not affect sweat gland function or have blood flow implications for subsequent research protocols or clinical procedures.

  1. Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction

    PubMed Central

    Umbrello, Michele; Dyson, Alex; Pinto, Bernardo Bollen; Fernandez, Bernadette O; Simon, Verena; Feelisch, Martin; Singer, Mervyn

    2014-01-01

    Local increases in blood flow – ‘hypoxic vasodilation’ – confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from preformed stores and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NO synthase inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite. PMID:24396056

  2. Transgenic mouse model of cutaneous adnexal tumors

    PubMed Central

    Kito, Yusuke; Saigo, Chiemi; Atsushi, Kurabayashi; Mutsuo, Furihata; Tamotsu, Takeuchi

    2014-01-01

    TMEM207 was first characterized as being an important molecule for the invasion activity of gastric signet-ring cell carcinoma cells. In order to unravel the pathological properties of TMEM207, we generated several transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), in which murine TMEM207 was ectopically expressed under a truncated (by ~200 bp) proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). Unexpectedly, a C57BL/6-Tg (ITF-TMEM207) mouse line exhibited a high incidence of spontaneous intradermal tumors with histopathological features that resembled those of various human cutaneous adnexal tumors. These tumors were found in ~14% female and 13% of male 6- to 12-month-old mice. TMEM207 immunoreactivity was found in hair follicle bulge cells in non-tumorous skin, as well as in cutaneous adnexal tumors of the transgenic mouse. The ITF-TMEM207 construct in this line appeared to be inserted to a major satellite repeat sequence at chromosome 2, in which no definite coding molecule was found. In addition, we also observed cutaneous adnexal tumors in three other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. We believe that the C57BL/6-Tg (ITF-TMEM207) mouse might be a useful model to understand human cutaneous adnexal tumors. PMID:25305140

  3. Ultrastructural patterns of secretory activity in poison cutaneous glands of larval and juvenile Dendrobates auratus (Amphibia, Anura).

    PubMed

    Angel, R; Delfino, G; Parra, G J

    2003-01-01

    A transmission electron-microscope study has been performed on larval and juvenile skin of the Central American arrow-frog Dendrobates auratus to investigate early secretory processes and maturational changes in the serous (poison) glands. Poison biosynthesis involves the endoplasmic reticulum (both smooth and rough types), as well as Golgi stacks which release early serous product as secretory vesicles (or pre-granules). These vesicles contain fine-grained material, along with single electron-opaque bodies, spheroidal in shape, that accompany the grained product throughout its post-Gogian, maturational change. The first steps of this process involve condensation and lead to the formation of secretory granules with a glomerular-like substructure, resulting from a thick, random aggregation of rods (secretory granule subunits). Advanced maturational activity causes the loss of peculiar granule substructure: the dense bodies split into fragments, whereas the thick glomerular arrangement becomes looser, until the secretory product changes into a dispersed material. This ultrastructural study revealed biosynthesis and maturation processes in close sequence, suggesting the poison of D. auratus contains proteins and/or peptides as well as lipophilic compounds. Molecules of both these classes are known to perform several roles relevant to survival strategies in extant anurans. Furthermore, the ephemeral granules with a glomerular-like substructure detected in tadpoles and froglets exhibit the complex patterns of mature poisons in adult specimens of other anurans: Hylidae and related families. This agrees with current trends in the taxonomy of these advanced frogs and underlines the pertinence of an ontogenetic approach in investigating anuran phylogenesis. PMID:12467659

  4. [Hepatic porphyrias with cutaneous symptoms].

    PubMed

    Timonen, Kaisa; Nuutinen, Pauliina; Raili, Kauppinen

    2012-01-01

    Hepatic porphyrias with cutaneous symptoms Cutaneous symptoms of porphyrias are initiated from a phototoxic reaction caused by sunlight and circulating porphyrins in the vascular walls of the skin. This leads in fragility, blistering and scarring of the skin on light-exposed areas. There are approximately 200 patients having hepatic porphyrias with cutaneous symptoms in Finland. Cutaneous symptoms of variegate porphyria and porphyria cutanea tarda are indistinguishable, but an effective treatment is available only for the latter. Differential diagnosis is important due to acute episodes occurring in variegate porphyria.

  5. Cutaneous manifestations of breast cancer.

    PubMed

    Tan, Antoinette R

    2016-06-01

    Breast cancer may present with cutaneous symptoms. The skin manifestations of breast cancer are varied. Some of the more common clinical presentations of metastatic cutaneous lesions from breast cancer will be described. Paraneoplastic cutaneous dermatoses have been reported as markers of breast malignancy and include erythema gyratum repens, acquired ichthyosis, dermatomyositis, multicentric reticulohistiocytosis, and hypertrichosis lanuginosa acquisita. Mammary Paget's disease, often associated with an underlying breast cancer, and Cowden syndrome, which has an increased risk of breast malignancy, each have specific dermatologic findings. Recognition of these distinct cutaneous signs is important in the investigation of either newly diagnosed or recurrent breast cancer. PMID:27178684

  6. Endothelial-dependent vasodilators preferentially increase subendocardial blood flow

    SciTech Connect

    Pelc, L.R.; Gross, G.J.; Warltier, D.C.

    1986-03-05

    Interference with arachidonic acid metabolism on the effect of acetylcholine (Ach) or arachidonic acid (AA) to preferentially increase subendocardial perfusion was investigated in anesthetized dogs. Hemodynamics, regional myocardial blood flow (MBF (ml/min/g):radioactive microspheres) and the left ventricular transmural distribution of flow (endo/epi) were measured. Intracoronary infusion of Ach (10 ..mu..g/min) and AA (585 ..mu..g/min) significantly (P < .05*) increased myocardial perfusion and selectively redistributed flow to the subendocardium (increased endo/epi) without changes in systemic hemodynamics. Inhibition of phospholipase A/sub 2/ by quinacrine (Q; 600 ..mu..g/min, ic) attenuated the increase in myocardial perfusion produced by Ach but not by AA and inhibited the redistribution of flow to the subendocardium. The present results suggest that endothelium-dependent vasodilators produce a preferential increase in subendocardial perfusion via a product of AA metabolism.

  7. AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension

    PubMed Central

    Sonkusare, Swapnil K.; Dalsgaard, Thomas; Bonev, Adrian D.; Hill-Eubanks, David C.; Kotlikoff, Michael I.; Scott, John D.; Santana, Luis F.; Nelson, Mark T.

    2015-01-01

    Endothelial cell dysfunction, characterized by a diminished response to endothelial cell–dependent vasodilators, is a hallmark of hypertension. TRPV4 channels play a major role in endothelial-dependent vaso-dilation, a function mediated by local Ca2+ influx through clusters of functionally coupled TRPV4 channels rather than by a global increase in endothelial cell Ca2+. We showed that stimulation of muscarinic acetylcholine receptors on endothelial cells of mouse arteries exclusively activated TRPV4 channels that were localized at myoendothelial projections (MEPs), specialized regions of endothelial cells that contact smooth muscle cells. Muscarinic receptor–mediated activation of TRPV4 depended on protein kinase C (PKC) and the PKC-anchoring protein AKAP150, which was concentrated at MEPs. Cooperative opening of clustered TRPV4 channels specifically amplified Ca2+ influx at MEPs. Cooperativity of TRPV4 channels at non-MEP sites was much lower, and cooperativity at MEPs was greatly reduced by chelation of intracellular Ca2+ or AKAP150 knockout, suggesting that Ca2+ entering through adjacent channels underlies the AKAP150-dependent potentiation of TRPV4 activity. In a mouse model of angiotensin II–induced hypertension, MEP localization of AKAP150 was disrupted, muscarinic receptor stimulation did not activate TRPV4 channels, cooperativity among TRPV4 channels at MEPs was weaker, and vasodilation in response to muscarinic receptor stimulation was reduced. Thus, endothelial-dependent dilation of resistance arteries is enabled by MEP-localized AKAP150, which ensures the proximity of PKC to TRPV4 channels and the coupled channel gating necessary for efficient communication from endothelial to smooth muscle cells in arteries. Disruption of this molecular assembly may contribute to altered blood flow in hypertension. PMID:25005230

  8. Augmented supraorbital skin sympathetic nerve activity responses to symptom trigger events in rosacea patients.

    PubMed

    Metzler-Wilson, Kristen; Toma, Kumika; Sammons, Dawn L; Mann, Sarah; Jurovcik, Andrew J; Demidova, Olga; Wilson, Thad E

    2015-09-01

    Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm(-2)·min(-1), P < 0.05). HR and MAP changes were not different between groups during sympathoexcitatory stressors or local heating. SSNA during early mental (32 ± 9 and 9 ± 4% increase) and physical (25 ± 4 and 5 ± 1% increase, rosacea and controls, respectively) stress was augmented in rosacea (both P < 0.05). Heat stress induced more rapid sweating and cutaneous vasodilation onset in rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component.

  9. Augmented supraorbital skin sympathetic nerve activity responses to symptom trigger events in rosacea patients.

    PubMed

    Metzler-Wilson, Kristen; Toma, Kumika; Sammons, Dawn L; Mann, Sarah; Jurovcik, Andrew J; Demidova, Olga; Wilson, Thad E

    2015-09-01

    Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm(-2)·min(-1), P < 0.05). HR and MAP changes were not different between groups during sympathoexcitatory stressors or local heating. SSNA during early mental (32 ± 9 and 9 ± 4% increase) and physical (25 ± 4 and 5 ± 1% increase, rosacea and controls, respectively) stress was augmented in rosacea (both P < 0.05). Heat stress induced more rapid sweating and cutaneous vasodilation onset in rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component. PMID:26133800

  10. Augmented supraorbital skin sympathetic nerve activity responses to symptom trigger events in rosacea patients

    PubMed Central

    Metzler-Wilson, Kristen; Toma, Kumika; Sammons, Dawn L.; Mann, Sarah; Jurovcik, Andrew J.; Demidova, Olga

    2015-01-01

    Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm−2·min−1, P < 0.05). HR and MAP changes were not different between groups during sympathoexcitatory stressors or local heating. SSNA during early mental (32 ± 9 and 9 ± 4% increase) and physical (25 ± 4 and 5 ± 1% increase, rosacea and controls, respectively) stress was augmented in rosacea (both P < 0.05). Heat stress induced more rapid sweating and cutaneous vasodilation onset in rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component. PMID:26133800

  11. Grape polyphenols reduce blood pressure and increase flow-mediated vasodilation in men with metabolic syndrome.

    PubMed

    Barona, Jacqueline; Aristizabal, Juan C; Blesso, Christopher N; Volek, Jeff S; Fernandez, Maria Luz

    2012-09-01

    We evaluated the effects of grape polyphenols in individuals classified with metabolic syndrome (MetS). Men (n = 24) aged 30-70 y were randomly assigned to consume either a freeze-dried grape polyphenol powder (GRAPE) or a placebo for 30 d in a double-blind, crossover design, separated by a 3-wk washout period. Participants were asked to maintain their usual diet and physical activity during the study and abstain from consuming polyphenol-rich foods. MetS criteria including blood pressure (BP) and markers of vascular endothelial function including brachial artery flow-mediated vasodilation (FMD), plasma total nitrite + nitrate (NOx) to estimate NO production, plasma soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured at the end of each dietary period. Systolic BP (P < 0.0025) and plasma sICAM-1 concentrations (P < 0.025) were lower, whereas the FMD response was higher (P < 0.0001), during the GRAPE compared with the placebo period. In addition, changes in sVCAM-1 concentrations between periods were positively correlated with changes in systolic BP (r = 0.45; P < 0.05). Although NOx concentrations did not differ between periods, changes in systolic BP were negatively correlated with changes in NOx concentrations (r = -0.44; P < 0.05), indicating the vasodilating properties of NO. Other MetS variables did not differ between the GRAPE and placebo periods. These results suggest that GRAPE polyphenols may potentiate vasorelaxation and reduce BP and circulating cell adhesion molecules, resulting in improvements in vascular function.

  12. Clinical characteristics of cutaneous lupus erythematosus

    PubMed Central

    Szczęch, Justyna; Rutka, Maja; Samotij, Dominik; Zalewska, Agnieszka

    2016-01-01

    Introduction Lupus erythematosus (LE) shows a wide variety of clinical manifestations, skin involvement being one of the most important. Aim To analyze the clinical presentation of cutaneous variants of lupus erythematosus in terms of skin lesion spectrum and extracutaneous involvement. Material and methods A total of 64 patients with cutaneous LE (CLE) were included. The study was based on the “Core Set Questionnaire” developed by the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Clinical severity of skin lesions was evaluated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). All results were subjected to statistical analysis. Results Fifteen (23.4%) patients had an acute CLE (ACLE), 26 (40.6%) subacute CLE (SCLE) and 21 (32.8%) chronic CLE (CCLE). Two (3.2%) individuals only demonstrated urticarial vasculitis as a cutaneous manifestation of LE and these patients were excluded. Patients with ACLE were characterized by the earliest onset of the disease (mean age of 31.9 ±15.0 years; p < 0.001). On average, 4.8 ±1.8 criteria of systemic LE were found in the ACLE group compared to 2.7 ±1.3 criteria in SCLE and 2.5 ±1.5 criteria in CCLE (p < 0.001). The highest activity of skin lesions according to CLASI was found in the SCLE group (p = 0.002). On the other hand, the most severe skin damage was observed in CCLE (p < 0.01). Conclusions Each variant of CLE differs significantly from the others in respect of various aspects of clinical manifestations. Due to a number of different variants of LE skin lesions, a unified classification of CLE still remains a challenge. PMID:26985173

  13. Circulating Immune Complexes in Cutaneous Vasculitis

    PubMed Central

    Mackel, Susan E.; Tappeiner, Gerhard; Brumfield, Hilton; Jordon, Robert E.

    1979-01-01

    To investigate the pathogeneic significance of immune complexes in cutaneous vasculitis, 107 patients with various forms of cutaneous vasculitis, including 59 patients with necrotizing (leukocytoclastic) vasculitis (group 1), and 48 patients with lymphocytic vasculitis, or a predominately lymphocytic perivascular infiltrate (group 2), were studied. Immunoglobulins or complement components in cutaneous blood vessels were detected by direct immunofluorescence in high frequency in both groups (91 and 88%, respectively). Using two radioassays for circulating immune complexes, Clq or monoclonal rheumatoid factor (mRF) reactive material was detected in 68% of the patients with necrotizing vasculitis but only 44% of the patients in the lymphocytic-perivascular group. The mRF radioassay was elevated in 58% of the first group of patients and 41% of the patients in group 2, although Clq binding activity was increased in 54% of the patients with necrotizing vasculitis but only in 9% of the patients with a lymphocytic vasculitis or lymphocytic perivascular infiltrate. By using both sucrose density gradient ultracentrifugation and Sepharose 6B gel filtration, the Clq and mRF reactive material detected in some patients with necrotizing vasculitis eluted in high molecular weight fractions that were also anticomplementary. In one patient with necrotizing vasculitis and hepatitis B antigenemia, these heavy molecular weight Clq and mRF reactive fractions contained a two- to three-fold increase in hepatitis B surface antigen when compared with lighter molecular weight fractions. Heavy and light molecular weight mRF reactive material could be detected in selected patients in the lymphocytic-perivascular group as well as in the necrotizing vasculitis group. These studies suggest that cutaneous vasculitis, including acute necrotizing (leukocytoclastic) vasculitis and some forms of lymphocytic vasculitis, and perhaps some diseases characterized by a lymphocytic perivascular infiltrate

  14. FK409, a novel vasodilator isolated from the acid-treated fermentation broth of Streptomyces griseosporeus. I. Taxonomy, fermentation, isolation, and physico-chemical and biological characteristics.

    PubMed

    Hino, M; Iwami, M; Okamoto, M; Yoshida, K; Haruta, H; Okuhara, M; Hosoda, J; Kohsaka, M; Aoki, H; Imanaka, H

    1989-11-01

    FK409, a novel vasodilator with anti-platelet aggregation activity, has been isolated from the acid-treated fermentation broth of Streptomyces griseosporeus No. 16917, which was cultured on a medium containing NaNO3 for 4 days. FK409 was purified from the culture-filtrate by extraction with ethyl acetate after adjusting the pH to 3.0 with HC1, followed by silica gel chromatography. The molecular formula of this compound was determined to be C8H13N3O4. In vitro, FK409 showed a potent relaxation activity on noradrenaline induced contraction of rat aorta. In addition to the vasodilating activity, this compound also showed potent anti-aggregation activities towards rabbit platelets. In vivo, intravenously administered FK409 resulted in marked blood pressure lowering in rats. PMID:2584140

  15. Leishmanicidal activity of amphotericin B encapsulated in PLGA-DMSA nanoparticles to treat cutaneous leishmaniasis in C57BL/6 mice.

    PubMed

    de Carvalho, Ricardo Fontoura; Ribeiro, Ieler Ferreira; Miranda-Vilela, Ana Luisa; de Souza Filho, José; Martins, Olímpia Paschoal; Cintra e Silva, Débora de Oliveira; Tedesco, Antônio Cláudio; Lacava, Zulmira Guerrero Marques; Báo, Sônia Nair; Sampaio, Raimunda Nonata Ribeiro

    2013-10-01

    The major goal of this work was to design a new nanoparticle drug delivery system for desoxycholate amphotericin B (D-AMB), based on controlled particle size, looking for the most successful release of the active agents in order to achieve the best site-specific action of the drug at the therapeutically optimal rate and dose regimen. For this, AMB nanoencapsulated in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles (Nano-D-AMB) has been developed, and its efficacy was evaluated in the treatment of experimental cutaneous leishmaniasis in C57BL/6 mice, to test if our nano-drug delivery system could favor the reduction of the dose frequency required to achieve the same therapeutic level of free D-AMB, and so, an extended dosing interval. Magnetic citrate-coated maghemite nanoparticles were added to this nanosystem (Nano-D-AMB-MG) aiming to increase controlled release of AMB by magnetohyperthermia. Female mice (N=6/group) were infected intradermally in the right footpad with promastigotes of Leishmania amazonensis in the metacyclic phase, receiving the following intraperitoneal treatments: 1% PBS for 10 consecutive days; D-AMB at 2 mg/kg/day for 10 days (totalizing 20 mg/kg/animal); Nano-D-AMB and Nano-D-AMB-MG at 6 mg/kg on the 1st, 4th and 7th days and at 2 mg/kg on the 10th day, also totalizing 20 mg/kg/animal by treatment end. The Nano-D-AMB-MG group was submitted to an AC magnetic field, allowing the induction of magnetohyperthermia. The evaluations were through paw diameter measurements; parasite number and cell viability were investigated by limiting dilution assay. D-AMB-coated PLGA-DMSA nanoparticles showed the same efficacy as free D-AMB to reduce paw diameter; however, the Nano-D-AMB treatment also promoted a significantly greater reduction in parasite number and cell viability compared with free D-AMB. The nano-drug AMB delivery system appeared more effective than free D-AMB therapy to reduce the dose frequency required

  16. Oestrogen compromises the facilitatory effect of chronic nicotine on adenosine A2B receptor-K(+) channel-mediated renal vasodilation.

    PubMed

    El-Mas, Mahmoud M; El-Gowilly, Sahar M; Elsalakawy, Lamia K; El-Gowelli, Hanan M

    2014-08-01

    We have shown previously that the renal vasodilatory action of the adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA) in female rats is mediated via preferential activation of adenosine A2B receptor (A2B R)-K(+) channel signalling. In the present study, we tested the hypothesis that the renal vasodilatory effect of NECA and its A2B R/K(+) channel specificities are altered by chronic nicotine administration. The oestrogenic modulation of the nicotine-NECA renovascular interaction was also evaluated by determining the effect of ovariectomy (OVX) and oestrogen replacement (OVXE2) on the evoked responses. In isolated phenylephrine-preconstricted perfused kidneys obtained from sham-operated rats, vasodilation in response to cumulative bolus injections of NECA (1.6-50 nmol) or papaverine (1-243 nmol) were not affected by nicotine (1-8 mg/kg per day, i.p., 2 weeks). However, vasodilator responses to NECA, but not papaverine, were reduced in kidneys of OVX rats and restored to near-sham values after E2 replacement. Further, nicotine increased NECA-induced vasodilation in perfused kidneys from OVX rats, but failed to do so in OVXE2 preparations. The enhanced NECA responsiveness in nicotine-treated OVX preparations was abolished after infusion (into isolated kidneys) of 10 μmol/L alloxazine (A2B R antagonist) or BaCl2 plus glibenclamide (blockers of inward rectifier and ATP-sensitive K(+) channels, respectively). Vasodilator responses to 0.05-1.6 μmol minoxidil (a K(+) channel opener) were increased by nicotine in OVX, but not OVXE2, preparations and this increase was abolished after infusion of BaCl2  + glibenclamide. Together, the data suggest that chronic nicotine enhances A2B R/K(+) channel-mediated renal vasodilation in oestrogen-depleted rats. PMID:24827542

  17. [Adhesive cutaneous pharmaceutical forms].

    PubMed

    Gafiţanu, E; Matei, I; Mungiu, O C; Pavelescu, M; Mîndreci, I; Apostol, I; Ionescu, G

    1989-01-01

    The adhesive cutaneous pharmaceutical forms aimed to local action release the drug substance in view of a dermatological, traumatological, antirheumatic, cosmetic action. Two such preparations were obtained and their stability, consistency and pH were determined. The "in vitro" tests of their bioavailability revealed the dynamics of calcium ions release according to the associations of each preparation. The bioavailability determined by evaluating the pharmacological response demonstrated the antiinflammatory action obtained by the association of calcium ions with the components extracted from poplar muds. The therapeutical efficiency of the studied preparations has proved in the treatment of some sport injuries.

  18. Pure cutaneous histiocytosis X.

    PubMed

    Magaña-García, M

    1986-03-01

    A 38-month-old boy presented with nodules in the skin of the genital region present for 2 1/2 years. These later spread to the skin of the trunk, head, and extremities. A complete clinical workup could not reveal involvement in any other organ sites and biopsy of one of the cutaneous lesions was diagnosed as histiocytosis X. Because the child was in generally good condition, no treatment was given. Follow-up revealed that the disease had remained limited to the skin, where 15% of the lesions disappeared spontaneously.

  19. [Cutaneous histiocytosis X].

    PubMed

    Metz, J; Metz, G; Lechner, W

    1980-09-01

    Histiocytosis X comprises three clinical entities whose common substrate is a localized or systemic proliferation of atypical histiocytes. On the basis of the age of manifestation, acuity of the clinical course and organ involvement Abt-Letterer-Siwe's disease, Hand-Schüller-Christian's disease and eosinophilic granuloma can be differentiated from each other, although transitional varieties of these syndromes are possible. Not infrequently oligosymptomatic forms are misinterpreted, especially when the skin is the only involved organ. In the following case report cutaneous histiocytosis X will be discussed in terms of its clinical expression. Electron-microscopy has proved to be the best methods to make the diagnosis of such atypical cases.

  20. Cutaneous bacillary angiomatosis.

    PubMed

    Asharaf, Mohammed; Letha, S

    2002-11-01

    Bacillary angiomatosis is characterized by unique vascular lesions caused by infection with a small Gram staining bacillus of the genus Bartonella. It usually occurs in immunocompromised persons but can also occur in immunocompetent persons. We report a case of cutaneous bacillary angiomatosis in a 5-year-old immunocompetent child. He had infected lesions on the lips, after an injury, which was followed by lesions over the knees, buttocks, near the ankles and the elbows. Diagnosis was proved on histology. The lesions cleared after administration of erythromycin for 3 months. It is well to be aware of this condition in the context of increasing prevalence of AIDS.

  1. Lack of limb or sex differences in the cutaneous vascular responses to exogenous norepinephrine

    PubMed Central

    Stanhewicz, Anna E.; Kenney, W. Larry; Alexander, Lacy M.

    2014-01-01

    The cutaneous circulation is used to examine vascular adrenergic function in clinical populations; however, limited studies have examined whether there are regional limb and sex differences in microvascular adrenergic responsiveness. We hypothesized that cutaneous adrenergic responsiveness would be greater in the leg compared with the arm and that these regional limb differences would be blunted in young women (protocol 1). We further hypothesized that cutaneous vasoconstriction to exogenous norepinephrine (NE) during β-adrenergic receptor antagonism would be augmented in young women (protocol 2). In protocol 1, one microdialysis fiber was placed in the skin of the calf and the ventral forearm in 20 healthy young adults (11 men and 9 women). Laser-Doppler flowmetry was used to measure red blood cell flux in response to graded intradermal microdialysis infusions of NE (10−12 to 10−2 M). In protocol 2, three microdialysis fibers were placed in the forearm (6 men and 8 women) for the local perfusion of lactated Ringer (control), 5 mM yohimbine (α-adrenergic receptor antagonist), or 2 mM propranolol (β-adrenergic receptor antagonist) during concurrent infusions of NE (10−12 to 10−2 M). There were no limb or sex differences in cutaneous adrenergic responsiveness (logEC50) to exogenous NE. During α-adrenergic receptor blockade, women had greater exogenous NE-induced cutaneous vasodilation at the lowest doses of NE (10−12 to 10−10 M). Collectively, these data indicate that there are no limb or sex differences in cutaneous adrenergic responsiveness to exogenous NE; however, young women have a greater β-adrenergic receptor-mediated component of the vascular responsiveness to exogenous NE. PMID:25342706

  2. [HPV-associated cutaneous lesions].

    PubMed

    Kiyofumi, Egawa

    2008-12-01

    More than 100 HPV genotypes are presently distinguished by comparing the DNA sequence of the L1 ORF of each HPV. Two important aspects of the nature of this group of heterogeneous viruses are the way in which specific HPV genotypes are associated with distinct clinical and histological morphologies and the way specific HPV genotypes affect distinct anatomical sites. The former is best evidenced by the HPV type specific cytopathic or cytopathogenic effect (CPE), whereas the latter is suggested by the marked preference of each HPV genotype for specific tissues and sites. Recent studies have also suggested that specific HPV genotypes may target epithelial stem cells at specific anatomical sites. HPV type-specific CPE is the central schema when we analyze and understand the HPV-associated diseases. The concept was suggested by the characterization of distinct HPVs from different types of warts: HPV 2/27/57 from common warts, HPV 3/10/28 from flat warts, HPV 6/11 from condyloma acuminatum, and HPV 5/8 from lesions of epidermodysplasia verruciformis (EV). In this paper, I summarize recent advances in HPV study field, especially on HPV-associated cutaneous lesions. These include inclusion warts, HPV-associated epidermoid cysts, HPV type specific activation of melanogenesis, a double infection with HPV 1 and HPV 63 within a single cell, primary target cells and life cycle of the virus, and the identification of novel genes that are associated EV. The HPV-associated cutaneous lesions thus pose important problems to be resolved in virology and human pathology. PMID:19374195

  3. Cystathionine γ-lyase, a H2S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids.

    PubMed

    Renga, Barbara; Bucci, Mariarosaria; Cipriani, Sabrina; Carino, Adriana; Monti, Maria Chiara; Zampella, Angela; Gargiulo, Antonella; d'Emmanuele di Villa Bianca, Roberta; Distrutti, Eleonora; Fiorucci, Stefano

    2015-07-01

    GPBAR1 is a bile acid-activated receptor (BAR) for secondary bile acids, lithocholic (LCA) and deoxycholic acid (DCA), expressed in the enterohepatic tissues and in the vasculature by endothelial and smooth muscle cells. Despite that bile acids cause vasodilation, it is unclear why these effects involve GPBAR1, and the vascular phenotype of GPBAR1 deficient mice remains poorly defined. Previous studies have suggested a role for nitric oxide (NO) in regulatory activity exerted by GPBAR1 in liver endothelial cells. Hydrogen sulfide (H2S) is a vasodilatory agent generated in endothelial cells by cystathionine-γ-lyase (CSE). Here we demonstrate that GPBAR1 null mice had increased levels of primary and secondary bile acids and impaired vasoconstriction to phenylephrine. In aortic ring preparations, vasodilation caused by chenodeoxycholic acid (CDCA), a weak GPBAR1 ligand and farnesoid-x-receptor agonist (FXR), was iberiotoxin-dependent and GPBAR1-independent. In contrast, vasodilation caused by LCA was GPBAR1 dependent and abrogated by propargyl-glycine, a CSE inhibitor, and by 5β-cholanic acid, a GPBAR1 antagonist, but not by N(5)-(1-iminoethyl)-l-ornithine (l-NIO), an endothelial NO synthase inhibitor, or iberiotoxin, a large-conductance calcium-activated potassium (BKCa) channels antagonist. In venular and aortic endothelial (HUVEC and HAEC) cells GPBAR1 activation increases CSE expression/activity and H2S production. Two cAMP response element binding protein (CREB) sites (CREs) were identified in the CSE promoter. In addition, TLCA stimulates CSE phosphorylation on serine residues. In conclusion we demonstrate that GPBAR1 mediates the vasodilatory activity of LCA and regulates the expression/activity of CSE. Vasodilation caused by CDCA involves BKCa channels. The GPBAR1/CSE pathway might contribute to endothelial dysfunction and hyperdynamic circulation in liver cirrhosis.

  4. A cutaneous positioning system.

    PubMed

    Martin, Bernard J; Lee, Beom-Chan; Sienko, Kathleen H

    2015-04-01

    Our previous work revealed that torso cutaneous information contributes to the internal representation of the torso and plays a role in postural control. Hence, the aims of this study were to assess whether posture could be manipulated by patterns of vibrotactile stimulation and to determine whether resulting modified postures were associated with specific and consistent spatial attitudes. Ten healthy young adults stood in normal and Romberg stances with six vibrating actuators positioned on the torso in contact with the skin over the anatomical locations corresponding to left and right external oblique, internal oblique and erector spinae muscles at the L4/L5 vertebrae level. A 250-Hz tactile vibration was applied for 5 s either at a single location or consecutively at each location in clockwise or counterclockwise sequences. Kinematic analysis of the body segments indicated that postural responses observed in response to single and sequential stimulation patterns were similar, while the center of pressure remained unaltered in any situations. Moreover, torso inclinations followed rectilinear-like path segments chartered by stimuli loci during sequential stimulations. Comparison of torso attitudes with previous results obtained with co-vibration patterns of the same duration showed that torso inclination amplitudes are equivalent for single (one location) and co-vibration (pairs of locations) patterns inducing the same directional effect. Hence, torso cutaneous information exhibits kinesthetic properties, appears to provide a map of upper body spatial configuration, and could assume the role of an internal positioning system for the upper body. PMID:25600816

  5. Cutaneous interstitial nitric oxide concentration does not increase during heat stress in humans

    NASA Technical Reports Server (NTRS)

    Crandall, C. G.; MacLean, D. A.

    2001-01-01

    Inhibition of cutaneous nitric oxide (NO) synthase reduces the magnitude of cutaneous vasodilation during whole body heating in humans. However, this observation is insufficient to conclude that NO concentration increases in the skin during a heat stress. This study was designed to test the hypothesis that whole body heating increases cutaneous interstitial NO concentration. This was accomplished by placing 2 microdialysis membranes in the forearm dermal space of 12 subjects. Both membranes were perfused with lactated Ringer solutions at a rate of 2 microl/min. In both normothermia and during whole body heating via a water perfused suit, dialysate from these membranes were obtained and analyzed for NO using the chemiluminescence technique. In six of these subjects, after the heat stress, the membranes were perfused with a 1 M solution of acetylcholine to stimulate NO release. Dialysate from these trials was also assayed to quantify cutaneous interstitial NO concentration. Whole body heating increased skin temperature from 34.6 +/- 0.2 to 38.8 +/- 0.2 degrees C (P < 0.05), which increased sublingual temperature (36.4 +/- 0.1 to 37.6 +/- 0.1 degrees C; P < 0.05), heart rate (63 +/- 5 to 93 +/- 5 beats/min; P < 0.05), and skin blood flow over the membranes (21 +/- 4 to 88 +/- 10 perfusion units; P < 0.05). NO concentration in the dialysate did not increase significantly during of the heat stress (7.6 +/- 0.7 to 8.6 +/- 0.8 microM; P > 0.05). After the heat stress, administration of acetylcholine in the perfusate significantly increased skin blood flow (128 +/- 6 perfusion units) relative to both normothermic and heat stress values and significantly increased NO concentration in the dialysate (15.8 +/- 2.4 microM). These data suggest that whole body heating does not increase cutaneous interstitial NO concentration in forearm skin. Rather, NO may serve in a permissive role in facilitating the effects of an unknown neurotransmitter, leading to cutaneous vasodilation

  6. Clinical outcome measures for Cutaneous Lupus Erythematosus

    PubMed Central

    Albrecht, Joerg; Werth, Victoria P.

    2011-01-01

    Cutaneous lupus erythematosus is a clinically heterogeneous group of rare skin diseases that only rarely have been subjected to controlled clinical trials. This may be have been partly due to a lack of suitable validated outcome instruments. Recently the FDA mandated that organ specific trials for lupus erythematosus need to use a combination of different outcome measures. The patient’s condition needs to be assessed in terms of quality of life, the patient’s global response and organ specific instruments that measure activity of the disease as well as damage due to the disease. For the skin the only formally validated and published instrument is currently the Cutaneous Lupus Erythematosis Disease Area and Severity Index (CLASI). This paper discusses the background of the development of the CLASI as well as issues related to its use and interpretation in the context of clinical research of CLE. PMID:20693208

  7. Progressive handgrip exercise: evidence of nitric oxide-dependent vasodilation and blood flow regulation in humans.

    PubMed

    Wray, D Walter; Witman, Melissa A H; Ives, Stephen J; McDaniel, John; Fjeldstad, Anette S; Trinity, Joel D; Conklin, Jamie D; Supiano, Mark A; Richardson, Russell S

    2011-03-01

    In the peripheral circulation, nitric oxide (NO) is released in response to shear stress across vascular endothelial cells. We sought to assess the degree to which NO contributes to exercise-induced vasodilation in the brachial artery (BA) and to determine the potential of this approach to noninvasively evaluate NO bioavailability. In eight young (25 ± 1 yr) healthy volunteers, we used ultrasound Doppler to examine BA vasodilation in response to handgrip exercise (4, 8, 12, 16, 20, and 24 kg) with and without endothelial NO synthase blockade [intra-arterial N(G)-monomethyl-L-arginine (L-NMMA), 0.48 mg · dl(-1) · min(-1)]. Higher exercise intensities evoked significant BA vasodilation (4-12%) that was positively correlated with the hyperemic stimulus (r = 0.98 ± 0.003, slope = 0.005 ± 0.001). During NO blockade, BA vasodilation at the highest exercise intensity was reduced by ∼70% despite similar exercise-induced increases in shear rate (control, +224 ± 30 s(-1); L-NMMA, +259 ± 46 s(-1)). The relationship and slope of BA vasodilation with increasing shear rate was likewise reduced (r = 0.48 ± 0.1, slope = 0.0007 ± 0.0005). We conclude that endothelial NO synthase inhibition with L-NMMA abolishes the relationship between shear stress and BA vasodilation during handgrip exercise, providing clear evidence of NO-dependent vasodilation in this experimental model. These results support this paradigm as a novel and valid approach for a noninvasive assessment of NO-dependent vasodilation in humans.

  8. Relationship between vasodilation capacity and phenolic content of Spanish wines.

    PubMed

    Padilla, Eugenia; Ruiz, Emilio; Redondo, Santiago; Gordillo-Moscoso, Antonio; Slowing, Karla; Tejerina, Teresa

    2005-07-01

    We aimed to determine: 1) the concentration of polyphenols in Spanish red wines, 2) the vasodilatory properties of those wines in relation with their polyphenol concentrations and 3) the vasodilation induced by some of these polyphenols in rat aortic rings. In the wines studied the concentration of rutin and kaempferol was high compared with other polyphenols. All wines relaxed precontracted rat aortic rings and this effect was directly related with the concentration of myricetin and kaempferol in the wines. Kaempferol and rutin also induced endothelium-dependent and independent relaxation, kaempferol was more potent. This relaxation was not inhibited by the estrogen receptor alpha antagonist ICI 182,760. Kaempferol also potentiated the endothelium-dependent relaxation induced by acetylcholine, which was reversed by Nw-nitro-l-arginine methyl ester (l-NAME). These findings show a good correlation between the concentration of polyphenols (especially kaempferol) of Spanish red wines and the vasodilatory effect, which may confer on them unique features in the prevention of cardiovascular disease.

  9. Liposomal nanoparticles encapsulating iloprost exhibit enhanced vasodilation in pulmonary arteries

    PubMed Central

    Jain, Pritesh P; Leber, Regina; Nagaraj, Chandran; Leitinger, Gerd; Lehofer, Bernhard; Olschewski, Horst; Olschewski, Andrea; Prassl, Ruth; Marsh, Leigh M

    2014-01-01

    Prostacyclin analogues are standard therapeutic options for vasoconstrictive diseases, including pulmonary hypertension and Raynaud’s phenomenon. Although effective, these treatment strategies are expensive and have several side effects. To improve drug efficiency, we tested liposomal nanoparticles as carrier systems. In this study, we synthesized liposomal nanoparticles tailored for the prostacyclin analogue iloprost and evaluated their pharmacologic efficacy on mouse intrapulmonary arteries, using a wire myograph. The use of cationic lipids, stearylamine, or 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP) in liposomes promoted iloprost encapsulation to at least 50%. The addition of cholesterol modestly reduced iloprost encapsulation. The liposomal nanoparticle formulations were tested for toxicity and pharmacologic efficacy in vivo and ex vivo, respectively. The liposomes did not affect the viability of human pulmonary artery smooth muscle cells. Compared with an equivalent concentration of free iloprost, four out of the six polymer-coated liposomal formulations exhibited significantly enhanced vasodilation of mouse pulmonary arteries. Iloprost that was encapsulated in liposomes containing the polymer polyethylene glycol exhibited concentration-dependent relaxation of arteries. Strikingly, half the concentration of iloprost in liposomes elicited similar pharmacologic efficacy as nonencapsulated iloprost. Cationic liposomes can encapsulate iloprost with high efficacy and can serve as potential iloprost carriers to improve its therapeutic efficacy. PMID:25045260

  10. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans.

    PubMed Central

    Creager, M A; Cooke, J P; Mendelsohn, M E; Gallagher, S J; Coleman, S M; Loscalzo, J; Dzau, V J

    1990-01-01

    The effect of hypercholesterolemia on vascular function was studied in humans. To eliminate the potential confounding effects of atherosclerosis, vascular reactivity was measured in the forearm resistance vessels of 11 normal subjects (serum LDL cholesterol = 111 +/- 7 mg/dl) and 13 patients with hypercholesterolemia (serum LDL cholesterol = 211 +/- 19 mg/dl, P less than 0.05). Each subject received intrabrachial artery infusions of methacholine, which releases endothelium-derived relaxant factor, and nitroprusside which directly stimulates guanylate cyclase in vascular smooth muscle. Maximal vasodilatory potential was determined during reactive hyperemia. Vasoconstrictive responsiveness was examined during intra-arterial phenylephrine infusion. Forearm blood flow was determined by venous occlusion plethysmography. Basal forearm blood flow in normal and hypercholesterolemic subjects was comparable. Similarly, reactive hyperemic blood flow did not differ between the two groups. In contrast, the maximal forearm blood flow response to methacholine in hypercholesterolemic subjects was less than that observed in normal subjects. In addition, the forearm blood flow response to nitroprusside was less in hypercholesterolemic subjects. There was no difference in the forearm vasoconstrictive response to phenylephrine in the two groups. Thus, the vasodilator responses to methacholine and nitroprusside were blunted in patients with hypercholesterolemia. We conclude that in humans with hypercholesterolemia, there is a decreased effect of nitrovasodilators, including endothelium-derived relaxing factor, on the vascular smooth muscle of resistance vessels. PMID:2195060

  11. Cutaneous protothecosis - Case report*

    PubMed Central

    da Silva, Pâmela Craveiro Gomes; Silva, Sabrina Beirão da Costa e; Lima, Ricardo Barbosa; D'Acri, Antonio Macedo; Lupi, Omar; Martins, Carlos José

    2013-01-01

    Cutaneous protothecosis is a rare infection caused by achlorophyllic algae of the genus Prototheca. The lesions usually occur on exposed areas, related with trauma, in immunocompromised patients. The most common clinical presentation is a vesicobullous and ulcerative lesion with pustules and scabs, simulating bacterial, fungal or herpetic infections or eczema. The diagnosis is determined by agent identification through histopathology, culture and the carbohydrates assimilation test. The finding of morula-like spherules is characteristic of Prototheca sp. Its rarity and non-specific clinical aspect may difficult the disease diagnosis. We report a case of a diabetic patient, in chronic use of systemic corticosteroids, that developed a skin lesion after trauma to the right leg. PMID:24346914

  12. Cutaneous vasculitis: a review.

    PubMed

    Crowson, A Neil; Mihm, Martin C; Magro, Cynthia M

    2003-03-01

    As the skin is commonly involved in systemic vasculitic disorders as well as those hypersensitivity states whose expression is largely skin-confined, cutaneous vasculitic lesions offer a window to diagnosis and a ready source of accessible tissue for biopsy. In this review, we discuss the pathologic manifestations of chronic vasculitic syndromes such as granuloma faciale and erythema elevatum diutinum; IgA-associated vasculitis including Henoch-Schonlein purpura; vasculitis seen in the setting of cryoglobulinemia and hypergammaglobulinemia of Waldenstrom, hereditary deficiencies of complement, and IgA deficiency; those leukocytoclastic vasculitides resulting from hypersensitivity reactions to drug, chemical and foodstuff ingestion; and those vasculitides seen in patients with systemic diseases such as polyarteritis nodosa, rheumatoid arthritis, mixed connective tissue disease, systemic lupus erythematosus, Sjogren's syndrome, relapsing polychondritis, Behcet's disease, Wegener's granulomatosis, and allergic granulomatosis of Churg and Strauss.

