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1.
Surg Endosc ; 36(1): 267-273, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33495879

RESUMO

BACKGROUND: Venous thromboembolic events (VTE) continue to be a major source of morbidity following colorectal surgery. Selective extended VTE prophylaxis for high-risk patients is recommended; however, provider compliance is low. The purpose of this study is to evaluate whether the "global" extended use of enoxaparin in all colorectal patients is feasible and safe. METHODS: This is a prospective study conducted at a tertiary care center. All Patients undergoing elective colorectal procedures from November 1, 2017 to October 31, 2018 were discharged on 30 days of enoxaparin. Safety of use and patient compliance were examined. RESULTS: Total of 270 patients received extended prophylaxis during the study period (100% of intended patients) with five VTE recorded (1.85%). There was no significant difference in rates of VTE or complications when compared to years of selective prophylaxis (1.26% for 2016, 2.32% for 2017). Only 64% of patients reported full compliance. CONCLUSION: Global use of extended enoxaparin prophylaxis is safe, but does not decrease rates of VTE when compared to selective use. Patient's non-adherence is likely a significant contributing factor.


Assuntos
Cirurgia Colorretal , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Humanos , Cooperação do Paciente , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle
2.
Cancer Med ; 9(22): 8301-8309, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32976697

RESUMO

BACKGROUND: Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, have severe function-limiting symptom burden that is experienced by the majority of patients. Previous studies have suggested that depression may be present in over a quarter of MPN patients, but to date no studies have evaluated the relationship between depression and other variables such as symptoms. METHODS: A 70-item internet based survey regarding fatigue and mood symptoms was developed by a multidisciplinary team of MPN investigators, patients and patient advocates including Patient Health Questionnaire and the Myeloproliferative Neoplasm Symptom Assessment Form was completed by over 1300 patients with MPN diagnosis. RESULTS: There were 309 respondents (23%) with PHQ-2 scores ≥ 3. In this analysis, we found worse systemic symptom burden in individuals reporting depressive symptoms. CONCLUSION: This analysis suggests the importance of depression in contributing to as well as confounding symptomatology in MPN patients, and suggests that this critical variable should also be addressed by clinicians and researchers alike when comprehensively assessing symptom burden etiologies.


Assuntos
Afeto , Depressão/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Questionário de Saúde do Paciente , Adulto , Idoso , Depressão/psicologia , Fadiga/diagnóstico , Fadiga/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/psicologia , Valor Preditivo dos Testes
3.
BMC Public Health ; 19(1): 1732, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870345

RESUMO

BACKGROUND: Finding effective intervention strategies to combat rising obesity levels could significantly reduce the burden that obesity and associated non-communicable diseases places on both individuals and the National Health Service. METHODS: In this parallel randomised-controlled trial, 76 participants who are overweight or obese (50 female) were given free access to a fitness centre for the duration of the 12-week intervention and randomised to one of three interventions. The commercial intervention, the Healthy Weight Programme, (HWP, n = 25, 10/15 men/women) consisted of twelve 1-h nutrition coaching sessions with a nutritionist delivered as a mixture of group and 1 to 1 sessions. In addition, twice-weekly exercise sessions (24 in total) were delivered by personal trainers for 12 weeks. The NHS intervention (n = 25, 8/17 men/women) consisted of following an entirely self-managed 12-week online NHS resource. The GYM intervention (n = 26, 8/18 men/women) received no guidance or formal intervention. All participants were provided with a gym induction for safety and both the NHS and GYM participants were familiarised with ACSM physical activity guidelines by way of a hand-out. RESULTS: The overall follow-up rate was 83%. Body mass was significantly reduced at post-intervention in all groups (HWP: N = 18, - 5.17 ± 4.22 kg, NHS: N = 21-4.19 ± 5.49 kg; GYM: N = 24-1.17 ± 3.00 kg; p < 0.001) with greater reductions observed in HWP and NHS groups compared to GYM (p < 0.05). Out with body mass and BMI, there were no additional statistically significant time x intervention interaction effects. CONCLUSIONS: This is the first study to evaluate the efficacy of both a free online NHS self-help weight-loss tool and a commercial weight loss programme that provides face-to-face nutritional support and supervised exercise. The findings suggest that both interventions are superior to an active control condition with regard to eliciting short-term weight-loss. TRIAL REGISTRATION: ISRCTN Registry - ISRCTN31489026. Prospectively registered: 27/07/16.