  13. Cutaneous hypersensitivity to gluten.

    PubMed

    Tammaro, Antonella; Narcisi, Alessandra; De Marco, Gabriella; Persechino, Severino

    2012-01-01

    We enrolled 14 female patients (aged 12-60 years) affected by celiac disease (confirmed by duodenal biopsy), presenting dermatologic eczematous lesions involving their face, neck, and overall arms, after application of gluten-containing emollient cream, bath, or face powder, or after contact with foods containing wheat and durum wheat. Five patients resulted positive to patch-by-patch with wheat and durum wheat (mild to moderate positivity) with erythema and vesicles, in correspondence of their sites of application. Utilizing gluten-free cream and bath, and wearing gloves before hand contact with food-containing wheat, in their common life, these patients showed an improvement of their cutaneous lesions and no relapses of dermatitis for a 6-month follow-up period.

  14. Cutaneous oxidative stress.

    PubMed

    Polefka, Thomas G; Meyer, Thomas A; Agin, Patricia P; Bianchini, Robert J

    2012-03-01

    The earliest known microfossil records suggest that microorganisms existed on the earth approximately 3.8 billion years ago. Not only did sunlight drive this evolutionary process, but it also allowed photosynthetic organisms to elaborate oxygen and fundamentally change the earth's atmosphere and subsequent evolution. Paradoxically, however, an atmosphere of 20% oxygen offers aerobic organisms both benefits and some key challenges, particularly, to the external integument. This mini-review summarizes almost 40 years of research and provides a "60 000-foot" perspective on cutaneous oxidative stress. Topics reviewed include the following: What are free radicals and reactive oxygen species? Where do they come from? What is their chemistry? What are their roles and/or impact on the skin? What antioxidant defenses are available to mitigate oxidative stress. PMID:22360336

  15. Cutaneous Leishmaniasis with HIV.

    PubMed

    Talat, Humaira; Attarwala, Sharmeen; Saleem, Mubasshir

    2014-05-01

    Cutaneous Leishmaniasis (CL) is a vector borne disease caused by various species of the Leishmania parasite. CL is endemic in the province of Balochistan in Pakistan. In certain instances a Human Immunodeficiency Virus (HIV)-related immunocompromised is associated with atypical clinical presentation and occurrence of reactivated lesions of CL. Such presentations respond poorly to the standard treatment and frequent relapses are noted. We are reporting three cases of localized and disseminated CL due to Leishmania tropica which responded to meglumine antimoniate. Due to the fact that CL is endemic in Balochistan, we did not consider HIV infection as a causative organism. It was their presentation with history of weight loss and fever that prompted Enzyme-linked Immunosorbent Assay (ELISA) tests for HIV, which turned out to be positive. CL is becoming visible as an opportunistic infection associated with HIV/AIDS and may even be the first symptom in HIV positive patients in an endemic area.

  16. Early Cutaneous Lupus Erythematosus

    PubMed Central

    Sams, Wiley M.

    1966-01-01

    Cutaneous disorders which manifest themselves on the exposed parts are more likely than are hidden lesions to cause the patient to seek professional services promptly. Usually he consults his family physician or the community dermatologist. The physician who first sees the patient is dependent upon his own resources for management and diagnosis. A background of experience, a measure of energy and an inquisitive attitude are the necessary ingredients for successful management. The difficulties involved in differentiating early lupus erythematosus and polymorphic light eruptions cannot be invariably resolved even with the most complete review. The course of the disorder and the response to environmental factors supply important clues. Investigative work, especially in the field of immunology, offers hope for the solution of some of our problems. PMID:5909872

  17. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans.

    PubMed Central

    Creager, M A; Gallagher, S J; Girerd, X J; Coleman, S M; Dzau, V J; Cooke, J P

    1992-01-01

    Endothelium-dependent vasodilation is impaired in hypercholesterolemia, even before the development of atherosclerosis. The purpose of this study was to determine whether infusion of L-arginine, the precursor of the endothelium-derived relaxing factor, nitric oxide, improves endothelium-dependent vasodilation in hypercholesterolemic humans. Vascular reactivity was measured in the forearm resistance vessels of 11 normal subjects (serum LDL cholesterol = 2.76 +/- 0.10 mmol/liter) and 14 age-matched patients with hypercholesterolemia (serum LDL cholesterol = 4.65 +/- 0.36 mmol/liter, P < 0.05). The vasodilative response to the endothelium-dependent vasodilator, methacholine chloride, was depressed in the hypercholesterolemic group, whereas endothelium-independent vasodilation, induced by nitroprusside, was similar in each group. Intravenous administration of L-arginine augmented the forearm blood flow response to methacholine in the hypercholesterolemic individuals, but not in the normal subjects. L-arginine did not alter the effect of nitroprusside in either group. D-arginine had no effect on forearm vascular reactivity in either group. It is concluded that endothelium-dependent vasodilation is impaired in hypercholesterolemic humans. This abnormality can be improved acutely by administration of L-arginine, possibly by increasing the synthesis of endothelium-derived relaxing factor. PMID:1401062

  18. Medial prefrontal cortex acetylcholine injection-induced hypotension: the role of hindlimb vasodilation

    NASA Technical Reports Server (NTRS)

    Crippa, G. E.; Lewis, S. J.; Johnson, A. K.; Correa, F. M.

    2000-01-01

    The injection of acetylcholine (ACh) into the cingulate region of the medial prefrontal cortex (MPFC) causes a marked fall in arterial blood pressure which is not accompanied by changes in heart rate. The purpose of the present study was to investigate the hemodynamic basis for this stimulus-induced hypotension in Sprague-Dawley rats. The study was designed to determine whether a change in the vascular resistance of hindlimb, renal or mesenteric vascular beds contributes to the fall in arterial pressure in response to ACh injection into the cingulate cortex. Miniature pulsed-Doppler flow probes were used to measure changes in regional blood flow and vascular resistance. The results indicated that the hypotensive response was largely due to a consistent and marked vasodilation in the hindlimb vascular bed. On this basis, an additional experiment was then undertaken to determine the mechanisms that contribute to hindlimb vasodilation. The effect of interrupting the autonomic innervation of one leg on the hindlimb vasodilator response was tested. Unilateral transection of the lumbar sympathetic chain attenuated the cingulate ACh-induced vasodilation in the ipsilateral, but not in the contralateral hindlimb. These results suggest that the hypotensive response to cingulate cortex-ACh injection is caused by skeletal muscle vasodilation mediated by a sympathetic chain-related vasodilator system.

  19. Tropical dermatology: cutaneous larva migrans, gnathostomiasis, cutaneous amebiasis and trombiculiasis.

    PubMed

    Eichelmann, Kristian; Tomecki, Kenneth J; Martínez, José Darío

    2014-09-01

    In today's world, many people can travel easily and quickly around the globe. Most travel travel-related illnesses include fever, diarrhea, and skin disease, which are relatively uncommon in returning travelers. We review four of the most common emerging infestations and skin infections in the Americas, which are important to the clinical dermatologist, focusing on the clinical presentation and treatment of cutaneous larva migrans, gnathostomiasis, cutaneous amebiasis, and trombiculiasis.

  20. Cutaneous inputs from the back abolish locomotor-like activity and reduce spastic-like activity in the adult cat following complete spinal cord injury

    PubMed Central

    Frigon, Alain; Thibaudier, Yann; Johnson, Michael D.; Heckman, C.J.; Hurteau, Marie-France

    2012-01-01

    Spasticity is a condition that can include increased muscle tone, clonus, spasms, and hyperreflexia. In this study, we report the effect of manually stimulating the dorsal lumbosacral skin on spontaneous locomotor-like activity and on a variety of reflex responses in 5 decerebrate chronic spinal cats treated with clonidine. Cats were spinalized 1 month before the terminal experiment. Stretch reflexes were evoked by stretching the left triceps surae muscles. Crossed reflexes were elicited by electrically stimulating the right tibial or superficial peroneal nerves. Windup of reflex responses was evoked by electrically stimulating the left tibial or superficial peroneal nerves. We found that pinching the skin of the back abolished spontaneous locomotor-like activity. We also found that back pinch abolished the rhythmic activity observed during reflex testing without eliminating the reflex responses. Some of the rhythmic episodes of activity observed during reflex testing were consistent with clonus with an oscillation frequency greater than 3 Hz. Pinching the skin of the back effectively abolished rhythmic activity occurring spontaneously or evoked during reflex testing, irrespective of oscillation frequency. The results are consistent with the hypothesis that locomotion and clonus are produced by common central pattern-generators. Stimulating the skin of the back could prove helpful in managing undesired rhythmic activity in spinal cord-injured humans. PMID:22487200

  1. A salivary vasodilator in the blood-sucking bug, Rhodnius prolixus.

    PubMed

    Ribeiro, J M; Marinotti, O; Gonzales, R

    1990-12-01

    1. Salivary gland homogenates of the blood-sucking bug, Rhodnius prolixus induced transient, dose-dependent relaxation of rabbit aortic preparations pre-constricted with 200 ng ml-1 noradrenaline, 1 microgram ml-1 histamine or 20 ng ml-1 angiotensin II. Such relaxations were less marked when the aorta was constricted by 60 mM KC1. These effects were observed with as little as 0.2 microgram ml-1 of crude salivary gland protein. 2. The vasodilator effect was endothelium-independent, abolished by 50 microM hydroquinone or 50 microM methylene blue, and potentiated by 30 mu ml-1 superoxide dismutase. 3. Salivary homogenates generated a coloured compound when reacted with sulfanilic acid in the presence of N-(1-naphthyl)-ethylediamine, indicating the presence of reactive nitrogen groups, equivalent to 35 +/- 3 ng of sodium nitrite per pair of glands. 4. Molecular sieving high performance liquid chromatography of salivary gland homogenates generated a single peak of vasorelaxant activity which coincided with the presence of platelet antiaggregating and spasmolytic (guinea-pig ileum contracted with histamine) activities, as well as with reactive nitrogen groups. 5. It is concluded that a protein of molecular weight 16.500 daltons in the salivary glands of R. prolixus contains reactive nitrogen groups which assist the bug during a blood meal. It is suggested that saliva of blood sucking anthropods is a natural resource of novel pharmacological activities. PMID:2085715

  2. Systemic diseases with cutaneous manifestations.

    PubMed

    Merchant, S R; Taboada, J

    1995-07-01

    The purpose of this article is to briefly discuss the following cutaneous manifestations of selected systemic diseases: poxvirus; feline leukemia virus (FeLV); feline immunodeficiency virus (FIV); herpesvirus; calcivirus; pseudorabies; plague; tularemia; toxoplasmosis; leishmania; hypothyroidism; hyperthyroidism; hyperadrenocorticism; diabetes mellitus; acromegaly; thallium poisoning; pancreatic disease; hypereosinophilic syndrome; mucopolysaccharidosis; and pansteatitis. Recognition of these cutaneous signs may help alert the clinician to the possibility of an internal disorder so that the appropriate diagnostic tests can be considered. PMID:8525575

  3. Cutaneous Lymphangioma circumscriptum - dermoscopic features**

    PubMed Central

    Massa, António Fernandes; Menezes, Nuno; Baptista, Armando; Moreira, Ana Isabel; Ferreira, Eduarda Osório

    2015-01-01

    Lymphangiomas are congenital lymphatic malformations and cutaneous lymphangioma circumscriptum is the most common type. It is clinically characterized by clusters of translucent vesicles and the presence of dermoscopically yellow lacunae surrounded by pale septa, as well as reddish to bluish lacunae. In our case, the recently described hypopyon-like feature manifested, aiding in the sometimes difficult differential diagnosis of cutaneous lymphangioma circumscriptum with vascular lesions, further highlighting the importance of dermoscopy in what can be a diagnostic challenge. PMID:25831002

  4. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

    SciTech Connect

    Agbor, Larry N.; Walsh, Mary T.; Boberg, Jason R.; Walker, Mary K.

    2012-11-01

    In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega − 3 polyunsaturated fatty acids (n − 3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n − 3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mm Hg, WT 103 ± 1, KO 116 ± 1, n = 5/genotype, p < 0.05), and exhibited a reduced heart rate (beats per minute, WT 575 ± 5; KO 530 ± 7; p < 0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n − 3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.

  5. Impaired Retinal Vasodilator Responses in Prediabetes and Type 2 Diabetes

    PubMed Central

    Lott, Mary E.J.; Slocomb, Julia E.; Shivkumar, Vikram; Smith, Bruce; Quillen, David; Gabbay, Robert A.; Gardner, Thomas W.; Bettermann, Kerstin

    2013-01-01

    Purpose In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycemic continuum and may be associated with markers of inflammation. Methods Individuals with prediabetes (n = 22), type 2 diabetes (n = 25) and healthy age and body composition matched controls (n = 19) were studied. We used the Dynamic Vessel Analyzer to assess retinal vasoreactivity (percent change in vessel diameter) during a flickering light stimulation. Fasting highly sensitive c-reactive protein (hs-CRP), a marker of inflammation, was measured in blood plasma. Results Prediabetic and diabetic individuals had attenuated peak vasodilator and relative amplitude changes in retinal vein diameters to the flickering light stimulus compared to healthy controls (peak dilation: prediabetic subjects 3.3 ± 1.8 %, diabetic subjects 3.3 ± 2.1% controls 5.6 ± 2.6%, p = .001; relative amplitude: prediabetic subjects 4.3 ± 2.2%, diabetic subjects 5.0 ± 2.6% and control subjects 7.2 ± 3.2%, p = .003). Similar findings were observed in retinal arteries. Levels of hs-CRP were not associated with either retinal vessel response parameters. Conclusion Retinal reactivity was impaired in prediabetic and type 2 diabetic individuals in parallel with reduced insulin sensitivity but not associated with levels of hs-CRP. Retinal vasoreactivity measurements may be a sensitive tool to assess early vascular risk. PMID:23742315

  6. Effect of body temperature on cold induced vasodilation.

    PubMed

    Flouris, Andreas D; Westwood, David A; Mekjavic, Igor B; Cheung, Stephen S

    2008-10-01

    Cold-induced vasodilation (CIVD) is an acute increase in peripheral blood flow observed during cold exposures. It is hypothesized to protect against cold injuries, yet despite continuous research it remains an unexplained phenomenon. Contrary to the traditionally held view, we propose that CIVD is a thermoregulatory reflex mechanism contributing to heat loss. Ten adults (4 females; 23.8 +/- 2.0 years) randomly underwent three 130-min exposures to -20 degrees C incorporating a 10-min moderate exercise period at the 65th min, while wearing a liquid conditioning garment (LCG) and military arctic clothing. In the pre-warming condition, rectal temperature was increased by 0.5 degrees C via the LCG before the cold exposure. In the warming condition, participants regulated the LCG throughout the cold exposure to subjective comfort. In the control condition, the LCG was worn but was not operated either before or during the cold exposure. Results demonstrated that the majority of CIVD occurred during the warming condition when the thermometrically-estimated mean body temperature (T (b)) was at its highest. A thermoregulatory pattern was identified whereby CIVD occurred soon after T (b) increased past a threshold (approximately 36.65 degrees C in warming and pre-warming; approximately 36.4 degrees C in control). When CIVD occurred, T (b) was reduced and CIVD ceased when T (b) fell below the threshold. These findings were independent of extremity temperature since CIVD episodes occurred at a large range of finger temperatures (7.2-33.5 degrees C). These observations were statistically confirmed by auto-regressive integrated moving average analysis (t = 9.602, P < 0.001). We conclude that CIVD is triggered by increased T (b) supporting the hypothesis that CIVD is a thermoregulatory mechanism contributing to heat loss.

  7. Diving Response in Rats: Role of the Subthalamic Vasodilator Area

    PubMed Central

    Golanov, Eugene V.; Shiflett, James M.; Britz, Gavin W.

    2016-01-01

    Diving response (DR) is a powerful integrative response targeted toward survival of the hypoxic/anoxic conditions. Being present in all animals and humans, it allows to survive adverse conditions like diving. Earlier, we discovered that forehead stimulation affords neuroprotective effect, decreasing infarction volume triggered by permanent occlusion of the middle cerebral artery in rats. We hypothesized that cold stimulation of the forehead induces DR in rats, which, in turn, exerts neuroprotection. We compared autonomic [AP, heart rate (HR), cerebral blood flow (CBF)] and EEG responses to the known DR-triggering stimulus, ammonia stimulation of the nasal mucosa, cold stimulation of the forehead, and cold stimulation of the glabrous skin of the tail base in anesthetized rats. Responses in AP, HR, CBF, and EEG to cold stimulation of the forehead and ammonia vapors instillation into the nasal cavity were comparable and differed significantly from responses to the cold stimulation of the tail base. Excitotoxic lesion of the subthalamic vasodilator area (SVA), which is known to participate in CBF regulation and to afford neuroprotection upon excitation, failed to affect autonomic components of the DR evoked by forehead cold stimulation or nasal mucosa ammonia stimulation. We conclude that cold stimulation of the forehead triggers physiological response comparable to the response evoked by ammonia vapor instillation into nasal cavity, which is considered as stimulus triggering protective DR. These observations may explain the neuroprotective effect of the forehead stimulation. Data demonstrate that SVA does not directly participate in the autonomic adjustments accompanying DR; however, it is involved in diving-evoked modulation of EEG. We suggest that forehead stimulation can be employed as a stimulus capable of triggering oxygen-conserving DR and can be used for neuroprotective therapy. PMID:27708614

  8. Polygonum aviculare L. and its active compounds, quercitrin hydrate, caffeic acid, and rutin, activate the Wnt/β-catenin pathway and induce cutaneous wound healing.

    PubMed

    Seo, Seol Hwa; Lee, Soung-Hoon; Cha, Pu-Hyeon; Kim, Mi-Yeon; Min, Do Sik; Choi, Kang-Yell

    2016-05-01

    Polygonum aviculare L. is a member of the Polygonaceae family of plants, which has been known for its antioxidant and anti-obesity effects. However, the wound healing function of P. aviculare extract has not been assessed. In this study, we identified a novel property of P. aviculare extract as a Wnt/β-catenin pathway activator based on a screen of 350 plant extracts using HEK293-TOP cells retaining the Wnt/β-catenin signaling reporter gene. P. aviculare extract accelerated the migration of HaCaT keratinocytes without showing significant cytotoxicity. Moreover, P. aviculare extract efficiently re-epithelized wounds generated on mice. Additionally, ingredients of P. aviculare extract, such as quercitrin hydrate, caffeic acid, and rutin, also accelerated the motility of HaCaT keratinocytes with the activation of Wnt/β-catenin signaling. Therefore, based on our findings, P. aviculare extract and its active ingredients could be potential therapeutic agents for wound healing. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Polygonum aviculare L. and its active compounds, quercitrin hydrate, caffeic acid, and rutin, activate the Wnt/β-catenin pathway and induce cutaneous wound healing.

    PubMed

    Seo, Seol Hwa; Lee, Soung-Hoon; Cha, Pu-Hyeon; Kim, Mi-Yeon; Min, Do Sik; Choi, Kang-Yell

    2016-05-01

    Polygonum aviculare L. is a member of the Polygonaceae family of plants, which has been known for its antioxidant and anti-obesity effects. However, the wound healing function of P. aviculare extract has not been assessed. In this study, we identified a novel property of P. aviculare extract as a Wnt/β-catenin pathway activator based on a screen of 350 plant extracts using HEK293-TOP cells retaining the Wnt/β-catenin signaling reporter gene. P. aviculare extract accelerated the migration of HaCaT keratinocytes without showing significant cytotoxicity. Moreover, P. aviculare extract efficiently re-epithelized wounds generated on mice. Additionally, ingredients of P. aviculare extract, such as quercitrin hydrate, caffeic acid, and rutin, also accelerated the motility of HaCaT keratinocytes with the activation of Wnt/β-catenin signaling. Therefore, based on our findings, P. aviculare extract and its active ingredients could be potential therapeutic agents for wound healing. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26929003

  10. Simulated Microgravity Increases Cutaneous Blood Flow in the Head and Leg of Humans

    NASA Technical Reports Server (NTRS)

    Stout, M. Shannon; Watenpaugh, Donald E.; Breit, Gregory A.; Hargens, Alan R.

    1995-01-01

    The cutaneous micro-circulation vasodilates during acute 6 deg. head-down tilt (HDT, simulated microgravity) relative to upright conditions, more in the lower body than in the upper body. We expected that relative magnitudes of and differences between upper and lower body cutaneous blood flow elevation would be sustained during initial acclimation to simulated microgravity. We measured cutaneous micro-vascular blood flow with laser-Doppler flowmetry at the leg (over the distal tibia) and cheek (over the zygomatic arch) of eight healthy men before, during, and after 24 h of HDT. Results were calculated as a percentage of baseline value (100% measured during pre-tilt upright sitting). Cutaneous blood flow in the cheek increased significantly to 165 +/- 37% (mean + SE, p less than 0.05) at 9-12 h HDT, then returned to near baseline values by 24 h HDT (114 +/- 29%, NSD), despite increased local arterial pressure. Microvascular flow in the leg remained significantly elevated above baseline throughout 24 h HDT (427 +/- 85% at 3 h HDT and 215 +/- 142% at 24 h HDT, p less than 0.05). During the 6-h upright sitting recovery period, cheek and leg blood flow levels returned to near pre-tilt baseline values. Because hydrostatic effects of HDT increase local arterial pressure at the carotid sinus, baroreflex-mediated withdrawal of sympathetic tone probably contributed to increased microvascular flows at the head and leg during HDT. In the leg, baroreflex effects combined with minimal stimulation of local veno-arteriolar and myogenic autoregulatory vasoconstriction to elicit relatively larger and more sustained increases in cutaneous flow during HDT. In the cheek, delayed myogenic vasoconstriction and/or humoral effects apparently compensated for flow elevation by 24 h of HDT. Therefore, localized vascular adaptations to gravity probably explain differences in acclimation of lower and upper body blood flow to HDT and actual microgravity.

  11. Role of Nitric Oxide and Hydrogen Sulfide in the Vasodilator Effect of Ursolic Acid and Uvaol from Black Cherry Prunus serotina Fruits.

    PubMed

    Luna-Vázquez, Francisco J; Ibarra-Alvarado, César; Rojas-Molina, Alejandra; Romo-Mancillas, Antonio; López-Vallejo, Fabián H; Solís-Gutiérrez, Mariana; Rojas-Molina, Juana I; Rivero-Cruz, Fausto

    2016-01-12

    The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE.

  12. Role of Nitric Oxide and Hydrogen Sulfide in the Vasodilator Effect of Ursolic Acid and Uvaol from Black Cherry Prunus serotina Fruits.

    PubMed

    Luna-Vázquez, Francisco J; Ibarra-Alvarado, César; Rojas-Molina, Alejandra; Romo-Mancillas, Antonio; López-Vallejo, Fabián H; Solís-Gutiérrez, Mariana; Rojas-Molina, Juana I; Rivero-Cruz, Fausto

    2016-01-01

    The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE. PMID:26771591

  13. NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease

    PubMed Central

    DuPont, Jennifer J.; Ramick, Meghan G.; Farquhar, William B.; Townsend, Raymond R.

    2014-01-01

    Oxidative stress promotes vascular dysfunction in chronic kidney disease (CKD). We utilized the cutaneous circulation to test the hypothesis that reactive oxygen species derived from NADPH oxidase and xanthine oxidase impair nitric oxide (NO)-dependent cutaneous vasodilation in CKD. Twenty subjects, 10 stage 3 and 4 patients with CKD (61 ± 4 yr; 5 men/5 women; eGFR: 39 ± 4 ml·min−1·1.73 m−2) and 10 healthy controls (55 ± 2 yr; 4 men/6 women; eGFR: >60 ml·min−1·1.73 m−2) were instrumented with 4 intradermal microdialysis fibers for the delivery of 1) Ringer solution (Control), 2) 10 μM tempol (scavenge superoxide), 3) 100 μM apocynin (NAD(P)H oxidase inhibition), and 4) 10 μM allopurinol (xanthine oxidase inhibition). Skin blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). Ng-nitro-l-arginine methyl ester (l-NAME; 10 mM) was infused to quantify the NO-dependent portion of the response. Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum CVC achieved during sodium nitroprusside infusion at 43°C. Cutaneous vasodilation was attenuated in patients with CKD (77 ± 3 vs. 88 ± 3%, P = 0.01), but augmented with tempol and apocynin (tempol: 88 ± 2 (P = 0.03), apocynin: 91 ± 2% (P = 0.001). The NO-dependent portion of the response was reduced in patients with CKD (41 ± 4 vs. 58 ± 2%, P = 0.04), but improved with tempol and apocynin (tempol: 58 ± 3 (P = 0.03), apocynin: 58 ± 4% (P = 0.03). Inhibition of xanthine oxidase did not alter cutaneous vasodilation in either group (P > 0.05). These data suggest that NAD(P)H oxidase is a source of reactive oxygen species and contributes to microvascular dysfunction in patients with CKD. PMID:24761000

  14. 6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation

    PubMed Central

    Ghareib, Salah A; El-Bassossy, Hany M; Elberry, Ahmed A; Azhar, Ahmad; Watson, Malcolm L; Banjar, Zainy Mohammed

    2015-01-01

    The aim of the present study is to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Male Wistar rats were divided into two experimental groups, control and diabetics. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg−1), and the rats were left for 10 weeks to develop vascular complications. The effect of in vitro incubation with 6-gingerol (0.3–3 μM) on the vasoconstrictor response of the isolated diabetic aortae to phenylephrine and the vasodilator response to acetylcholine was examined. Effect of 6-gingerol was also examined on aortae incubated with methylglyoxal as an advanced glycation end product (AGE). To investigate the mechanism of action of 6-gingerol, the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride (100 μM), guanylate cyclase inhibitor methylene blue (5 μM), calcium-activated potassium channel blocker tetraethylammonium chloride (10 mM), and cyclooxygenase inhibitor indomethacin (5 μM) were added 30 minutes before assessing the direct vasorelaxant effect of 6-gingerol. Moreover, in vitro effects of 6-gingerol on NO release and the effect of 6-gingerol on AGE production were examined. Results showed that incubation of aortae with 6-gingerol (0.3–10 μM) alleviated the exaggerated vasoconstriction of diabetic aortae to phenylephrine in a concentration-dependent manner with no significant effect on the impaired relaxatory response to acetylcholine. Similar results were seen in the aortae exposed to methylglyoxal. In addition, 6-gingerol induced a direct vasodilation effect that was significantly inhibited by Nω-nitro-l-arginine methyl ester hydrochloride and methylene blue. Furthermore, 6-gingerol stimulated aortic NO generation but had no effect on AGE formation. In conclusion, 6-gingerol ameliorates enhanced vascular contraction in diabetic aortae, which may be partially

  15. Familial cutaneous melanoma.

    PubMed

    Hansson, Johan

    2010-01-01

    Approximately 5-10 % of all cutaneous melanomas occur in families with hereditary melanoma predisposition. Worldwide, approximately 20-40% of kindreds with familial elanoma harbor germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence. In different populations several recurring CDKN2A founder mutations have been described. The risk of melanoma in CDKN2A mutations carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population. Some CDKN2A mutations have been associated not only with melanoma but also with increased risk of other malignancies--most notably pancreatic carcinoma. A much smaller number of families have germline mutations in the CDK4 gene on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A. The management of families with hereditary melanoma is discussed. PMID:20687502

  16. Jabuticaba-Induced Endothelium-Independent Vasodilating Effect on Isolated Arteries

    PubMed Central

    de Andrade, Daniela Medeiros Lobo; Borges, Leonardo Luis; Torres, Ieda Maria Sapateiro; da Conceição, Edemilson Cardoso; Rocha, Matheus Lavorenti

    2016-01-01

    Background: Despite the important biological effects of jabuticaba, its actions on the cardiovascular system have not been clarified. Objectives: To determine the effects of jabuticaba hydroalcoholic extract (JHE) on vascular smooth muscle (VSM) of isolated arteries. Methods: Endothelium-denuded aortic rings of rats were mounted in isolated organ bath to record isometric tension. The relaxant effect of JHE and the influence of K+ channels and Ca2+ intra- and extracellular sources on JHE-stimulated response were assessed. Results: Arteries pre-contracted with phenylephrine showed concentration-dependent relaxation (0.380 to 1.92 mg/mL). Treatment with K+ channel blockers (tetraethyl-ammonium, glibenclamide, 4-aminopyridine) hindered relaxation due to JHE. In addition, phenylephrine-stimulated contraction was hindered by previous treatment with JHE. Inhibition of sarcoplasmic reticulum Ca2+ ATPase did not change relaxation due to JHE. In addition, JHE inhibited the contraction caused by Ca2+ influx stimulated by phenylephrine and KCl (75 mM). Conclusion: JHE induces endothelium-independent vasodilation. Activation of K+ channels and inhibition of Ca2+ influx through the membrane are involved in the JHE relaxant effect. PMID:27533258

  17. Age Impaired endothelium-dependent vasodilation is improved by resveratrol in rat mesenteric arteries

    PubMed Central

    Gocmez, Semil S; Scarpace, Philip J; Whidden, Melissa A; Erdos, Benedek; Kirichenko, Nataliya; Sakarya, Yasemin; Utkan, Tijen; Tumer, Nihal

    2016-01-01

    [Purpose] To determine whether resveratrol improves the adverse effects age on vascular function in mesenteric arteries (MAs), and diminishes the hyperactivity in adrenal gland with age. [Methods] Male F344 x Brown Norway rats were assigned to 6-month control (YC), 6-month resveratrol (YR), 24-month control (OC) and 24-month resveratrol (OR). Resveratrol (15 mg/kg) was provided to resveratrol groups in drinking water for 14 days. [Results] Concentration response curves to phenylephrine (PE, 10-9-10-5M), acetylcholine (Ach, 10-9-10-5M) and resveratrol (10-8-10-4M) were evaluated in pressurized isolated MAs. The Ach concentration-response curve was right shifted with maximal response diminished in OC compared with YC rats. These effects were reversed by resveratrol treatment. The resveratrol-mediated relaxant responses were unchanged with age or resveratrol suggesting an endothelium-independent mechanism. Resveratrol tended to increase endothelial nitric oxide synthase; caused no effect on copper-zinc superoxide dismutase; and normalized the age-related elevatation in DβH and NPY levels in adrenal medulla, two indicators of sympathetic activity [Conclusion] These data indicate that resveratrol reverses age-related dysfunction in endothelium-dependent vasodilation in MAs and partially reverses hyperactivity of adrenomedullary function with age. This treatment may have a therapeuticpotential in the treatment of cardiovascular diseases or hypertension in the elderly. PMID:27298812

  18. Chlorpyrifos-induced hypothermia and vasodilation in the tail of the rat: blockade by scopolamine.

    PubMed

    Gordon, C J; Yang, Y L

    2000-07-01

    Organophosphate pesticides such as chlorpyrifos reduce core temperature (Tc) in laboratory rodents. The mechanism(s) responsible for the chlorpyrifos-induced hypothermia are not well known. This study assessed the role of a key effector for thermoregulation in the rat, vasomotor control of heat loss from the tail, and its possible cholinergic control during chlorpyrifos-induced hypothermia. Tc and motor activity were monitored by telemetry in female Long-Evans rats maintained at an ambient temperature (Ta) of 25 degrees. Tail skin temperature (Tsk(t)) was measured hourly. Rats were dosed with chlorpyrifos (0 or 25 mg/kg orally). Two hr later the rats were dosed with saline or scopolamine (1.0 mg/kg intraperitoneally). Two hr after chlorpyrifos treatment there was a marked elevation in Tsk(t)) concomitant with a 0.5 degrees reduction in Tc. Scopolamine administered to control rats led to a marked elevation in Tc with little change in Tsk(t). Rats treated with chlorpyrifos and administered scopolamine underwent a marked vasoconstriction and elevation in Tc. Vasodilation of the tail is an important thermoeffector to reduce Tc during the acute stages of chlorpyrifos exposure. The blockade of the response by scopolamine suggests that the hypothermic and vasodilatory response to chlorpyrifos is mediated via a cholinergic muscarinic pathway in the CNS. PMID:10987209

  19. Cardiac output and vasodilation in the vasovagal response: An analysis of the classic papers.

    PubMed

    Wieling, Wouter; Jardine, David L; de Lange, Frederik J; Brignole, Michele; Nielsen, Henning B; Stewart, Julian; Sutton, Richard

    2016-03-01

    The simple faint is secondary to hypotension and bradycardia resulting in transient loss of consciousness. According to Ohm's law applied to the circulation, BP = SVR × CO, hypotension can result from a decrease in systemic vascular resistance (SVR), cardiac output (CO), or both. It is important to understand that when blood pressure (BP) is falling, SVR and CO do not change reciprocally as they do in the steady state. In 1932, Lewis, assuming that decreased SVR alone accounted for hypotension, defined "the vasovagal response" along pathophysiologic lines to denote the association of vasodilation with vagal-induced bradycardia in simple faint. Studies performed by Barcroft and Sharpey-Schafer between 1940 and 1950 used volume-based plethysmography to demonstrate major forearm vasodilation during extreme hypotension and concluded that the main mechanism for hypotension was vasodilation. Plethysmographic measurements were intermittent and not frequent enough to capture rapid changes in blood flow during progressive hypotension. However, later investigations by Weissler, Murray, and Stevens performed between 1950 and 1970 used invasive beat-to-beat BP measurements and more frequent measurements of CO using the Fick principle. They demonstrated that CO significantly fell before syncope, and little vasodilation occurred until very late in the vasovagal reaction Thus, since the 1970s, decreasing cardiac output rather than vasodilation has been regarded as the principal mechanism for the hypotension of vasovagal syncope.

  20. The Effect of Cromakalim on the Hindlimb Vascular Bed of the Male Rat: Do Glybenclamide and/or Nitric Oxide Modulate the Vasodilation?

    PubMed

    Jahr, Jonathan S.; Feng, Chang Jian; Wang, Junke; Holton, Ronald; Cheng, David Y.

    1994-06-01

    Cromakalim, a benzopyran derivative, is a member of a novel class of antihypertensive agents that increase membrane K(+) conductance through ATP-sensitive K(+) channels. The effects of glybenclamide and N(omega)-L-arginine methyl ester (L-NAME), a specific inhibitor of nitric oxide synthesis from L-arginine were investigated on the vasodilator response to cromakalim in the hindlimb vascular bed in the male rat, as well as the combination glybenclamide and L-NAME. Thirty male Sprague--Dawley rats (350--450 g) were studied. Cromakalim in three doses (10, 30, 100 &mgr;g) injected into the hindlimb through a catheter induced a significant dose-dependent decrease in both mean arterial pressure (MAP) and hindlimb perfusion pressure (HPP). These responses were significantly modified by either glybenclamide or L-NAME. The role of a combination of glybenclamide and L-NAME on the vasodilator responses to cromakalim, acetylcholine, and nitroglycerin were also investigated. Three doses of either acetylcholine, nitroglycerin, or cromakalim caused dose-dependent reduction in HPP of the rats. The responses to acetylcholine were significantly blocked by L-NAME, but the responses to nitroglycerin were not. The vasodilation induced by cromakalim was not only partly blocked by glybenclamide but also by L-NAME. This blockade was significantly augmented when both glybenclamide and L-NAME were infused. These results suggest that nitric oxide may play an important role in regulating hindlimb vascular tone under physiologic conditions. The data also suggest that nitric oxide may be an additional mediator for cromakalim vasodilation as well as K(APT)(+) channel activation in the hindlimb vascular bed of the male rat. PMID:11835061

  1. Pharmacologic analysis of 7-O-ethyl-fangchinoline-induced vasodilation properties in isolated perfused common carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats.

    PubMed

    Matsuura, M; Zenda, H; Chiba, S

    1991-10-01

    Using the cannula insertion method, we investigated vascular effects of 7-O-ethyl-fangchinoline (TJN-220) derived from tetrandrine in isolated and perfused common carotid arteries of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). A single dose of TJN-220 caused a vasodilation in a dose-related manner in arteries preconstricted by phenylephrine. The vasodilation was not inhibited by propranolol, a potent beta-adrenoceptor antagonist. A potent alpha-antagonist bunazosin inhibited the vasoconstriction to norepinephrine while TJN-220 did not modify the norepinephrine-induced constriction, indicating TJN-220 had no alpha-blocking activity. A potent calcium entry blocker, diltiazem, markedly attenuated the KCl-induced vasoconstriction, and TJN-220 slightly but significantly attenuated the KCl-induced one in large doses. The vasodilation of TJN-220 was not abolished after removing the endothelium by an intraluminal administration of saponin, although the ACh-induced dilation was completely abolished by it. A comparison of vascular responses in WKY and SHR revealed no significant differences. From these results, it is concluded that 1) a new tetrandrine derivative, TJN-220 has relatively long-lasting vasorelaxant properties, 2) the dilatory effects might not be related to adrenergic, muscarinic or endothelium-dependent mechanisms, and 3) the effects might partially be due to calcium entry antagonistic properties. PMID:1806292

  2. Thalidomide in cutaneous lupus erythematosus.

    PubMed

    Pelle, Michelle T; Werth, Victoria P

    2003-01-01

    For nearly 50 years, thalidomide has struggled between success and controversy. After causing an epidemic of phocomelia and other birth defects during the 1960s, affecting thousands of neonates, thalidomide was used as a sedative in selective disorders including leprosy. The potent anti-inflammatory properties of thalidomide were serendipitously discovered while treating patients with erythema nodosum leprosum, and the drug is now approved by the US FDA for the treatment of this disease. Subsequently, the immunosuppressant effects of thalidomide, including the complex modulation of many cytokines, have been recognized. One promising application of thalidomide has been the treatment of cutaneous lupus erythematosus. Among the largest series reviewed, the drug has been found to ameliorate cutaneous lupus erythematosus in 90% of patients, on average. Remission is achieved in approximately 15-20% of patients with cutaneous lupus erythematosus at doses between 50-400 mg daily. Contraceptive concerns and the recognized neuropathic effects of thalidomide limit the use of the drug in patients with cutaneous lupus. Physicians who prescribe thalidomide in the US must be registered with the drug manufacturer. With appropriate control of drug access and close physician monitoring, thalidomide provides a needed therapeutic option for the treatment of refractory cases of cutaneous lupus erythematosus.

  3. Contribution of K(+) channels to endothelium-derived hypolarization-induced renal vasodilation in rats in vivo and in vitro.

    PubMed

    Rasmussen, Kasper Moller Boje; Braunstein, Thomas Hartig; Salomonsson, Max; Brasen, Jens Christian; Sorensen, Charlotte Mehlin

    2016-07-01

    We investigated the mechanisms behind the endothelial-derived hyperpolarization (EDH)-induced renal vasodilation in vivo and in vitro in rats. We assessed the role of Ca(2+)-activated K(+) channels and whether K(+) released from the endothelial cells activates inward rectifier K(+) (Kir) channels and/or the Na(+)/K(+)-ATPase. Also, involvement of renal myoendothelial gap junctions was evaluated in vitro. Isometric tension in rat renal interlobar arteries was measured using a wire myograph. Renal blood flow was measured in isoflurane anesthetized rats. The EDH response was defined as the ACh-induced vasodilation assessed after inhibition of nitric oxide synthase and cyclooxygenase using L-NAME and indomethacin, respectively. After inhibition of small conductance Ca(2+)-activated K(+) channels (SKCa) and intermediate conductance Ca(2+)-activated K(+) channels (IKCa) (by apamin and TRAM-34, respectively), the EDH response in vitro was strongly attenuated whereas the EDH response in vivo was not significantly reduced. Inhibition of Kir channels and Na(+)/K(+)-ATPases (by ouabain and Ba(2+), respectively) significantly attenuated renal vasorelaxation in vitro but did not affect the response in vivo. Inhibition of gap junctions in vitro using carbenoxolone or 18α-glycyrrhetinic acid significantly reduced the endothelial-derived hyperpolarization-induced vasorelaxation. We conclude that SKCa and IKCa channels are important for EDH-induced renal vasorelaxation in vitro. Activation of Kir channels and Na(+)/K(+)-ATPases plays a significant role in the renal vascular EDH response in vitro but not in vivo. The renal EDH response in vivo is complex and may consist of several overlapping mechanisms some of which remain obscure.

  4. Cutaneous Lupus Erythematosus: Diagnosis and treatment

    PubMed Central

    Okon, Lauren G.; Werth, Victoria P.

    2013-01-01

    Cutaneous lupus erythematosus encompasses a wide range of dermatologic manifestations, which may or may not be associated with the development of systemic disease. Cutaneous lupus is divided into several subtypes, including acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus erythematosus. Chronic cutaneous lupus erythematosus includes discoid lupus erythematosus, lupus erythematosus profundus, chilblain cutaneous lupus, and lupus tumidus. Diagnosis of these diseases requires proper classification of the subtype, through a combination of physical exam, laboratory studies, histology, antibody serology, and occasionally direct immunofluorescence, while ensuring to exclude systemic disease. Treatment of cutaneous lupus consists of patient education on proper sun protection along with appropriate topical and systemic agents. Systemic agents are indicated in cases of widespread, scarring, or treatment-refractory disease. In this review, we discuss issues in classification and diagnosis of the various subtypes of CLE, as well as provide an update on therapeutic management. PMID:24238695

  5. Genomic landscape of cutaneous T cell lymphoma

    PubMed Central

    Choi, Jaehyuk; Goh, Gerald; Walradt, Trent; Hong, Bok S.; Bunick, Christopher G.; Chen, Kan; Bjornson, Robert D.; Maman, Yaakov; Wang, Tiffany; Tordoff, Jesse; Carlson, Kacie; Overton, John D.; Liu, Kristina J.; Lewis, Julia M.; Devine, Lesley; Barbarotta, Lisa; Foss, Francine M.; Subtil, Antonio; Vonderheid, Eric C.; Edelson, Richard L.; Schatz, David G.; Boggon, Titus J.; Girardi, Michael; Lifton, Richard P.

    2015-01-01

    Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole genome DNA sequence and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NFκB signaling, chromatin remodeling, and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs vs. 1.0 somatic single nucleotide variants per CTCL). These findings have implications for novel therapeutics. PMID:26192916

  6. [Cutaneous lupus erythematosus, a multidimensional entity].

    PubMed

    Méndez-Flores, Silvia; Tinoco-Fragoso, Fátima; Hernández-Molina, Gabriela

    2015-01-01

    Skin lesions caused by systemic lupus erythematosus are among the most frequent manifestations of this disease. These lesions show great variability in both their clinical and histological expression, making their understanding and study difficult. Patients presenting with cutaneous lupus do not necessarily have serious systemic complications, but they do have significant morbidity from impact on quality of life given the extent of the lesions, chronic tendency, and the risk of scarring; hence the importance of establishing a fast and effective treatment. This paper addresses the different varieties of specific injuries attributed to lupus erythematosus, correlation with systemic activity, quality of life, and the treatments available.

  7. Robust Brain Hyperglycemia during General Anesthesia: Relationships with Metabolic Brain Inhibition and Vasodilation

    PubMed Central

    Bola, R. Aaron; Kiyatkin, Eugene A.

    2016-01-01

    Glucose is the main energetic substrate for the metabolic activity of brain cells and its proper delivery into the extracellular space is essential for maintaining normal neural functions. Under physiological conditions, glucose continuously enters the extracellular space from arterial blood via gradient-dependent facilitated diffusion governed by the GLUT-1 transporters. Due to this gradient-dependent mechanism, glucose levels rise in the brain after consumption of glucose-containing foods and drinks. Glucose entry is also accelerated due to local neuronal activation and neuro-vascular coupling, resulting in transient hyperglycemia to prevent any metabolic deficit. Here, we explored another mechanism that is activated during general anesthesia and results in significant brain hyperglycemia. By using enzyme-based glucose biosensors we demonstrate that glucose levels in the nucleus accumbens (NAc) strongly increase after iv injection of Equthesin, a mixture of chloral hydrate and sodium pentobarbital, which is often used for general anesthesia in rats. By combining electrochemical recordings with brain, muscle, and skin temperature monitoring, we show that the gradual increase in brain glucose occurring during the development of general anesthesia tightly correlate with decreases in brain-muscle temperature differentials, suggesting that this rise in glucose is related to metabolic inhibition. While the decreased consumption of glucose by brain cells could contribute to the development of hyperglycemia, an exceptionally strong positive correlation (r = 0.99) between glucose rise and increases in skin-muscle temperature differentials was also found, suggesting the strong vasodilation of cerebral vessels as the primary mechanism for accelerated entry of glucose into brain tissue. Our present data could explain drastic differences in basal glucose levels found in awake and anesthetized animal preparations. They also suggest that glucose entry into brain tissue could be

  8. Robust Brain Hyperglycemia during General Anesthesia: Relationships with Metabolic Brain Inhibition and Vasodilation.

    PubMed

    Bola, R Aaron; Kiyatkin, Eugene A

    2016-01-01

    Glucose is the main energetic substrate for the metabolic activity of brain cells and its proper delivery into the extracellular space is essential for maintaining normal neural functions. Under physiological conditions, glucose continuously enters the extracellular space from arterial blood via gradient-dependent facilitated diffusion governed by the GLUT-1 transporters. Due to this gradient-dependent mechanism, glucose levels rise in the brain after consumption of glucose-containing foods and drinks. Glucose entry is also accelerated due to local neuronal activation and neuro-vascular coupling, resulting in transient hyperglycemia to prevent any metabolic deficit. Here, we explored another mechanism that is activated during general anesthesia and results in significant brain hyperglycemia. By using enzyme-based glucose biosensors we demonstrate that glucose levels in the nucleus accumbens (NAc) strongly increase after iv injection of Equthesin, a mixture of chloral hydrate and sodium pentobarbital, which is often used for general anesthesia in rats. By combining electrochemical recordings with brain, muscle, and skin temperature monitoring, we show that the gradual increase in brain glucose occurring during the development of general anesthesia tightly correlate with decreases in brain-muscle temperature differentials, suggesting that this rise in glucose is related to metabolic inhibition. While the decreased consumption of glucose by brain cells could contribute to the development of hyperglycemia, an exceptionally strong positive correlation (r = 0.99) between glucose rise and increases in skin-muscle temperature differentials was also found, suggesting the strong vasodilation of cerebral vessels as the primary mechanism for accelerated entry of glucose into brain tissue. Our present data could explain drastic differences in basal glucose levels found in awake and anesthetized animal preparations. They also suggest that glucose entry into brain tissue could be

  9. Signal transduction pathways involved in kinin B2 receptor-mediated vasodilation in the rat isolated perfused kidney

    PubMed Central

    Bagaté, Karim; Grima, Michèle; Imbs, Jean-Louis; Jong, Wybren De; Helwig, Jean-Jacques; Barthelmebs, Mariette

    2001-01-01

    The signal transduction pathways involved in kinin B2 receptor-related vasodilation were investigated in rat isolated perfused kidneys. During prostaglandin F2α or KCl-induced constriction, the vasodilator response to a selective B2 receptor agonist, Tyr(Me)8bradykinin (Tyr(Me)8BK), was assessed.Tyr(Me)8BK produced a concentration- and endothelium-dependent relaxation that was decreased by about 30 – 40% after inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine (L-NOARG) or of cyclo-oxygenase by indomethacin; a greater decrease (about 40 – 50%) was observed after concomitant inhibition of the two pathways.High extracellular K+ diminished Tyr(Me)8BK-induced relaxation by about 75% suggesting a major contribution of endothelium-derived hyperpolarization. The residual response was almost completely suppressed by NO synthase and cyclo-oxygenase inhibition. The K+ channel inhibitors, tetrabutylammonium (non-specific) and charybdotoxin (specific for Ca2+-activated K+ channel), suppressed Tyr(Me)8BK-induced relaxation resistant to L-NOARG and indomethacin.Inhibition of cytochrome P450 (clotrimazole or 7-ethoxyresorufin) decreased the NO/prostanoids-independent relaxation to Tyr(Me)8BK by more than 60%, while inhibition of the cannabinoid CB1 receptor (SR 141716A) had only a moderate effect.Acetylcholine induced a concentration-dependent relaxation with characteristics nearly similar to the response to Tyr(Me)8BK. In contrast, the relaxation elicited by sodium nitroprusside was potentiated in the absence of NO (L-NOARG or removal of endothelium) but remained unchanged otherwise.These results indicate that the activation of kinin B2 receptors in the rat isolated kidney elicits an endothelium-dependent vasorelaxation, mainly dependent on the activation of charybdotoxin-sensitive Ca2+-activated K+ channels. In addition, cytochrome P450 derivatives appear to be involved. PMID:11309245

  10. Chronic active Epstein-Barr virus infection with cutaneous and sinus lymphoproliferation in a white female patient with 25 years' follow-up: an original case report.

    PubMed

    Picard, C; Gouarin, S; Comoz, F; Barreau, M; Verneuil, L; Troussard, X; Dompmartin, A

    2015-11-01

    Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic infectious mononucleosis-like symptoms associated with very high viral load, as assessed by quantitative polymerase chain reaction. We present an unusual case in a French woman who was followed up over 25 years with cutaneous and sinus lymphoproliferation. This white woman presented with a long history of recurrent cutaneous necrotic papules of the skin, which started during childhood and healed spontaneously with depressed scars. The lesions spread to the left maxillary sinus and were associated with hepatomegaly and splenomegaly with no other visceral locations. Pathological examination of the skin and sinus revealed a dermal monoclonal T-cell lymphoproliferative disorder, CD7(+) and CD20(-) , with no epidermotropism. T-cell receptor rearrangement was positive, showing the monoclonality from the first biopsy. This T-cell proliferation was positive for EBV-encoded small RNA and was associated with a high EBV viral load. Since then, the patient has been in good health, despite a permanently high EBV viral load. Hydroa vacciniforme (HV)-like lymphoma and natural killer/T-cell lymphoma were discussed, but none really fit our case. Natural killer cell lymphoma was ruled out because of the indolent course, but sinus lesions do not exist in HV-like lymphoma. A therapeutic approach is difficult because of the coexistence of viral infection and monoclonal T-cell proliferation. Chemotherapy is not efficient and induces immunosuppression, which may worsen the prognosis. Although rituximab may have an immunomodulatory function, it was not effective in our case. PMID:26148205

  11. Acute dietary nitrate supplementation enhances compensatory vasodilation during hypoxic exercise in older adults.

    PubMed

    Casey, Darren P; Treichler, David P; Ganger, Charles T; Schneider, Aaron C; Ueda, Kenichi

    2015-01-15

    We have previously demonstrated that aging reduces the compensatory vasodilator response during hypoxic exercise due to blunted nitric oxide (NO) signaling. Recent evidence suggests that NO bioavailability can be augmented by dietary nitrate through the nitrate-nitrite pathway. Thus we tested the hypothesis that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise, particularly in older adults. Thirteen young (25 ± 1 yr) and 12 older (64 ± 2 yr) adults performed rhythmic forearm exercise at 20% of maximum voluntary contraction during normoxia and hypoxia (∼80% O2 saturation); both before (control) and 3 h after beetroot juice (BR) consumption. Forearm vascular conductance (FVC; ml·min(-1)·100 mmHg(-1)) was calculated from forearm blood flow (ml/min) and blood pressure (mmHg). Compensatory vasodilation was defined as the relative increase in FVC due to hypoxic exercise (i.e., % increase compared with respective normoxic exercise trial). Plasma nitrite was determined from venous blood samples obtained before the control trials and each of the exercise trials (normoxia and hypoxia) after BR. Consumption of BR increased plasma nitrite in both young and older adults (P < 0.001). During the control condition, the compensatory vasodilator response to hypoxic exercise was attenuated in older compared with young adults (3.8 ± 1.7% vs. 14.2 ± 1.2%, P < 0.001). Following BR consumption, compensatory vasodilation did not change in young (13.7 ± 3.3%, P = 0.81) adults but was substantially augmented in older adults (11.4 ± 2.1%, P < 0.01). Our data suggest that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise in older but not young adults.

  12. Chronic Hindlimb Ischemia Impairs Functional Vasodilation and Vascular Reactivity in Mouse Feed Arteries

    PubMed Central

    Cardinal, Trevor R.; Struthers, Kyle R.; Kesler, Thomas J.; Yocum, Matthew D.; Kurjiaka, David T.; Hoying, James B.

    2011-01-01

    Vasodilation of lower leg arterioles is impaired in animal models of chronic peripheral ischemia. In addition to arterioles, feed arteries are a critical component of the vascular resistance network, accounting for as much as 50% of the pressure drop across the arterial circulation. Despite the critical importance of feed arteries in blood flow control, the impact of ischemia on feed artery vascular reactivity is unknown. At 14 days following unilateral resection of the femoral–saphenous artery–vein pair, functional vasodilation of the profunda femoris artery was severely impaired, 11 ± 9 versus 152 ± 22%. Although endothelial and smooth muscle-dependent vasodilation were both impaired in ischemic arteries compared to control arteries (Ach: 40 ± 14 versus 81 ± 11%, SNP: 43 ± 12 versus and 85 ± 11%), the responses to acetylcholine and sodium nitroprusside were similar, implicating impaired smooth muscle-dependent vasodilation. Conversely, vasoconstriction responses to norepinephrine were not different between ischemic and control arteries, −68 ± 3 versus −66 ± 3%, indicating that smooth muscle cells were functional following the ischemic insult. Finally, maximal dilation responses to acetylcholine, ex vivo, were significantly impaired in the ischemic artery compared to control, 71 ± 9 versus 97 ± 2%, despite a similar generation of myogenic tone to the same intravascular pressure (80 mmHg). These data indicate that ischemia impairs feed artery vasodilation by impairing the responsiveness of the vascular wall to vasodilating stimuli. Future studies to examine the mechanistic basis for the impact of ischemia on vascular reactivity or treatment strategies to improve vascular reactivity following ischemia could provide the foundation for an alternative therapeutic paradigm for peripheral arterial occlusive disease. PMID:22164145

  13. 21 CFR 882.1320 - Cutaneous electrode.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cutaneous electrode. 882.1320 Section 882.1320...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1320 Cutaneous electrode. (a) Identification. A cutaneous electrode is an electrode that is applied directly to a patient's skin either...

  14. 21 CFR 882.1320 - Cutaneous electrode.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cutaneous electrode. 882.1320 Section 882.1320...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1320 Cutaneous electrode. (a) Identification. A cutaneous electrode is an electrode that is applied directly to a patient's skin either...

  15. 21 CFR 882.1320 - Cutaneous electrode.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cutaneous electrode. 882.1320 Section 882.1320...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1320 Cutaneous electrode. (a) Identification. A cutaneous electrode is an electrode that is applied directly to a patient's skin either...

  16. 21 CFR 882.1320 - Cutaneous electrode.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cutaneous electrode. 882.1320 Section 882.1320...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1320 Cutaneous electrode. (a) Identification. A cutaneous electrode is an electrode that is applied directly to a patient's skin either...

  17. 21 CFR 882.1320 - Cutaneous electrode.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cutaneous electrode. 882.1320 Section 882.1320...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1320 Cutaneous electrode. (a) Identification. A cutaneous electrode is an electrode that is applied directly to a patient's skin either...

  18. Cutaneous lesions of the nose

    PubMed Central

    2010-01-01

    Skin diseases on the nose are seen in a variety of medical disciplines. Dermatologists, otorhinolaryngologists, general practitioners and general plastic and dermatologic surgeons are regularly consulted regarding cutaneous lesions on the nose. This article is the second part of a review series dealing with cutaneous lesions on the head and face, which are frequently seen in daily practice by a dermatologic surgeon. In this review, we focus on those skin diseases on the nose where surgery or laser therapy is considered a possible treatment option or that can be surgically evaluated. PMID:20525327

  19. "Pure" cutaneous histiocytosis-X.

    PubMed

    Wolfson, S L; Botero, F; Hurwitz, S; Pearson, H A

    1981-11-15

    The case histories of two young children who experienced skin rashes involving various areas of the body are reported. The diagnosis of pure cutaneous histiocytosis-X was established after extensive studies revealed no other organ involvement. The patients were treated with oral corticosteroids. Currently, both children are in good health, show no evidence of disease, and have been followed over a four-to-five-year period. Therapy with corticosteroids may not be indicated with pure cutaneous histiocytosis-X unless there is evidence of extracutaneous dissemination or rapid progression of the disease.

  20. Cutaneous manifestation of gastrointestinal disease

    PubMed Central

    Kerstetter, Justin

    2016-01-01

    The gastrointestinal (GI) and cutaneous systems are closely linked in origin. Skin manifestations are frequently seen as a part of different GI syndromes. Gastroenterologists play an important role in recognizing the symptoms, patient workup and arriving at appropriate diagnoses, often in consultation with dermatologists. This review discusses the diseases with both cutaneous and intestinal involvement. Hereditary polyposis GI cancers, hereditary nonpolyposis colorectal cancers (CRCs), hamartomatous disorders, and inflammatory bowel disease (IBD) are reviewed with emphasis on the genetic basis, diagnostic, histologic findings, screening modalities, and therapeutic options. PMID:27034812

  1. Topical Application of Fingolimod Perturbs Cutaneous Inflammation.

    PubMed

    Sun, Wai Y; Dimasi, David P; Pitman, Melissa R; Zhuang, YiZhong; Heddle, Robert; Pitson, Stuart M; Grimbaldeston, Michele A; Bonder, Claudine S

    2016-05-01

    The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation. PMID:27001955

  2. The sandfly fauna, anthropophily and the seasonal activities of Pintomyia spinicrassa (Diptera: Psychodidae: Phlebotominae) in a focus of cutaneous leishmaniasis in northeastern Colombia

    PubMed Central

    Ovallos, Fredy Galvis; Silva, Yanis Ricardo Espinosa; Fernandez, Nelson; Gutierrez, Reynaldo; Galati, Eunice Aparecida Bianchi; Sandoval, Claudia Magaly

    2013-01-01

    This study was conducted to identify the sandfly fauna and the anthropophilic species in a coffee-growing area of Villanueva, Norte de Santander, Colombia, a focus of American cutaneous leishmaniasis, and to analyse the relationship between the most frequent species and rainfall, relative humidity and temperature, with the aim of contributing to epidemiological surveillance in the area. Sandfly collections were performed fortnightly between February 2006-September 2007 using automatic light traps, Shannon traps, protected human bait and aspiration in resting places. A total of 7,051 sandflies belonging to 12 species were captured. Pintomyia spinicrassa (95.7%) predominated. Pintomyia oresbia and Lutzomyia sp. of Pichinde were found in the state of Norte de Santander for the first time. Pi. spinicrassa, Pintomyia nuneztovari, Micropygomyia venezuelensis, Lutzomyia (Helcocyrtomyia) scorzai and Lu. (Helcocyrtomyia) sp. were captured on the protected human bait. A significant association between Pi. spinicrassa abundance and the total rainfall and the average temperature and humidity 10 days before the collection was observed. The dominance of Pi. spinicrassa, a recognised vector of Leishmania braziliensis, especially during the dry periods, indicates that the risk of parasite transmission may increase. PMID:23778653

  3. Pulmonary Arterial Hypertension Associated with Congenital Portosystemic Shunts Treated with Transcatheter Embolization and Pulmonary Vasodilators.

    PubMed

    Sato, Haruka; Miura, Masanobu; Yaoita, Nobuhiro; Yamamoto, Saori; Tatebe, Shunsuke; Aoki, Tatsuo; Satoh, Kimio; Ota, Hideki; Takase, Kei; Sugimura, Koichiro; Shimokawa, Hiroaki

    2016-01-01

    Cardiopulmonary abnormalities are often present in patients with liver diseases. We herein report a case of congenital portosystemic shunts complicated by hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH). A 57-year-old woman complained of dyspnea and was subsequently diagnosed with HPS and PoPH caused by congenital portosystemic shunts. Although shunt closure by transcatheter embolization was successfully performed, her dyspnea worsened and pulmonary artery pressure and pulmonary vascular resistance elevated. Conventional vasodilator therapy was started, resulting in an improvement of pulmonary hypertension (PH). In some patients with congenital portosystemic shunts, shunt closure could exacerbate PH, and vasodilator therapy may be effective. PMID:27580545

  4. The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation.

    PubMed

    Williamson, D J; Shepheard, S L; Hill, R G; Hargreaves, R J

    1997-06-01

    These studies in anaesthetised rats showed, using intravital microscopy, that the novel anti-migraine agent, rizatriptan, significantly reduced electrically stimulated dural vasodilation but had no effect on increases in dural vessel diameter produced by exogenous substance P or calcitonin gene-related peptide (CGRP). Rizatriptan also significantly inhibited dural plasma protein extravasation produced by high intensity electrical stimulation of the trigeminal ganglion. We suggest that rizatriptan inhibits the release of sensory neuropeptides from perivascular trigeminal nerves to prevent neurogenic vasodilation and extravasation in the dura mater. These prejunctional inhibitory effects may be involved in the anti-migraine action of rizatriptan. PMID:9203569

  5. Evidence for a vasomotor cyclo-oxygenase dependent mechanism of sensitization at the cutaneous level

    PubMed Central

    Mahé, G; Abraham, P; Humeau-Heurtier, A; Gascoin, L; Lefthériotis, G; Durand, S

    2015-01-01

    Aims Current-induced vasodilation (CIV) is an axon-reflex response observed during monopolar current application such as iontophoresis. Cyclo-oxygenase derivates (COD) participate in CIV and act as sensitizing agents at the anodal level. Mechanisms involved during cathodal current application (CCA) are partially unknown. In a randomized double-blind crossover trial, we tested in 16 healthy subjects (i) the influence of the inter-stimulation interval (I-I) by comparing CIV following all-at-once 10 s CCA against 2 × 5 s CCA with intervals ranging from15 s–16 min and (ii) the participation of COD in CIV using 1 g aspirin or placebo intake. Methods Measurements were repeated 2 h and 14 days after treatment. Laser Doppler flowmetry assessed cutaneous blood flow, reported in multiples of baseline. Results Before treatment, peak vasodilation 10 min after the last current application (CVCstim2) increased compared with baseline whatever the I-I. Increase in CVCstim2 from baseline was greater for the 4 min (9.4 (5.3, 10.9) times; median (1st percentile, 3rd percentile)) and higher I-Is compared with all-at-once delivery (3.0 (2.1, 4.3) times, P < 0.05). The response was similar after placebo but aspirin abolished this vasodilation (increase by 1.2 (1.1, 1.3) times for all-at-once delivery and by 1.5 (1.3, 1.7) ± 0.3 times for 4 min interval, 2 h after aspirin intake) that recovered after 14 days. Conclusions This confirms the participation of COD in CIV with CCA and their sensitizing action. This model can represent an attractive way to study the axon-reflex and sensitizing function of COD in humans. PMID:25753207

  6. Green and black tea are equally potent stimuli of NO production and vasodilation: new insights into tea ingredients involved.

    PubMed

    Lorenz, Mario; Urban, Janka; Engelhardt, Ulrich; Baumann, Gert; Stangl, Karl; Stangl, Verena

    2009-01-01

    Epidemiological studies suggest that consumption of tea is associated with beneficial cardiovascular effects. Since different types of tea are consumed throughout the world, a question of much interest is whether green tea is superior to black tea in terms of cardiovascular protection. We therefore compared the effects of green and black tea on nitric oxide (NO) production and vasodilation and elucidated the tea compounds involved. We chose a highly fermented black tea and determined concentrations of individual tea compounds in both green and black tea of the same type (Assam). The fermented black tea was almost devoid of catechins. However, both teas stimulated eNOS activity and phosphorylation in bovine aortic endothelial cells (BAEC) as well as vasorelaxation in rat aortic rings to a similar extent. In green tea, only epigallocatechin-3-gallate (EGCG) resulted in pronounced NO production and NO-dependent vasorelaxation in aortic rings. During tea processing to produce black tea, the catechins are converted to theaflavins and thearubigins. Individual black tea theaflavins showed a higher potency than EGCG in NO production and vasorelaxation. The thearubigins in black tea are highly efficient stimulators of vasodilation and NO production. Green and black tea compounds induced comparable phosphorylation of eNOS and upstream signalling kinases. Whereas stimulation of eNOS activity by EGCG was only slightly affected by pretreatment of cells with various ROS scavengers, TF3(theaflavin-3',3-digallate)-induced eNOS activity was partially inhibited by PEG-catalase. These results implicate that highly fermented black tea is equally potent as green tea in promoting beneficial endothelial effects. Theaflavins and thearubigins predominantly counterbalance the lack of catechins in black tea. The findings may underline the contribution of black tea consumption in prevention of cardiovascular diseases. PMID:19101751

  7. Cutaneous Metastases From Esophageal Adenocarcinoma

    PubMed Central

    Triantafyllou, Stamatina; Georgia, Doulami; Gavriella-Zoi, Vrakopoulou; Dimitrios, Mpistarakis; Stulianos, Katsaragakis; Theodoros, Liakakos; Georgios, Zografos; Dimitrios, Theodorou

    2015-01-01

    The aim of this study is to present 2 rare cases of cutaneous metastases originated from adenocarcinoma of the gastro-esophageal junction, thus, underline the need for early diagnosis and possible treatment of suspicious skin lesions among patients with esophageal malignancy. Metastatic cancer to the skin originated from internal malignancies, mostly lung cancer, breast cancer, and colorectal cancer, constitute 0.5 to 9% of all metastatic cancers.5,8,15 Skin metastases, mainly from squamous cell carcinomas of the esophagus, are rarely reported. Cutaneous metastasis is a finding indicating progressiveness of the disease.17 More precisely, median survival is estimated approximately 4.7 months.2,14 This study is a retrospective review of 2 cases of patients with adenocarcinoma of the esophagus and a review of the literature. Two patients aged 60 and 32 years old, respectively, underwent esophagectomy. Both pathologic reports disclosed adenocarcinoma of the gastro-esophageal junction staged T3 N2 M0 (stage IIIB). During follow-up time, the 2 patients were diagnosed with cutaneous metastases originated from the primary esophageal tumor 11 and 4 months after surgery, respectively. The first patient is alive 37 months after diagnosis, while the second one died 16 months after surgery. Cutaneous metastasis caused by esophageal adenocarcinoma is possible. Therefore, follow-up of patients who were diagnosed with esophageal malignancy and underwent esophagectomy is mandatory in order to reveal early surgical stages. PMID:25785344

  8. Vacuum enhanced cutaneous biopsy instrument

    DOEpatents

    Collins, Joseph

    2000-01-01

    A syringe-like disposable cutaneous biopsy instrument equipped with a tubular blade at its lower end, and designed so that a vacuum is created during use, said vacuum serving to retain undeformed a plug of tissue cut from a patient's skin.

  9. Hyaline fibromatosis syndrome: cutaneous manifestations*

    PubMed Central

    Marques, Silvio Alencar; Stolf, Hamilton Ometto; Polizel, Juliana Ocanha; Munhoz, Tânia; Brandão, Marcela Calixto; Marques, Mariangela Esther Alencar

    2016-01-01

    Hyaline fibromatosis syndrome is the current name for clinical manifestations of diseases previously known as “infantile systemic hyalinosis” and “juvenile hyaline fibromatosis”. The authors report representative clinical cases of each one of the above subtypes with emphasis on cutaneous manifestations and difficulties for early diagnosis in this syndrome, essentially of multidisciplinary approach. PMID:27192526

  10. Cutaneous manifestations of genitourinary malignancy.

    PubMed

    Raghavan, Derek

    2016-06-01

    Genitourinary cancers are associated with a range of cutaneous syndromes, which can reflect direct metastatic spread, non-metastatic manifestations of malignancy or the consequences of treatment. More than 220,000 new cases of prostate cancer occur each year in the United States, and thus the associations with cutaneous involvement are quite well documented-rare metastatic spread, vasculitic and hemorrhagic syndromes. Cancers of the bladder and kidney may be associated with direct cutaneous metastases, vasculitic syndromes, hereditary leiomyomatosis, and other familial syndromes. Testicular cancer occasionally metastasizes to the skin but more commonly is associated with the dysplastic nevus (multiple atypical nevus) syndrome. A structured approach to history-taking, examination, and investigation is essential for optimal management, especially when these syndromes precede the diagnosis of a known malignancy. A brief review of the more common iatrogenic cutaneous complications is provided, and includes Raynaud's phenomenon, purpura, rash, hand-foot syndrome, the consequences of marrow failure, and bleomycin-induced pigmentation. PMID:27178687

  11. Cutaneous innervation: form and function.

    PubMed

    Oaklander, Anne Louise; Siegel, Sandra M

    2005-12-01

    It is useful for dermatologists to know about the innervation of the skin because dysfunction of cutaneous neurons can cause symptoms--such as itching, pain, and paresthesias--that are evaluated by dermatologists. We review the innervation of the skin and update readers about recent neuroscientific discoveries.

  12. Vacuum Enhanced Cutaneous Biopsy Instrument

    SciTech Connect

    Collins, Joseph

    1999-06-25

    A syringe-like disposable cutaneous biopsy instrument equipped with a tubular blade at its lower end, and designed so that a vacuum is created during use, said vacuum serving to retain undeformed a plug of tissue cut from a patient's skin.

  13. A new mathematical model to simulate AVA cold-induced vasodilation reaction to local cooling.

    PubMed

    Rida, Mohamad; Karaki, Wafaa; Ghaddar, Nesreen; Ghali, Kamel; Hoballah, Jamal

    2014-11-01

    The purpose of this work was to integrate a new mathematical model with a bioheat model, based on physiology and first principles, to predict thermoregulatory arterio-venous anastomoses (AVA) and cold-induced vasodilation (CIVD) reaction to local cooling. The transient energy balance equations of body segments constrained by thermoregulatory controls were solved numerically to predict segmental core and skin temperatures, and arterial blood flow for given metabolic rate and environmental conditions. Two similar AVA-CIVD mechanisms were incorporated. The first was activated during drop in local skin temperature (<32 °C). The second mechanism was activated at a minimum finger skin temperature, T(CIVD, min), where the AVA flow is dilated and constricted once the skin temperature reached a maximum value. The value of T(CIVD,min) was determined empirically from values reported in literature for hand immersions in cold fluid. When compared with published data, the model predicted accurately the onset time of CIVD at 25 min and T(CIVD,min) at 10 °C for hand exposure to still air at 0 °C. Good agreement was also obtained between predicted finger skin temperature and experimentally published values for repeated immersion in cold water at environmental conditions of 30, 25, and 20 °C. The CIVD thermal response was found related to core body temperature, finger skin temperature, and initial finger sensible heat loss rate upon exposure to cold fluid. The model captured central and local stimulations of the CIVD and accommodated observed variability reported in literature of onset time of CIVD reaction and T(CIVD,min).

  14. Prolonged (9 h) poikilocapnic hypoxia (12% O2) augments cutaneous thermal hyperaemia in healthy humans.

    PubMed

    Lawley, Justin S; Oliver, Samuel J; Mullins, Paul G; Macdonald, Jamie H; Moore, Jonathan P

    2014-06-01

    The primary aim of this study was to investigate the effect of systemic poikilocapnic hypoxia on forearm cutaneous thermal hyperaemia. A secondary aim was to examine the relationship between the individual susceptibility to oxygen desaturation and cutaneous vasodilator capacity. Twelve healthy participants (seven male) were exposed to 9 h of normoxia and 12% poikilocapnic hypoxia in a temperature- and humidity-controlled environmental chamber. Skin blood flow was assessed at the ventral forearm using laser Doppler flowmetry combined with rapid local heating. After 6 min at baseline (skin temperature clamped at 33°C), local skin temperature was elevated at a rate of 0.5°C every 5 s up to 42°C to elicit a sensory axon response and then held constant for 30 min to cause a plateau. Skin blood flow was calculated as cutaneous vascular conductance [CVC; in perfusion units/mean arterial blood pressure (APU mmHg(-1))] and expressed in raw format and relative to heating at 44°C in normoxia (%CVC44). During hypoxaemia, vasodilatation was greater during the initial peak (raw, Δ0.35 APU mmHg(-1), P = 0.09; %CVC44, Δ18%, P = 0.05) and the plateau phase (raw, Δ0.55 APU mmHg(-1), P = 0.03; %CVC44, Δ26%, P = 0.02). The rate of rise in cutaneous blood flow during the initial peak was significantly greater during poikilocapnic hypoxia (P < 0.01). We observed a negative relationship between oxygen saturation in poikilocapnic hypoxia and the change in baseline (P = 0.06), initial peak (P = 0.01) and plateau phase of thermal hyperaemia (P = 0.01). Prolonged poikilocapnic hypoxia causes robust increases in CVC during both phases of thermal hyperaemia that are dependent on the oxygen saturation of the individual. PMID:24706191

  15. Prolonged (9 h) poikilocapnic hypoxia (12% O2) augments cutaneous thermal hyperaemia in healthy humans.

    PubMed

    Lawley, Justin S; Oliver, Samuel J; Mullins, Paul G; Macdonald, Jamie H; Moore, Jonathan P

    2014-06-01

    The primary aim of this study was to investigate the effect of systemic poikilocapnic hypoxia on forearm cutaneous thermal hyperaemia. A secondary aim was to examine the relationship between the individual susceptibility to oxygen desaturation and cutaneous vasodilator capacity. Twelve healthy participants (seven male) were exposed to 9 h of normoxia and 12% poikilocapnic hypoxia in a temperature- and humidity-controlled environmental chamber. Skin blood flow was assessed at the ventral forearm using laser Doppler flowmetry combined with rapid local heating. After 6 min at baseline (skin temperature clamped at 33°C), local skin temperature was elevated at a rate of 0.5°C every 5 s up to 42°C to elicit a sensory axon response and then held constant for 30 min to cause a plateau. Skin blood flow was calculated as cutaneous vascular conductance [CVC; in perfusion units/mean arterial blood pressure (APU mmHg(-1))] and expressed in raw format and relative to heating at 44°C in normoxia (%CVC44). During hypoxaemia, vasodilatation was greater during the initial peak (raw, Δ0.35 APU mmHg(-1), P = 0.09; %CVC44, Δ18%, P = 0.05) and the plateau phase (raw, Δ0.55 APU mmHg(-1), P = 0.03; %CVC44, Δ26%, P = 0.02). The rate of rise in cutaneous blood flow during the initial peak was significantly greater during poikilocapnic hypoxia (P < 0.01). We observed a negative relationship between oxygen saturation in poikilocapnic hypoxia and the change in baseline (P = 0.06), initial peak (P = 0.01) and plateau phase of thermal hyperaemia (P = 0.01). Prolonged poikilocapnic hypoxia causes robust increases in CVC during both phases of thermal hyperaemia that are dependent on the oxygen saturation of the individual.

  16. Simulated Microgravity Increases Cutaneous Blood Flow in the Head and Leg of Humans

    NASA Technical Reports Server (NTRS)

    Stout, M. Shannon; Watenpaugh, Donald E.; Breit, Gregory A.; Hargens, Alan R.

    1995-01-01

    The cutaneous microcirculation vasodilates during acute 6 degree head-down tilt (HDT, simulated microgravity) relative to upright conditions, more in the lower body than in the upper body. Cutaneous microvascular blood flow was measured with laser-Doppler flowmetry at the leg (over the distal tibia) and cheek (over the zygomatic arch) of eight healthy men before, during, and after 24 h of HDT. Results were calculated as a percentage of baseline value (100% measured during pre-tilt upright sitting). Cutaneous blood flow in the cheek increased significantly to 165 +/- 37% (mean +/- SE, p less than 0.05) at 9-12 h HDT, then returned to near baseline values by 24 h HDT (114 +/- 29%, NSD), despite increased local arterial pressure. Microvascular flow in the leg remained significantly elevated above baseline througout 24 h HDT (427 +/- 85% at 3 h HDT and 215 +/- 142% at 24 h HDT, p less than 0.05). During the 6-h upright sitting recovery period, cheek and leg blood flow levels returned to near pre-tilt baseline values. Because hydrostatic effects of HDT increase local arterial pressure at the carotid sinus, baroreflex-mediated withdrawal of sympathetic tone probably contributed to increased microvascular flows at the head and leg during HDT. In the leg baroreflex effects combined with minimal stimulation of local veno-arteriolar and myogenic autoregulatory vasoconstriction to elicit relatively larger and more sustained increases in cutaneous flow during HDT. In the cheek, delayed myogenic vasoconstriction and/or hurmonal effects apparently compensated for flow elevation by 24 h of HDT. Therefore, localized vascular adaptations to gravity probably explain differences in acclimation of lower and upper body blood flow to HDT and actual microgravity.

  17. Association of Piebaldism, multiple café-au-lait macules, and intertriginous freckling: clinical evidence of a common pathway between KIT and sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1).

    PubMed

    Chiu, Yvonne E; Dugan, Stefanie; Basel, Donald; Siegel, Dawn H

    2013-01-01

    Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5-year-old boy who had the white forelock and leukoderma of piebaldism, but the presence of many café-au-lait macules and axillary and inguinal freckling complicated the diagnosis. Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty-related, Ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) mutations that also has multiple café-au-lait macules and intertriginous freckling. Based on our current understanding of KIT and SPRED1 protein interactions, we propose that café-au-lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1.

  18. Central nitric oxide modulates hindquarter vasodilation elicited by AMPA receptor stimulation in the NTS of conscious rats.

    PubMed

    Dias, Ana Carolina Rodrigues; Colombari, Eduardo

    2006-05-01

    Microinjection of S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the nucleus of the solitary tract (NTS) of conscious rats causes hypertension, bradycardia, and vasoconstriction in the renal, mesenteric, and hindquarter vascular beds. In the hindquarter, the initial vasoconstriction is followed by vasodilation with AMPA doses >5 pmol/100 nl. To test the hypothesis that this vasodilation is caused by activation of a nitroxidergic pathway in the NTS, we examined the effect of pretreatment with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10 nmol/100 nl, microinjected into the NTS) on changes in mean arterial pressure, heart rate, and regional vascular conductance (VC) induced by microinjection of AMPA (10 pmol/100 nl in the NTS) in conscious rats. AMPA increased hindquarter VC by 18 +/- 4%, but after pretreatment with L-NAME, AMPA reduced hindquarter VC by 16 +/- 7% and 17 +/- 9% (5 and 15 min after pretreatment, P < 0.05 compared with before pretreatment). Pretreatment with L-NAME reduced AMPA-induced bradycardia from 122 +/- 40 to 92 +/- 32 beats/min but did not alter the hypertension induced by AMPA (35 +/- 5 mmHg before pretreatment, 43 +/- 6 mmHg after pretreatment). Control injections with D-NAME did not affect resting values or the response to AMPA. The present study shows that stimulation of AMPA receptors in the NTS activates both vasodilatatory and vasoconstrictor mechanisms and that the vasodilatatory mechanism depends on production of nitric oxide in the NTS.

  19. Wound Healing of Cutaneous Sulfur Mustard Injuries

    PubMed Central

    Graham, John S.; Chilcott, Robert P.; Rice, Paul; Milner, Stephen M.; Hurst, Charles G.; Maliner, Beverly I.