Assuntos
Obesidade/terapia , Sobrepeso/terapia , Programas de Redução de Peso/métodos , Adulto , Feminino , Humanos , Intervenção Baseada em Internet/economia , Masculino , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de Saúde , Medicina Estatal , Reino Unido , Programas de Redução de Peso/economia , Adulto Jovem
4.
J Diabetes Res ; 2017: 4729284, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28293643

RESUMO

Spinal glial cell activation and cytokine secretion have been implicated in the etiology of neuropathic pain in a number of experimental models, including diabetic neuropathy. In this study, streptozotocin- (STZ-) induced diabetic rats were either untreated or treated with gabapentin (50 mg/kg/day by gavage for 2 weeks, from 6 weeks after STZ). At 8 weeks after STZ, hypersensitivity was confirmed in the untreated diabetic rats as a reduced response threshold to touch, whilst mechanical thresholds in gabapentin-treated diabetic rats were no different from controls. Diabetes-associated thermal hypersensitivity was also ameliorated by gabapentin. We performed a cytokine profiling array in lumbar spinal cord samples from control and diabetic rats. This revealed an increase in L-selectin, an adhesion molecule important for neutrophil transmigration, in the spinal cord of diabetic rats but not diabetic rats treated with gabapentin. Furthermore, we found an increase in the number of neutrophils present in the parenchyma of the spinal cord, which was again ameliorated in gabapentin-treated diabetic rats. Therefore, we suggest that dysregulated spinal L-selectin and neutrophil infiltration into the spinal cord could contribute to the pathogenesis of painful diabetic neuropathy.


Assuntos
Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/patologia , Neuralgia/patologia , Infiltração de Neutrófilos/fisiologia , Medula Espinal/patologia , Aminas/farmacologia , Aminas/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Ácidos Cicloexanocarboxílicos/farmacologia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Diabetes Mellitus Experimental/imunologia , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/imunologia , Gabapentina , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/imunologia , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêutico
5.
Cancer ; 122(3): 477-85, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26670597

RESUMO

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) experience a high persistence, prevalence, and severity of fatigue. There is currently only limited information regarding factors that contribute to fatigue in patients with MPNs. METHODS: A 70-item, Internet-based survey regarding fatigue was developed by MPN investigators and patients/advocates and hosted by the Mayo Clinic Survey Research Center. RESULTS: Fatigue was found to be prevalent and severe among international survey respondents (1788 respondents). Higher body mass index (P<.001), current use of alcohol (P<.001), and current tobacco use (P = .0025) were found to be significantly associated with greater fatigue. Moderate/severe fatigue was present more frequently in those individuals who did not exercise compared with those who reported exercising at least once per week (P<.001). Medical comorbidities found to be significantly associated with greater fatigue included restless leg syndrome (P = .006), diabetes mellitus (P = .045), fibromyalgia (P < 0.001), chronic fatigue syndrome (P = .006), and chronic kidney disease (P = .02). Current use of antidepressants (P<.001), antihistamines (P = .0276), antianxiety medications (P = .0357), and prescription pain medications (P<.001) were found to be associated with worsened fatigue. Nearly 25% of respondents scored > 2 on the Patient Health Questionnaire, indicating a high probability of depression. Higher Brief Fatigue Inventory score, Myeloproliferative Neoplasm Total Symptom Score, and individual symptom items were all associated with a higher likelihood of depressive symptoms (P<.0001). CONCLUSIONS: The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. Patients with MPNs likely have a higher prevalence of mood disturbances compared with the general population, suggesting the need to assess and intervene in this domain.