    2005-01-01

    Sulfur mustard is an alkylating chemical warfare agent that primarily affects the eyes, skin, and airways. Sulfur mustard injuries can take several months to heal, necessitate lengthy hospitalizations, and result in significant cosmetic and/or functional deficits. Historically, blister aspiration and/or deroofing (epidermal removal), physical debridement, irrigation, topical antibiotics, and sterile dressings have been the main courses of action in the medical management of cutaneous sulfur mustard injuries. Current treatment strategy consists of symptomatic management and is designed to relieve symptoms, prevent infections, and promote healing. There are currently no standardized or optimized methods of casualty management that prevent or minimize deficits and provide for speedy wound healing. Several laboratories are actively searching for improved therapies for cutaneous vesicant injury, with the aim of returning damaged skin to optimal appearance and normal function in the shortest time. Improved treatment will result in a better cosmetic and functional outcome for the patient, and will enable the casualty to return to normal activities sooner. This editorial gives brief overviews of sulfur mustard use, its toxicity, concepts for medical countermeasures, current treatments, and strategies for the development of improved therapies. PMID:16921406

  20. Molecular Bases of Cutaneous and Uveal Melanomas

    PubMed Central

    Gaudi, Sudeep; Messina, Jane L.

    2011-01-01

    Intensive research in recent years has begun to unlock the mysteries surrounding the molecular pathogenesis of melanoma, the deadliest of skin cancers. The high-penetrance, low-frequency susceptibility gene CDKN2A produces tumor suppressor proteins that function in concert with p53 and retinoblastoma protein to thwart melanomagenesis. Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma. Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes. The proliferative effects of the MAPK pathway may be complemented by the antiapoptotic signals of the PI3K/AKT pathway. After skin, melanoma most commonly affects the eye. Data for the constitutive activation of the MAPK pathway in uveal melanoma exists as well, however, not through mutations of RAS and RAF. Rather, evidence implicates the proto-oncogene GNAQ. In the following discussion, we review the major molecular pathways implicated in both familial and sporadic cutaneous melanomagenesis, the former accounting for approximately 10% of cases. Additionally, we discuss the molecular pathways for which preliminary evidence suggests a role in uveal melanomagenesis. PMID:21876842

  1. Clinical Practice Guidelines for Cutaneous Lymphomas.

    PubMed

    Sutton, Angela M; Hurley, M Yadira

    2015-01-01

    Primary cutaneous lymphomas are non-Hodgkin lymphomas, which are broadly divided into cutaneous T-cell lymphomas and cutaneous B-cell lymphomas. These classifications include numerous distinct entities, all with varying clinical presentations and disease courses. Herein, we will review the cutaneous T-cell lymphomas, including Mycosis Fungoides, Sézary syndrome, CD30+ lymphoproliferative disorders, as well as other less common entities. Cutaneous B-cell lymphomas will also be discussed, including primary cutaneous marginal zoned lymphoma, cutaneous follicle-center lymphoma, diffuse large B-cell lymphoma, leg type, as well as other less common entities. Accurate and early diagnosis is key, as the treatment and prognosis varies significantly between conditions. PMID:26455060

  2. Vasodilator Effects of Elcatonin, a Synthetic Eel Calcitonin, on Retinal Blood Vessels in Rats.

    PubMed

    Mori, Asami; Suzawa, Hironori; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2015-01-01

    The aim of this study was to examine the effects of elcatonin, a synthetic derivative of eel calcitonin, on rat retinal blood vessels, and to determine how diabetes affects the retinal vascular responses. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate were continuously recorded. Elcatonin increased the diameter of retinal blood vessels but decreased mean blood pressure in a dose-dependent manner, whereas it had no significant effect on heart rate. A diminished retinal vasodilator response and significant pressor response to elcatonin were observed in rats injected intravenously with N(G)-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. Intravitreal injection of indomethacin, a non-selective cyclooxygenase (COX) inhibitor, and SQ22536, an adenylyl cyclase inhibitor, markedly attenuated the vasodilator effects of elcatonin on retinal blood vessels. The retinal vasodilator responses to elcatonin were unaffected 2 weeks after the induction of diabetes by a combination of streptozotocin treatment and D-glucose feeding. These results suggest that elcatonin dilates rat retinal blood vessels via NO- and COX-dependent mechanisms and that the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate system plays a major role in the vasodilator mechanisms. The retinal vasodilatory effects of elcatonin seem to be preserved at early stages of diabetes.

  3. Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia.

    PubMed

    Ozkor, Muhiddin A; Hayek, Salim S; Rahman, Ayaz M; Murrow, Jonathan R; Kavtaradze, Nino; Lin, Ji; Manatunga, Amita; Quyyumi, Arshed A

    2015-02-01

    The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. CLINICAL TRIAL REGISTRATION IDENTIFIER NCT00166166: PMID:25648989

  4. Different patterns of soluble adhesion molecules in systemic and cutaneous lupus erythematosus.

    PubMed

    Nyberg, F; Acevedo, F; Stephansson, E

    1997-10-01

    Circulating isoforms of cellular adhesion molecules (CAMs) have been described recently, and elevated levels of certain sCAMs have been reported in various inflammatory diseases such as systemic lupus erythematosus (SLE). There are previously no reports on sCAMs in cutaneous LE. Sera from 61 patients with LE: systemic (SLE: n=24), chronic cutaneous (discoid LE, DLE: n= 19) or subacute cutaneous (SCLE: n=8), chronic biologically false positive (CBFP) reactors for syphilis (n= 10) and 32 controls were examined for sICAM-1, sVCAM-1 and sE-Selectin with specific ELISA kits. Protocol forms were reviewed. We found significantly elevated levels of sE-Selectin in patients with DLE and widespread cutaneous symptoms, and a correlation between active cutaneous disease as well as polymorphous light eruption (PLE) and elevated levels of sE-Selectin. In contrast, patients with systemic LE did not have elevated levels of sE-Selectin, but in concordance with earlier reports, sICAM-1 and sVCAM-1 levels were elevated compared to controls in SLE, as well as in SCLE patients, which has not been reported previously. Since activated endothelial cells are the only source for E-Selectin, the elevated sE-Selectin level in patients with widespread and active cutaneous disease suggests a more important role for endothelial cells in the pathogenesis of cutaneous LE than previously assumed.

  5. Influence of habitual high dietary fat intake on endothelium-dependent vasodilation.

    PubMed

    Dow, Caitlin A; Stauffer, Brian L; Greiner, Jared J; DeSouza, Christopher A

    2015-07-01

    High-fat diets are associated with an increased risk of cardiovascular disease. A potential underlying mechanism for the increased cardiovascular risk is endothelial dysfunction. Nitric oxide (NO)-mediated endothelium-dependent vasodilation is critical in the regulation of vascular tone and overall vascular health. The aim of this study was to determine the influence of dietary fat intake on endothelium-dependent vasodilation. Forty-four middle-aged and older sedentary, healthy adults were studied: 24 consumed a lower fat diet (LFD; 29% ± 1% calories from fat) and 20 consumed a high-fat diet (HFD; 41% ± 1% calories from fat). Four-day diet records were used to assess fat intake, and classifications were based on American Heart Association guidelines (<35% of total calories from fat). Forearm blood flow (FBF) responses to acetylcholine, in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA), as well as responses to sodium nitroprusside were determined by plethysmography. The FBF response to acetylcholine was lower (∼15%; P < 0.05) in the HFD group (4.5 ± 0.2 to 12.1 ± 0.8 mL/100 mL tissue/min) than in the LFD group (4.6 ± 0.2 to 14.4 ± 0.6 mL/100 mL tissue/min). L-NMMA significantly reduced the FBF response to acetylcholine in the LFD group (∼25%) but not in the HFD group. There were no differences between groups in the vasodilator response to sodium nitroprusside. These data indicate that a high-fat diet is associated with endothelium-dependent vasodilator dysfunction due, in part, to diminished NO bioavailability. Impaired NO-mediated endothelium-dependent vasodilation may contribute to the increased cardiovascular risk with high dietary fat intake.

  6. Rapid vasodilation in isolated skeletal muscle arterioles: impact of branch order.

    PubMed

    Roseguini, Bruno T; Davis, Michael J; Harold Laughlin, M

    2010-02-01

    We tested the hypothesis that segmental differences in the responsiveness and time course of vasodilation to metabolic signals putatively involved in rapid onset vasodilation (ROV) at the start of exercise exist within the skeletal muscle vasculature. Cannulated first-order (1As) and third-order arterioles (3As) of the rat gastrocnemius (G) muscle were exposed to cumulative doses of KCl, acetylcholine (Ach), or adenosine (Ado). In addition, time course and magnitude of vasodilation to localized application of these agonists were determined. 1As and 3As dilated similarly to incremental doses of the agonists. Continuous monitoring of internal diameter revealed a fast and transient dilatory response to microinjections of the agonists, with an average time delay (TD) before the onset of vasodilation of 2.8 +/- 0.2 seconds (1As: 3.0 +/- 0.3 seconds and 3As: 2.6 +/- 0.3 seconds) and time-to-peak (TP) of 8.2 +/- 0.7 seconds (1As: 10.3 +/- 1 seconds and 3As:5.7 +/- 0.5 seconds). No significant differences were detected for all parameters between 1As and 3As for KCl or Ado application, while 1As had a significantly longer TP and greater peak dilation than 3As to Ach. These findings demonstrate that 1As and 3As from the rat G muscle appear to have similar responsiveness to vasoactive agonists. Furthermore, the average TD before vasodilation supports a role for metabolic signals as contributors to the ROV. PMID:20163535

  7. Effect of Dietary Docosahexaenoic Acid Supplementation on the Participation of Vasodilator Factors in Aorta from Orchidectomized Rats

    PubMed Central

    Largo, Carlota; Muñoz, David; Tabernero, María; Baeza, Ramiro; Otero, Cristina; García, Hugo S.; Ferrer, Mercedes

    2015-01-01

    Benefits of n-3 polyunsaturated fatty acids (PUFAs) against cardiovascular diseases have been reported. Vascular tone regulation is largely mediated by endothelial factors whose release is modulated by sex hormones. Since the incidence of cardiovascular pathologies has been correlated with decreased levels of sex hormones, the aim of this study was to analyze whether a diet supplemented with the specific PUFA docosahexaenoic acid (DHA) could prevent vascular changes induced by an impaired gonadal function. For this purpose, control and orchidectomized rats were fed with a standard diet supplemented with 5% (w/w) sunflower oil or with 3% (w/w) sunflower oil plus 2% (w/w) DHA. The lipid profile, the blood pressure, the production of prostanoids and nitric oxide (NO), and the redox status of biological samples from control and orchidectomized rats, fed control or DHA-supplemented diet, were analyzed. The vasodilator response and the contribution of NO, prostanoids and hyperpolarizing mechanisms were also studied. The results showed that orchidectomy negatively affected the lipid profile, increased the production of prostanoids and reactive oxygen species (ROS), and decreased NO production and the antioxidant capacity, as well as the participation of hyperpolarizing mechanisms in the vasodilator responses. The DHA-supplemented diet of the orchidectomized rats decreased the release of prostanoids and ROS, while increasing NO production and the antioxidant capacity, and it also improved the lipid profile. Additionally, it restored the participation of hyperpolarizing mechanisms by activating potassium. Since the modifications induced by the DHA-supplemented diet were observed in the orchidectomized, but not in the healthy group, DHA seems to exert cardioprotective effects in physiopathological situations in which vascular dysfunction exists. PMID:26540339

  8. Effect of Dietary Docosahexaenoic Acid Supplementation on the Participation of Vasodilator Factors in Aorta from Orchidectomized Rats.

    PubMed

    Villalpando, Diva M; Navarro, Rocío; Del Campo, Lara; Largo, Carlota; Muñoz, David; Tabernero, María; Baeza, Ramiro; Otero, Cristina; García, Hugo S; Ferrer, Mercedes

    2015-01-01

    Benefits of n-3 polyunsaturated fatty acids (PUFAs) against cardiovascular diseases have been reported. Vascular tone regulation is largely mediated by endothelial factors whose release is modulated by sex hormones. Since the incidence of cardiovascular pathologies has been correlated with decreased levels of sex hormones, the aim of this study was to analyze whether a diet supplemented with the specific PUFA docosahexaenoic acid (DHA) could prevent vascular changes induced by an impaired gonadal function. For this purpose, control and orchidectomized rats were fed with a standard diet supplemented with 5% (w/w) sunflower oil or with 3% (w/w) sunflower oil plus 2% (w/w) DHA. The lipid profile, the blood pressure, the production of prostanoids and nitric oxide (NO), and the redox status of biological samples from control and orchidectomized rats, fed control or DHA-supplemented diet, were analyzed. The vasodilator response and the contribution of NO, prostanoids and hyperpolarizing mechanisms were also studied. The results showed that orchidectomy negatively affected the lipid profile, increased the production of prostanoids and reactive oxygen species (ROS), and decreased NO production and the antioxidant capacity, as well as the participation of hyperpolarizing mechanisms in the vasodilator responses. The DHA-supplemented diet of the orchidectomized rats decreased the release of prostanoids and ROS, while increasing NO production and the antioxidant capacity, and it also improved the lipid profile. Additionally, it restored the participation of hyperpolarizing mechanisms by activating potassium. Since the modifications induced by the DHA-supplemented diet were observed in the orchidectomized, but not in the healthy group, DHA seems to exert cardioprotective effects in physiopathological situations in which vascular dysfunction exists.

  9. 4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice

    SciTech Connect

    Park, Kui Lea; Ko, Na Young; Lee, Jun Ho; Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Her, Erk; Kim, Bokyung; Kim, Hyung Sik; Moon, Eun-Yi; Kim, Young Mi; Kim, Hang-Rae; Choi, Wahn Soo

    2011-12-15

    4-Chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. We aimed to study the effects of 4-chlorotetrazolo[1,5-a]quinoxaline on activation of mast cells in vitro and in mice. 4-Chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited degranulation of mast cells in a dose-dependent manner, and also suppressed the expression and secretion of TNF-{alpha} and IL-4 in mast cells. Mechanistically, 4-chlorotetrazolo[1,5-a]quinoxaline inhibited activating phosphorylation of Syk and LAT, which are crucial for early Fc{epsilon}RI-mediated signaling events, as well as Akt and MAP kinases, which play essential roles in the production of various pro-inflammatory cytokines in mast cells. Notably, although 4-chlorotetrazolo[1,5-a]quinoxaline inhibited the activation of Fyn and Syk, minimal inhibition was observed in mast cells in the case of Lyn. Furthermore, consistent with its in vitro activity, 4-chlorotetrazolo[1,5-a]quinoxaline significantly suppressed mast cell-mediated passive cutaneous anaphylaxis in mice. In summary, the results from this study demonstrate that 4-chlorotetrazolo[1,5-a]quinoxaline shows an inhibitory effect on mast cells in vitro and in vivo, and that this is mediated by inhibiting the activation of Syk in mast cells. Therefore, 4-chlorotetrazolo[1,5-a]quinoxaline could be useful in the treatment of mast cell-mediated allergic diseases. -- Highlights: Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. Black-Right-Pointing-Pointer The effect of 4-chlorotetrazolo[1,5-a]quinoxaline on mast cells was investigated. Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited Syk activation. Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline could be useful for IgE-mediated allergy.

  10. Reconstructive dosimetry for cutaneous radiation syndrome

    PubMed Central

    Lima, C.M.A.; Lima, A.R.; Degenhardt, Ä.L.; Valverde, N.J.; Da Silva, F.C.A.

    2015-01-01

    According to the International Atomic Energy Agency (IAEA), a relatively significant number of radiological accidents have occurred in recent years mainly because of the practices referred to as potentially high-risk activities, such as radiotherapy, large irradiators and industrial radiography, especially in gammagraphy assays. In some instances, severe injuries have occurred in exposed persons due to high radiation doses. In industrial radiography, 80 cases involving a total of 120 radiation workers, 110 members of the public including 12 deaths have been recorded up to 2014. Radiological accidents in industrial practices in Brazil have mainly resulted in development of cutaneous radiation syndrome (CRS) in hands and fingers. Brazilian data include 5 serious cases related to industrial gammagraphy, affecting 7 radiation workers and 19 members of the public; however, none of them were fatal. Some methods of reconstructive dosimetry have been used to estimate the radiation dose to assist in prescribing medical treatment. The type and development of cutaneous manifestations in the exposed areas of a person is the first achievable gross dose estimation. This review article presents the state-of-the-art reconstructive dosimetry methods enabling estimation of local radiation doses and provides guidelines for medical handling of the exposed individuals. The review also presents the Chilean and Brazilian radiological accident cases to highlight the importance of reconstructive dosimetry. PMID:26445332

  11. Molecular genetics of cutaneous lymphomas.

    PubMed

    Whittaker, S

    2001-09-01

    The underlying molecular basis of primary cutaneous lymphomas has not yet been clarified. However, abnormalities of cell cycle control genes and well-defined tumor suppressor genes such as p53 are common and may contribute to disease progression and treatment resistance. Biallelic inactivation of tumor suppressor genes usually occurs by a combination of deletion, point mutation, and/or promotor hypermethylation. The detection of UVB-specific mutations of p53 requires confirmation but may have important implications for the management of patients with mycosis fungoides. Molecular cytogenetic studies have identified common regions of chromosomal deletion and amplification, which suggests the presence and location of genes that are of critical importance in the pathogenesis of cutaneous lymphoma.

  12. Cutaneous metastatic pigmented breast carcinoma.

    PubMed

    Gaitan-Gaona, Francisco; Said, Mirra C; Valdes-Rodriguez, Rodrigo

    2016-01-01

    A 66-year-old woman presented with a 3 cm black, ulcerated nodule located on the skin of the upper abdomen, just below the breast. The lesion was painful to the touch, but the patient reported no other associated symptoms and was otherwise healthy. A 4-mm punch biopsy of the affected skin was obtained and the histological diagnosis was cutaneous metastatic pigmented breast carcinoma. PMID:27136637

  13. Cutaneous Markers of Internal Disease

    PubMed Central

    Forsey, R. R.; Reardon, P. Michael

    1982-01-01

    Cutaneous markers of internal disease are legion. This article discusses the pigmentary disorders, acanthosis nigricans, pruritus, the xanthomas and problems of photosensitivity, outlining the appropriate procedures to establish a definite diagnosis, and in some cases the management of such patients. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11 PMID:21286147

  14. Parasitic Diseases With Cutaneous Manifestations.

    PubMed

    Ash, Mark M; Phillips, Charles M

    2016-01-01

    Parasitic diseases result in a significant global health burden. While often thought to be isolated to returning travelers, parasitic diseases can also be acquired locally in the United States. Therefore, clinicians must be aware of the cutaneous manifestations of parasitic diseases to allow for prompt recognition, effective management, and subsequent mitigation of complications. This commentary also reviews pharmacologic treatment options for several common diseases. PMID:27621348

  15. [Cutaneous adverse effects of TNFalpha antagonists].

    PubMed

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  16. [Acute poisoning of an infant by cutaneous application of a local counterirritant and pulmonary antiseptic salve].

    PubMed

    Dupeyron, J P; Quattrocchi, F; Castaing, H; Fabiani, P

    1976-01-01

    The case of acute poisoning reported here raises the question of the harmlessness of preparations destined for cutaneous application in infants. After describing the method perfected for the identification and estimation of camphor, menthol and thymol in biological material, the authors present the toxicological, clinical and biological arguments in favour of the notion that the cutaneous resorption of these substances was responsible for this acute intoxication in an infant. Particular attention should be paid to poisoning which may result, in the newborn and infant, from the cutaneous application of active substances. PMID:1010000

  17. A wearable diffuse reflectance sensor for continuous monitoring of cutaneous blood content

    NASA Astrophysics Data System (ADS)

    Zakharov, P.; Talary, M. S.; Caduff, A.

    2009-09-01

    An optical diffuse reflectance sensor for characterization of cutaneous blood content and optimized for continuous monitoring has been developed as part of a non-invasive multisensor system for glucose monitoring. A Monte Carlo simulation of the light propagation in the multilayered skin model has been performed in order to estimate the optimal geometrical separation of the light source and detector for skin and underlying tissue. We have observed that the pathlength within the upper vascular plexus of the skin which defines the sensor sensitivity initially grows with increasing source-detector distance (SDD) before reaching a maximum at 3.5 mm and starts to decay with further increase. At the same time, for distances above 2.4 mm, the sensor becomes sensitive to muscle blood content, which decreases the specificity to skin perfusion monitoring. Thus, the SDDs in the range from 1.5 mm to 2.4 mm satisfy the requirements of sensor sensitivity and specificity. The hardware implementation of the system has been realized and tested in laboratory experiments with a venous occlusion procedure and in an outpatient clinical study in 16 patients with type 1 diabetes mellitus. For both testing procedures, the optical sensor demonstrated high sensitivity to perfusion change provoking events. The general build-up of cutaneous blood under the sensor has been observed which can be associated with pressure-induced vasodilation as a response to the sensor application.

  18. [Cutaneous radiation syndrome: clinical features, diagnosis and therapy].

    PubMed

    Gottlöber, P; Krähn, G; Peter, R U

    2000-08-01

    Accidental exposure to ionizing radiation may occur during such catastrophic events as the Chernobyl accident in 1986 or over days to weeks as in Goiania in 1987 and in the military camp during the training of soldiers in Lilo/Georgia in 1997, as well as in medical institutions. The cutaneous symptoms after radiation exposure are based on a combination of inflammatory processes and alteration of cellular proliferation as a result of a specific pattern of transcriptionally activated proinflammatory cytokines and growth factors. They follow a time course consisting of prodromal erythema, latency period, acute stage, chronic stage and late stage. The entire complex is referred to as cutaneous radiation syndrome. The time course depends on several factors such as the radiation dose, radiation quality, individual radiation sensitivity, the extent of contamination and absorption and amount of skin exposed. For the diagnosis of the cutaneous radiation syndrome the following procedures are used: 7.5 MHz to 20 MHz-B-scan sonography, thermography, capillary microscopy, profilometry, nuclear magnetic resonance imaging, bone scintigraphy and histology. Based on the results of experimental and clinical research, today treatment may include topical or systemic corticosteroids, gamma-interferon, pentoxifylline, vitamin E and superoxide dismutase. The treatment depends on the stage of the cutaneous radiation syndrome. Due to the complexity of the clinical manifestations of radiation disease, most patients require interdisciplinary treatment in specialized centres. Dermatologists are essential partners in the life-long follow-up and therapy of such patients.

  19. Cutaneous colesional acquired immunodeficiency syndrome associated Kaposi sarcoma and cryptococcosis.

    PubMed

    Ramdial, Pratistadevi K; Sing, Yetish; Subrayan, Sumeshini; Calonje, Eduardo

    2010-12-01

    The clinicopathologic features of 4 AIDS patients with cutaneous colesional Kaposi sarcoma (KS) and cryptococcosis, a rare phenomenon, are described. Biopsies from 3 patients who were highly active antiretroviral therapy (HAART)-naive demonstrated predominant KS with a conspicuous spindle cell component and small aggregates of cryptococcal yeasts in 2 biopsies and predominant gelatinous cryptococcosis with attenuated KS spindle cells in 1 biopsy. One patient was HAART exposed. He had childhood pulmonary tuberculosis, was treated for disseminated cutaneous cryptococcosis 18 months earlier and presented with cutaneous lesions, odynophagia and massive cervical lymphadenopathy in the eighth week of HAART, after achieving viral suppression and a CD4 cell increase from 28 to 184 cells/μL. His skin biopsy demonstrated a dense lymphoplasmacytic infiltrate, neutrophils, and granulomas with admixed aggregates and single Cryptococcus neoformans and focal aggregation of human herpes virus 8-immunopositive spindle cells. Acid fast bacilli were not identified and mycobacterial molecular studies were negative. The features were compatible with cutaneous cryptococcal immune reconstitution inflammatory syndrome. His nodal and oropharyngeal biopsies demonstrated dense mixed, including granulomatous, inflammation with few cryptococcal yeasts and acid fast bacilli, confirmed to be Mycobacterium tuberculosis on polymerase chain reaction testing, without KS. These features were also compatible with immune reconstitution inflammatory syndrome, but the exact role of each infection in the extracutaneous sites was unconfirmed. Colesional KS and cryptococcosis served as the sentinel lesion of AIDS in 3 patients and of immune reconstitution inflammatory syndrome in 1 patient.

  20. Cutaneous Larva Migrans in Early Infancy

    PubMed Central

    Siddalingappa, Karjigi; Murthy, Sambasiviah Chidambara; Herakal, Kallappa; Kusuma, Marganahalli Ramachandra

    2015-01-01

    Cutaneous larva migrans or creeping eruptions is a cutaneous dermatosis caused by hookworm larvae, Ancylostoma braziliense. A 2-month-old female child presented with a progressive rash over the left buttock of 4 days duration. Cutaneous examination showed an urticarial papule progressing to erythematous, tortuous, thread-like tract extending a few centimeters from papule over the left gluteal region. A clinical diagnosis of cutaneous larva migrans was considered. Treatment with albendazole led to complete resolution, confirming the diagnosis. This is to the best of our knowledge, the youngest age at which this condition is being reported. PMID:26538729

  1. Detection of MYB Alterations and Other Immunohistochemical Markers in Primary Cutaneous Adenoid Cystic Carcinoma.

    PubMed

    North, Jeffrey P; McCalmont, Timothy H; Fehr, André; van Zante, Annemieke; Stenman, Göran; LeBoit, Philip E

    2015-10-01

    Adenoid cystic carcinoma (ACC) can arise in several organs, and prognosis is highly dependent on the primary tumor site. Primary cutaneous ACC has an excellent prognosis compared with salivary or lacrimal ACC. Activation of MYB by gene fusion or other mechanisms has been found in salivary, breast, and lacrimal ACCs but has not been described in cutaneous ACC. We analyzed the histopathologic and immunohistochemical features of 19 primary cutaneous ACCs, 2 periorbital ACCs, and 12 salivary gland ACCs and assessed for MYB activation in primary cutaneous ACC by immunohistochemistry and molecular methods. The presence of perineural invasion differed significantly among ACCs of various sites (83% salivary, 50% eyelid, 11% skin, P=0.0002). Over 90% of all ACCs were grade 1 or 2 and exhibited diffuse (>50%) positivity with CD117, SOX-10, and smooth muscle actin immunostains. CK15 and vimentin showed diffuse positivity in 36% and 57% of cutaneous ACCs, respectively, and were negative or only focally positive in all salivary ACCs (P=0.04 and 0.002). Six of the 11 cutaneous and periorbital ACCs tested with reverse transcriptase polymerase chain reaction and/or fluorescence in situ hybridization had MYB rearrangements including 2 cases that expressed MYB-NFIB fusion transcripts. Diffuse expression of MYB protein assessed by immunostaining was present in 8 of 9 cutaneous ACCs, including cases both with and without MYB rearrangements. These results indicate that cutaneous ACCs possess the same types of MYB alterations as ACCs of other anatomic sites. Vimentin and CK15 appear to have some discriminatory value in differentiating between primary cutaneous and salivary gland ACCs. PMID:26076064

  2. Soluble epoxide hydrolase contamination of specific catalase preparations inhibits epoxyeicosatrienoic acid vasodilation of rat renal arterioles.

    PubMed

    Gauthier, Kathryn M; Olson, Lauren; Harder, Adam; Isbell, Marilyn; Imig, John D; Gutterman, David D; Falck, J R; Campbell, William B

    2011-10-01

    Cytochrome P-450 metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H(2)O(2)), are important signaling molecules in the kidney. In renal arteries, EETs cause vasodilation whereas H(2)O(2) causes vasoconstriction. To determine the physiological contribution of H(2)O(2), catalase is used to inactivate H(2)O(2). However, the consequence of catalase action on EET vascular activity has not been determined. In rat renal afferent arterioles, 14,15-EET caused concentration-related dilations that were inhibited by Sigma bovine liver (SBL) catalase (1,000 U/ml) but not Calbiochem bovine liver (CBL) catalase (1,000 U/ml). SBL catalase inhibition was reversed by the soluble epoxide hydrolase (sEH) inhibitor tAUCB (1 μM). In 14,15-EET incubations, SBL catalase caused a concentration-related increase in a polar metabolite. Using mass spectrometry, the metabolite was identified as 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), the inactive sEH metabolite. 14,15-EET hydrolysis was not altered by the catalase inhibitor 3-amino-1,2,4-triazole (3-ATZ; 10-50 mM), but was abolished by the sEH inhibitor BIRD-0826 (1-10 μM). SBL catalase EET hydrolysis showed a regioisomer preference with greatest hydrolysis of 14,15-EET followed by 11,12-, 8,9- and 5,6-EET (V(max) = 0.54 ± 0.07, 0.23 ± 0.06, 0.18 ± 0.01 and 0.08 ± 0.02 ng DHET·U catalase(-1)·min(-1), respectively). Of five different catalase preparations assayed, EET hydrolysis was observed with two Sigma liver catalases. These preparations had low specific catalase activity and positive sEH expression. Mass spectrometric analysis of the SBL catalase identified peptide fragments matching bovine sEH. Collectively, these data indicate that catalase does not affect EET-mediated dilation of renal arterioles. However, some commercial catalase preparations are contaminated with sEH, and these contaminated preparations diminish the biological activity of H(2)O(2) and EETs.

  3. Soluble epoxide hydrolase contamination of specific catalase preparations inhibits epoxyeicosatrienoic acid vasodilation of rat renal arterioles.

    PubMed

    Gauthier, Kathryn M; Olson, Lauren; Harder, Adam; Isbell, Marilyn; Imig, John D; Gutterman, David D; Falck, J R; Campbell, William B

    2011-10-01

    Cytochrome P-450 metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H(2)O(2)), are important signaling molecules in the kidney. In renal arteries, EETs cause vasodilation whereas H(2)O(2) causes vasoconstriction. To determine the physiological contribution of H(2)O(2), catalase is used to inactivate H(2)O(2). However, the consequence of catalase action on EET vascular activity has not been determined. In rat renal afferent arterioles, 14,15-EET caused concentration-related dilations that were inhibited by Sigma bovine liver (SBL) catalase (1,000 U/ml) but not Calbiochem bovine liver (CBL) catalase (1,000 U/ml). SBL catalase inhibition was reversed by the soluble epoxide hydrolase (sEH) inhibitor tAUCB (1 μM). In 14,15-EET incubations, SBL catalase caused a concentration-related increase in a polar metabolite. Using mass spectrometry, the metabolite was identified as 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), the inactive sEH metabolite. 14,15-EET hydrolysis was not altered by the catalase inhibitor 3-amino-1,2,4-triazole (3-ATZ; 10-50 mM), but was abolished by the sEH inhibitor BIRD-0826 (1-10 μM). SBL catalase EET hydrolysis showed a regioisomer preference with greatest hydrolysis of 14,15-EET followed by 11,12-, 8,9- and 5,6-EET (V(max) = 0.54 ± 0.07, 0.23 ± 0.06, 0.18 ± 0.01 and 0.08 ± 0.02 ng DHET·U catalase(-1)·min(-1), respectively). Of five different catalase preparations assayed, EET hydrolysis was observed with two Sigma liver catalases. These preparations had low specific catalase activity and positive sEH expression. Mass spectrometric analysis of the SBL catalase identified peptide fragments matching bovine sEH. Collectively, these data indicate that catalase does not affect EET-mediated dilation of renal arterioles. However, some commercial catalase preparations are contaminated with sEH, and these contaminated preparations diminish the biological activity of H(2)O(2) and EETs. PMID:21753077

  4. Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy.

    PubMed

    Koivisto, Ari; Hukkanen, Mika; Saarnilehto, Marja; Chapman, Hugh; Kuokkanen, Katja; Wei, Hong; Viisanen, Hanna; Akerman, Karl E; Lindstedt, Ken; Pertovaara, Antti

    2012-01-01

    Peripheral diabetic neuropathy (PDN) is a devastating complication of diabetes mellitus (DM). Here we test the hypothesis that the transient receptor potential ankyrin 1 (TRPA1) ion channel on primary afferent nerve fibers is involved in the pathogenesis of PDN, due to sustained activation by reactive compounds generated in DM. DM was induced by streptozotocin in rats that were treated daily for 28 days with a TRPA1 channel antagonist (Chembridge-5861528) or vehicle. Laser Doppler flow method was used for assessing axon reflex induced by intraplantar injection of a TRPA1 channel agonist (cinnamaldehyde) and immunohistochemistry to assess substance P-like innervation of the skin. In vitro calcium imaging and patch clamp were used to assess whether endogenous TRPA1 agonists (4-hydroxynonenal and methylglyoxal) generated in DM induce sustained activation of the TRPA1 channel. Axon reflex induced by a TRPA1 channel agonist in the plantar skin was suppressed and the number of substance P-like immunoreactive nerve fibers was decreased 4 weeks after induction of DM. Prolonged treatment with Chembridge-5861528 reduced the DM-induced attenuation of the cutaneous axon reflex and loss of substance P-like immunoreactive nerve fibers. Moreover, in vitro calcium imaging and patch clamp results indicated that reactive compounds generated in DM (4-hydroxynonenal and methylglyoxal) produced sustained activations of the TRPA1 channel, a prerequisite for adverse long-term effects. The results indicate that the TRPA1 channel exerts an important role in the pathogenesis of PDN. Blocking the TRPA1 channel provides a selective disease-modifying treatment of PDN. PMID:22133672

  5. Simultaneous Disruption of Mouse ASIC1a, ASIC2 and ASIC3 Genes Enhances Cutaneous Mechanosensitivity

    PubMed Central

    Kang, Sinyoung; Jang, Jun Ho; Price, Margaret P.; Gautam, Mamta; Benson, Christopher J.; Gong, Huiyu; Welsh, Michael J.; Brennan, Timothy J.

    2012-01-01

    Three observations have suggested that acid-sensing ion channels (ASICs) might be mammalian cutaneous mechanoreceptors; they are structurally related to Caenorhabditis elegans mechanoreceptors, they are localized in specialized cutaneous mechanosensory structures, and mechanical displacement generates an ASIC-dependent depolarization in some neurons. However, previous studies of mice bearing a single disrupted ASIC gene showed only subtle or no alterations in cutaneous mechanosensitivity. Because functional redundancy of ASIC subunits might explain limited phenotypic alterations, we hypothesized that disrupting multiple ASIC genes would markedly impair cutaneous mechanosensation. We found the opposite. In behavioral studies, mice with simultaneous disruptions of ASIC1a, -2 and -3 genes (triple-knockouts, TKOs) showed increased paw withdrawal frequencies when mechanically stimulated with von Frey filaments. Moreover, in single-fiber nerve recordings of cutaneous afferents, mechanical stimulation generated enhanced activity in A-mechanonociceptors of ASIC TKOs compared to wild-type mice. Responses of all other fiber types did not differ between the two genotypes. These data indicate that ASIC subunits influence cutaneous mechanosensitivity. However, it is unlikely that ASICs directly transduce mechanical stimuli. We speculate that physical and/or functional association of ASICs with other components of the mechanosensory transduction apparatus contributes to normal cutaneous mechanosensation. PMID:22506072

  6. Response to Antimalarials in Cutaneous Lupus Erythematosus A Prospective Analysis

    PubMed Central

    Chang, Aileen Y.; Piette, Evan W.; Foering, Kristen P.; Tenhave, Thomas R.; Okawa, Joyce; Werth, Victoria P.

    2012-01-01

    Objective To demonstrate response to antimalarials in patients with cutaneous lupus erythematosus using activity scores from the Cutaneous Lupus Erythematosus Disease Area and Severity Index, a validated outcome measure. Design Prospective, longitudinal cohort study. Setting University cutaneous autoimmune disease clinic. Participants One hundred twenty-eight patients with cutaneous lupus erythematosus who presented from January 2007-July 2010 and had at least 2 visits with activity scores. Main Outcome Measures Response defined by 4-point or 20% decrease in activity score. Response to initiation determined with score before treatment and first visit at least 2 months after treatment. Response to continuation determined with score at first visit and most recent visit on treatment. Results Of 11 patients initiated on hydroxychloroquine, 55% were responders with a decrease in median (interquartile range) activity score from 8.0 (3.5-13) to 3.0 (1.8-7.3) (p=0.03). Of 15 patients who had failed hydroxychloroquine, 67% were responders to initiation of hydroxychloroquine-quinacrine, with a decrease in median (interquartile range) activity score from 6.0 (4.8-8.3) to 3.0 (0.75-5.0) (p=0.004). Nine out of 21 patients (43%) continued on hydroxychloroquine and 9 out of 21 patients (43%) continued on hydroxychloroquine-quinacrine were responders with a decrease in median (interquartile range) activity score from 6.0 (1.5-9.5) to 1.0 (0-4.5) (p=0.009) and 8.5 (4.25-17.5) to 5.0 (0.5-11.5) (p=0.01), respectively. Conclusion The use of quinacrine with hydroxychloroquine is associated with response in patients who fail hydroxychloroquine monotherapy. Further reduction in disease activity can be associated with continuation of antimalarials. PMID:21768444

  7. Acute ascorbic acid ingestion increases skeletal muscle blood flow and oxygen consumption via local vasodilation during graded handgrip exercise in older adults

    PubMed Central

    Richards, Jennifer C.; Crecelius, Anne R.; Larson, Dennis G.

    2015-01-01

    Human aging is associated with reduced skeletal muscle perfusion during exercise, which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that 1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (V̇o2) via local vasodilation during graded rhythmic handgrip exercise in older adults (protocol 1), and 2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise (protocol 2). In protocol 1 (n = 8; 65 ± 3 yr), AA did not influence FBF or V̇o2 during rest or 5% maximal voluntary contraction (MVC) exercise, but increased FBF (199 ± 13 vs. 248 ± 16 ml/min and 343 ± 24 vs. 403 ± 33 ml/min; P < 0.05) and V̇o2 (26 ± 2 vs. 34 ± 3 ml/min and 43 ± 4 vs. 50 ± 5 ml/min; P < 0.05) at both 15 and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 (n = 10; 63 ± 2 yr), following AA, FBF was similarly elevated during 15% MVC (∼20%); however, vasoconstriction to reflex increases in sympathetic activity during −40 mmHg lower-body negative pressure at rest (ΔFVC: −16 ± 3 vs. −16 ± 2%) or during 15% MVC (ΔFVC: −12 ± 2 vs. −11 ± 4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow and V̇o2 during exercise in older adults via local vasodilation. PMID:25980023

  8. Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion

    PubMed Central

    Limberg, Jacqueline K.; Kellawan, J. Mikhail; Harrell, John W.; Johansson, Rebecca E.; Eldridge, Marlowe W.; Proctor, Lester T.; Sebranek, Joshua J.

    2014-01-01

    We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise − rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = −0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA. PMID:25038148

  9. Effect of alpha1-adrenoceptor blockade on coronary vasodilator reserve in cardiac syndrome X.

    PubMed

    Rosen, S D; Lorenzoni, R; Kaski, J C; Foale, R A; Camici, P G

    1999-10-01

    We sought to test the response of the coronary microcirculation to alpha-adrenoceptor blockade in patients with syndrome X (angina, ischemia-like stress electrocardiogram, and a normal coronary arteriogram). The response of the microcirculation was assessed by quantification of coronary vasodilator reserve (the ratio of hyperemic to resting myocardial blood flow). We investigated 28 patients with syndrome X [18 women, age 54.4 (7.6) years]. Myocardial blood flow was measured at rest and after dipyridamole by using positron emission tomography with H(2)15O. The measurements were made before and after treatment for 10 days with doxazosin (1 mg o.d. for 3 days, followed by 2 mg o.d. for 7 days) or a matched placebo, similarly administered. Patients were randomized to alpha1-blockade or to placebo in double-blind fashion. No significant differences were demonstrable between syndrome X patients treated with doxazosin and those receiving placebo, with respect to resting myocardial blood flow, myocardial blood flow after dipyridamole, or coronary vasodilator reserve (the ratio of the latter two). In addition, no relations were demonstrable among myocardial blood flow, coronary vasodilator reserve, development of chest pain after dipyridamole, or development of ischemia-like ECG changes. Doxazosin had no effect on the perception of chest pain after dipyridamole. No differences were found between the effects of alpha1-blockade with doxazosin or those of placebo with respect to myocardial blood flow in syndrome X. The values obtained for myocardial blood flow and coronary vasodilator reserve for the patients were within the normal range. The data do not support the case for alpha1-mediated vasoconstriction having an etiologic role in the chest pain of syndrome X.