Assuntos
Neoplasias da Medula Óssea/complicações , Fadiga/etiologia , Fadiga/prevenção & controle , Transtornos do Humor/complicações , Transtornos do Humor/terapia , Adulto , Idoso , Ansiedade/complicações , Ansiedade/terapia , Doença Crônica/epidemiologia , Comorbidade , Depressão/complicações , Depressão/terapia , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/prevenção & controle , Fadiga/psicologia , Síndrome de Fadiga Crônica/complicações , Síndrome de Fadiga Crônica/epidemiologia , Feminino , Fibromialgia/complicações , Fibromialgia/epidemiologia , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/epidemiologia , Qualidade de Vida , Síndrome das Pernas Inquietas/complicações , Síndrome das Pernas Inquietas/epidemiologia , Fatores de Risco , Comportamento de Redução do Risco , Autorrelato , Índice de Gravidade de Doença
6.
Nat Rev Urol ; 11(4): 231-41, 2014 04.
Artigo em Inglês | MEDLINE | ID: mdl-24619381

RESUMO

Benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and erectile dysfunction commonly coexist, and both respond to phosphodiesterase (PDE) 5 inhibitors, suggesting a shared pathophysiological mechanism. We propose that both BPH-LUTS and erectile dysfunction are caused by microvascular dysfunction within the pelvic organs, and we present an overview of preclinical and clinical studies supporting the hypothesis that, within both the penis and the lower urinary tract, a combination of endothelial and neural dysfunction leads to a vicious cycle of hypoxia, vasoconstriction, altered smooth muscle contractility, and degeneration of autonomic neurons and ganglia. This hypothesis explains much of the preclinical and clinical research relating to these two conditions, and provides a rationale for further investigation into the effects of PDE5 inhibitors on the pathophysiology and symptoms of BPH-LUTS.


Assuntos
Disfunção Erétil/tratamento farmacológico , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Doenças Vasculares/complicações , Disfunção Erétil/etiologia , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Microvasos , Hiperplasia Prostática/complicações
7.
J Sex Med ; 10(12): 2967-74, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24034566

RESUMO

INTRODUCTION: The vasa nervorum comprises a network of small diameter blood vessels that provide blood supply to nerves and ganglia. The cell bodies of autonomic nerves innervating the urogenital organs are housed in the major pelvic ganglia (MPG) in rats. The vasa nervorum of rat MPG have not been characterized previously, and it is not known whether these blood vessels are innervated by neuronal nitric oxide synthase (nNOS) containing nitrergic nerves. AIM: To characterize the blood vessels in and around the rat MPG and to assess their nitrergic innervation. MAIN OUTCOME MEASURES: Characterization of small blood vessels in and around the rat MPG and expression of nNOS in nerve fibers around those blood vessels. METHODS: MPG were obtained from healthy Sprague Dawley rats, fixed in paraformaldehyde, frozen and sectioned using a cryostat. The blood vessels and their nitrergic innervation were assessed with immunohistochemistry using antibodies against alpha-smooth muscle actin (smooth muscle marker), CD31 (endothelial marker), collagen IV (basal membrane marker) and nNOS. The immunofluorescence was imaged using a laser scanning confocal microscope. RESULTS: The neuronal cell bodies were contained within a capsule in the MPG. Blood vessels were observed within the capsule of the MPG as well as outside the capsule. The blood vessels inside the capsule were CD31-positive capillaries with no smooth muscle staining. Outside the capsule capillaries, arterioles and venules were observed. The extra-capsular arterioles and venules, but not the capillaries were innervated by nNOS-positive nerve fibers. CONCLUSIONS: This study, to our knowledge, is the first to demonstrate the blood vessel distribution pattern and their nitrergic innervation in the rat MPG. While similar studies in human pelvic plexus are warranted, these results suggest that the blood flow in the MPG may be regulated by nitrergic nerve fibers and reveal a reciprocal relationship between nerves and blood vessels.


Assuntos
Gânglios Sensitivos/irrigação sanguínea , Plexo Hipogástrico/irrigação sanguínea , Fibras Nervosas/fisiologia , Neurônios Nitrérgicos/fisiologia , Vasa Nervorum/inervação , Actinas/metabolismo , Animais , Humanos , Imuno-Histoquímica , Masculino , Músculo Liso/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Eur J Pharmacol ; 719(1-3): 180-186, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-23872412

RESUMO

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials.


Assuntos
Vasos Sanguíneos/fisiopatologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/fisiopatologia , Animais , Humanos , Isquemia/complicações , Nervos Periféricos/irrigação sanguínea , Vasa Nervorum/fisiopatologia
9.
Am J Pathol ; 181(2): 719-27, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22677420

RESUMO

We investigated the phenotype of cells involved in leukostasis in the early stages of streptozotocin-induced diabetes in mice by direct observation and by adoptive transfer of calcein-AM-labeled bone marrow-derived leukocytes from syngeneic mice. Retinal whole mounts, confocal microscopy, and flow cytometry ex vivo and scanning laser ophthalmoscopy in vivo were used. Leukostasis in vivo and ex vivo in retinal capillaries was increased after 2 weeks of diabetes (Hb A(1c), 14.2 ± 1.2) when either donor or recipient mice were diabetic. Maximum leukostasis occurred when both donor and recipient were diabetic. CD11b(+), but not Gr1(+), cells were preferentially entrapped in retinal vessels (fivefold increase compared with nondiabetic mice). In diabetic mice, circulating CD11b(+) cells expressed high levels of CCR5 (P = 0.04), whereas spleen (P = 0.0001) and retinal (P = 0.05) cells expressed increased levels of the fractalkine chemokine receptor. Rosuvastatin treatment prevented leukostasis when both recipient and donor were treated but not when donor mice only were treated. This effect was blocked by treatment with mevalonate. We conclude that leukostasis in early diabetic retinopathy involves activated CCR5(+)CD11b(+) myeloid cells (presumed monocytes). However, leukostasis also requires diabetes-induced changes in the endothelium, because statin therapy prevented leukostasis only when recipient mice were treated. The up-regulation of the HMG-CoA reductase pathway in the endothelium is the major metabolic dysregulation promoting leukostasis.


Assuntos
Células da Medula Óssea/patologia , Antígeno CD11b/metabolismo , Capilares/patologia , Diabetes Mellitus Experimental/patologia , Leucostasia/patologia , Monócitos/patologia , Receptores CCR5/sangue , Transferência Adotiva , Animais , Receptor 1 de Quimiocina CX3C , Capilares/efeitos dos fármacos , Capilares/metabolismo , Capilares/fisiopatologia , Adesão Celular/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Contagem de Células , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fluorescência , Fluorbenzenos/farmacologia , Leucostasia/sangue , Leucostasia/complicações , Leucostasia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Pirimidinas/farmacologia , Receptores CCR2/metabolismo , Receptores de Quimiocinas/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Vasos Retinianos/fisiopatologia , Rosuvastatina Cálcica , Estreptozocina , Sulfonamidas/farmacologia
10.
Angiology ; 61(7): 651-68, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20547541

RESUMO

In diabetes mellitus (DM) reduced motor and sensory properties of peripheral nerves are linked with the dysfunction of neural vasculature. We investigated C-fibers and microvessels of sciatic nerve of normal, DM, and DM + epoetin delta-treated rats. C-fibers immunoreactive for calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), epoetin receptor (EpoR), and common beta receptor subunit of the interleukin 3 receptor (IL-3Rbeta) were present in all rats, whereas in DM and epoetin-treated rats C-fibers also showed neuronal (nNOS) and inducible (iNOS) nitric oxide synthases. The cross-sectional area of CGRP-positive C-fibers was decreased in DM, but it recovered after epoetin treatment. In all conditions, vascular endothelium showed scarce immunolabeling for endothelial nitric oxide synthase (eNOS); the profound immunoreactivity for eNOS, EpoR, and IL-3Rbeta was in pericytes. Some perivascular autonomic nerves were damaged and IL-3Rbeta positive. Findings are discussed in terms of declined sensory conduction velocity in DM, its improvement after epoetin treatment, and the possible vascular contribution to these phenomena.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Eritropoetina/farmacologia , Microvasos/patologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Pericitos/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Eritropoetina/uso terapêutico , Imuno-Histoquímica , Masculino , Microvasos/efeitos dos fármacos , Fibras Nervosas Amielínicas/patologia , Fibras Nervosas Amielínicas/ultraestrutura , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pericitos/efeitos dos fármacos , Pericitos/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Fluxo Sanguíneo Regional/efeitos dos fármacos , Nervo Isquiático/citologia
11.
J Sex Med ; 7(10): 3396-403, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20456626