  10. Vasodilator effects of L-arginine are stereospecific and augmented by insulin in humans.

    PubMed

    Dallinger, Susanne; Sieder, Anna; Strametz, Jeanette; Bayerle-Eder, Michaela; Wolzt, Michael; Schmetterer, Leopold

    2003-06-01

    The amino acid l-arginine, the precursor of nitric oxide (NO) synthesis, induces vasodilation in vivo, but the mechanism behind this effect is unclear. There is, however, some evidence to assume that the l-arginine membrane transport capacity is dependent on insulin plasma levels. We hypothesized that vasodilator effects of l-arginine may be dependent on insulin plasma levels. Accordingly, we performed two randomized, double-blind crossover studies in healthy male subjects. In protocol 1 (n = 15), subjects received an infusion of insulin (6 mU x kg(-1) x min(-1) for 120 min) or placebo and, during the last 30 min, l-arginine or d-arginine (1 g/min for 30 min) x In protocol 2 (n = 8), subjects received l-arginine in stepwise increasing doses in the presence (1.5 mU x kg(-1) x min(-1)) or absence of insulin. Renal plasma flow and glomerular filtration rate were assessed by the para-aminohippurate and inulin plasma clearance methods, respectively. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation, and mean flow velocity in the ophthalmic artery was measured with Doppler sonography. l-arginine, but not d-arginine, significantly increased renal and ocular hemodynamic parameters. Coinfusion of l-arginine with insulin caused a dose-dependent leftward shift of the vasodilator effect of l-arginine. This stereospecific renal and ocular vasodilator potency of l-arginine is enhanced by insulin, which may result from facilitated l-arginine membrane transport, enhanced intracellular NO formation, or increased NO bioavailability.

  11. Role of nitric oxide in adenosine-induced vasodilation in humans

    NASA Technical Reports Server (NTRS)

    Costa, F.; Biaggioni, I.; Robertson, D. (Principal Investigator)

    1998-01-01

    Vasodilation is one of the most prominent effects of adenosine and one of the first to be recognized, but its mechanism of action is not completely understood. In particular, there is conflicting information about the potential contribution of endothelial factors. The purpose of this study was to explore the role of nitric oxide in the vasodilatory effect of adenosine. Forearm blood flow responses to intrabrachial adenosine infusion (125 microg/min) were assessed with venous occlusion plethysmography during intrabrachial infusion of saline or the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (12.5 mg/min). Intrabrachial infusions of acetylcholine (50 microg/min) and nitroprusside (3 microg/min) were used as a positive and negative control, respectively. These doses were chosen to produce comparable levels of vasodilation. In a separate study, a second saline infusion was administered instead of L-NMMA to rule out time-related effects. As expected, pretreatment with L-NMMA reduced acetylcholine-induced vasodilation; 50 microg/min acetylcholine increased forearm blood flow by 150+/-43% and 51+/-12% during saline and L-NMMA infusion, respectively (P<.01, n=6). In contrast, L-NMMA did not affect the increase in forearm blood flow produced by 3 microg/min nitroprusside (165+/-30% and 248+/-41% during saline and L-NMMA, respectively) or adenosine (173+/-48% and 270+/-75% during saline and L-NMMA, respectively). On the basis of our observations, we conclude that adenosine-induced vasodilation is not mediated by nitric oxide in the human forearm.

  12. Pulmonary vasodilation in acute and chronic heart failure: empiricism and evidence.

    PubMed

    Guglin, Maya

    2011-09-01

    Pulmonary hypertension in heart failure is associated with exercise intolerance and adverse outcomes. With the availability of multiple drugs that cause pulmonary vasodilation and decrease pulmonary arterial pressure, pulmonary hypertension becomes an attractive therapeutic target. Out of several classes of medications, oral phosphodiesterase inhibitors emerge as the most promising in terms of symptomatic improvement, hemodynamic benefits, reverse cardiac remodeling, and functional capacity. Future trials will show whether the use of these drugs translates to decreased morbidity and mortality in heart failure.

  13. Nitric oxide-mediated endothlium-dependent vasodilation is impaired with borderline high-LDL cholesterol.

    PubMed

    Diehl, Kyle J; Stauffer, Brian L; Greiner, Jared J; Weil, Brian R; DeSouza, Christopher A

    2012-02-01

    The experimental aims of this study were to determine: (1) whether nitric oxide-mediated endothelium-dependent vasodilation is blunted in adult humans with borderline high plasma low-density lipoprotein (LDL)-cholesterol compared with adults with optimal/near optimal LDL-cholesterol levels; and, if so: (2) whether the magnitude of impairment in adults with borderline high LDL-cholesterol is similar to adults with high LDL-cholesterol. Forearm blood flow responses to intraarterial infusions of acetylcholine and sodium nitroprusside were measured in 50 middle-aged (43-64 year) adults: 20 in the optimal/near optimal LDL-cholesterol range (<130 mg/dL); 20 with borderline high LDL-cholesterol (130-159 mg/dL); and 10 with high LDL-cholesterol ($160 mg/dL). In addition, blood flow responses to acetylcholine were determined in the absence and presence of the endothelial nitric oxide synthase inhibitor N(G) -monomethyl-L-arginine (L-NMMA). Vasodilation to acetylcholine was ~20% lower (p < 0.05) in the borderline high (from 4.3 ± 0.2 to 12.3 ± 0.8 mL/100 mL tissue/min) and high (from 4.3 ± 0.3 to 12.0 ± 0.5 mL/100 mL tissue/min) LDL-cholesterol groups compared with the optimal/near optimal (from 4.4 ± 0.2 to 14.5 ± 0.5 mL/100 mL tissue/min) LDL-cholesterol group. L-NMMA significantly reduced (~30%) the vasodilator response to acetylcholine in the optimal/near optimal LDL-cholesterol group but not the borderline high or high LDL-cholesterol groups. Borderline high LDL-cholesterol is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation.

  14. Quantitative immunohistochemical investigation of the intrinsic vasodilator innervation of the guinea pig lingual artery.

    PubMed

    Henrich, Michael; Haberberger, Rainer V; Hempelmann, Gunter; Kummer, Wolfgang

    2003-01-31

    The vasculature of the guinea pig tongue is supplied by parasympathetic vasodilator nerve fibres of intrinsic origin. Here, we investigated first to what extent neuropeptides and the synthesizing enzymes of NO, CO and acetylcholine are contained and colocalized within periarterial lingual vasodilator axons of intrinsic origin. Then it was determined whether perivascular innervation by these fibre types changes with vascular diameter, in particular in comparison with the sensory substance P (SP)-positive and sympathetic noradrenergic vascular innervation. To this end, single, double and triple labelling histochemical techniques were performed on control tongues and tongues kept in short-term organotypic culture to induce degeneration of extrinsically originating nerve fibres. Cell bodies of intrinsic microganglia and their periarterial axons contained, simultaneously, NO synthase, vasoactive intestinal peptide and the acetylcholine-synthesizing enzyme choline acetyltransferase. Additionally, neuropeptide Y (NPY) was observed in a small percentage (12%) of neurons that increased to 39% after 36 h of organotypic culture. The CO synthesizing enzyme heme oxygenase-2 was detected only in perikarya but not in periarterial axons. Intrinsic vasodilator fibres were invariably present at arteries down to a luminal diameter of 150 microm, and reached 65% of section profiles of smallest arterioles, while noradrenergic and substance P-positive axons reached 80% of arteriolar profiles. These findings show that the intrinsic lingual vasodilator innervation of the guinea pig is far extending although slightly less developed than that by sensory and sympathetic axons, and differs both in this aspect and in patterns of colocalization from that reported for other organs, e.g. lung and pelvic organs. PMID:12531400

  15. Ayadualin, a novel RGD peptide with dual antihemostatic activities from the sand fly Lutzomyia ayacuchensis, a vector of Andean-type cutaneous leishmaniasis.

    PubMed

    Kato, Hirotomo; Gomez, Eduardo A; Fujita, Megumi; Ishimaru, Yuka; Uezato, Hiroshi; Mimori, Tatsuyuki; Iwata, Hiroyuki; Hashiguchi, Yoshihisa

    2015-05-01

    Sequence analysis of the Lutzomyia (Lu.) ayacuchensis salivary gland cDNA library identified a short peptide containing an RGD (Arg-Gly-Asp) sequence flanked by two cysteine residues in the C-terminal end as the most abundant transcript. In the present study, a recombinant protein of the RGD-containing peptide, designated ayadualin, was expressed in Escherichia coli and its activity was characterized. Ayadualin inhibited both collagen and ADP-induced platelet aggregations by interfering with the binding of integrin αIIbβ3 to fibrinogen. The RGD sequence and cysteine residues located on both sides of the RGD sequence were essential for the inhibitory action. Moreover, ayadualin efficiently inhibited the intrinsic blood coagulation pathway irrespective of the RGD sequence. Measuring the enzymatic activity of coagulation factors using chromogenic substrates revealed that ayadualin efficiently inhibited factor XIIa (FXIIa) activity in a dose-dependent manner. In addition, pre-incubation of ayadualin with FXII inhibited FXIIa activity, while activated FXIIa was not affected by ayadualin, indicating that ayadualin inhibits the activation of FXII, but not enzymatic activity of FXIIa. These results indicated that ayadualin plays an important role in the blood feeding of Lu. ayacuchensis by inhibiting host hemostasis via dual mechanisms.

  16. Ayadualin, a novel RGD peptide with dual antihemostatic activities from the sand fly Lutzomyia ayacuchensis, a vector of Andean-type cutaneous leishmaniasis.

    PubMed

    Kato, Hirotomo; Gomez, Eduardo A; Fujita, Megumi; Ishimaru, Yuka; Uezato, Hiroshi; Mimori, Tatsuyuki; Iwata, Hiroyuki; Hashiguchi, Yoshihisa

    2015-05-01

    Sequence analysis of the Lutzomyia (Lu.) ayacuchensis salivary gland cDNA library identified a short peptide containing an RGD (Arg-Gly-Asp) sequence flanked by two cysteine residues in the C-terminal end as the most abundant transcript. In the present study, a recombinant protein of the RGD-containing peptide, designated ayadualin, was expressed in Escherichia coli and its activity was characterized. Ayadualin inhibited both collagen and ADP-induced platelet aggregations by interfering with the binding of integrin αIIbβ3 to fibrinogen. The RGD sequence and cysteine residues located on both sides of the RGD sequence were essential for the inhibitory action. Moreover, ayadualin efficiently inhibited the intrinsic blood coagulation pathway irrespective of the RGD sequence. Measuring the enzymatic activity of coagulation factors using chromogenic substrates revealed that ayadualin efficiently inhibited factor XIIa (FXIIa) activity in a dose-dependent manner. In addition, pre-incubation of ayadualin with FXII inhibited FXIIa activity, while activated FXIIa was not affected by ayadualin, indicating that ayadualin inhibits the activation of FXII, but not enzymatic activity of FXIIa. These results indicated that ayadualin plays an important role in the blood feeding of Lu. ayacuchensis by inhibiting host hemostasis via dual mechanisms. PMID:25724270

  17. ADP is a vasodilator component from Lasiodora sp. mygalomorph spider venom.

    PubMed

    Horta, C C; Rezende, B A; Oliveira-Mendes, B B R; Carmo, A O; Capettini, L S A; Silva, J F; Gomes, M T; Chávez-Olórtegui, C; Bravo, C E S; Lemos, V S; Kalapothakis, E

    2013-09-01

    Members of the spider genus Lasiodora are widely distributed in Brazil, where they are commonly known as caranguejeiras. Lasiodora spider venom is slightly harmful to humans. The bite of this spider causes local pain, edema and erythema. However, Lasiodora sp. spider venom may be a source of important pharmacological tools. Our research group has described previously that Lasiodora sp. venom produces bradycardia in the isolated rat heart. In the present work, we sought to evaluate the vascular effect of Lasiodora sp. venom and to isolate the vasoactive compounds from the venom. The results showed that Lasiodora spider venom induced a concentration-dependent vasodilation in rat aortic rings, which was dependent on the presence of a functional endothelium and abolished by the nitric oxide synthase (NOS) inhibitor L-NAME. Western blot experiments revealed that the venom also increased endothelial NOS function by increasing phosphorylation of the Ser¹¹⁷⁷ residue. Assay-directed fractionation isolated a vasoactive fraction from Lasiodora sp. venom. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) assays identified a mixture of two compounds: adenosine diphosphate (ADP, approximately 90%) and adenosine monophosphate (AMP, approximately 10%). The vasodilator effects of Lasiodora sp. whole venom, as well as ADP, were significantly inhibited by suramin, which is a purinergic P2-receptor antagonist. Therefore, the results of the present work indicate that ADP is a main vasodilator component of Lasiodora sp. spider venom.

  18. Mechanisms of vasodilation in the dorsal aorta of the elephant fish, Callorhinchus milii (Chimaeriformes: Holocephali).

    PubMed

    Jennings, Brett L; Bell, Justin D; Hyodo, Susumu; Toop, Tes; Donald, John A

    2007-07-01

    This study investigated vasodilator mechanisms in the dorsal aorta of the elephant fish, Callorhinchus milii, using anatomical and physiological approaches. Nitric oxide synthase could only be located in the perivascular nerve fibres and not the endothelium of the dorsal aorta, using NADPH histochemistry and immunohistochemistry. In vitro organ bath experiments demonstrated that a NO/soluble guanylyl cyclase (GC) system appeared to be absent in the vascular smooth muscle, since the NO donors SNP (10(-4) mol l(-1)) and SIN-1 (10(-5) mol l(-1)) were without effect. Nicotine (3 x 10(-4) mol l(-1)) mediated a vasodilation that was not affected by ODQ (10(-5) mol l(-1)), L-NNA (10(-4) mol l(-1)), indomethacin (10(-5) mol l(-1)), or removal of the endothelium. In contrast, the voltage-gated sodium channel inhibitor, tetrodotoxin (10(-5) mol l(-1)), significantly decreased the dilation induced by nicotine, suggesting that it contained a neural component. Pre-incubation of the dorsal aorta with the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP(8-37) (10(-6) mol l(-1)) also caused a significant decrease in the nicotine-induced dilation. We propose that nicotine is mediating a neurally-derived vasodilation in the dorsal aorta that is independent of NO, prostaglandins and the endothelium, and partly mediated by CGRP. PMID:17342492

  19. Single-walled carbon nanotubes (SWCNTs) induce vasodilation in isolated rat aortic rings.

    PubMed

    Gutiérrez-Hernández, J M; Ramirez-Lee, M A; Rosas-Hernandez, H; Salazar-García, S; Maldonado-Ortega, D A; González, F J; Gonzalez, C

    2015-06-01

    Single-walled carbon nanotubes (SWCNTs) are used in biological systems with impact in biomedicine in order to improve diagnostics and treatment of diseases. However, their effects upon the vascular system, are not fully understood. Endothelium and smooth muscle cells (SMC) communicate through release of vasoactive factors as nitric oxide (NO) to maintain vascular tone. The aim of this study was to evaluate the effect of SWCNTs on vascular tone using isolated rat aortic rings, which were exposed to SWCNTs (0.1, 1 and 10 μg/mL) in presence and absence of endothelium. SWCNTs induced vasodilation in both conditions, indicating that this effect was independent on endothelium; moreover that vasodilation was NO-independent, since its blockage with L-NAME did not modify the observed effect. Together, these results indicate that SWCNTs induce vasodilation in the macrovasculature, may be through a direct interaction with SMC rather than endothelium independent of NO production. Further investigation is required to fully understand the mechanisms of action and mediators involved in the signaling pathway induced by SWCNTs on the vascular system.

  20. Cutaneous response to irritants.

    PubMed

    Santucci, B; Cannistraci, C; Lesnoni, I; Ferraro, C; Rocco, M G D E; Dell'Anna, L; Giannarelli, D; Cristaudo, A

    2003-02-01

    We evaluated the role of pre-existing dermatitis in the response to irritants by patch testing the skin of 40 healthy volunteers and the uninvolved skin of 480 subjects for 2 days. These latter were affected by active atopic dermatitis, psoriasis, eczema with positive and negative patch test reactions, urticaria and generalized pruritus. A first panel containing 15 micro L of aq. solutions of disodium laureth sulfosuccinate (NaLSS) 5% and 10%, potassium cocoate (KCC) 5%, potassium oleate (KOL) 5%, zinc coleth sulphate (ZnCS) 5%, sodium mireth sulphate (NaMS) 5%, sodium cocoamphoacetate (NaCCAA) 3% and 5%, was simultaneously applied to 1 site on the upper back. The results, scored by visual assessment, were compared to those observed when testing on the opposite side a second panel containing 15 micro L of aq. solutions of 3 well-known irritants, benzalkonium chloride (BAK) 1%, sodium lauryl sulphate (SLS) 1%, and dimethylsulphoxide (DMSO) 10%. Whilst the substances of the first panel and DMSO gave, on the whole, a scarce number of positive responses in all the tested groups, more evident differences in number, percent and mean intensity of the positive responses to BAK and SLS were found between the different groups. Although some of them seemed statistically significant, when the same values were evaluated by means of chi2 and Student t-test, they did not differ in a statistically significant way from the values found in healthy subjects. The results of this study seem to indicate that the substances of the first panel have a chemical structure that makes them quite safe in real-life conditions. In contrast, BAK and SLS have chemical properties that condition the number and intensity of the responses, making the role exerted by the pre-existing dermatosis quite marginal. In particular, there is no proof that the healthy skin of active atopic subjects is the most susceptible to the irritating effects of the tested substances.

  1. Reflex control of the cutaneous circulation during passive body core heating in humans.

    PubMed

    Peters, J K; Nishiyasu, T; Mack, G W

    2000-05-01

    The impact of body core heating on the interaction between the cutaneous and central circulation during blood pressure challenges was examined in eight adults. Subjects were exposed to -10 to -90 mmHg lower body negative pressure (LBNP) in thermoneutral conditions and -10 to -60 mmHg LBNP during heat stress. We measured forearm vascular conductance (FVC; ml. min(-1). 100 ml(-1). mmHg(-1)) by plethysmography; cutaneous vascular conductance (CVC) by laser-Doppler techniques; and central venous pressure, arterial blood pressure, and cardiac output by impedance cardiography. Heat stress increased FVC from 5.7 +/- 0.9 to 18.8 +/- 1.3 conductance units (CU) and CVC from 0.21 +/- 0.07 to 1.02 +/- 0.20 CU. The FVC-CVP relationship was linear over the entire range of LBNP and was shifted upward during heat stress with a slope increase from 0. 46 +/- 0.10 to 1.57 +/- 0.3 CU/mmHg CVP (P < 0.05). Resting CVP was lower during heat stress (6.3 +/- 0.6 vs. 7.7 +/- 0.6 mmHg; P < 0. 05) but fell to similar levels during LBNP as in normothermic conditions. Data analysis indicates an increased capacity, but not sensitivity, of peripheral baroreflex responses during heat stress. Laser-Doppler techniques detected thermoregulatory responses in the skin, but no significant change in CVC occurred during mild-to-moderate LBNP. Interestingly, very high levels of LBNP produced cutaneous vasodilation in some subjects.

  2. Acute Cutaneous Microvascular Flow Responses to Whole-Body Tilting in Humans

    NASA Technical Reports Server (NTRS)

    Breit, Gregory A.; Watenpaugh, Donald E.; Ballard, Richard E.; Hargens, Alan R.

    1993-01-01

    The transition from upright to head-down tilt (HDT) posture in humans increases blood pressure superior to the heart and decreases pressure inferior to the heart. Consequently, above heart level, myogenic arteriolar tone probably increases with HDT, in opposition to the withdrawal of baroreceptor-mediated sympathetic tone. We hypothesized that due to antagonism between central and local controls, the response of the facial cutaneous micro- circulation to acute postural change will be weaker than that in the leg, where these two mechanisms reinforce each other. Cutaneous microvascular flow was measured by laser Doppler flowmetry simultaneously at the shin and the neck of 7 male and 3 female subjects. Subjects underwent a stepwise tilt protocol from standing control to 54 deg head-up tilt (HUT), 30 deg, 12 deg, 0 deg, -6 deg (HDT), -12 deg, -6 deg, 0 deg, 12 deg, 30 deg, 54 deg, and standing, for 30-sec periods with 10-sec transitions between postures. Flows at the shin and the neck increased significantly (P < 0.05) from standing baseline to 12 deg HUT (252 +/- 55 and 126 +/- 9% (bar-X +/- SE) of baseline, respectively). From 12 deg to -12 deg tilt, flows continued to increase at the shin (509 +/- 71% of baseline) but decreased at the neck to baseline levels (100 +/- 15% of baseline). Cutaneous microvascular flow recovered at both sites during the return to standing posture with significant hysteresis. Flow increases from standing to near-supine posture are attributed at both sites to baroreceptor-mediated vasodilation. The great dissimilarity in flow response magnitudes at the two measurement sites may be indicative of central/local regulatory antagonism above heart level and reinforcement below heart level.

  3. Acute Cutaneous Microvascular Flow Responses to Whole-Body Tilting in Humans

    NASA Technical Reports Server (NTRS)

    Breit, Gregory A.; Watenpaugh, Donald E.; Ballard, Richard E.; Hargens, Alan R.

    1993-01-01

    The transition from upright to head-down tilt (HDT) posture in humans increases blood pressure superior to the heart and decreases pressure inferior to the heart. Consequently, above heart level, myogenic arteriolar tone probably increases with HDT, in opposition to the withdrawal of baroreceptor-mediated sympathetic tone. We hypothesized that due to antagonism between central and local controls, the response of the facial cutaneous microcirculation to acute postural change will be weaker than that in the leg, where these two mechanisms reinforce each other. Cutaneous microvascular flow was measured by laser Doppler flowmetry simultaneously at the shin and the neck of 7 male and 3 female subjects. Subjects underwent a stepwise tilt protocol from standing control to 54 deg head-up tilt (HUT), 30 deg, 12 deg, O deg, -6 deg (HDT), -12 deg, -6 deg, O deg, 12 deg, 30 deg, 54 deg, and standing, for 30-sec periods with 10-sec transitions between postures. Flows at the shin and the neck increased significantly (P less than 0.05) from standing baseline to 12 deg HUT (252 +/- 55 and 126 +/- 9% (bar X +/- SE) of baseline, respectively). From 12 deg to -12 deg tilt, flows continued to increase at the shin (509 +/- 71% of baseline) but decreased at the neck to baseline levels (100 +/- 15% of baseline). Cutaneous microvascular flow recovered at both sites during the return to standing posture with significant hysteresis. Flow increases from standing to near-supine posture are attributed at both sites to baroreceptor-mediated vasodilation. The great dissimilarity in flow response magnitudes at the two measurement sites may be indicative of central/local regulatory antagonism above heart level and reinforcement below heart level.

  4. Cutaneous manifestations of chikungunya fever.

    PubMed

    Seetharam, K A; Sridevi, K; Vidyasagar, P

    2012-01-01

    Chikungunya fever, a re-emerging RNA viral infection produces different cutaneous manifestations in children compared to adults. 52 children with chikungunya fever, confirmed by positive IgM antibody test were seen during 2009-2010. Pigmentary lesions were common (27/52) followed by vesiculobullous lesions (16/52) and maculopapular lesions (14/52). Vesiculobullous lesions were most common in infants, although rarely reported in adults. Psoriasis was exacerbated in 4 children resulting in more severe forms. In 2 children, guttate psoriasis was observed for the first time.

  5. Disseminated cutaneous histoplasmosis in newly diagnosed HIV

    PubMed Central

    Soza, Gabriela M.; Patel, Mahir; Readinger, Allison

    2016-01-01

    We present a woman with a widespread severe papulopustular eruption, fever, and fatigue of 5 weeks' duration. HIV infection was diagnosed, with an absolute CD4+ count of 3 cells/µL. The eruption was consistent with disseminated cutaneous histoplasmosis. The clinical manifestations and management of cutaneous histoplasmosis are reviewed. PMID:26722169

  6. [Cutaneous lymphomas: new entities and rare variants].

    PubMed

    Kempf, W; Mitteldorf, C

    2015-02-01

    Primary cutaneous lymphomas are the second most common group of extranodal non-Hodgkin lymphomas. Recently several new variants and entities have been described but have not yet become part of the World Health Organization (WHO) classification. These forms include the granulomatous form of mycosis fungoides, which is associated with a poorer prognosis, as well as indolent CD8+ lymphoproliferations on the head and at acral localizations. Within the group of cutaneous CD30+ lymphoproliferative disorders, new histological types of lymphomatoid papulosis have been identified, such as type D (CD8+ epidermotropic) and type E (angioinvasive) which simulate aggressive lymphomas. Cutaneous peripheral T-cell lymphomas are a prognostically heterogeneous group of cutaneous lymphomas. The cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are very aggressive neoplasms, whereas cutaneous CD4+ small to medium-sized T-cell lymphoma in its solitary or localized form represents an indolent lymphoproliferation: the terminology, histogenesis and differentiation from nodular T-cell pseudolymphoma are still a matter of debate. Among B-cell lymphomas, disorders associated with Epstein-Barr virus (EBV) are discussed focusing on EBV diffuse large B-cell lymphoma of the elderly and EBV-associated mucocutaneous ulcer. This review describes the clinical, histological and immunophenotypic features of new and rare entities and variants of cutaneous lymphomas and highlights the impact of the clinicopathological correlation in the diagnostic process.

  7. The expanding spectrum of cutaneous borreliosis.

    PubMed

    Eisendle, K; Zelger, B

    2009-04-01

    The known spectrum of skin manifestations in cutaneous Lyme disease is continuously expanding and can not be regarded as completed. Besides the classical manifestations of cutaneous borreliosis like erythema (chronicum) migrans, borrelial lymphocytoma and acrodermatitis chronica atrophicans evidence is growing that at least in part also other skin manifestations, especially morphea, lichen sclerosus and cases of cutaneous B-cell lymphoma are causally related to infections with Borrelia. Also granuloma annulare and interstitial granulomatous dermatitis might be partly caused by Borrelia burgdorferi or similar strains. There are also single reports of other skin manifestations to be associated with borrelial infections like cutaneous sarcoidosis, necrobiosis lipoidica and necrobiotic xanthogranuloma. In addition, as the modern chameleon of dermatology, cutaneous borreliosis, especially borrelial lymphocytoma, mimics other skin conditions, as has been shown for erythema annulare centrifugum or lymphocytic infiltration (Jessner Kanof) of the skin. PMID:19357623

  8. Enhancement of Experimental Cutaneous Leishmaniasis by Leishmania Molecules Is Dependent on Interleukin-4, Serine Protease/Esterase Activity, and Parasite and Host Genetic Backgrounds ▿

    PubMed Central

    Silva, Virgínia M. G.; Larangeira, Daniela F.; Oliveira, Pablo R. S.; Sampaio, Romina B.; Suzart, Paula; Nihei, Jorge S.; Teixeira, Márcia C. A.; Mengel, José O.; dos-Santos, Washington L. C.; Pontes-de-Carvalho, Lain

    2011-01-01

    Most inbred strains of mice, like the BALB/c strain, are susceptible to Leishmania amazonensis infections and resistant to Leishmania braziliensis infections. This parasite-related difference could result from the activity of an L. amazonensis-specific virulence factor. In agreement with this hypothesis, it is shown here that the intravenous injection of BALB/c mice with L. amazonensis amastigote extract (LaE) but not the L. braziliensis extract confers susceptibility to L. braziliensis infection. This effect was associated with high circulating levels of IgG1 anti-L. amazonensis antibodies and with an increase in interleukin-4 (IL-4) production and a decrease in gamma interferon production by draining lymph node cells. Moreover, the effect was absent in IL-4-knockout mice. The biological activity in the LaE was not mediated by amphiphilic molecules and was inhibited by pretreatment of the extract with irreversible serine protease inhibitors. These findings indicate that the LaE contains a virulence-related factor that (i) enhances the Leishmania infection by promoting Th2-type immune responses, (ii) is not one of the immunomodulatory Leishmania molecules described so far, and (iii) is either a serine protease or has an effect that depends on that protease activity. In addition to being Leishmania species specific, the infection-enhancing activity was also shown to depend on the host genetic makeup, as LaE injections did not affect the susceptibility of C57BL/6 mice to L. braziliensis infection. The identification of Leishmania molecules with infection-enhancing activity could be important for the development of a vaccine, since the up- or downmodulation of the immune response against a virulence factor could well contribute to controlling the infection. PMID:21173308

  9. Cutaneous fistulization of the hydatid disease

    PubMed Central

    Bahce, Zeynep Sener; Akbulut, Sami; Aday, Ulas; Demircan, Firat; Senol, Ayhan

    2016-01-01

    Abstract Aim: To provide an overview of the medical literature on cutaneous fistulization in patients with hydatid disease (HD). Methods: According to PRISMA guidelines a literature search was made in PubMed, Medline, Google Scholar, and Google databases were searched using keywords to identify articles related to cutaneous fistulization of the HD. Keywords used were hydatid disease, hydatid cyst, cutaneous fistulization, cysto-cutaneous fistulization, external rupture, and external fistulization. The literature search included case reports, review articles, original articles, and meeting presentations published until July 2016 without restrictions on language, journal, or country. Articles and abstracts containing adequate information, such as age, sex, cyst size, cyst location, clinical presentation, fistula opening location, and management, were included in the study, whereas articles with insufficient clinical and demographic data were excluded. We also present a new case of cysto-cutaneous fistulization of a liver hydatid cyst. Results: The literature review included 38 articles (32 full text, 2 abstracts, and 4 unavailable) on cutaneous fistulization in patients with HD. Among the 38 articles included in the study, 22 were written in English, 13 in French, 1 in German, 1 in Italian, and 1 in Spanish. Forty patients (21 males and 19 females; mean age ± standard deviation, 54.0 ± 21.5 years; range, 7–93 years) were involved in the study. Twenty-four patients had cysto-cutaneous fistulization (Echinococcus granulosus); 10 had cutaneous fistulization (E multilocularis), 3 had cysto-cutaneo-bronchio-biliary fistulization, 2 had cysto-cutaneo-bronchial fistulization; and 1 had cutaneo-bronchial fistulization (E multilocularis). Twenty-nine patients were diagnosed with E granulosis and 11 had E multilocularis detected by clinical, radiological, and/or histopathological examinations. Conclusion: Cutaneous fistulization is a rare complication of HD

  10. Cutaneous phaeohyphomycosis caused by Alternaria longipes in an immunosuppressed patient.

    PubMed Central

    Gené, J; Azón-Masoliver, A; Guarro, J; Ballester, F; Pujol, I; Llovera, M; Ferrer, C

    1995-01-01

    Alternaria longipes was reported as the agent of a cutaneous infection in a patient with a neoplastic disease. The fungus has not been reported previously as causing disease in humans. It was distinguished by its rather small conidia with smooth or slightly verruculose walls and a pale brown beak which rarely extended into a secondary conidiophore. In vitro inhibitory activities of amphotericin B, ketoconazole, itraconazole, and miconazole were shown. PMID:8567925

  11. Drug-induced cutaneous vasculitides.

    PubMed

    Antiga, E; Verdelli, A; Bonciani, D; Bonciolini, V; Quintarelli, L; Volpi, W; Fabbri, P; Caproni, M

    2015-04-01

    Cutaneous vasculitides (CV) can be idiopathic or secondary to several triggers, including drugs, which account for up to 30% of all the cases of CV. Several drugs can induce CV, including some medications commonly used in dermatology, including minocycline, and several new drugs, such as anti-TNF agents. Different pathomecanisms are involved in the development of drug-induced CV, including the formation and deposition of immune complexes, the induction of neutrophil apoptosis, the formation of neoantigens between the drugs and proteins from the host, the shift of the immune response, and others. Although the diagnosis is difficult, because the clinical picture of drug-induced CV is in general indistinguishable from that of other forms of CV, it is important to recognize such entities in order to correctly manage the patient. Anamnesis, diagnostic algorithms to assess the likelihood of the association between a drug and a cutaneous reaction, skin biopsy and laboratory testing (including the search for antineutrophil cytoplasmic antibodies) are useful tools to make a diagnosis of drug-induced CV. About the therapy, while in idiopathic vasculitides the treatment is usually more aggressive and long-lasting, very often requiring a maintenance therapy with immunosuppressive drugs, in drug-induced CV the discontinuation of the suspected drug alone is usually enough to achieve complete remission, making the prognosis usually very good.

  12. Cutaneous activation of the inhibitory L30 interneurons provides a mechanism for regulating adaptive gain control in the siphon withdrawal reflex of Aplysia.

    PubMed

    Fischer, T M; Carew, T J

    1995-01-01

    The functional role of inhibition in the neural network underlying the siphon withdrawal response (SWR) of Aplysia was assessed by examining a recurrent circuit comprised of identified inhibitory interneurons (L30s), and excitatory interneurons (L29s). We previously showed that activity-dependent potentiation of the L30 inhibitory synapse onto L29 can regulate the net excitatory input elicited by tactile siphon stimulation onto siphon motor neurons (LFS cells) (Fischer and Carew, 1993a). To explore the functional significance of L30 potentiated inhibition, we have examined how a behaviorally relevant stimulus that activates the L30 interneurons modulates the SWR circuit. Utilizing a reduced preparation, we show that weak tactile stimulation of the tail strongly activates the L30s, and leads to significant potentiation of the L30 synapse. Next, we demonstrate that similar weak tail stimulation produces significant inhibition of siphon tap-evoked responses in both L29 interneurons and LFS motor neurons. We further show that this form of inhibition is transient, having a time course of approximately 60 sec. Finally, we directly tested the role of the L30s in mediating this form of inhibition by hyperpolarizing two (of three) L30 interneurons during tail stimulation. L30 inactivation significantly attenuated tail stimulation-induced inhibition of siphon-evoked input to both L29 interneurons and LFS motor neurons. Based on these results, we suggest that L30-potentiated inhibition may have an important adaptive role in optimizing the signal-to-noise ratio for activation of the SWR circuit by providing stabilization of SWR responsiveness under a wide range of environmental conditions.

  13. TRPV3 expression and vasodilator function in isolated uterine radial arteries from non-pregnant and pregnant rats.

    PubMed

    Murphy, Timothy V; Kanagarajah, Arjna; Toemoe, Sianne; Bertrand, Paul P; Grayson, T Hilton; Britton, Fiona C; Leader, Leo; Senadheera, Sevvandi; Sandow, Shaun L

    2016-08-01

    This study investigated the expression and function of transient receptor potential vanilloid type-3 ion channels (TRPV3) in uterine radial arteries isolated from non-pregnant and twenty-day pregnant rats. Immunohistochemistry (IHC) suggested TRPV3 is primarily localized to the smooth muscle in arteries from both non-pregnant and pregnant rats. IHC using C' targeted antibody, and qPCR of TRPV3 mRNA, suggested pregnancy increased arterial TRPV3 expression. The TRPV3 activator carvacrol caused endothelium-independent dilation of phenylephrine-constricted radial arteries, with no difference between vessels from non-pregnant and pregnant animals. Carvacrol-induced dilation was reduced by the TRPV3-blockers isopentenyl pyrophosphate and ruthenium red, but not by the TRPA1 or TRPV4 inhibitors HC-030031 or HC-067047, respectively. In radial arteries from non-pregnant rats only, inhibition of NOS and sGC, or PKG, enhanced carvacrol-mediated vasodilation. Carvacrol-induced dilation of arteries from both non-pregnant and pregnant rats was prevented by the IKCa blocker TRAM-34. TRPV3 caused an endothelium-independent, IKCa-mediated dilation of the uterine radial artery. NO-PKG-mediated modulation of TRPV3 activity is lost in pregnancy, but this did not alter the response to carvacrol.

  14. Endothelium-Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions.

    PubMed

    Ellinsworth, David C; Sandow, Shaun L; Shukla, Nilima; Liu, Yanping; Jeremy, Jamie Y; Gutterman, David D

    2016-01-01

    Myocardial perfusion and coronary vascular resistance are regulated by signaling metabolites released from the local myocardium that act either directly on the VSMC or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is EDH of the arteriolar smooth muscle, with EETs and H(2)O(2) playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H(2)O(2) are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H(2)O(2) can also promote endothelial KCa activity secondary to the amplification of extracellular Ca(2+) influx and Ca(2+) mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions or potentially lead to the release of a chemically distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signaling involving EETs and H(2)O(2) may be integrated, being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H(2)O(2) regulate vessel tone and also examines the hypothesis that myoendothelial microdomain signaling facilitates EDH activity in the human heart.

  15. Skin vasodilator response to local heating in multiple system atrophy.

    PubMed

    Yamanaka, Yoshitaka; Asahina, Masato; Mathias, Christopher J; Akaogi, Yuichi; Koyama, Yu; Hattori, Takamichi

    2007-12-01

    Local heating of nonglabrous skin increases skin blood flow (SkBF) in two phases. The initial peak (P1) is mediated by a sensory-axon reflex and the plateau phase (P2) by local production of substances such as nitric oxide. We evaluated the SkBF response to local heating in 15 multiple system atrophy (MSA) patients with autonomic failure and 12 age-matched healthy controls. The mean ratio of SkBF at P1 to that at baseline (SkBF(P1)/SkBF(base) ratio) in MSA was significantly lower than that in controls (P < 0.01). The mean ratio of SkBF at P2 seemed to be slightly reduced in the MSA patients, compared with controls, although there was no significant difference. The P1 phase is thought to be mediated by a sensory-axon reflex modulated by sympathetic nerve activity. These findings are indicative of the skin sympathetic vasomotor dysfunction in MSA.

  16. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis.

    PubMed

    Bolognesi, Massimo; Di Pascoli, Marco; Verardo, Alberto; Gatta, Angelo

    2014-03-14

    Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.

  17. WHO-EORTC classification for cutaneous lymphomas.

    PubMed

    Willemze, Rein; Jaffe, Elaine S; Burg, Günter; Cerroni, Lorenzo; Berti, Emilio; Swerdlow, Steven H; Ralfkiaer, Elisabeth; Chimenti, Sergio; Diaz-Perez, José L; Duncan, Lyn M; Grange, Florent; Harris, Nancy Lee; Kempf, Werner; Kerl, Helmut; Kurrer, Michael; Knobler, Robert; Pimpinelli, Nicola; Sander, Christian; Santucci, Marco; Sterry, Wolfram; Vermeer, Maarten H; Wechsler, Janine; Whittaker, Sean; Meijer, Chris J L M

    2005-05-15

    Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, Sezary syndrome, and the group of primary cutaneous CD30+ lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification.

  18. Actinic DNA damage and the pathogenesis of cutaneous malignant melanoma.

    PubMed

    Ross, P M; Carter, D M

    1989-05-01

    The near epidemic of melanoma and non-melanoma skin cancer in the United States and certain other industrialized nations is attributable to cutaneous exposure to sunlight more than to any other factor. Chronic exposure to UV irradiation and a high total cumulative dose may be less deleterious than are periodic bursts of large amounts of sun exposure leading to severe sunburn. Such an exposure pattern is characteristic of individuals such as office workers whose outdoor activities are irregular rather than daily, as with farmers or fisherman. Although UV irradiation is injurious to many cellular elements, the mechanisms underlying UV-mediated skin cancer are thought to be most likely related to DNA damage to cutaneous cells. Various types of UV-induced DNA damage have been identified, and they differ in biologic significance. Damage which is apt to be most cytotoxic is probably less effective as an inducer of skin cancer than is more subtle damage, which is tolerated but can initiate malignant transformation. Repair of DNA damage involves specific cellular activities which vary in their effectiveness in restoring cutaneous cell function to normal. Other biologic effects of UV irradiation may contribute to the development of skin cancer through effects on such defenses as pigmentation and the immune response. Sun-induced damage to DNA, however, is apparently necessary. Biologic consequences of dangerous environmental exposure to UV irradiation can be modulated by changes in life-style, the depth of the ozone layer, use of sunscreens, and possibly by hormones or their synthetic analogs.