RESUMO

INTRODUCTION: Activation of the DNA repair enzyme, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), in response to hyperglycemia-driven oxidative/nitrosative stress, may be an important mechanism in the development of vascular and neural complications in diabetes mellitus. However, a role for PARP in diabetic erectile dysfunction (ED) has not been demonstrated. AIM: To assess whether treatment with a novel PARP-1 inhibitor, GPI 15427, could improve neurovascular dysfunction in corpus cavernosum (CC) from diabetic mice. METHODS: Diabetes was induced by streptozotocin in male MF1 mice; duration was 6 weeks. Intervention GPI 15427 treatment (20mg/kg/day intraperitoneal [i.p.]) was given for 2 weeks following 4 weeks of untreated diabetes. CC strips were mounted in aerated organ baths for measurement of pharmacological or electrical stimulation-evoked changes in smooth muscle tension. MAIN OUTCOME MEASURES: Contractile responses to noradrenergic stimulation and to pharmacological agents stimulating endothelium-dependent and -independent relaxation, and nerve-mediated relaxations against a background precontraction. RESULTS: Contractions in response to phenylephrine or activation of noradrenergic nerves were not significantly altered by diabetes. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted CC was approximately 28% reduced by diabetes: GPI 15427 treatment completely corrected this diabetic deficit. Similarly, maximal nitric oxide (NO)-mediated endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, against phenylephrine precontraction, were attenuated approximately 37% and 23% by diabetes, respectively. These deficits were completely reversed by PARP-1 inhibition. Furthermore, GPI 15427 corrected a modest diabetic deficit in sensitivity to nitroprusside (EC(50) reduced by 0.14 log units); a similar trend was observed for acetylcholine-induced relaxation. CONCLUSIONS: GPI 15427 treatment provides marked benefits for NO-dependent neurovascular function in diabetic mouse CC. Therefore, PARP-1 inhibition may be worthy of further investigation for diabetes-associated ED.


Assuntos
Diabetes Mellitus Experimental/complicações , Impotência Vasculogênica/tratamento farmacológico , Compostos Orgânicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases , Acetilcolina/farmacologia , Animais , Glicemia/análise , Relação Dose-Resposta a Droga , Impotência Vasculogênica/etiologia , Masculino , Camundongos , Nitroprussiato/farmacologia , Compostos Orgânicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/efeitos dos fármacos , Pênis/fisiopatologia , Fenilefrina/farmacologia , Poli(ADP-Ribose) Polimerases/fisiologia
12.
Angiology ; 61(4): 405-14, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19815604

RESUMO

Erythropoiesis-stimulating agents (ESAs) are used to treat anemia associated with renal failure. It is now known that these agents also show a broad range of cell- and tissue-protective effects. In the current study, we explored whether an ESA, epoetin delta, affects vascular pathology linked to diabetes mellitus (DM). In a rat model of streptozotocin-induced DM, we investigated, by pre-embedding electron-immunocytochemistry, whether epoetin delta affects DM-induced structural changes in cerebrovascular endothelium of the rat basilar artery and influences the subcellular distribution of endothelial nitric oxide synthase (eNOS). Epoetin delta treatment influenced DM-induced changes to the distribution of eNOS in, and the structure of, the endothelial cell. This may indicate potential beneficial effects of epoetin delta on cerebrovascular endothelium and suggests eNOS as a possible target molecule of epoetin delta in DM.


Assuntos
Artéria Basilar/efeitos dos fármacos , Artéria Basilar/patologia , Diabetes Mellitus Experimental/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Eritropoetina/farmacologia , Animais , Artéria Basilar/enzimologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Endotélio Vascular/enzimologia , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Estreptozocina
13.
Lab Anim (NY) ; 37(3): 112-3, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18292772

RESUMO

This column presents a step-by-step procedure for trimming a rabbit's nails. The technique requires only one person, who uses the rabbit's feedback to determine where to cut the nail, minimizing stress in the animal.


Assuntos
Criação de Animais Domésticos/métodos , Casco e Garras/cirurgia , Animais , Coelhos , Ferimentos e Lesões/prevenção & controle , Ferimentos e Lesões/veterinária
14.
Curr Drug Targets ; 9(1): 60-7, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18220713

RESUMO

Neuropathy is a common complication of diabetes mellitus, which reduces the quality of life and may be life-threatening. The etiology is complex and multifactorial: hyperglycemia and dyslipidemia give rise to oxidative stress and formation of advanced glycation and lipoxidation end products. These stimulate inflammatory processes, nuclear factor kappa B (NFkappaB) activation being of central importance. Many of the drugs that have been developed for treatment of diabetic complication at least in part work through suppressing either NFkappaB activation itself, or the production of cytokines that stimulate NFkappaB, such as tumor necrosis factor (TNF) alpha. To date there have been few tests of drugs that are specific inhibitors of the NFkappaB / TNFalpha axis. However preliminary results in animal models are encouraging and go some way in establishing the NFkappaB cascade as an important therapeutic target for diabetic vascular complications in general, and neuropathy in particular.


Assuntos
Neuropatias Diabéticas/imunologia , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Humanos , NF-kappa B/metabolismo , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo
15.
Exp Neurol ; 207(1): 23-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17560573

RESUMO

Interleukin-6 (IL-6) is a member of the neuropoietic cytokine family and has a multifunctional biological role in regulating the immune response, acute phase reactions, and hematopoiesis. IL-6 is also important in neural development and has neurotrophic actions. The aim was to ascertain whether IL-6 treatment could rectify some of the adverse early changes in neurovascular function in streptozotocin-induced diabetic rats. After 4 weeks of untreated diabetes, rats were treated with IL-6 (1-10 microg/kg thrice weekly) for 4 weeks. Diabetes caused 22% and 22.5% reductions in sciatic nerve motor and saphenous nerve sensory conduction velocity, respectively, which were dose dependently corrected by treatment. Diabetic rats also showed thermal hyperalgesia and tactile allodynia, which were completely corrected by IL-6; however, IL-6 was ineffective against mechanical hyperalgesia. Sciatic nerve endoneurial perfusion was 42.2% reduced by diabetes and blood flow was returned to the nondiabetic range by 10 microg/kg IL-6 treatment. The ED(50) values for these actions ranged from 1.2 microg/kg for sensory conduction velocity to 3.2 microg/kg for sciatic nerve perfusion. Thus, IL-6 treatment improved several measures of nerve dysfunction in experimental diabetes, and these effects correlated with a recovery of nerve blood flow. The magnitude of these beneficial effects and the potential joint neurotrophic and vascular action suggests that IL-6 could be a candidate for further evaluation in clinical trials of diabetic neuropathy.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Interleucina-6/farmacologia , Nervos Periféricos/irrigação sanguínea , Nervos Periféricos/fisiopatologia , Animais , Relação Dose-Resposta a Droga , Nervo Femoral/fisiopatologia , Hiperalgesia/fisiopatologia , Interleucina-6/administração & dosagem , Masculino , Condução Nervosa/efeitos dos fármacos , Neurônios Aferentes , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Nervo Isquiático/fisiopatologia
16.
Eur J Pharmacol ; 561(1-3): 63-71, 2007 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-17291486