  19. Cutaneous tuberculosis and squamous-cell carcinoma.

    PubMed

    Ljubenovic, Milanka S; Ljubenovic, Dragisa B; Binic, Ivana I; Jankovic, Aleksandar S; Jancic, Snezana A

    2011-01-01

    The incidence of all forms of cutaneous tuberculosis, including lupus vulgaris (the most common form) decreased progressively in developed countries during the twentieth century, this change being attributed to improved living standards and specific therapy. Despite the decrease in cutaneous tuberculosis, some cases are still found and correct diagnosis and management are fundamental, both for the patients and for public health. Long lasting, misdiagnosed or untreated cutaneous tuberculosis may lead to different forms of cancer. This case report involves a 74-year old male farmer with lupus vulgaris on his face. During anti-tuberculosis treatment he developed a tumor on his forehead, which was histologically confirmed as a squamous cell carcinoma.

  20. An overview of cutaneous T cell lymphomas

    PubMed Central

    Bagherani, Nooshin; Smoller, Bruce R.

    2016-01-01

    Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. They typically afflict adults with a median age of 55 to 60 years, and the annual incidence is about 0.5 per 100,000. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T cell lymphomas not otherwise specified are the most important subtypes of CTCL. CTCL is a complicated concept in terms of etiopathogenesis, diagnosis, therapy, and prognosis. Herein, we summarize advances which have been achieved in these fields. PMID:27540476

  1. Cutaneous cylindroma: it's all about MYB.

    PubMed

    Corda, Gabriele; Sala, Arturo

    2016-08-01

    Cutaneous cylindroma is a rare benign tumour that occasionally turns into malignant cylindrocarcinoma. The cancer can be sporadic or emerge in the context of Brooke-Spiegler syndrome (BSS), an inheritable condition characterized by mutation of the gene CYLD, encoding a tumour suppressor protein that controls the activity of the transcription factor NF-kB. Sporadic cylindromas present histological features shared with adenoid cystic carcinoma (ACC), a head and neck cancer originating from salivary or other exocrine glands. Like ACCs, sporadic cylindromas express, although at lower frequency, the aberrant fusion transcript MYB-NFIB. In a paper recently published in the Journal of Pathology, the research teams led by Neil Rajan and Goran Stenman demonstrate that CYLD-defective cyclindromas in BSS patients are negative for the MYB-NFIB fusion. Only the wild-type MYB oncoprotein is activated in the majority of these tumours. RNA interference studies in cells derived from BSS patients indicate that ablating MYB expression results in a striking reduction of cylindroma cell proliferation, suggesting that MYB plays a pivotal role in the biology of this cancer. The take-home message of the study is that activation of MYB, in its wild-type form or fusion derivatives, is a common feature of spontaneous and hereditary cylindromas, constituting a potentially actionable therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  2. Cutaneous protothecosis--case report.

    PubMed

    Silva, Pâmela Craveiro Gomes da; Costa e Silva, Sabrina Beirão da; Lima, Ricardo Barbosa; D'Acri, Antonio Macedo; Lupi, Omar; Martins, Carlos José

    2013-01-01

    Cutaneous protothecosis is a rare infection caused by achlorophyllic algae of the genus Prototheca. The lesions usually occur on exposed areas, related with trauma, in immunocompromised patients. The most common clinical presentation is a vesicobullous and ulcerative lesion with pustules and scabs, simulating bacterial, fungal or herpetic infections or eczema. The diagnosis is determined by agent identification through histopathology, culture and the carbohydrates assimilation test. The finding of morula-like spherules is characteristic of Prototheca sp. Its rarity and non-specific clinical aspect may difficult the disease diagnosis. We report a case of a diabetic patient, in chronic use of systemic corticosteroids, that developed a skin lesion after trauma to the right leg. PMID:24346914

  3. Cutaneous Scarring: A Clinical Review

    PubMed Central

    Baker, Richard; Urso-Baiarda, Fulvio; Linge, Claire; Grobbelaar, Adriaan

    2009-01-01

    Cutaneous scarring can cause patients symptoms ranging from the psychological to physical pain. Although the process of normal scarring is well described the ultimate cause of pathological scarring remains unknown. Similarly, exactly how early gestation fetuses can heal scarlessly remains unsolved. These questions are crucial in the search for a preventative or curative antiscarring agent. Such a discovery would be of enormous medical and commercial importance, not least because it may have application in other tissues. In the clinical context the assessment of scars is becoming more sophisticated and new physical, medical and surgical therapies are being introduced. This review aims to summarise some of the recent developments in scarring research for non-specialists and specialists alike. PMID:20585482

  4. Cutaneous manifestations of lung cancer.

    PubMed

    Owen, Cindy England

    2016-06-01

    Skin findings can serve as a clue to internal disease. In this article, cutaneous manifestations of underlying lung malignancy are reviewed. Paraneoplastic dermatoses are rare, but when recognized early, can lead to early diagnosis of an underlying neoplasm. Malignancy-associated dermatoses comprise a broad group of hyperproliferative and inflammatory disorders, disorders caused by tumor production of hormonal or metabolic factors, autoimmune connective tissue diseases, among others. In this review, paraneoplastic syndromes associated with lung malignancy are discussed, including ectopic ACTH syndrome, bronchial carcinoid variant syndrome, secondary hypertrophic osteoarthropathy/digital clubbing, erythema gyratum repens, malignant acanthosis nigricans, sign of Leser-Trélat, tripe palms, hypertrichosis lanuginosa, acrokeratosis paraneoplastica, and dermatomyositis. PMID:27178690

  5. Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase

    PubMed Central

    Johansson, Rebecca E.; Harrell, John W.; Sebranek, Joshua J.; Walker, Benjamin J.; Eldridge, Marlowe W.; Schrage, William G.

    2015-01-01

    Purpose We hypothesized exercise vasodilation would be greater in women due to nitric oxide synthase (NOS) and cyclooxygenase (COX) signaling. Methods 45 healthy adults (23 women, W, 22 men, M, 26 ± 1 years) completed two 10-min trials of dynamic forearm exercise at 15 % intensity. Forearm blood flow (FBF; Doppler ultrasound), arterial pressure (brachial catheter), and forearm lean mass were measured to calculate relative forearm vascular conductance (FVCrel) = F BF 100 mmHg−1 100 g−1 lean mass. Local intra-arterial infusion of L-NMMA or ketorolac acutely inhibited NOS and COX, respectively. In Trial 1, the first 5 min served as control exercise (CON), followed by 5 min of L-NMMA or ketorolac over the last 5 min of exercise. In Trial 2, the remaining drug was infused during 5–10 min, to achieve combined NOS–COX inhibition (double blockade, DB). Results Are mean ± SE. Women exhibited 29 % greater vasodilation in CON (AFVCrel, 19 ± 1 vs. 15 ± 1, p = 0.01). L-NMMA reduced AFVCrel (p < 0.001) (W: Δ −2.3 ± 1.3 vs. M: Δ −3.7 ± 0.8, p = 0.25); whereas, ketorolac modestly increased ΔFVCrel (p = 0.04) similarly between sexes (W: Δ 1.6 ± 1.1 vs. M: Δ 2.0 ± 1.6, p = 0.78). DB was also found to be similar between the sexes (p = 0.85). Conclusion These data clearly indicate women produce a greater exercise vasodilator response. Furthermore, contrary to experiments in animal models, these data are the first to demonstrate vascular control by NOS and COX is similar between sexes. PMID:25820143

  6. Correlative intravital imaging of cGMP signals and vasodilation in mice

    PubMed Central

    Thunemann, Martin; Schmidt, Kjestine; de Wit, Cor; Han, Xiaoxing; Jain, Rakesh K.; Fukumura, Dai; Feil, Robert

    2014-01-01

    Cyclic guanosine monophosphate (cGMP) is an important signaling molecule and drug target in the cardiovascular system. It is well known that stimulation of the vascular nitric oxide (NO)-cGMP pathway results in vasodilation. However, the spatiotemporal dynamics of cGMP signals themselves and the cGMP concentrations within specific cardiovascular cell types in health, disease, and during pharmacotherapy with cGMP-elevating drugs are largely unknown. To facilitate the analysis of cGMP signaling in vivo, we have generated transgenic mice that express fluorescence resonance energy transfer (FRET)-based cGMP sensor proteins. Here, we describe two models of intravital FRET/cGMP imaging in the vasculature of cGMP sensor mice: (1) epifluorescence-based ratio imaging in resistance-type vessels of the cremaster muscle and (2) ratio imaging by multiphoton microscopy within the walls of subcutaneous blood vessels accessed through a dorsal skinfold chamber. Both methods allow simultaneous monitoring of NO-induced cGMP transients and vasodilation in living mice. Detailed protocols of all steps necessary to perform and evaluate intravital imaging experiments of the vasculature of anesthetized mice including surgery, imaging, and data evaluation are provided. An image segmentation approach is described to estimate FRET/cGMP changes within moving structures such as the vessel wall during vasodilation. The methods presented herein should be useful to visualize cGMP or other biochemical signals that are detectable with FRET-based biosensors, such as cyclic adenosine monophosphate or Ca2+, and to correlate them with respective vascular responses. With further refinement and combination of transgenic mouse models and intravital imaging technologies, we envision an exciting future, in which we are able to “watch” biochemistry, (patho-)physiology, and pharmacotherapy in the context of a living mammalian organism. PMID:25352809

  7. Delay in cutaneous melanoma diagnosis

    PubMed Central

    Xavier, Marcus H.S.B.; Drummond-Lage, Ana P.; Baeta, Cyntia; Rocha, Lorena; Almeida, Alessandra M.; Wainstein, Alberto J.A.

    2016-01-01

    Abstract Advanced melanoma is an incurable disease with complex and expensive treatments. The best approach to prevent melanoma at advanced stages is an early diagnosis. A knowledge of factors associated with the process of detecting cutaneous melanomas and the reasons for delays in diagnosis is essential for the improvement of the secondary prevention of the disease. Identify sociodemographic, individual, and medical aspects related to cutaneous melanoma diagnosis delay. Interviews evaluated the knowledge of melanoma, signals, symptoms, persons who were suspected, delays in seeking medical attention, physician's deferrals, and related factors of 211 patients. Melanomas were self-discovered in 41.7% of the patients; healthcare providers detected 29.9% of patients and others detected 27%. The main component in delay was patient-related. Only 31.3% of the patients knew that melanoma was a serious skin cancer, and most thought that the pigmented lesion was not important, causing a delay in seeking medical assistance. Patients (36.4%) reported a wait interval of more than 6 months from the onset of an observed change in a pigmented lesion to the first visit to a physician. The delay interval from the first physician visit to a histopathological diagnosis was shorter (<1 month) in 55.5% of patients. Improper treatments without a histopathological confirmation occurred in 14.7% of patients. A professional delay was related to both inappropriate treatments performed without histopathological confirmation (P = 0.003) and long requirements for medical referrals (P < 0.001). A deficient knowledge in the population regarding melanoma and physicians’ misdiagnoses regarding suspicious lesions contributed to delays in diagnosis. PMID:27495055

  8. Immunopathology of experimental cutaneous leishmaniasis.

    PubMed Central

    Andrade, Z. A.; Reed, S. G.; Roters, S. B.; Sadigursky, M.

    1984-01-01

    Relatively susceptible BALB/c and relatively resistant A/J mice were infected subcutaneously in the right hind footpad with promastigotes of Leishmania mexicana amazonensis. A large localized lesion developed within 2 months after infection in the BALB/c mice, while A/J mice exhibited a small discrete fibrotic nodule. Sequential immunologic and histologic examination demonstrated that BALB/c mice developed a nodular foam-cell type of lesion and progressive depression of a delayed-type hypersensitivity (DTH) response to leishmania antigen, while the A/J mice had a mixed cellular fibrosing and encapsulating reaction and developed and maintained positive DTH responses to leishmania antigen. Anti-leishmania antibody responses were positive at similar levels in both strains. The lesions in BALB/c mice were found in bone marrow, tendon, skin appendages, and regional lymph nodes, with a tendency toward cutaneous metastases. Lesions in A/J mice remained localized. Fibrosis, focal fibrinoid necrosis, and lymphocytic and macrophagic infiltration were the outstanding features. Light and transmission electron microscopic studies indicated that no outstanding destruction of leishmanias seemed to occur within macrophages of either mouse strain. In the more resistant A/J mice, however, parasitized macrophages were frequently necrotic, and degenerating leishmanias were often seen free in the interstitial tissue. These observations help the interpretation of the histologic features, as well as the pathogenesis, of cutaneous and mucocutaneous leishmaniasis in man. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 PMID:6691411

  9. Ferrofluid-associated Cutaneous Dyschromia

    PubMed Central

    Arfa, Kenneth S.

    2016-01-01

    Background: Ferrofluid is a colloidal suspension that usually consists of surfactant-coated nanoparticles of magnetite (Fe3O4) in a carrier liquid. Ferromagnetic fluid forms spikes when the liquid is exposed to a magnetic field. Purpose: The authors describe a man who developed temporary discoloration of his right palm and fingers after accidental cutaneous contact with ferrofluid and discuss some of the current and potential applications of this unique liquid. Methods: A 28-year-old man was evaluating the effects of magnetic fields using ferrofluid. He performed a modification of the “leaping ferrofluid” demonstration in which he held a superstrong (14,800 gauss magnetic field strength) N52 rare earth neodymium magnet in his palm and slowly lowered that hand over an open bowl that was filled with ferrofluid. Results: As the magnet approached the liquid, the ferrofluid became magnetized. The liquid leaped from the bowl and contacted not only the magnet, but also the palmar surface of his hand and fingers, resulting in a black-brown dyschromia of the affected skin. The discoloration completely resolved after two weeks without any adverse sequellae. Conclusion: Ferrofluid has numerous current and potential applications; in addition to being of value educationally and aesthetically (after being subjected to magnetic fields), it is also utilized for audio loudspeakers, medical innovations (such as a component of either a research tool, a diagnostic aid, or a treatment modality), and seals. Although the authors’ patient did not experience any acute or chronic toxicity from his cutaneous exposure to ferrofluid, conservative follow-up for individuals who experience skin contact with ferromagnetic fluid may be appropriate. PMID:27354890

  10. Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

    PubMed Central

    Jang, Hyun-Ju; Kim, Hae-Suk; Hwang, Daniel H.; Quon, Michael J.

    2013-01-01

    Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity. PMID:23531618

  11. Cutaneous T cell lymphoma mimicking cutaneous histiocytosis: differentiation by flow cytometry.

    PubMed

    Baines, S J; McCormick, D; McInnes, E; Dunn, J K; Dobson, J M; McConnell, I

    2000-07-01

    A two-year-old, neutered female cross-bred labrador had multiple cutaneous nodules, biopsies of which revealed pathological changes consistent with cutaneous histiocytosis. During a period of one month the dog developed multicentric lymphadenopathy, a retrobulbar mass and masses within the quadriceps and cervical muscles. Fine needle aspiration cytology of the cutaneous nodules and lymph nodes and histological examination of the cutaneous nodules and muscle masses suggested the presence of lymphoblastic lymphoma. A definitive diagnosis of CD8+ T cell lymphoma was achieved by immunophenotyping the tumour cells by flow cytometry.

  12. Vasodilator-stimulated phosphoprotein (VASP) regulates actin polymerization and contraction in airway smooth muscle by a vinculin-dependent mechanism.

    PubMed

    Wu, Yidi; Gunst, Susan J

    2015-05-01

    Vasodilator-stimulated phosphoprotein (VASP) can catalyze actin polymerization by elongating actin filaments. The elongation mechanism involves VASP oligomerization and its binding to profilin, a G-actin chaperone. Actin polymerization is required for tension generation during the contraction of airway smooth muscle (ASM); however, the role of VASP in regulating actin dynamics in ASM is not known. We stimulated ASM cells and tissues with the contractile agonist acetylcholine (ACh) or the adenylyl cyclase activator, forskolin (FSK), a dilatory agent. ACh and FSK stimulated VASP Ser(157) phosphorylation by different kinases. Inhibition of VASP Ser(157) phosphorylation by expression of the mutant VASP S157A in ASM tissues suppressed VASP phosphorylation and membrane localization in response to ACh, and also inhibited contraction and actin polymerization. ACh but not FSK triggered the formation of VASP-VASP complexes as well as VASP-vinculin and VASP-profilin complexes at membrane sites. VASP-VASP complex formation and the interaction of VASP with vinculin and profilin were inhibited by expression of the inactive vinculin mutant, vinculin Y1065F, but VASP phosphorylation and membrane localization were unaffected. We conclude that VASP phosphorylation at Ser(157) mediates its localization at the membrane, but that VASP Ser(157) phosphorylation and membrane localization are not sufficient to activate its actin catalytic activity. The interaction of VASP with activated vinculin at membrane adhesion sites is a necessary prerequisite for VASP-mediated molecular processes necessary for actin polymerization. Our results show that VASP is a critical regulator of actin dynamics and tension generation during the contractile activation of ASM.

  13. What's eating you? Cutaneous larva migrans.

    PubMed

    Prickett, Kyle A; Ferringer, Tammie C

    2015-03-01

    This article provides a focused update and clinical review on cutaneous larva migrans (CLM), including atypical clinical presentations and newer management recommendations. The results and recommendations are subject to modification based on future studies.

  14. Initial cutaneous manifestation of lymphomas in children.

    PubMed

    Oliveira, Maria Christina Lopes Araujo de; Pereira, Luciana Baptista; Rodrigues, Priscila Cezarino; Sampaio, Keyla Cunha; Oliveira, Benigna Maria de; Viana, Marcos Borato

    2011-01-01

    Cutaneous lymphomas comprise a heterogeneous group of lymphoproliferative disorders with skin involvement and are classified as a subgroup of non-Hodgkin lymphomas. From 1981 to 2007, 100 children with non-Hodgkin lymphomas were admitted to the Hematology Unit of the Federal University of Minas Gerais Teaching Hospital. In nine of these children, the skin was involved at the onset of the disease. Three patients were classified as having primary cutaneous lymphoma, while in six the disease was systemic with cutaneous involvement. In seven patients, the immunophenotype was T-cell, in one it was B-cell, and in the remaining case the immunophenotype was indefinable. No deaths occurred in any of the children with primary cutaneous lymphoma. PMID:21987155

  15. Objective evaluation of cutaneous thermal sensivity

    NASA Technical Reports Server (NTRS)

    Vanbeaumont, W.

    1972-01-01

    The possibility of obtaining reliable and objective quantitative responses was investigated under conditions where only temperature changes in localized cutaneous areas evoked measurable changes in remote sudomotor activity. Both male and female subjects were studied to evaluate sex difference in thermal sensitivity. The results discussed include: sweat rate responses to contralateral cooling, comparison of sweat rate responses between men and women to contralateral cooling, influence of the menstrual cycle on the sweat rate responses to contralateral cooling, comparison of threshold of sweating responses between men and women, and correlation of latency to threshold for whole body sweating. It is concluded that the quantitative aspects of the reflex response is affected by both the density and activation of receptors as well as the rate of heat loss; men responded 8-10% more frequently than women to thermode cooling, the magnitude of responses being greater for men; and women responded 7-9% more frequently to thermode cooling on day 1 of menstruation, as compared to day 15.

  16. Sympathetic control of reflex cutaneous vasoconstriction in human aging.

    PubMed

    Greaney, Jody L; Alexander, Lacy M; Kenney, W Larry

    2015-10-01

    This Synthesis highlights a series of recent studies that has systematically interrogated age-related deficits in cold-induced skin vasoconstriction. In response to cold stress, a reflex increase in sympathetic nervous system activity mediates reductions in skin blood flow. Reflex vasoconstriction during cold exposure is markedly impaired in aged skin, contributing to the relative inability of healthy older adults to maintain core temperature during mild cold stress in the absence of appropriate behavioral thermoregulation. This compromised reflex cutaneous vasoconstriction in healthy aging can occur as a result of functional deficits at multiple points along the efferent sympathetic reflex axis, including blunted sympathetic outflow directed to the skin vasculature, reduced presynaptic neurotransmitter synthesis and/or release, and altered end-organ responsiveness at several loci, in addition to potential alterations in afferent thermoreceptor function. Arguments have been made that the relative inability of aged skin to appropriately constrict is due to the aging cutaneous arterioles themselves, whereas other data point to the neural circuitry controlling those vessels. The argument presented herein provides strong evidence for impaired efferent sympathetic control of the peripheral cutaneous vasculature during whole body cold exposure as the primary mechanism responsible for attenuated vasoconstriction.

  17. POLE mutations in families predisposed to cutaneous melanoma.

    PubMed

    Aoude, Lauren G; Heitzer, Ellen; Johansson, Peter; Gartside, Michael; Wadt, Karin; Pritchard, Antonia L; Palmer, Jane M; Symmons, Judith; Gerdes, Anne-Marie; Montgomery, Grant W; Martin, Nicholas G; Tomlinson, Ian; Kearsey, Stephen; Hayward, Nicholas K

    2015-12-01

    Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.

  18. POLE mutations in families predisposed to cutaneous melanoma.

    PubMed

    Aoude, Lauren G; Heitzer, Ellen; Johansson, Peter; Gartside, Michael; Wadt, Karin; Pritchard, Antonia L; Palmer, Jane M; Symmons, Judith; Gerdes, Anne-Marie; Montgomery, Grant W; Martin, Nicholas G; Tomlinson, Ian; Kearsey, Stephen; Hayward, Nicholas K

    2015-12-01

    Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer. PMID:26251183

  19. Sympathetic control of reflex cutaneous vasoconstriction in human aging

    PubMed Central

    Alexander, Lacy M.; Kenney, W. Larry

    2015-01-01

    This Synthesis highlights a series of recent studies that has systematically interrogated age-related deficits in cold-induced skin vasoconstriction. In response to cold stress, a reflex increase in sympathetic nervous system activity mediates reductions in skin blood flow. Reflex vasoconstriction during cold exposure is markedly impaired in aged skin, contributing to the relative inability of healthy older adults to maintain core temperature during mild cold stress in the absence of appropriate behavioral thermoregulation. This compromised reflex cutaneous vasoconstriction in healthy aging can occur as a result of functional deficits at multiple points along the efferent sympathetic reflex axis, including blunted sympathetic outflow directed to the skin vasculature, reduced presynaptic neurotransmitter synthesis and/or release, and altered end-organ responsiveness at several loci, in addition to potential alterations in afferent thermoreceptor function. Arguments have been made that the relative inability of aged skin to appropriately constrict is due to the aging cutaneous arterioles themselves, whereas other data point to the neural circuitry controlling those vessels. The argument presented herein provides strong evidence for impaired efferent sympathetic control of the peripheral cutaneous vasculature during whole body cold exposure as the primary mechanism responsible for attenuated vasoconstriction. PMID:26272321

  20. The Role of Systemic Retinoids in the Treatment of Cutaneous T-Cell Lymphoma.

    PubMed

    Huen, Auris O; Kim, Ellen J

    2015-10-01

    Retinoids are natural and synthetic vitamin A analogs with effects on cell proliferation, differentiation, and apoptosis. They have significant activity in hematologic malignancies and have been studied extensively in cutaneous T-cell lymphoma. Retinoids bind to nuclear receptors and exert their effects through moderation of gene expression. Retinoic acid receptor and retinoic X receptor exert regulatory activity in vivo, binding to distinct ligands. Studies investigating systemic retinoids as monotherapy and in combination with other agents active against cutaneous lymphoma are reviewed. Side effects associated with retinoids include teratogenicity, dyslipidemias, and hypothyroidism, which should be carefully monitored in patients receiving treatment. PMID:26433844

  1. Cutaneous Manifestations of Common Liver Diseases

    PubMed Central

    Dogra, Sunil; Jindal, Rashmi

    2012-01-01

    Skin functions as a window to our overall health and a number of systemic diseases result in various cutaneous changes. Knowledge of these manifestations helps in suspecting an underlying systemic illness. Cutaneous abnormalities are quite common in patients with liver diseases and this article aims to focus on these dermatoses. Cutaneous manifestations seen in patients with liver disease though common are nonspecific. They can also be seen in patients without liver diseases and generally do not indicate about a specific underlying hepatic disorder. The presence of a constellation of signs and symptoms is more useful in pointing toward an underlying hepatobiliary condition. The commonest symptom in patients with liver disease is pruritus which is often protracted and disabling. Other common features include spider angiomas, palmar erythema, paper money skin, xanthelasmas, pigmentary changes, and nutritional deficiencies. In this article, first the common cutaneous manifestations that may be associated with liver disorders are discussed and then common liver diseases with their specific cutaneous findings are discussed. Cutaneous abnormalities may be the first clue to the underlying liver disease. Identifying them is crucial for early diagnosis and better management. PMID:25755383

  2. Cutaneous mechanisms of isometric ankle force control.

    PubMed

    Choi, Julia T; Lundbye-Jensen, Jesper; Leukel, Christian; Nielsen, Jens Bo

    2013-07-01

    The sense of force is critical in the control of movement and posture. Multiple factors influence our perception of exerted force, including inputs from cutaneous afferents, muscle afferents and central commands. Here, we studied the influence of cutaneous feedback on the control of ankle force output. We used repetitive electrical stimulation of the superficial peroneal (foot dorsum) and medial plantar nerves (foot sole) to disrupt cutaneous afferent input in 8 healthy subjects. We measured the effects of repetitive nerve stimulation on (1) tactile thresholds, (2) performance in an ankle force-matching and (3) an ankle position-matching task. Additional force-matching experiments were done to compare the effects of transient versus continuous stimulation in 6 subjects and to determine the effects of foot anesthesia using lidocaine in another 6 subjects. The results showed that stimulation decreased cutaneous sensory function as evidenced by increased touch threshold. Absolute dorsiflexion force error increased without visual feedback during peroneal nerve stimulation. This was not a general effect of stimulation because force error did not increase during plantar nerve stimulation. The effects of transient stimulation on force error were greater when compared to continuous stimulation and lidocaine injection. Position-matching performance was unaffected by peroneal nerve or plantar nerve stimulation. Our results show that cutaneous feedback plays a role in the control of force output at the ankle joint. Understanding how the nervous system normally uses cutaneous feedback in motor control will help us identify which functional aspects are impaired in aging and neurological diseases.

  3. The vasodilator papaverine stimulates L-type Ca(2+) current in rat tail artery myocytes via a PKA-dependent mechanism.

    PubMed

    Fusi, Fabio; Manetti, Fabrizio; Durante, Miriam; Sgaragli, Giampietro; Saponara, Simona

    2016-01-01

    Papaverine is an opium alkaloid, primarily used as an antispasmodic drug and as a cerebral and coronary vasodilator. Its phosphodiesterase inhibitory activity promotes increase of cAMP levels mainly in the cytosol. As cAMP is known to modulate L-type Ca(2+) channel activity, here we tested the proposition that papaverine could affect vascular channel function. An in-depth analysis of the effect of papaverine on Ba(2+) or Ca(2+) current through L-type Ca(2+) channel [IBa(L) or ICa(L)], performed in rat tail artery myocytes using either the whole-cell or the perforated patch-clamp method, was accompanied by a functional study on rat aorta rings. Papaverine increased current amplitude under both the perforated or whole-cell configuration. Stimulation of the current by papaverine was concentration-, Vh-, frequency-, and charge carrier-dependent, and fully reverted by drug washout. The PKA inhibitor H89, but not the PKG inhibitor Rp-8-Br-cGMPS, antagonised papaverine- as well as IBMX- (another phosphodiesterase inhibitor) induced IBa(L) stimulation. In cells pre-treated with IBMX, application of papaverine failed to increase current amplitude. Papaverine sped up the inactivation kinetics of IBa(L), though only at concentrations ≥ 30 μM, and shifted the voltage dependence of the inactivation curve to more negative potentials. In rings, the vasorelaxing activity of papaverine was enhanced by previous treatment with nifedipine. In conclusion, papaverine stimulates vascular L-type Ca(2+) channel via a PKA-dependent mechanism, thus antagonising its main vasodilating activity. PMID:26586313

  4. Characterizing rapid-onset vasodilation to single muscle contractions in the human leg.

    PubMed

    Credeur, Daniel P; Holwerda, Seth W; Restaino, Robert M; King, Phillip M; Crutcher, Kiera L; Laughlin, M Harold; Padilla, Jaume; Fadel, Paul J

    2015-02-15

    Rapid-onset vasodilation (ROV) following single muscle contractions has been examined in the forearm of humans, but has not yet been characterized in the leg. Given known vascular differences between the arm and leg, we sought to characterize ROV following single muscle contractions in the leg. Sixteen healthy men performed random ordered single contractions at 5, 10, 20, 40, and 60% of their maximum voluntary contraction (MVC) using isometric knee extension made with the leg above and below heart level, and these were compared with single isometric contractions of the forearm (handgrip). Single thigh cuff compressions (300 mmHg) were utilized to estimate the mechanical contribution to leg ROV. Continuous blood flow was determined by duplex-Doppler ultrasound and blood pressure via finger photoplethysmography (Finometer). Single isometric knee extensor contractions produced intensity-dependent increases in peak leg vascular conductance that were significantly greater than the forearm in both the above- and below-heart level positions (e.g., above heart level: leg 20% MVC, +138 ± 28% vs. arm 20% MVC, +89 ± 17%; P < 0.05). Thigh cuff compressions also produced a significant hyperemic response, but these were brief and smaller in magnitude compared with single isometric contractions in the leg. Collectively, these data demonstrate the presence of a rapid and robust vasodilation to single muscle contractions in the leg that is largely independent of mechanical factors, thus establishing the leg as a viable model to study ROV in humans. PMID:25539935

  5. Brugia malayi Asparaginyl - tRNA Synthetase Stimulates Endothelial Cell Proliferation, Vasodilation and Angiogenesis

    PubMed Central

    D, Jeeva Jothi; Dhanraj, Muthu; Solaiappan, Shanmugam; Sivanesan, Sanjana; Kron, Michael; Dhanasekaran, Anuradha

    2016-01-01

    A hallmark of chronic infection with lymphatic filarial parasites is the development of lymphatic disease which often results in permanent vasodilation and lymphedema, but all of the mechanisms by which filarial parasites induce pathology are not known. Prior work showed that the asparaginyl-tRNA synthetase (BmAsnRS) of Brugia malayi, an etiological agent of lymphatic filariasis, acts as a physiocrine that binds specifically to interleukin-8 (IL-8) chemokine receptors. Endothelial cells are one of the many cell types that express IL-8 receptors. IL-8 also has been reported previously to induce angiogenesis and vasodilation, however, the effect of BmAsnRS on endothelial cells has not been reported. Therefore, we tested the hypothesis that BmAsnRS might produce physiological changes in endothelial by studying the in vitro effects of BmAsnRS using a human umbilical vein cell line EA.hy926 and six different endothelial cell assays. Our results demonstrated that BmAsnRS produces consistent and statistically significant effects on endothelial cells that are identical to the effects of VEGF, vascular endothelial growth factor. This study supports the idea that new drugs or immunotherapies that counteract the adverse effects of parasite-derived physiocrines may prevent or ameliorate the vascular pathology observed in patients with lymphatic filariasis. PMID:26751209

  6. Characterizing rapid-onset vasodilation to single muscle contractions in the human leg.

    PubMed

    Credeur, Daniel P; Holwerda, Seth W; Restaino, Robert M; King, Phillip M; Crutcher, Kiera L; Laughlin, M Harold; Padilla, Jaume; Fadel, Paul J

    2015-02-15

    Rapid-onset vasodilation (ROV) following single muscle contractions has been examined in the forearm of humans, but has not yet been characterized in the leg. Given known vascular differences between the arm and leg, we sought to characterize ROV following single muscle contractions in the leg. Sixteen healthy men performed random ordered single contractions at 5, 10, 20, 40, and 60% of their maximum voluntary contraction (MVC) using isometric knee extension made with the leg above and below heart level, and these were compared with single isometric contractions of the forearm (handgrip). Single thigh cuff compressions (300 mmHg) were utilized to estimate the mechanical contribution to leg ROV. Continuous blood flow was determined by duplex-Doppler ultrasound and blood pressure via finger photoplethysmography (Finometer). Single isometric knee extensor contractions produced intensity-dependent increases in peak leg vascular conductance that were significantly greater than the forearm in both the above- and below-heart level positions (e.g., above heart level: leg 20% MVC, +138 ± 28% vs. arm 20% MVC, +89 ± 17%; P < 0.05). Thigh cuff compressions also produced a significant hyperemic response, but these were brief and smaller in magnitude compared with single isometric contractions in the leg. Collectively, these data demonstrate the presence of a rapid and robust vasodilation to single muscle contractions in the leg that is largely independent of mechanical factors, thus establishing the leg as a viable model to study ROV in humans.

  7. Occurrence of parasympathetic vasodilator fibers in the lower lip of the guinea-pig.

    PubMed

    Watanabe, H; Ishii, H; Niioka, T; Yamamuro, M; Izumi, H

    2008-03-01

    The present study was designed to examine whether there are parasympathetic vasodilator fibers in the lower lip of the guinea-pig. Electrical stimulation of the central cut end of the lingual nerve of guinea-pigs evoked intensity- and frequency-dependent decreases in lower lip blood flow and systemic arterial blood pressure (SABP). Pretreatment with guanethidine, a postganglionic sympathetic nerve blocker and antihypertensive drug (30 mg kg(-1), s.c., 24 h prior to experiments), reduced the magnitude of the decrease in SABP while the intensity- and frequency-dependent increases of the lip blood flow occurred by the lingual nerve stimulation only on the side ipsilateral to stimulation. Increases in the lip blood flow evoked by lingual nerve stimulation in guanethidine pretreated guinea-pigs were reduced by hexamethonium (an autonomic ganglion cholinergic blocker) in a dose-dependent manner. When fluoro-gold (a retrograde neural tracer) was injected into the lower lip, labeled neurons were observed in the ipsilateral otic ganglion. The present study indicates the presence of parasympathetic vasodilator fibers originating from the otic parasympathetic ganglion in the guinea-pig lower lip, similar to those reported previously in rats, cats, rabbits and humans. PMID:18030480

  8. Diversity in Mechanisms of Endothelium-Dependent Vasodilation in Health and Disease

    PubMed Central

    Durand, Matthew J.; Gutterman, David D.

    2013-01-01

    Small arterioles (40–150 μm) contribute to the majority of vascular resistance within organs and tissues. Under resting conditions, the basal tone of these vessels is determined by a delicate balance between vasodilator and vasoconstrictor influences. Cardiovascular homeostasis and regional tissue perfusion is largely a function of the ability of these small blood vessels to constrict or dilate in response to the changing metabolic demands of specific tissues. The endothelial cell layer of these microvessels is a key modulator of vasodilation through the synthesis and release of vasoactive substances. Beyond their vasomotor properties, these compounds importantly modulate vascular cell proliferation, inflammation, and thrombosis. Thus the balance between local regulation of vascular tone and vascular pathophysiology can vary depending upon which factors are released from the endothelium. This review will focus on the dynamic nature of the endothelial released dilator factors depending on species, anatomic site, and presence of disease, with a focus on the human coronary microcirculation. Knowledge how endothelial signaling changes with disease may provide insights into the early stages of developing vascular inflammation and atherosclerosis, or related vascular pathologies. PMID:23311975

  9. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction.

    PubMed

    Münzel, Thomas; Steven, Sebastian; Daiber, Andreas

    2014-12-01

    Given acutely, organic nitrates, such as nitroglycerin (GTN), isosorbide mono- and dinitrates (ISMN, ISDN), and pentaerythrityl tetranitrate (PETN), have potent vasodilator and anti-ischemic effects in patients with acute coronary syndromes, acute and chronic congestive heart failure and arterial hypertension. During long-term treatment, however, side effects such as nitrate tolerance and endothelial dysfunction occur, and therapeutic efficacy of these drugs rapidly vanishes. Recent experimental and clinical studies have revealed that organic nitrates per se are not just nitric oxide (NO) donors, but rather a quite heterogeneous group of drugs considerably differing for mechanisms underlying vasodilation and the development of endothelial dysfunction and tolerance. Based on this, we propose that the term nitrate tolerance should be avoided and more specifically the terms of GTN, ISMN and ISDN tolerance should be used. The present review summarizes preclinical and clinical data concerning organic nitrates. Here we also emphasize the consequences of chronic nitrate therapy on the supersensitivity of the vasculature to vasoconstriction and on the increased autocrine expression of endothelin. We believe that these so far rather neglected and underestimated side effects of chronic therapy with at least GTN and ISMN are clinically important.

  10. Reclassification of cardiovascular risk in patients with normal myocardial perfusion imaging using heart rate response to vasodilator stress.

    PubMed

    Iqbal, Fahad M; Al Jaroudi, Wael; Sanam, Kumar; Sweeney, Aaron; Heo, Jaekyeong; Iskandrian, Ami E; Hage, Fadi G

    2013-01-15

    Previous studies have shown that patients with normal vasodilator myocardial perfusion imaging (MPI) findings remain at a greater risk of future cardiac events than patients with normal exercise MPI findings. The aim was to assess improvement in risk classification provided by the heart rate response (HRR) in patients with normal vasodilator MPI findings when added to traditional risk stratification. We retrospectively studied 2,000 patients with normal regadenoson or adenosine MPI findings. Risk stratification was performed using Adult Treatment Panel III framework. Patients were stratified by HRR (percentage of increase from baseline) into tertiles specific to each vasodilator. All-cause mortality and cardiac death/nonfatal myocardial infarction (MI) ≤2 years from the index MPI were recorded. During follow-up, 11.8% patients died and 2.7% patients experienced cardiac death/nonfatal MI in the adenosine and regadenoson groups, respectively. The patients who died had a greater Framingham risk score (12 ± 4 vs 11 ± 4, p = 0.009) and lower HRR (22 ± 16 vs 32 ± 21, p <0.0001). In an adjusted Cox model, the lowest tertile HRR was associated with an increased risk of mortality (hazard ratio 2.1) and cardiac death/nonfatal MI (hazard ratio 2.9; p <0.01). Patients in the highest HRR tertile, irrespective of the Adult Treatment Panel III category, were at low risk. When added to the Adult Treatment Panel III categories, the HRR resulted in net reclassification improvement in mortality of 18% and cardiac death/nonfatal MI of 22%. In conclusion, a blunted HRR to vasodilator stress was independently associated with an increased risk of cardiac events and overall mortality in patients with normal vasodilator MPI findings. The HRR correctly reclassified a substantial proportion of these patients in addition to the traditional risk classification models and identified patients with normal vasodilator MPI findings, who had a truly low risk of events.

  11. Dynamic cutaneous information is sufficient for precise curvature discrimination

    PubMed Central

    Cheeseman, Jacob R.; Norman, J. Farley; Kappers, Astrid M. L.

    2016-01-01

    Our tactual perceptual experiences occur when we interact, actively and passively, with environmental objects and surfaces. Previous research has demonstrated that active manual exploration often enhances the tactual perception of object shape. Nevertheless, the factors that contribute to this enhancement are not well understood. The present study evaluated the ability of 28 younger (mean age was 23.1 years) and older adults (mean age was 71.4 years) to discriminate curved surfaces by actively feeling objects with a single index finger and by passively feeling objects that moved relative to a restrained finger. While dynamic cutaneous stimulation was therefore present in both conditions, active exploratory movements only occurred in one. The results indicated that there was a significant and large effect of age, such that the older participants’ thresholds were 43.8 percent higher than those of the younger participants. Despite the overall adverse effect of age, the pattern of results across the active and passive touch conditions was identical. For both age groups, the curvature discrimination thresholds obtained for passive touch were significantly lower than those that occurred during active touch. Curvature discrimination performance was therefore best in the current study when dynamic cutaneous stimulation occurred in the absence of active movement. PMID:27137417

  12. Dynamic cutaneous information is sufficient for precise curvature discrimination.

    PubMed

    Cheeseman, Jacob R; Norman, J Farley; Kappers, Astrid M L

    2016-01-01

    Our tactual perceptual experiences occur when we interact, actively and passively, with environmental objects and surfaces. Previous research has demonstrated that active manual exploration often enhances the tactual perception of object shape. Nevertheless, the factors that contribute to this enhancement are not well understood. The present study evaluated the ability of 28 younger (mean age was 23.1 years) and older adults (mean age was 71.4 years) to discriminate curved surfaces by actively feeling objects with a single index finger and by passively feeling objects that moved relative to a restrained finger. While dynamic cutaneous stimulation was therefore present in both conditions, active exploratory movements only occurred in one. The results indicated that there was a significant and large effect of age, such that the older participants' thresholds were 43.8 percent higher than those of the younger participants. Despite the overall adverse effect of age, the pattern of results across the active and passive touch conditions was identical. For both age groups, the curvature discrimination thresholds obtained for passive touch were significantly lower than those that occurred during active touch. Curvature discrimination performance was therefore best in the current study when dynamic cutaneous stimulation occurred in the absence of active movement. PMID:27137417

  13. Interactions of the Extracellular Matrix and Progenitor Cells in Cutaneous Wound Healing

    PubMed Central

    Volk, Susan W.; Iqbal, Syed Amir; Bayat, Ardeshir

    2013-01-01

    Significance Both chronic wounds and excessive scar formation after cutaneous injury create a formidable clinical problem resulting in considerable morbidity and healthcare expenditure. The deposition and remodeling of extracellular matrix (ECM) components are critical processes in cutaneous healing. Understanding the role of the ECM in directing progenitor and reparative cell fate and activities during wound repair is required to improve wound-care strategies. Recent Advances In addition to providing structural integrity, the ECM is recognized to play critical roles in regulating progenitor and reparative cell behaviors such as migration, differentiation, proliferation, and survival. The ECM dictates these activities through its binding of adhesion receptors as well as its ability to regulate growth factor bioavailability and signaling. More recently, a key role for mechanical control of cell fate through interaction with the ECM has emerged. Critical Issues Despite significant advances in understanding the pathophysiology of cutaneous wound repair, problematic wounds remain a significant healthcare challenge. Regenerative medical strategies that either target endogenous stem cells or utilize applications of exogenous stem cell populations have emerged as promising approaches to pathologic wounds. However, the identification of smart biomaterials and matrices may allow for further optimization of such therapies. Future Directions An efficient and appropriate healing response in the skin postinjury is regulated by a fine balance of the quantity and quality of ECM proteins. A more complete understanding of ECM regulation of the cell fate and activities during cutaneous wound repair is vital for the development of novel treatment strategies for improvement of cutaneous healing. PMID:24527348

  14. Cutaneous reflex modulation and self-induced reflex attenuation in cerebellar patients.

    PubMed

    Hoogkamer, Wouter; Van Calenbergh, Frank; Swinnen, Stephan P; Duysens, Jacques

    2015-02-01

    Modulation of cutaneous reflexes is important in the neural control of walking, yet knowledge about underlying neural pathways is still incomplete. Recent studies have suggested that the cerebellum is involved. Here we evaluated the possible roles of the cerebellum in cutaneous reflex modulation and in attenuation of self-induced reflexes. First we checked whether leg muscle activity during walking was similar in patients with focal cerebellar lesions and in healthy control subjects. We then recorded cutaneous reflex activity in leg muscles during walking. Additionally, we compared reflexes after standard (computer triggered) stimuli with reflexes after self-induced stimuli for both groups. Biceps femoris and gastrocnemius medialis muscle activity was increased in the patient group compared with the control subjects, suggesting a coactivation strategy to reduce instability of gait. Cutaneous reflex modulation was similar between healthy control subjects and cerebellar patients, but the latter appeared less able to attenuate reflexes to self-induced stimuli. This suggests that the cerebellum is not primarily involved in cutaneous reflex modulation but that it could act in attenuation of self-induced reflex responses. The latter role in locomotion would be consistent with the common view that the cerebellum predicts sensory consequences of movement.

  15. Effects of ATP-induced leg vasodilation on VO2 peak and leg O2 extraction during maximal exercise in humans.

    PubMed

    Calbet, J A L; Lundby, C; Sander, M; Robach, P; Saltin, B; Boushel, R

    2006-08-01

    During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active

  16. Cutaneous candidiasis: treatment with miconazole nitrate.

    PubMed

    Cullin, S I

    1977-01-01

    In a well-controlled, double-blind, randomized study, 30 patients with cutaneous candidiasis were treated with a 2% miconazole nitrate lotion or its placebo control. By the 14th day, 13 of the 15 patients [87%] treated with miconazole nitrate achieved clinical and mycologic cures. Only a single patient treated with the placebo lotion would be classified as a therapeutic cure. In a second portion of the study those patients judged to be therapeutic failures were treated with the lotion containing 2% miconazole nitrate. By combining the results of both portions of the study we find that miconazole nitrate lotion produced both a clinical and mycologic cure in all patients receiving the active lotion. The miconazole lotion formula was well tolerated by all patients and no side effects were noted. The fact that miconazole nitrate acts rapidly in relieving symptoms, is well tolerated, and is highly effective against dermatophytes, yeasts and gram-positive bacteria, makes it a welcome addition to available topical therapy of skin infections.

  17. Mechanosensory neurons, cutaneous mechanoreceptors, and putative mechanoproteins.

    PubMed

    Del Valle, M E; Cobo, T; Cobo, J L; Vega, J A

    2012-08-01

    The mammalian skin has developed sensory structures (mechanoreceptors) that are responsible for different modalities of mechanosensitivity like touch, vibration, and pressure sensation. These specialized sensory organs are anatomically and functionally connected to a special subset of sensory neurons called mechanosensory neurons, which electrophysiologically correspond with Aβ fibers. Although mechanosensory neurons and cutaneous mechanoreceptors are rather well known, the biology of the sense of touch still remains poorly understood. Basically, the process of mechanosensitivity requires the conversion of a mechanical stimulus into an electrical signal through the activation of ion channels that gate in response to mechanical stimuli. These ion channels belong primarily to the family of the degenerin/epithelium sodium channels, especially the subfamily acid-sensing ion channels, and to the family of transient receptor potential channels. This review compiles the current knowledge on the occurrence of putative mechanoproteins in mechanosensory neurons and mechanoreceptors, as well as the involvement of these proteins on the biology of touch. Furthermore, we include a section about what the knock-out mice for mechanoproteins are teaching us. Finally, the possibilities for mechanotransduction in mechanoreceptors, and the common involvement of the ion channels, extracellular membrane, and cytoskeleton, are revisited.

  18. Acceleration of cutaneous wound healing by brassinosteroids.

    PubMed

    Esposito, Debora; Rathinasabapathy, Thirumurugan; Schmidt, Barbara; Shakarjian, Michael P; Komarnytsky, Slavko; Raskin, Ilya

    2013-01-01

    Brassinosteroids are plant growth hormones involved in cell growth, division, and differentiation. Their effects in animals are largely unknown, although recent studies showed that the anabolic properties of brassinosteroids are possibly mediated through the phosphoinositide 3-kinase/protein kinase B signaling pathway. Here, we examined biological activity of homobrassinolide (HB) and its synthetic analogues in in vitro proliferation and migration assays in murine fibroblast and primary keratinocyte cell culture. HB stimulated fibroblast proliferation and migration and weakly induced keratinocyte proliferation in vitro. The effects of topical HB administration on progression of wound closure were further tested in the mouse model of cutaneous wound healing. C57BL/6J mice were given a full-thickness dermal wound, and the rate of wound closure was assessed daily for 10 days, with adenosine receptor agonist CGS-21680 as a positive control. Topical application of brassinosteroid significantly reduced wound size and accelerated wound healing in treated animals. mRNA levels of transforming growth factor beta and intercellular adhesion molecule 1 were significantly lower, while tumor necrosis factor alpha was nearly suppressed in the wounds from treated mice. Our data suggest that topical application of brassinosteroids accelerates wound healing by positively modulating inflammatory and reepithelialization phases of the wound repair process, in part by enhancing Akt signaling in the skin at the edges of the wound and enhancing migration of fibroblasts in the wounded area. Targeting this signaling pathway with brassinosteroids may represent a promising approach to the therapy of delayed wound healing.

  19. Choroidal Metastases From Cutaneous Melanoma.

    PubMed

    Mercado, Carmel L; Toy, Brian C; Kistler, Henry B; Moshfeghi, Darius M

    2016-05-01

    A 92-year-old man presented with months of progressive blurry vision, worsening acutely in his right eye. He denied pain, diplopia, or photopsias. His history was significant for multiple myeloma, prostate cancer, and malignant melanoma of his right shoulder treated with local excision. He had local recurrence with hepatic metastasis of the melanoma treated with radiation and chemotherapy. On examination, his visual acuity was counting fingers in the right eye and 20/60 in the left eye. Amsler grid testing demonstrated metamorphopsia in the right eye. Fundus exam of the right and left eyes revealed multiple, elevated, pigmented choroidal lesions, with associated subretinal fluid in the right macula. This appearance is consistent with hematogenous metastasis of cutaneous malignant melanoma to the choroid and associated serous fluid-causing metamorphopsia. The patient was enrolled in a clinical trial combining plasmid IL-12 with pembrolizumab (Keytruda; Merck, Whitehouse Station, NJ). He passed away 2 months after initial presentation to our clinic. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:497.]. PMID:27183558

  20. Cutaneous blood flow in psoriasis

    SciTech Connect

    Klemp, P.; Staberg, B.

    1983-12-01

    The disappearance rate of /sup 133/Xe was studied in 20 patients with psoriasis vulgaris, using an epicutaneous labeling technique in involved skin lesions or normal-appearing skin of the proximal extensor site of the forearm. Control experiments were performed in 10 normal subjects. Calculations of the cutaneous blood flow (CBF) in psoriatic skin lesions were performed using a tissue-to-blood partition coefficient for /sup 133/Xe, lambda c,pso, of 1.2 ml/100 g/min. lambda c,pso was estimated after the relative content of water, lipids, and proteins had been analyzed in psoriatic skin biopsies of 6 patients with untreated psoriasis. The mean relative content of water was markedly reduced to 23.5 +/- 1.5% (SEM), and lipids and proteins were markedly increased to 2.5 +/- 0.7% and 74.0 +/- 2.2, respectively, compared to previously published data for normal skin (water 72.5%, lipids 1%, proteins 26.5%). Mean CBF in untreated psoriatic skin was 63.5 +/- 9.0 ml/100 g/min. This was significantly higher than the mean CBF in 10 normal subjects, 6.3 +/- 0.5 ml/100 g/min (p much less than 0.0001). Mean CBF in normal-appearing skin in patients with psoriasis was 11.0 +/- 1.3 ml/100 g/min. This was significantly higher than CBF in normal subjects (p less than 0.0002).

  1. Epidemiology of chronic cutaneous wounds in China.

    PubMed

    Jiang, Yufeng; Huang, Sha; Fu, Xiaobing; Liu, Hongwei; Ran, Xingwu; Lu, Shuliang; Hu, Dahai; Li, Qiang; Zhang, Hongwei; Li, Ying; Wang, Runxiu; Xie, Ting; Cheng, Biao; Wang, Lingfeng; Liu, Yi; Ye, Xiangbai; Han, Chunmao; Chen, Huade

    2011-01-01

    Chronic cutaneous wounds represent a major health care burden in China. However, limited information exists regarding the epidemiologic changes associated with recent social and economic development. We designed a cross-sectional survey in 2,513 patients who underwent treatment of chronic cutaneous wounds from a nationally representative sample in 17 hospitals between 2007 and 2008. Results revealed the prevalence of chronic cutaneous wounds among hospitalized patients was 1.7‰. Patient ages ranged from 18 days to 96 years (median, 58 years). The highest ratios were among 40-60 and 60-80-year-old patients (31% and 38%, respectively). The leading causes of chronic cutaneous wounds were diabetes (31.3% men, 35.3% women) trauma (26.4% men, 19.2% women). Manual workers (38.5% men, 29.3% women) and retirees (27.9% men, 23.5% women) accounted for over half the chronic cutaneous wound patients. Regarding treatments, only 22.4% were treated with modern dressings or other novel technologies and more patients received antibiotics (77.8%). Treatment was paid for by the patients in 42.3% of cases, by social medical insurance in 25.0%, by commercial medical insurance in 4.8%, while 27.9% received free medical care. Approximately half the patients' wounds were completely healed at discharge (1,345/2,513). In conclusion, diabetes has recently become the leading cause of chronic cutaneous wounds in China. The large population and considerable financial burden mean that serious attention should be paid to the early detection, prevention and diagnosis of chronic cutaneous wounds, and suggest that an overall health insurance system should be established, especially for the elderly. PMID:21362085

  2. Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation: Chemical Chaperones as Potential Novel Antidotes.

    PubMed

    Li, Changzhao; Srivastava, Ritesh K; Weng, Zhiping; Croutch, Claire R; Agarwal, Anupam; Elmets, Craig A; Afaq, Farrukh; Athar, Mohammad

    2016-10-01

    Lewisite is a potent arsenic-based chemical warfare agent known to induce painful cutaneous inflammation and blistering. Only a few modestly effective antidotes have so far been described in the literature. However, the discovery of effective antidotes for lewisite was hampered by the paucity of the exact molecular mechanism underlying its cutaneous pathogenesis. We investigated the molecular mechanism underlying lewisite-induced cutaneous blistering and inflammation and describe its novel antidotes. On the basis of our initial screening, we used a highly sensitive murine model that recapitulates the known human pathogenesis of arsenicals-induced cutaneous inflammation and blistering. Topically administered lewisite induced potent acute inflammation and microvesication in the skin of Ptch1(+/-)/SKH-1 mice. Even at a very low dose, lewisite up-regulates unfolded protein response signaling, inflammatory response, and apoptosis. These cutaneous lesions were associated with production of reactive oxygen species and extensive apoptosis of the epidermal keratinocytes. We confirmed that activation of reactive oxygen species-dependent unfolded protein response signaling is the underlying molecular mechanism of skin damage. Similar alterations were noticed in lewisite-treated cultured human skin keratinocytes. We discovered that chemical chaperone 4-phenyl butyric acid and antioxidant N-acetylcysteine, which significantly attenuate lewisite-mediated skin injury, can serve as potent antidotes. These data reveal a novel molecular mechanism underlying the cutaneous pathogenesis of lewisite-induced lesions. We also identified novel potential therapeutic targets for lewisite-mediated cutaneous injury. PMID:27528504

  3. Dairy cheese consumption ameliorates single-meal sodium-induced cutaneous microvascular dysfunction by reducing ascorbate-sensitive oxidants in healthy older adults.

    PubMed

    Stanhewicz, Anna E; Alba, Billie K; Kenney, W Larry; Alexander, Lacy M

    2016-08-01

    Chronic dairy product intake is associated with improved cardiovascular outcomes, whereas high dietary Na impairs endothelial function through increased oxidative stress and reduced nitric oxide (NO) bioavailability. The purpose of this study was to compare the effect of acute cheese consumption with consumption of Na from non-dairy sources on microvascular function. We hypothesised that dairy cheese ingestion would augment NO-dependent vasodilation compared with Na from non-dairy sources. On five visits, fourteen subjects (61 (sem 2) years, eight male/six female) consumed either 85 g dairy cheese (560 mg Na), 85 g soya cheese (560 mg Na), 65 g pretzels (560 mg Na), 170 g dairy cheese (1120 mg Na) or 130 g pretzels (1120 mg Na). Two intradermal microdialysis fibres were inserted in the ventral forearm for delivery of lactated Ringer's solution or 10 mm-ascorbate (antioxidant) during local skin heating (approximately 50 min). Erythrocyte flux was measured continuously by laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC=LDF/mean arterial pressure) was normalised as %CVCmax (28 mm-sodium nitroprusside). Following a plateau in CVC, 15 mm-N G -nitro-l-arginine-methyl-ester was perfused to quantify NO-dependent vasodilation (approximately 45 min). NO-dependent vasodilation was greater following consumption of dairy products (560 mg Na 57 (sem 3) %) (1120 mg Na 55 (sem 5) %) compared with soya (560 mg Na 42 (sem 3) %; P=0·002) or pretzels (560 mg Na 43 (sem 4) %; P=0·004) (1120 mg Na 46 (sem 3) %; P=0·04). Ascorbate augmented NO-dependent vasodilation following intake of soya (control: 42 (sem 3) v. ascorbate: 54 (sem 3) %; P=0·01) or pretzels (560 mg Na; control: 43 (sem 4) v. ascorbate: 56 (sem 3) %; P=0·006) (1120 mg Na; control: 46 (sem 5) v. ascorbate: 56 (sem 3) %; P=0·02), but not dairy products. Na ingestion via dairy products was associated with greater NO-dependent vasodilation compared with non-dairy products, a difference that was

  4. Dairy cheese consumption ameliorates single-meal sodium-induced cutaneous microvascular dysfunction by reducing ascorbate-sensitive oxidants in healthy older adults.

    PubMed

    Stanhewicz, Anna E; Alba, Billie K; Kenney, W Larry; Alexander, Lacy M

    2016-08-01

    Chronic dairy product intake is associated with improved cardiovascular outcomes, whereas high dietary Na impairs endothelial function through increased oxidative stress and reduced nitric oxide (NO) bioavailability. The purpose of this study was to compare the effect of acute cheese consumption with consumption of Na from non-dairy sources on microvascular function. We hypothesised that dairy cheese ingestion would augment NO-dependent vasodilation compared with Na from non-dairy sources. On five visits, fourteen subjects (61 (sem 2) years, eight male/six female) consumed either 85 g dairy cheese (560 mg Na), 85 g soya cheese (560 mg Na), 65 g pretzels (560 mg Na), 170 g dairy cheese (1120 mg Na) or 130 g pretzels (1120 mg Na). Two intradermal microdialysis fibres were inserted in the ventral forearm for delivery of lactated Ringer's solution or 10 mm-ascorbate (antioxidant) during local skin heating (approximately 50 min). Erythrocyte flux was measured continuously by laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC=LDF/mean arterial pressure) was normalised as %CVCmax (28 mm-sodium nitroprusside). Following a plateau in CVC, 15 mm-N G -nitro-l-arginine-methyl-ester was perfused to quantify NO-dependent vasodilation (approximately 45 min). NO-dependent vasodilation was greater following consumption of dairy products (560 mg Na 57 (sem 3) %) (1120 mg Na 55 (sem 5) %) compared with soya (560 mg Na 42 (sem 3) %; P=0·002) or pretzels (560 mg Na 43 (sem 4) %; P=0·004) (1120 mg Na 46 (sem 3) %; P=0·04). Ascorbate augmented NO-dependent vasodilation following intake of soya (control: 42 (sem 3) v. ascorbate: 54 (sem 3) %; P=0·01) or pretzels (560 mg Na; control: 43 (sem 4) v. ascorbate: 56 (sem 3) %; P=0·006) (1120 mg Na; control: 46 (sem 5) v. ascorbate: 56 (sem 3) %; P=0·02), but not dairy products. Na ingestion via dairy products was associated with greater NO-dependent vasodilation compared with non-dairy products, a difference that was

  5. The Role of Poly N Acetyl Glucosamine Nanofibers in Cutaneous Wound Healing

    NASA Astrophysics Data System (ADS)

    Buff-Lindner, Amanda Haley

    Treatment of cutaneous wounds with poly-N-acetyl-glucosamine nanofibers (pGlcNAc), a novel polysaccharide material derived from a marine diatom, results in increases in wound closure, antibacterial activities and innate immune responses. Treatment with nanofibers results in increased defensin, small antimicrobial peptides, expression both in vitro and in vivo. Induction of defensin expression results in bacterial clearance in a cutaneous wound model. Our data show that Akt1 plays a central role in the regulation of these activities. Interestingly, pGlcNAc treatment of cutaneous wounds in mice results in decreased scar sizes. Additionally, treatment of cutaneous wounds with pGlcNAc results in increased elasticity and a rescue of tensile strength. Masson Trichrome staining suggests that pGlcNAc treated wounds exhibit decreased collagen content as well as increased collagen alignment with collagen fibers oriented similarly to unwounded tissue. Utilizing a fibrin gel assay to analyze the effect of pGlcNAc nanofiber treatment on fibroblast alignment in vitro, pGlcNAc stimulation of embedded fibroblasts results in fibroblasts alignment as compared to untreated controls, by a process that is Akt1 dependent. Our data show that in Akt1 null animals pGlcNAc treatment does not increase tensile strength or elasticity. Taken together, our findings suggest that pGlcNAc nanofibers stimulate an Akt1 dependent pathway that results in wound closure, the proper alignment of fibroblasts, decreased scarring, and increased tensile strength during cutaneous wound healing.

  6. Involvements of calcium channel and potassium channel in Danshen and Gegen decoction induced vasodilation in porcine coronary LAD artery.

    PubMed

    Hu, Fan; Koon, Chi Man; Chan, Judy Yuet Wa; Lau, Kit Man; Kwan, Y W; Fung, Kwok Pui

    2012-09-15

    Danshen (Salviae Miltiorrhizae Radix) and Gegen (Puerariae Lobatae Radix) have been widely used in treating cardiovascular diseases for thousands of years in China. The present study was carried out to evaluate the effects of a Danshen and Gegen decoction (DG) on the vascular reactivity of a porcine isolated coronary artery and the underlying mechanisms involved. Porcine coronary rings were precontracted with 15 nM U46619. The involvement of endothelium-dependent mechanisms was explored by removing the endothelium; the involvement of potassium channels was investigated by the pretreatment of the artery rings with various blockers, and the involvement of the calcium channels was investigated by incubating the artery rings with Ca²⁺-free buffer and priming them with high [K⁺] prior to adding CaCl₂ to elicit contraction. The involvement of Ca²⁺ sensitization was explored by evaluating the Rho-activity expression. The results revealed that DG elicited a concentration-dependent relaxation on a U46619-precontracted coronary artery ring. These relaxation responses were not altered by the pretreatment of inhibitors of endothelium-related dilator synthases, cGMP and cAMP pathway inhibitors, potassium channel (BK(Ca), SK(Ca), K(V) and K(ATP)) blockers and endothelium removal. The K(IR) channel blocker BaCl₂ only slightly attenuated the DG-induced relaxation. However, the Ca²⁺-induced artery contraction was inhibited by DG. Additionally, the expression of the phosphorylated myosin light chain was inhibited by DG whereas the activity of RhoA was not affected. Therefore, DG could be a useful cardioprotective agent for vasodilation in patients who have hypertension.

  7. Oscillatory dynamics of vasoconstriction and vasodilation identified by time-localized phase coherence

    NASA Astrophysics Data System (ADS)

    Sheppard, L. W.; Vuksanović, V.; McClintock, P. V. E.; Stefanovska, A.

    2011-06-01

    We apply wavelet-based time-localized phase coherence to investigate the relationship between blood flow and skin temperature, and between blood flow and instantaneous heart rate (IHR), during vasoconstriction and vasodilation provoked by local cooling or heating of the skin. A temperature-controlled metal plate (≈10 cm2) placed on the volar side of the left arm was used to provide the heating and cooling. Beneath the plate, the blood flow was measured by laser Doppler flowmetry and the adjacent skin temperature by a thermistor. Two 1 h datasets were collected from each of the ten subjects. In each case a 30 min basal recording was followed by a step change in plate temperature, to either 24 °C or 42 °C. The IHR was derived from simultaneously recorded ECG. We confirm the changes in the energy and frequency of blood flow oscillations during cooling and heating reported earlier. That is, during cooling, there was a significant decrease in the average frequency of myogenic blood flow oscillations (p < 0.05) and the myogenic spectral peak became more prominent. During heating, there was a significant (p < 0.05) general increase in spectral energy, associated with vasodilation, except in the myogenic interval. Weak phase coherence between temperature and blood flow was observed for unperturbed skin, but it increased in all frequency intervals as a result of heating. It was not significantly affected by cooling. We also show that significant (p < 0.05) phase coherence exists between blood flow and IHR in the respiratory and myogenic frequency intervals. Cooling did not affect this phase coherence in any of the frequency intervals, whereas heating enhanced the phase coherence in the respiratory and myogenic intervals. This can be explained by the reduction in vascular resistance produced by heating, a process where myogenic mechanisms play a key role. We conclude that the mechanisms of vasodilation and vasoconstriction, in response to temperature change, are

  8. Ho:YAG laser irradiation in blood vessel as a vasodilator: ex vivo study

    NASA Astrophysics Data System (ADS)

    Nakatani, E.; Iwasaki, T.; Kaneko, K.; Shimazaki, N.; Arai, T.

    2007-02-01

    We studied Ho:YAG laser irradiation in blood vessel as a vasodilator ex vivo. We thought that the Ho:YAG laser-induced bubble expansion might be able to dilate the vessel because we found the vessel wall expansion after the Ho:YAG laser irradiation, that is steady deformation, in the vessel ex vivo. There have been many reports regarding to the Ho:YAG laser irradiation in the vessel. Most of studies concentrated on the interaction between Ho:YAG laser irradiation and vessel wall to investigate side effect on Ho:YAG laser angioplasty. We proposed to use the Ho:YAG laser-induced bubble expansion as a vasodilator. We studied vasodilation effect of the Ho:YAG laser-induced bubble ex vivo. The flash lamp excited Ho:YAG laser surgical unit (IH102, NIIC, Japan) (λ=2.1μm) was used. The laser energy was delivered by a silica glass fiber (outer diameter: 1000μm, core diameter: 600μm). The laser-induced bubble was generated in the extracted fresh porcine carotid artery with the warmed saline perfusion. The laser energy at the fiber tip was ranging from 170-1300mJ per pulse. Number of the laser irradiation was ranged from 20pulses to 100pulses. The outer diameter of the vessel was observed. To examine the change in mechanical properties of the vessel wall, the stress-strain curve of the laser-irradiated vessel was measured. Birefringence observation and microscopic observation of staining specimen were performed. When the laser energy was set to 1300mJ per pulse, the outer diameter of the vessel after the laser irradiation was expanded by 1.4 times comparing with that of before the laser irradiation and the dilatation effect was kept even at 10minutes after the irradiation. The elasticity modulus of the artery by collagen was changed by the laser irradiation. In the polarized microscopic observation, the brightness of the intimal side of the vessel is increased comparing with that of the normal. We think this brightness increasing may be attributed to birefringence change

  9. Passive leg movement-induced vasodilation in women: the impact of age.

    PubMed

    Groot, H Jonathan; Rossman, Matthew J; Trinity, Joel D; Layec, Gwenael; Ives, Stephen J; Richardson, Russell S

    2015-09-01

    Passive leg movement (PLM), an assessment of predominantly nitric oxide-dependent vasodilation, is decreased with age and cannot be augmented by posture-induced increases in femoral perfusion pressure in older men. However, this novel method of assessing vascular function has yet to be used to evaluate alterations in nitric oxide-dependent vasodilation with age in females. PLM was performed in 10 young (20 ± 1 yr) and 10 old (73 ± 2 yr) women in both the supine and upright-seated postures, whereas central and peripheral hemodynamic measurements were acquired second by second using noninvasive techniques (finger photoplethysmography and Doppler ultrasound, respectively). The heart rate response to PLM was attenuated in the old compared with the young in both the supine (young, 10 ± 1; and old, 5 ± 1 beats/min; P < 0.05) and upright-seated posture (young, 10 ± 2; and old, 5 ± 1 beats/min; P < 0.05), leading to a blunted cardiac output response in the old in the upright-seated posture (young, 1.0 ± 0.2; and old, 0.3 ± 0.1 l/min; P < 0.05). The PLM-induced peak change in leg vascular conductance was lower in the old compared with the young in both postures (young supine, 5.7 ± 0.5; old supine, 2.6 ± 0.3; young upright, 9.2 ± 0.7; and old upright, 2.2 ± 0.4 ml·min(-1)·mmHg(-1); P < 0.05) and was significantly augmented by the upright-seated posture in the young only, revealing a vasodilatory reserve capacity in the young (3.5 ± 0.6 ml·min(-1)·mmHg(-1), P < 0.05) that was absent in the old (-0.5 ± 0.3 ml·min(-1)·mmHg(-1), P = 0.18). These data support previous literature demonstrating attenuated PLM-induced vasodilation with age and extend these findings to include the female population, thus bolstering the utility of PLM as a novel assessment of vascular function across the life span in humans.

  10. Stimulation of Baroresponsive Parts of the Nucleus of the Solitary Tract Produces Nitric Oxide-mediated Choroidal Vasodilation in Rat Eye

    PubMed Central

    Li, Chunyan; Fitzgerald, Malinda E. C.; Del Mar, Nobel; Reiner, Anton

    2016-01-01

    Preganglionic parasympathetic neurons of the ventromedial part of the superior salivatory nucleus (SSN) mediate vasodilation of orbital and choroidal blood vessels, via their projection to the nitrergic pterygopalatine ganglion (PPG) neurons that innervate these vessels. We recently showed that the baroresponsive part of the nucleus of the solitary tract (NTS) innervates choroidal control parasympathetic preganglionic neurons of SSN in rats. As this projection provides a means by which blood pressure (BP) signals may modulate choroidal blood flow (ChBF), we investigated if activation of baroresponsive NTS evokes ChBF increases in rat eye, using Laser Doppler Flowmetry (LDF) to measure ChBF transclerally. We found that electrical activation of ipsilateral baroresponsive NTS and its efferent fiber pathway to choroidal SSN increased mean ChBF by about 40–80% above baseline, depending on current level. The ChBF responses obtained with stimulation of baroresponsive NTS were driven by increases in both choroidal blood volume (ChBVol; i.e., vasodilation) and choroidal blood velocity (ChBVel; possibly due to orbital vessel dilation). Stimulation of baroresponsive NTS, by contrast, yielded no significant mean increases in systemic arterial blood pressure (ABP). We further found that the increases in ChBF with NTS stimulation were significantly reduced by administration of the neuronal nitric oxide (NO) synthase inhibitor Nω-propyl-l-arginine (NPA), thus implicating nitrergic PPG terminals in the NTS-elicited ChBF increases. Our results show that the NTS neurons projecting to choroidal SSN do mediate increase in ChBF, and thus suggest a role of baroresponsive NTS in the BP-dependent regulation of ChBF. PMID:27774055

  11. Primary cutaneous B-cell lymphoma.

    PubMed

    Bogle, Melissa A; Riddle, Christy C; Triana, Emily M; Jones, Dan; Duvic, Madeleine

    2005-09-01

    Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.

  12. Histological types of polypoid cutaneous melanoma II.

    PubMed

    Knezević, Fabijan; Duancić, Vjekoslav; Sitić, Sanda; Horvat-Knezević, Anica; Benković, Vesna; Ramić, Snjezana; Kostović, Kresimir; Ramljak, Vesna; Vrdoljak, Danko Velemir; Stanec, Mladen; Bozović, Angelina

    2007-12-01

    The aim of this study was to ascertain which histological types of melanoma can clinically and morphologically appear as polypoid melanomas. In 645 cases of primary cutaneous melanoma we have analyzed criteria for diagnosis of polypoid cutaneous melanoma and afterwards we have analyzed growth phase in each polypoid melanoma, histological type of atypical melanocytes, the number of epidermal ridges which are occupied by atypical melanocytes, and distribution according to age, sex and location, as well as the disease free survival. According to the criteria for polypoid melanomas we have found 147 (22.8%) polypoid cutaneous melanomas. Analyzing the growth phases, histological types of atypical melanocytes and the number of affected epidermal ridges in the group of polypoid melanomas we have ascertained 2 (1.4%) ALMs, 4 (2.8%) LMMs, 42 (28.6%) SSMs and 99 (67.2%) NMs. Our conclusion is that polypoid cutaneous melanomas are morphological forms of various histological melanoma types (ALM, LMM, SSM and NM) and they can all display polypoid morphological form. Polypoid cutaneous melanomas are most often of nodular histological type. PMID:18217457

  13. Management of cutaneous metastases using electrochemotherapy

    PubMed Central

    Matthiessen, Louise Wichmann; Chalmers, Richard Ling; Sainsbury, David Christopher George; Veeramani, Sivakumar; Kessell, Gareth; Humphreys, Alison Claire; Bond, Jane Elisabeth; Muir, Tobian; Gehl, Julie

    2011-01-01

    Background. Cutaneous metastases may cause considerable discomfort as a consequence of ulceration, oozing, bleeding and pain. Electrochemotherapy has proven to be highly effective in the treatment of cutaneous metastases. Electrochemotherapy utilises pulses of electricity to increase the permeability of the cell membrane and thereby augment the effect of chemotherapy. For the drug bleomycin, the effect is enhanced several hundred-fold, enabling once-only treatment. The primary endpoint of this study is to evaluate the efficacy of electrochemotherapy as a palliative treatment. Methods. This phase II study is a collaboration between two centres, one in Denmark and the other in the UK. Patients with cutaneous metastases of any histology were included. Bleomycin was administered intratumourally or intravenously followed by application of electric pulses to the tumour site. Results. Fifty-two patients were included. Complete and partial response rate was 68% and 18%, respectively, for cutaneous metastases <3 cm and 8% and 23%, respectively, for cutaneous metastases >3 cm. Treatment was well-tolerated by patients, including the elderly, and no serious adverse events were observed. Conclusions. ECT is an efficient and safe treatment and clinicians should not hesitate to use it even in the elderly. PMID:21574833

  14. Combined statistical analysis of vasodilation and flow curves in brachial ultrasonography: technique and its connection to cardiovascular risk factors

    NASA Astrophysics Data System (ADS)

    Boisrobert, Loic; Laclaustra, Martin; Bossa, Matias; Frangi, Andres G.; Frangi, Alejandro F.

    2005-04-01

    Clinical studies report that impaired endothelial function is associated with Cardio-Vascular Diseases (CVD) and their risk factors. One commonly used mean for assessing endothelial function is Flow-Mediated Dilation (FMD). Classically, FMD is quantified using local indexes e.g. maximum peak dilation. Although such parameters have been successfully linked to CVD risk factors and other clinical variables, this description does not consider all the information contained in the complete vasodilation curve. Moreover, the relation between flow impulse and the vessel vasodilation response to this stimulus, although not clearly known, seems to be important and is not taken into account in the majority of studies. In this paper we propose a novel global parameterization for the vasodilation and the flow curves of a FMD test. This parameterization uses Principal Component Analysis (PCA) to describe independently and jointly the variability of flow and FMD curves. These curves are obtained using computerized techniques (based on edge detection and image registration, respectively) to analyze the ultrasound image sequences. The global description obtained through PCA yields a detailed characterization of the morphology of such curves allowing the extraction of intuitive quantitative information of the vasodilation process and its interplay with flow changes. This parameterization is consistent with traditional measurements and, in a database of 177 subjects, seems to correlate more strongly (and with more clinical parameters) than classical measures to CVD risk factors and clinical parameters such as LDL- and HDL-Cholesterol.

  15. Endothelial-derived hyperpolarization contributes to acetylcholine-mediated vasodilation in human skin in a dose-dependent manner.

    PubMed

    Brunt, Vienna E; Fujii, Naoto; Minson, Christopher T

    2015-11-01

    Cutaneous acetylcholine (ACh)-mediated dilation is commonly used to assess microvascular function, but the mechanisms of dilation are poorly understood. Depending on dose and method of administration, nitric oxide (NO) and prostanoids are involved to varying extents and the roles of endothelial-derived hyperpolarizing factors (EDHFs) are unclear. In the present study, five incremental doses of ACh (0.01-100 mM) were delivered either as a 1-min bolus (protocol 1, n = 12) or as a ≥20-min continuous infusion (protocol 2, n = 10) via microdialysis fibers infused with 1) lactated Ringer, 2) tetraethylammonium (TEA) [a calcium-activated potassium channel (KCa) and EDHF inhibitor], 3) L-NNA+ketorolac [NO synthase (NOS) and cyclooxygenase (COX) inhibitors], and 4) TEA+L-NNA+Ketorolac. The hyperemic response was characterized as peak and area under the curve (AUC) cutaneous vascular conductance (CVC) for bolus infusions or plateau CVC for continuous infusions, and reported as %maximal CVC. In protocol 1, TEA, alone and combined with NOS+COX inhibition, attenuated peak CVC (100 mM Ringer 59 ± 6% vs. TEA 43 ± 5%, P < 0.05; L-NNA+ketorolac 35 ± 4% vs. TEA+L-NNA+ketorolac 25 ± 4%, P < 0.05) and AUC (Ringer 25,414 ± 3,528 vs. TEA 21,403 ± 3,416%·s, P < 0.05; L-NNA+ketorolac 25,628 ± 3,828%(.)s vs. TEA+L-NNA+ketorolac 20,772 ± 3,711%·s, P < 0.05), although these effects were only significant at the highest dose of ACh. At lower doses, TEA lengthened the total time of the hyperemic response (10 mM Ringer 609 ± 78 s vs. TEA 860 ± 67 s, P < 0.05). In protocol 2, TEA alone did not affect plateau CVC, but attenuated plateau in combination with NOS+COX inhibition (100 mM 50.4 ± 6.6% vs. 30.9 ± 6.3%, P < 0.05). Therefore, EDHFs contribute to cutaneous ACh-mediated dilation, but their relative contribution is altered by the dose and infusion procedure. PMID:26384409

  16. Genetics Home Reference: laryngo-onycho-cutaneous syndrome

    MedlinePlus

    ... LOC syndrome is missing patches of skin (cutaneous erosions). The erosions heal slowly and may become infected. People with ... These abnormalities of laminin 332 cause the cutaneous erosions and overgrowth of granulation tissue that are characteristic ...

  17. The Cutaneous Ciliated Cyst in Young Male: The Possibility of Ciliated Cutaneous Eccrine Cyst

    PubMed Central

    Kim, Youngjoon; Kim, Hyunjung

    2015-01-01

    Cutaneous ciliated cyst was described as a painless cyst occurring on the lower limbs of women between the ages of 15 and 30 years. The cysts are typically lined by ciliated cuboidal to columnar epithelium with pseudostratified areas and focal squamous metaplasia is occasionally present. Immunohistochemical studies have demonstrated that the cysts are PR and ER positive, similar to the epithelia of the fallopian tubes. However, outliers of cutaneous ciliated cysts, including those in male patients and in unexpected locations such as the scalp, finger, and scapular area, have been reported. Thus, some hypotheses have been proposed including the Mullerian heterotopias, ciliated metaplasia of eccrine sweat glands, and embryonic remnants of the cloacal membrane. We report a rare case of cutaneous ciliated cyst on the left shoulder of a 7-year-old boy and this is the eighth case of cutaneous ciliated cyst in male patients. Moreover, through reviewing the articles, we try to propose the classification of the cutaneous ciliated cysts into the cutaneous Mullerian cysts and the ciliated cutaneous eccrine cysts. PMID:26491452

  18. Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naïve hypertensive patients.

    PubMed

    Perticone, Francesco; Perticone, Maria; Maio, Raffaele; Sciacqua, Angela; Andreucci, Michele; Tripepi, Giovanni; Corrao, Salvatore; Mallamaci, Francesca; Sesti, Giorgio; Zoccali, Carmine

    2015-10-01

    Tissue nonspecific alkaline phosphatase, promoting arterial calcification in experimental models, is a powerful predictor of total and cardiovascular mortality in general population and in patients with renal or cardiovascular diseases. For this study, to evaluate a possible correlation between serum alkaline phosphatase levels and endothelial function, assessed by strain gauge plethysmography, we enrolled 500 naïve hypertensives divided into increasing tertiles of alkaline phosphatase. The maximal response to acetylcholine was inversely related to alkaline phosphatase (r=−0.55; P<0.001), and this association was independent (r=−0.61; P<0.001) of demographic and classical risk factors, body mass index, estimated glomerular filtration rate, serum phosphorus and calcium, C-reactive protein, and albuminuria. At multiple logistic regression analysis, the risk of endothelial dysfunction was ≈3-fold higher in patients in the third tertile than that of patients in the first tertile. We also tested the combined role of alkaline phosphatase and serum phosphorus on endothelial function. The steepness of the alkaline phosphatase/vasodilating response to acetylcholine relationship was substantially attenuated (P<0.001) in patients with serum phosphorus above the median value when compared with patients with serum phosphorus below the median (−5.0% versus −10.2% per alkaline phosphatase unit, respectively), and this interaction remained highly significant (P<0.001) after adjustment of all the previously mentioned risk factors. Our data support a strong and significant inverse relationship between alkaline phosphatase and endothelium-dependent vasodilation, which was attenuated by relatively higher serum phosphorus levels.