RESUMO

Several putative sources of reactive oxygen species could potentially contribute to diabetic neuropathy and vasculopathy. The aim was to assess the involvement of elevated xanthine oxidase activity. After 6 weeks of streptozotocin-diabetes, groups of rats were given 2 weeks of high-dose allopurinol treatment (50 and 250 mg/kg) to gauge the effect of maximal blockade of xanthine oxidase. In the final experiments, rats were subjected to sensory testing and, under butabarbital anaesthesia, measurements were made on nerve conduction velocities and neural tissue blood flow estimated by hydrogen clearance microelectrode polarography. Further groups were used to study detailed responses of the isolated mesenteric vascular bed after 4 weeks of diabetes and allopurinol (150 mg/kg) treatment. Diabetes caused 20% and 14% reduction in motor and sensory conduction velocity, which were 78% and 81% corrected by allopurinol treatment respectively, both doses giving similar results. Diabetic rats showed tactile allodynia and thermal hyperalgesia, which were completely corrected by allopurinol, whereas mechanical hyperalgesia was only 45% ameliorated. Sciatic nerve and superior cervical ganglion blood flow was halved by diabetes and allopurinol corrected this by approximately 63%. Mesenteric endothelium-dependent vascular responses to acetylcholine, which depend upon nitric oxide and endothelium derived hyperpolarizing factor, were attenuated by diabetes. Allopurinol treatment gave approximately 50% protection for both components. Thus, xanthine oxidase is an important source of reactive oxygen species that contributes to neurovascular dysfunction in experimental diabetes. Inhibition of xanthine oxidase could be a potential therapeutic approach to diabetic neuropathy and vasculopathy.


Assuntos
Alopurinol/farmacologia , Angiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Condução Nervosa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Xantina Oxidase/efeitos dos fármacos , Acetilcolina/metabolismo , Alopurinol/administração & dosagem , Animais , Diabetes Mellitus Experimental , Angiopatias Diabéticas/enzimologia , Nefropatias Diabéticas/enzimologia , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Gânglios Autônomos/irrigação sanguínea , Gânglios Autônomos/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Artéria Mesentérica Superior/patologia , Dor/tratamento farmacológico , Polarografia , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Nervo Isquiático/irrigação sanguínea , Nervo Isquiático/efeitos dos fármacos , Xantina Oxidase/metabolismo
17.
Curr Diabetes Rev ; 3(3): 149-58, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18220666

RESUMO

Diabetes is a major risk factor for erectile dysfunction. The condition degrades both neural and vascular endothelium penile control systems. Experimental and epidemiological evidence suggest that both hyperglycemia and dyslipidemia contribute to the etiology. These are the driving forces for elevated oxidative stress and the formation of advanced glycation and lipoxygenation end products, the major target being the nitric oxide systems of nerve and endothelium. This causes reversible functional loss followed by less reversible degenerative changes. These mechanisms have direct effects, such as the nitric oxide quenching, but perhaps more importantly, indirect effects on the regulation of nitric oxide synthase expression and activity, which can involve recruitment of proinflammatory cell signaling pathways. The latter include protein kinase C, mitogen-activated kinases, and the nuclear factor kappa B cascade. Diabetes also changes the trophic influences on nerve and endothelium. Together, these form potential therapeutic targets against diabetic erectile function, and indeed vascular disease in general.


Assuntos
Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/complicações , Disfunção Erétil/etiologia , Animais , Colesterol/biossíntese , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/etiologia , Masculino , Modelos Biológicos , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/fisiologia , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Espécies Reativas de Oxigênio/farmacologia , Transdução de Sinais/fisiologia , Quinases Associadas a rho/fisiologia , Proteína rhoA de Ligação ao GTP/fisiologia
18.
Urology ; 68(1): 214-8, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16806421