  19. Chronic endurance exercise training offsets the age-related attenuation in contraction-induced rapid vasodilation.

    PubMed

    Hughes, William E; Ueda, Kenichi; Casey, Darren P

    2016-06-01

    Aging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). We sought to examine whether chronic exercise training would improve ROV in older adults. Additionally, we examined whether a relationship between cardiorespiratory fitness and ROV exists in young and older adults. Chronically exercise-trained older adults (n = 16; 66 ± 2 yr, mean ± SE) performed single muscle contractions in the forearm and leg at various intensities. Brachial and femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC) was calculated as the quotient of blood flow (ml/min) and mean arterial pressure (mmHg). These data were compared with our previously published work from an identical protocol in 16 older untrained (66 ± 1 yr, mean ± SE) and 14 young (23 ± 1 yr) adults. Peak (ΔVCpeak) and total vasodilator (VCtotal) responses were greater in trained compared with untrained older adults across leg exercise intensities (P < 0.05). There were no differences in responses between trained older and young adults in the arm or leg at any exercise intensity (P > 0.05). Comparison of ΔVCpeak in a subset of subjects at an absolute workload in the leg revealed that trained older adults exhibited augmented responses relative to untrained older adults. Exercise capacity (V̇o2 peak) was associated with ΔVCpeak and VCtotal across arm (r = 0.59-0.64) and leg exercise intensities (r = 0.55-0.68, P < 0.05) in older adults. Our data demonstrate that 1) chronic exercise training improves ROV in the arm and leg of trained older adults, such that age-related differences in ROV are abolished, and 2) VO2peak is associated with ΔVCpeak responses in both limbs of older adults. PMID:27032899

  20. Transmural coronary vasodilator reserve and flow distribution during maximal exercise in normal and splenectomized ponies.

    PubMed Central

    Manohar, M

    1987-01-01

    1. Transmural distribution of myocardial blood flow was studied using 15 micron diameter radionuclide-labelled microspheres in six normal ponies and nine splenectomized ponies at rest, and during maximal exercise performed without as well as with adenosine infusion (3 microM kg-1 min-1). The splenectomized ponies were also studied during submaximal exercise performed at 75% of the workload. 2. Maximal exertion in normal ponies increased heart rate (348%), mean arterial blood pressure (40.9%), rate-pressure product (563%), arterial O2 content (43.2%), and mean pulmonary artery pressure (247%). Accompanying these changes, the left ventricular, septal and right ventricular myocardial blood flows increased 419, 500, and 921% above control values, respectively, and the perfusion in all regions became nearly homogeneous. 3. Adenosine infusion during maximal exercise in normal ponies caused further significant increments in transmural myocardial blood flow in all regions as coronary vascular resistance decreased, thereby demonstrating considerable unutilized coronary vasodilator capacity. 4. In splenectomized ponies, with maximal exercise heart rate rose to a similar value as in normal ponies but mean aortic pressure, rate pressure product, pulmonary artery pressure and arterial O2 content were significantly less than in normal ponies (P less than 0.01). 5. Transmural myocardial perfusion in the splenectomized ponies also increased markedly with both exercise intensities and no significant differences were observed. 6. In the left ventricle and the septum of splenectomized ponies, transmural blood flow levels during maximal exertion were significantly higher (P less than 0.05) than in normal ponies. Adenosine infusion during maximal exercise in splenectomized ponies failed to cause further increments in blood flow to the inner layers of the left ventricle and the septum. 7. It is concluded that marked augmentation of arterial O2 content in normal ponies helped limit the

  1. Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension

    PubMed Central

    Gupta, Vivek; Gupta, Nilesh; Shaik, Imam H.; Mehvar, Reza; McMurtry, Ivan F.; Oka, Masahiko; Nozik-Grayck, Eva; Komatsu, Masanobu; Ahsan, Fakhrul

    2013-01-01

    Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1±0.8% and 73.6±2.3%, and the cumulative release at 37°C was 98–99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39±0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71±0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6±5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH. PMID:23353807

  2. Selective pulmonary vasodilation by low-dose infusion of adenosine triphosphate in newborn lambs.

    PubMed

    Konduri, G G; Woodard, L L

    1991-07-01

    The systemic and pulmonary vascular effects of adenosine 5'-triphosphate (ATP) were investigated in 12 newborn lambs during normoxia and during alveolar hypoxia (10% oxygen, 5% carbon dioxide, and 85% nitrogen). Lambs had catheters in the descending aorta, main pulmonary artery, and were studied after a 3-day recovery. We infused ATP or an equal volume of saline solution (control) into the right atrial line in doses ranging from 0.01 to 2.5 mumol/kg per minute. In normoxic lambs, ATP caused a significant decrease in pulmonary vascular resistance in doses of 0.08 to 2.5 mumol/kg per minute, and in systemic vascular resistance in doses of 0.3 to 2.5 mumol/kg per minute. Infusion of ATP in hypoxic lambs caused decreases in pulmonary artery pressure and pulmonary vascular resistance in all the doses tested. Systemic vascular resistance decreased, and cardiac output and heart rate increased in doses greater than 0.3 mumol/kg per minute in hypoxic lambs during ATP infusion. The effects of ATP in hypoxic lambs were not blocked by propranolol, indomethacin, or theophylline. Plasma ATP levels in left atrial blood samples did not change significantly during the infusion of ATP. We conclude that ATP is a vasodilator in lambs, and its effects are specific for pulmonary circulation at doses of less than or equal to 0.15 mumol/kg per minute. The vasodilator effects of ATP appear to be independent of P1 purinergic and beta-adrenergic mechanisms, and of prostacyclin synthesis. PMID:1906103

  3. Nitric oxide-mediated vasodilation increases blood flow during the early stages of stress fracture healing.

    PubMed

    Tomlinson, Ryan E; Shoghi, Kooresh I; Silva, Matthew J

    2014-02-15

    Despite the strong connection between angiogenesis and osteogenesis in skeletal repair conditions such as fracture and distraction osteogenesis, little is known about the vascular requirements for bone formation after repetitive mechanical loading. Here, established protocols of damaging (stress fracture) and nondamaging (physiological) forelimb loading in the adult rat were used to stimulate either woven or lamellar bone formation, respectively. Positron emission tomography was used to evaluate blood flow and fluoride kinetics at the site of bone formation. In the group that received damaging mechanical loading leading to woven bone formation (WBF), (15)O water (blood) flow rate was significantly increased on day 0 and remained elevated 14 days after loading, whereas (18)F fluoride uptake peaked 7 days after loading. In the group that received nondamaging mechanical loading leading to lamellar bone formation (LBF), (15)O water and (18)F fluoride flow rates in loaded limbs were not significantly different from nonloaded limbs at any time point. The early increase in blood flow rate after WBF loading was associated with local vasodilation. In addition, Nos2 expression in mast cells was increased in WBF-, but not LBF-, loaded limbs. The nitric oxide (NO) synthase inhibitor N(ω)-nitro-l-arginine methyl ester was used to suppress NO generation, resulting in significant decreases in early blood flow rate and bone formation after WBF loading. These results demonstrate that NO-mediated vasodilation is a key feature of the normal response to stress fracture and precedes woven bone formation. Therefore, patients with impaired vascular function may heal stress fractures more slowly than expected. PMID:24356518

  4. Role of protein sulfation in vasodilation induced by minoxidil sulfate, a K+ channel opener

    SciTech Connect

    Meisheri, K.D.; Oleynek, J.J.; Puddington, L. )

    1991-09-01

    Evidence from contractile, radioisotope ion flux and electrophysiological studies suggest that minoxidil sulfate (MNXS) acts as a K+ channel opener in vascular smooth muscle. This study was designed to examine possible biochemical mechanisms by which MNXS exerts such an effect. Experiments performed in the isolated rabbit mesenteric artery (RMA) showed that MNXS, 5 microM, but not the parent compound minoxidil, was a potent vasodilator. Whereas the relaxant effects of an another K+ channel opener vasodilator, BRL-34915 (cromakalim), were removed by washing with physiological saline solution, the effects of MNXS persisted after repeated washout attempts. Furthermore, after an initial exposure of segments of intact RMA to (35S) MNXS, greater than 30% of the radiolabel was retained 2 hr after removal of the drug. In contrast, retention of radiolabel was not detected with either (3H)MNXS (label on the piperidine ring of MNXS) or (3H)minoxidil (each less than 3% after a 2-hr washout). These data suggested that the sulfate moiety from MNXS was closely associated with the vascular tissue. To determine if proteins were the acceptors of sulfate from MNXS, intact RMAs were incubated with (35S)MNXS, and then 35S-labeled proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analyzed by fluorography. Preferential labeling of a 116 kD protein was detected by 2 and 5 min of treatment. A 43 kD protein (resembling actin) also showed significant labeling. A similar profile of 35S-labeled proteins was observed in (35S) MNXS-treated A7r5 rat aortic smooth muscle cells, suggesting that the majority of proteins labeled by (35S)MNXS in intact RMA were components of smooth muscle cells.

  5. Effect of vasodilators on pulmonary perfusion defects in asthma using sequential Kr-81m perfusion imaging

    SciTech Connect

    Ertle, A.R.; Tashkin, D.P.; Webber, M.M.; Soffer, M.J.; Frank, G.W.

    1984-01-01

    The investigation was undertaken to determine if vasodilator agents may enhance the diagnostic utility of perfusion lung imaging (Q) by normalizing regional perfusion abnormalities in bronchospastic patients. The effect of oxygen (02), nitroglycerine (NTG), hydralazine (H), and nifedipine (N) on regional lung perfusion defects was studied in 6 mild to severe asthmatics (ages defects was studied in 6 mild to severe asthmatics (ages 31-72yrs) using sequential Kr-81m imaging which permits repetitive imaging due to very low radiation dose and 13 sec T-1/2. Each patient was studied once weekly for 3 wks. Baseline Q scans were obtained using 10mCi of I.V. Kr-81m. the best view showing perfusion defects was used for subsequent images. At each visits, 30% 02 by ventimask was given for 20 min followed by a repeat Q scan. Subsequently, on separate visits, subjects were given either 1 dose of sublingual (sl)N 20 mg or 2 doses (1 hr between) of s1 NTG 1/150gr or po H 25mg according to a random-order crossover design. Q scans were obtained 2 min after NTG, 60 min after H, and 30 and 60 min after N. 30% 02 was given again for 20 min, and a final scan was obtained. Scan were reviewed by 2 observers and showed relatively fixed defects in 4 pts improvement in defects in 3 pts with NTG, 1 with N, 1 with H, and 2 with 02 alone. Additive effects of 02 and N or NTG were seen in 2 pts. These preliminary results suggest that vasodilators and 02 may improve regional perfusion in patients with bronchospastic disease and that this effect may be additive. These medications may thus improve the specificity of perfusion lung scanning in the diagnostic evaluation of pulmonary embolism.

  6. ACE Inhibitor in the treatment of cutaneous and lymphatic sarcoidosis.

    PubMed

    Kaura, Vinod; Kaura, Samantha H; Kaura, Claire S

    2007-01-01

    Angiotensin-converting enzyme is used as a marker for sarcoid activity. We describe a case of remission of cutaneous and lymphatic sarcoidosis in a patient treated with an ACE inhibitor for congestive heart failure and hypertension; the remission has continued over 4 years of follow-up. Because this is a report of only one case, there is a possibility of sampling error. Whether the patient's remission in this case was a serendipitous spontaneous remission that happened to occur during ACE inhibitor therapy or whether ACE inhibitor therapy can play a role in the treatment of sarcoidosis needs to be determined in a large clinical trial.

  7. Histone Deacetylase Inhibitors for Cutaneous T-Cell Lymphoma.

    PubMed

    Duvic, Madeleine

    2015-10-01

    Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin's T-cell lymphomas that present as skin lesions. Mycosis fungoides with large cell transformation has a 5-year overall survival of 32% with involved skin and 7% with extracutaneous involvement. Failure to cure advanced MF with large cell transformation and peripheral T-cell lymphoma has resulted in a search for novel targeted agents including antibodies and gene modulators. Histone deacetylase inhibitors are small molecules that seem to be particularly active for T-cell lymphoma. PMID:26433847

  8. Cell mediated immunity in American cutaneous and mucosal leishmaniasis.

    PubMed

    Carvalho, E M; Johnson, W D; Barreto, E; Marsden, P D; Costa, J L; Reed, S; Rocha, H

    1985-12-01

    Cellular immune responses were studied in 35 Brazilian patients with either active cutaneous leishmaniasis (CL), active mucosal leishmaniasis (ML), or healed cutaneous leishmaniasis. The mean age and duration of illness in the two groups were as follows: 14 CL patients, age 28 +/- 13 yr, disease 5 +/- mo; and 16 ML patients, age 34 +/- 15 yr, disease 86 +/- 117 mo. Patients with CL and ML responded well to leishmania antigen in blastogenesis assays. However, the response of ML patients was over three times greater than the response of CL patients. There was a significant correlation between the magnitude of the lymphoproliferative response and the duration of disease activity. There were no significant differences between CL and ML patients in terms of the following parameters: lymphoproliferative responsiveness to mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen) and peripheral blood lymphocyte subpopulations (T and B cells, oKT8+ and OKT4+ cells, OKT4:OKT8 ratio). Peripheral blood mononuclear cells from ML patients also generated interferon-gamma containing lymphokine in response to stimulation with leishmania antigen. This lymphokine was capable of inducing macrophages from ML patients to inhibit the intracellular multiplication of leishmania in vitro. These studies have determined that the parameters of lymphocyte and macrophage functions evaluated in ML and CL patients are comparable, except for an enhanced lymphoproliferative response, with leishmania antigen in ML patients. This later finding may be a function of the long duration of active disease in this population and unrelated to the pathogenesis of their mucosal lesions.

  9. Serum level of vitamin D3 in cutaneous melanoma

    PubMed Central

    de Oliveira, Renato Santos; de Oliveira, Daniel Arcuschin; Martinho, Vitor Augusto Melão; Antoneli, Célia Beatriz Gianotti; Marcussi, Ludmilla Altino de Lima; Ferreira, Carlos Eduardo dos Santos

    2014-01-01

    Objective To compare the level of vitamin D3 in cutaneous melanoma patients, with or without disease activity, with reference values and with patients from a general hospital. Methods The serum levels of vitamin D3 were measured in cutaneous melanoma patients, aged 20 to 88 years, both genders, from January 2010 to December 2013. The samples from the general group were processed at Hospital Israelita Albert Einstein (control group). Data analysis was performed using the Statistics software. Results A total of 100 patients were studied, 54 of them men, with mean age of 54.67 years, and 95 Caucasian. Out of these 100 patients, 17 had active disease. The average levels of vitamin D3 in the melanoma patients were lower than the level considered sufficient, but above the average of the control group. Both groups (with or without active disease) of patients showed a similar distribution of vitamin D3 deficiency. Conclusion Vitamin D3 levels in melanoma patients were higher than those of general patients and lower than the reference level. If the reference values are appropriate, a large part of the population had insufficient levels of vitamin D, including those with melanoma, or else, this standard needs to be reevaluated. No difference in vitamin D3 levels was found among melanoma patients with or without active disease. More comprehensive research is needed to assess the relation between vitamin D and melanoma. PMID:25628199

  10. Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine 5′-diphosphoribose) synthase

    PubMed Central

    Chabot, Francois; Mitchell, Jane A; Quinlan, Gregory J; Evans, Timothy W

    1997-01-01

    The pulmonary vasculature is constantly exposed to oxygen and reactive oxygen species such as nitric oxide (NO) and superoxide anions which can combine at a near diffusion limited rate, to form the powerful oxidant, peroxynitrite (ONOO−). When formed in large amounts, ONOO− is thought to contribute to tissue injury and vascular dysfunction seen in diseases such as the acute respiratory distress syndrome (ARDS) and septic shock. Recent studies have shown that ONOO− can cause vasodilatation and at higher concentrations can activate poly (adenosine 5′-diphosphoribose) synthase (PARS) leading to consumption of nicotinamide adenine dinucleotide (NAD+) and adenosine 5′-triphosphate (ATP). As the lung represents a prime site for ONOO− formation, we characterized its effects on pulmonary vascular tone and on endothelial function. In addition, we have assessed the role of PARS in producing the vasoactive properties of ONOO− on pulmonary artery rings. Isolated pulmonary artery rings from rats were mounted in organ baths containing warmed and gassed (95% O2: 5% CO2) Krebs buffer. Force was measured with isometric force transducers. After equilibration, ONOO− (10 nM–100 μM) was added in a cumulative manner. In separate experiments designed to assess any vasodilator properties of ONOO−, tissues were pre-contracted with the thromboxane mimetic U46619 (1 μM). Once a stable base-line was achieved, ONOO− was added in a cumulative fashion. ONOO− had no significant effect on resting pulmonary artery tone but caused concentration-dependent relaxations of pre-contracted vessels in the range 1 μM to 100 μM. In some experiments the effects of freshly prepared ONOO− solutions were compared with those allowed to decay at 4°C for 2 days. In some experiments either vehicle or ONOO− (1, 10 or 100 μM) was added for 15 min before U46619 (1 μM). Concentration-response curves to the endothelium-dependent vasodilator, acetylcholine (10 nM–100

  11. Novel Cutaneous Manifestations of Pleuroparenchymal Fibroelastosis.

    PubMed

    Lowther, Christopher M; Morrison, Annie O; Candelario, Nicole M; Khalafbeigi, Sheva; Cockerell, Clay J

    2016-10-01

    Pleuroparenchymal fibroelastosis (PPFE) is a rare progressive disease that manifests as parenchymal fibrosis of the upper lobe and pleura. Approximately 100 cases have been reported. Cutaneous manifestations of PPFE have not previously been described. Diagnosis is dependent on histologic identification of fibrosis with atypical elastic fibers, necessitating an invasive peripheral lung wedge biopsy.A 68-year-old male with a history of pleuroparenchymal fibroelastosis presented with an asymptomatic, telangiectatic erythematous eruption on bilateral lower extremities. Biopsies demonstrated a subtle perivascular infiltrate with marked increase in atypical elastic fibers, similar to the elastosis in the patient's lungs.This is the first documented case of cutaneous manifestations in PPFE. Clinicians need to be aware that cutaneous eruptions clinically simulating telangiectasia macularis eruptiva perstans but lacking a mast cell infiltrate histologically, may have increased abnormal elastic fibers. Thus, early recognition of these lesions in patients with an undefined restrictive lung disorder, may facilitate the diagnosis of PPFE in some patients.

  12. Creation of a virtual cutaneous tissue bank

    NASA Astrophysics Data System (ADS)

    LaFramboise, William A.; Shah, Sujal; Hoy, R. W.; Letbetter, D.; Petrosko, P.; Vennare, R.; Johnson, Peter C.

    2000-04-01

    Cellular and non-cellular constituents of skin contain fundamental morphometric features and structural patterns that correlate with tissue function. High resolution digital image acquisitions performed using an automated system and proprietary software to assemble adjacent images and create a contiguous, lossless, digital representation of individual microscope slide specimens. Serial extraction, evaluation and statistical analysis of cutaneous feature is performed utilizing an automated analysis system, to derive normal cutaneous parameters comprising essential structural skin components. Automated digital cutaneous analysis allows for fast extraction of microanatomic dat with accuracy approximating manual measurement. The process provides rapid assessment of feature both within individual specimens and across sample populations. The images, component data, and statistical analysis comprise a bioinformatics database to serve as an architectural blueprint for skin tissue engineering and as a diagnostic standard of comparison for pathologic specimens.

  13. Novel Cutaneous Manifestations of Pleuroparenchymal Fibroelastosis.

    PubMed

    Lowther, Christopher M; Morrison, Annie O; Candelario, Nicole M; Khalafbeigi, Sheva; Cockerell, Clay J

    2016-10-01

    Pleuroparenchymal fibroelastosis (PPFE) is a rare progressive disease that manifests as parenchymal fibrosis of the upper lobe and pleura. Approximately 100 cases have been reported. Cutaneous manifestations of PPFE have not previously been described. Diagnosis is dependent on histologic identification of fibrosis with atypical elastic fibers, necessitating an invasive peripheral lung wedge biopsy.A 68-year-old male with a history of pleuroparenchymal fibroelastosis presented with an asymptomatic, telangiectatic erythematous eruption on bilateral lower extremities. Biopsies demonstrated a subtle perivascular infiltrate with marked increase in atypical elastic fibers, similar to the elastosis in the patient's lungs.This is the first documented case of cutaneous manifestations in PPFE. Clinicians need to be aware that cutaneous eruptions clinically simulating telangiectasia macularis eruptiva perstans but lacking a mast cell infiltrate histologically, may have increased abnormal elastic fibers. Thus, early recognition of these lesions in patients with an undefined restrictive lung disorder, may facilitate the diagnosis of PPFE in some patients. PMID:27643829

  14. Evaluation, Diagnosis, and Staging of Cutaneous Lymphoma.

    PubMed

    Olsen, Elise A

    2015-10-01

    Primary cutaneous lymphomas (PCLs) are an extremely heterogeneous group of non-Hodgkin lymphomas that manifest in the skin. Their diagnosis is complex and based on clinical lesion type and evaluation of findings on light microscopic examination, immunohistochemistry and molecular analysis of representative skin biopsies. The evaluation, classification, and staging system is unique for mycosis fungoides (MF) and Sézary syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma (CTCL) versus the other subtypes of Non-MF/Non-SS CTCL and the subtypes of cutaneous B-cell lymphoma (CBCL). Since current treatment is stage-based, it is particularly important that the correct diagnosis and stage be ascertained initially. The purpose of this article is to review the current evaluation, diagnosis, classification, staging, assessment techniques, and response criteria for the various types of both T-cell and B-cell PCLs. PMID:26433839

  15. Vasodilating and hypotensive effects of fangchinoline and tetrandrine on the rat aorta and the stroke-prone spontaneously hypertensive rat.

    PubMed

    Kim, H S; Zhang, Y H; Oh, K W; Ahn, H Y

    1997-10-01

    Comparative studies of the effects of tetrandrine (TET) and fangchinoline (FAN), two major components of the Radix of Stephannia tetrandrae, on vasodilations and on calcium movement in vascular smooth muscle, and studies of hypotensive effects on stroke-prone spontaneously hypertensive rats (SHRSP) were performed in the following experiments. TET and FAN inhibited high K+ (65.4 mM) and induced sustained contraction in the rat aorta smooth muscle strips. IC50 values for TET and FAN were 0.27 +/- 0.05 microM (n = 6) and 9.53 +/- 1.57 microM (n = 6), respectively, and this inhibition was antagonized by increasing the Ca2+ concentration in the medium. The IC50 of TET for norepinephrine (NE)-induced contraction (0.86 +/- 0.04 g) was 3.08 +/- 0.05 microM (n = 4), and the IC50 of FAN for NE-induced contraction (0.88 +/- 0.07 g) was 14.20 +/- 0.40 microM (n = 4). At the molecular level, radiolabelled 45Ca2+ uptake tests revealed that TET and FAN also inhibited high K+ (65.4 mM) and 1 microM NE-stimulated Ca2+ influx in rat aorta strips at the maximal concentration was needed to inhibit the contraction. TET (3 mg/kg) and FAN (30 mg/kg) administered by intravenous (i.v.) bolus injection also lowered the mean arterial pressure (MAP) significantly during the period of observation in conscious SHRSP, respectively. These results showed that TET was more potent than FAN in blocking calcium channels and antihypertensive activity. PMID:9406900

  16. Ascorbic acid improves brachial artery vasodilation during progressive handgrip exercise in the elderly through a nitric oxide-mediated mechanism.

    PubMed

    Trinity, Joel D; Wray, D Walter; Witman, Melissa A H; Layec, Gwenael; Barrett-O'Keefe, Zachary; Ives, Stephen J; Conklin, Jamie D; Reese, Van; Zhao, Jia; Richardson, Russell S

    2016-03-15

    The proposed mechanistic link between the age-related attenuation in vascular function and free radicals is an attractive hypothesis; however, direct evidence of free radical attenuation and a concomitant improvement in vascular function in the elderly is lacking. Therefore, this study sought to test the hypothesis that ascorbic acid (AA), administered intra-arterially during progressive handgrip exercise, improves brachial artery (BA) vasodilation in a nitric oxide (NO)-dependent manner, by mitigating free radical production. BA vasodilation (Doppler ultrasound) and free radical outflow [electron paramagnetic resonance (EPR) spectroscopy] were measured in seven healthy older adults (69 ± 2 yr) during handgrip exercise at 3, 6, 9, and 12 kg (∼13-52% of maximal voluntary contraction) during the control condition and nitric oxide synthase (NOS) inhibition via N(G)-monomethyl-L-arginine (L-NMMA), AA, and coinfusion of l-NMMA + AA. Baseline BA diameter was not altered by any of the treatments, while L-NMMA and L-NMMA + AA diminished baseline BA blood flow and shear rate. AA improved BA dilation compared with control at 9 kg (control: 6.5 ± 2.2%, AA: 10.9 ± 2.5%, P = 0.01) and 12 kg (control: 9.5 ± 2.7%, AA: 15.9 ± 3.7%, P < 0.01). NOS inhibition blunted BA vasodilation compared with control and when combined with AA eliminated the AA-induced improvement in BA vasodilation. Free radical outflow increased with exercise intensity but, interestingly, was not attenuated by AA. Collectively, these results indicate that AA improves BA vasodilation in the elderly during handgrip exercise through an NO-dependent mechanism; however, this improvement appears not to be the direct consequence of attenuated free radical outflow from the forearm.

  17. Study of the histopathological types of cutaneous melanoma in Palmas-TO from 2001 to 2011*

    PubMed Central

    da Costa, Nilo Fernandes; Fernandes, Nurimar Conceição; Borges, Myrlena Regina Machado Mescouto

    2015-01-01

    BACKGROUND Cutaneous melanoma (CM) is considered serious for causing frequent metastasis, presenting high mortality, resistance to available therapies and incidences in laboring activity. OBJECTIVES To study the histopathological types of cutaneous melanoma in Palmas-TO from 2001 to 2011, according to risk factors, location of lesions, Clark levels and Breslow thickness. METHODS A descriptive, retrospective and quantitative research in reports of the Serviços de Anatomia Patológica in Palmas (SAPP) and Registro de Câncer de Base Populacional de Palmas (RCBPP). RESULTS The years of highest incidences were: 2004 (8 cases/17.8%), 2008 and 2011 (7 cases each/15.6%) and 2010 (6 cases/13.3%). Among the 45 cases studied, there were predominance in patients between 41 and 60 years old, women, caucasians, farmers, located in trunk, in situ type, superficial extensive and metastatic cutaneous, Clark levels I (20%) and IV (17.7%), Breslow thickness ≤1 mm (35.5%) and 2.01 to 4 mm (24.4%). CONCLUSIONS The most common histopathological types were: cutaneous melanoma in situ, superficial extensive and metastatic, followed by nodular cutaneous melanoma, and finally, by other forms. In this study, Clark levels and Breslow thickness pointed to greater importance of thin melanomas and sun exposure without appropriate protection in farmers. PMID:26560208

  18. GABAB receptors in the NTS mediate the inhibitory effect of trigeminal nociceptive inputs on parasympathetic reflex vasodilation in the rat masseter muscle.

    PubMed

    Ishii, Hisayoshi; Izumi, Hiroshi

    2012-03-15

    The present study was designed to examine whether trigeminal nociceptive inputs are involved in the modulation of parasympathetic reflex vasodilation in the jaw muscles. This was accomplished by investigating the effects of noxious stimulation to the orofacial area with capsaicin, and by microinjecting GABA(A) and GABA(B) receptor agonists or antagonists into the nucleus of the solitary tract (NTS), on masseter hemodynamics in urethane-anesthetized rats. Electrical stimulation of the central cut end of the cervical vagus nerve (cVN) in sympathectomized animals bilaterally increased blood flow in the masseter muscle (MBF). Increases in MBF evoked by cVN stimulation were markedly reduced following injection of capsaicin into the anterior tongue in the distribution of the lingual nerve or lower lip, but not when injected into the skin of the dorsum of the foot. Intravenous administration of either phentolamine or propranolol had no effect on the inhibitory effects of capsaicin injection on the increases of MBF evoked by cVN stimulation, which were largely abolished by microinjecting the GABA(B) receptor agonist baclofen into the NTS. Microinjection of the GABA(B) receptor antagonist CGP-35348 into the NTS markedly attenuated the capsaicin-induced inhibition of MBF increase evoked by cVN stimulation, while microinjection of the GABA(A) receptor antagonist bicuculline did not. Our results indicate that trigeminal nociceptive inputs inhibit vagal-parasympathetic reflex vasodilation in the masseter muscle and suggest that the activation of GABA(B) rather than GABA(A) receptors underlies the observed inhibition in the NTS.

  19. The CLASI (Cutaneous LE Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus

    PubMed Central

    Albrecht, Joerg; Taylor, Lynne; Berlin, Jesse A.; Dulay, Samuel; Ang, Gina; Fakharzadeh, Steven; Kantor, Jonathan; Kim, Ellen; Militello, Giuseppe; McGinnis, Karen; Richardson, Stephen; Treat, James; Vittorio, Carmela; Van Voorhees, Abby; Werth, Victoria P.

    2013-01-01

    We developed and validated a measurement instrument (CLASI - Cutaneous Lupus Erythematosus Disease Area and Severity Index) for lupus erythematosus that could be used in clinical trials. The instrument has separate scores for damage and activity. A group of 7 American Dermato-Rheumatologists and the “American College of Rheumatology Response Criteria Committee on SLE” assessed content validity. After a preliminary session, we conducted standardized interviews with the raters and made slight changes to the instrument. The final instrument was evaluated by 5 dermatologists and 6 residents who scored 9 patients to estimate inter-rater reliability and intra-rater reliability in two sessions. Consultation with experts has established content validity of the instrument. Reliability studies demonstrated an Intraclass Correlation Coefficient (ICC) for inter-rater reliability of 0.86 for the activity score (95% Confidence Interval [CI] 0.73 to 0.99) and of 0.92 for the damage score (95% CI 0.85 to 1.00). The Spearman’s Rho for intra-rater reliability for the activity score was 0.96 (95% CI 0.89 to 1.00) and for the damage score Spearman’s Rho was 0.99 (95% CI 0.97 to 1.00). Clinical responsiveness needs to be evaluated in a prospective clinical trial, which is ongoing. PMID:16297185

  20. Problems in Cutaneous Communication from Psychophysics to Information Processing.

    ERIC Educational Resources Information Center

    Gilmer, B. VonHaller; Clark, Leslie L., Ed.

    After reviewing the history of communication through the skin, this paper considers recent research into the problem of cutaneous stimulation induced both mechanically and electrically. The general demands of a cutaneous communication system are discussed, and four primary dimensions of cutaneous stimulation are summarized (locus, intensity,…

  1. Cutaneous metastasis from gastrointestinal adenocarcinoma of unknown primary origin.

    PubMed

    Junqueira, Ana Lucia Ariano; Corbett, Ana Maria França; Oliveira Filho, Jayme de; Nasser, Kassila da Rosa; Haddad, Natalie Nejem; Tebet, Ana Carolina Franco

    2015-01-01

    Cutaneous metastasis is a rare manifestation of visceral malignancies that indicates primarily advanced disease. Due to its low incidence and similarity to other cutaneous lesions, it is not uncommon to have a delayed diagnosis and a shortened prognosis. We describe the case of a patient who presented with a cutaneous nodule in the sternal region as a first sign of malignancy.

  2. Porcine models of cutaneous wound healing.

    PubMed

    Seaton, Max; Hocking, Anne; Gibran, Nicole S

    2015-01-01

    Cutaneous wound healing in the pig is frequently used as a model for human cutaneous wound healing. In this review, we examine the appropriateness of this model for studying normal and pathological wound healing, and describe models for chronic nonhealing wounds, diabetic wounds, burns, and hypertrophic scars. In addition, we focus on studies that have used pigs to evaluate wound-healing therapies, and discuss genetic engineering technology in the pig that may advance our knowledge of wound healing. We conclude that, although not perfect, the pig offers a versatile model that can be adjusted to mimic a wide range of clinical scenarios.

  3. Cutaneous mosaicisms: concepts, patterns and classifications*

    PubMed Central

    Kouzak, Samara Silva; Mendes, Marcela Sena Teixeira; Costa, Izelda Maria Carvalho

    2013-01-01

    A mosaic is an organism composed of two or more genetically distinct cell populations derived from a genetically homogeneous zygote. Cutaneous mosaicisms are the clinical expressions of these disorders. The main event which allows the existence of mosaicism is a genetic mutation, either structural or functional. Cutaneous mosaicisms usually manifest by specific patterns on the skin and the archetypic pattern is the system of Blaschko lines, but others include checkerboard, phylloid, large patches without midline separation and lateralization. Since 1901, when Blaschko lines were first described, the study of mosasicism has helped to elucidate the behavior of numerous genetic diseases, generating therapeutic perspectives for these pathologies, including the promising gene therapy. PMID:24068120

  4. Paraneoplastic cutaneous manifestations: concepts and updates*

    PubMed Central

    da Silva, Josenilson Antônio; Mesquita, Kleyton de Carvalho; Igreja, Ana Carolina de Souza Machado; Lucas, Isabella Cristina Rodrigues Naves; Freitas, Aline Ferreira; de Oliveira, Sandra Maximiano; Costa, Izelda Maria Carvalho; Campbell, Iphis Tenfuss

    2013-01-01

    The skin often signals systemic changes. Some neoplastic diseases that affect internal organs may trigger several cutaneous manifestations. Although these dermatoses are relatively unusual, the recognition of some typical paraneoplastic dermatoses may lead to the early diagnosis of a neoplasm and determine a better prognosis. In this review article, we discuss the paraneoplastic cutaneous manifestations strongly associated with neoplasms, which include acanthosis nigricans maligna, tripe palms, erythema gyratum repens, Bazex syndrome, acquired hypertrichosis lanuginosa, necrolytic migratory erythema, Leser-Trélat sign and paraneoplastic pemphigus. We also review the clinical manifestations of each condition and include updated knowledge on disease pathogenesis. PMID:23538999

  5. Cutaneous malignancies in immunosuppressed organ transplant recipients.

    PubMed

    Seda, Ivette M Sosa; Zubair, Adeel; Brewer, Jerry D

    2014-01-01

    During the past century, organ transplantation has delivered the miracle of life to more than 500,000 patients in need. Secondary malignancies have developed as an unforeseen consequence of intense immunosuppressive regimens. Cutaneous malignancies have been recognized as the most frequent cancer that arises post-transplantation. Among organ transplant recipients (OTRs), skin cancer is a substantial cause of morbidity and potential mortality. The authors discuss epidemiology and clinical presentation of cutaneous malignancies; associated risk factors; recommendation for the care of immunosuppressed OTRs, and emerging therapies on the horizon.

  6. Primary Axillary Porocarcinoma: A Rare Cutaneous Tumour.

    PubMed

    Devi, Nalli R Sumitra; Valarmathi, K; Lilly, Mary; Satish, Selvi; Mishra, Nidhi

    2016-02-01

    Eccrine porocarcinoma, a rare cutaneous malignant tumour accounts for a fraction of sweat gland tumours. This tumour is found to originate from the intraepithelial parts of the sweat glands. It commonly involves the lower extremities in elderly patients and carries an aggressive behaviour. Cutaneous and visceral metastasis can occur and hence prompt treatment is mandatory. Surgical excision is the mainstay of treatment modality. We hereby present a case of eccrine porocarcinoma in a 50-year-old male in the right axillary region presenting as a verrucous lesion. PMID:27042472

  7. Romidepsin for cutaneous T-cell lymphoma.

    PubMed

    Prince, H Miles; Dickinson, Michael; Khot, Amit

    2013-12-01

    Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.

  8. Primary cutaneous lymphomas: diagnosis and treatment

    PubMed Central

    Olek-Hrab, Karolina; Ruckemann-Dziurdzińska, Katarzyna

    2015-01-01

    Primary cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative neoplasms, with lymphatic proliferation limited to the skin with no involvement of lymph nodes, bone marrow or viscera at the diagnosis. Cutaneous lymphomas originate from mature T-lymphocytes (65% of all cases), mature B-lymphocytes (25%) or NK cells. Histopathological evaluation including immunophenotyping of the skin biopsy specimen is the basis of the diagnosis, which must be complemented with a precise staging of the disease and identification of prognostic factors, to allow for the choice of the best treatment method as well as for the evaluation of the treatment results. PMID:26759546

  9. Three eyelid localized cutaneous anthrax cases.

    PubMed

    Esmer, Oktay; Karadag, Remzi; Bilgili, Serap Gunes; Gultepe, Bilge; Bayramlar, Huseyin; Karadag, Ayse Serap

    2014-12-01

    Anthrax is primarily seen in the developing countries, but it can be a worldwide medical concern due to bioterrorism threats. Palpebral anthrax is a rare form of cutaneous anthrax. Untreated cutaneous anthrax can be lethal. Patients with palpebral anthrax can develop complications including cicatrisation and ectropion. Thus, anthrax should be considered in differential diagnosis for patients presenting with preseptal cellulitis in high-risk regions. Herein, we report three anthrax cases (with different age) involving eyelids that were cured without any complications due to early diagnosis and treatment.

  10. Primary cutaneous lymphomas: diagnosis and treatment.

    PubMed

    Sokołowska-Wojdyło, Małgorzata; Olek-Hrab, Karolina; Ruckemann-Dziurdzińska, Katarzyna

    2015-10-01

    Primary cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative neoplasms, with lymphatic proliferation limited to the skin with no involvement of lymph nodes, bone marrow or viscera at the diagnosis. Cutaneous lymphomas originate from mature T-lymphocytes (65% of all cases), mature B-lymphocytes (25%) or NK cells. Histopathological evaluation including immunophenotyping of the skin biopsy specimen is the basis of the diagnosis, which must be complemented with a precise staging of the disease and identification of prognostic factors, to allow for the choice of the best treatment method as well as for the evaluation of the treatment results. PMID:26759546

  11. Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.

    PubMed

    Bardoni, Rita; Tawfik, Vivianne L; Wang, Dong; François, Amaury; Solorzano, Carlos; Shuster, Scott A; Choudhury, Papiya; Betelli, Chiara; Cassidy, Colleen; Smith, Kristen; de Nooij, Joriene C; Mennicken, Françoise; O'Donnell, Dajan; Kieffer, Brigitte L; Woodbury, C Jeffrey; Basbaum, Allan I; MacDermott, Amy B; Scherrer, Grégory

    2014-03-19

    Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity. PMID:24583022

  12. Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn

    PubMed Central

    Bardoni, Rita; Tawfik, Vivianne L.; Wang, Dong; François, Amaury; Solorzano, Carlos; Shuster, Scott A.; Choudhury, Papiya; Betelli, Chiara; Cassidy, Colleen; Smith, Kristen; de Nooij, Joriene C.; Mennicken, Françoise; O’Donnell, Dajan; Kieffer, Brigitte L.; Woodbury, C. Jeffrey; Basbaum, Allan I.; MacDermott, Amy B.; Scherrer, Grégory

    2014-01-01

    SUMMARY Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity. PMID:24583022

  13. Heat acclimation improves cutaneous vascular function and sweating in trained cyclists

    PubMed Central

    Lorenzo, Santiago

    2010-01-01

    The aim of this study was to explore heat acclimation effects on cutaneous vascular responses and sweating to local ACh infusions and local heating. We also sought to examine whether heat acclimation altered maximal skin blood flow. ACh (1, 10, and 100 mM) was infused in 20 highly trained cyclists via microdialysis before and after a 10-day heat acclimation program [two 45-min exercise bouts at 50% maximal O2 uptake (V̇o2max) in 40°C (n = 12)] or control conditions [two 45-min exercise bouts at 50% V̇o2max in 13°C (n = 8)]. Skin blood flow was monitored via laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC) was calculated as LDF ÷ mean arterial pressure. Sweat rate was measured by resistance hygrometry. Maximal brachial artery blood flow (forearm blood flow) was obtained by heating the contralateral forearm in a water spray device and measured by Doppler ultrasound. Heat acclimation increased %CVCmax responses to 1, 10, and 100 mM ACh (43.5 ± 3.4 vs. 52.6 ± 2.6% CVCmax, 67.7 ± 3.4 vs. 78.0 ± 3.0% CVCmax, and 81.0 ± 3.8 vs. 88.5 ± 1.1% CVCmax, respectively, all P < 0.05). Maximal forearm blood flow remained unchanged after heat acclimation (290.9 ± 12.7 vs. 269.9 ± 23.6 ml/min). The experimental group showed significant increases in sweating responses to 10 and 100 mM ACh (0.21 ± 0.03 vs. 0.31 ± 0.03 mg·cm−2·min−1 and 0.45 ± 0.05 vs. 0.67 ± 0.06 mg·cm−2·min−1, respectively, all P < 0.05), but not to 1 mM ACh (0.13 ± 0.02 vs. 0.18 ±