RESUMO

OBJECTIVES: Oxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-kappaB, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-kappaB deactivation against direct antioxidant effects has been difficult. NF-kappaB is negatively regulated by the inhibitor of kappaB (IkappaB) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the IkappaB kinase 2 inhibitor, AS602868, on corpus cavernosum function in diabetic mice. METHODS: Diabetes was induced by streptozotocin; the duration was 6 weeks. Intervention AS602868 treatment (100 mg/kg/day) was given for 2 weeks after 4 weeks of untreated diabetes. Corpora cavernosum were isolated in organ baths for measurement of agonist-evoked or electrical stimulation-evoked smooth muscle tensions. RESULTS: The maximal nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was reduced approximately 30% by diabetes (P <0.001). AS602868 treatment completely reversed the deficit (P <0.001). Maximal nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 32% by diabetes (P <0.05). This was completely restored by IkappaB kinase 2 inhibition (P <0.01). Furthermore, AS602868 treatment also completely corrected (P <0.01) an approximate 20% diabetic deficit (P <0.001) in maximal endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside. CONCLUSIONS: Inhibition of IkappaB kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-kappaB activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Quinase I-kappa B/antagonistas & inibidores , NF-kappa B/fisiologia , Ereção Peniana/fisiologia , Animais , Atropina/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Guanetidina/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Mutantes , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Pênis/irrigação sanguínea , Pênis/fisiologia , Fenilefrina/farmacologia , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
19.
Planta Med ; 72(6): 494-500, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16773532

RESUMO

Hyperglycaemia in diabetes mellitus results in oxidative stress and pro-inflammatory changes which contribute to vascular complications including endothelial dysfunction and peripheral neuropathy. The aim of this study was to examine whether treatment with the dominant ingredient of clove oil, eugenol, which has antioxidant and anti-inflammatory properties, could improve diabetic vascular and nerve function in streptozotocin-induced diabetic rats. Intervention treatment was given for 2 weeks following 6 weeks of untreated diabetes. Dose-ranging studies on diabetic deficits in sciatic nerve motor and saphenous nerve sensory nerve conduction velocities gave ED50 values of 28 mg/kg and 9 mg/kg, respectively, conduction velocity being within the non-diabetic range at a dose of 200 mg/kg. Sciatic nerve endoneurial blood flow was 49% reduced by diabetes and this was completely corrected by 200 mg/kg eugenol treatment. Gastric fundus maximum nitrergic nerve-mediated relaxation was 44% reduced by diabetes; eugenol corrected this deficit by 69%. For renal artery rings, maximum endothelium-dependent relaxation to acetylcholine was 51% reduced by diabetes; eugenol corrected this deficit by 60%, with improvements in both nitric oxide and endothelium-derived hyperpolarising factor (EDHF)-mediated vasorelaxation components. Diabetes increased renal artery sensitivity to phenylephrine-mediated contraction, however, this was unaffected by eugenol treatment. Thus, aspects of both vascular and neural complications in experimental diabetes are improved by eugenol, which could have potential therapeutic implications for diabetic neuropathy and vasculopathy.


Assuntos
Antioxidantes/farmacologia , Óleo de Cravo/farmacologia , Angiopatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Eugenol , Fitoterapia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Óleo de Cravo/administração & dosagem , Óleo de Cravo/uso terapêutico , Diabetes Mellitus Experimental , Angiopatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/induzido quimicamente , Relação Dose-Resposta a Droga , Masculino , Condução Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Artéria Renal/fisiologia , Nervo Isquiático/irrigação sanguínea , Nervo Isquiático/fisiologia , Neuropatia Ciática/induzido quimicamente , Neuropatia Ciática/tratamento farmacológico , Circulação Esplâncnica/efeitos dos fármacos , Estreptozocina , Vasodilatação/efeitos dos fármacos
20.
Eur J Pharmacol ; 538(1-3): 148-53, 2006 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-16650403

RESUMO

Calpains, a superfamily of Ca(2+)-activated proteases, are associated with an array of physiological and pathological events, including susceptibility to diabetes. Recently, increased calpain activity has been linked to reduced endothelium-derived nitric oxide-mediated vasodilatation in diabetes. However, a similar mechanism for neuronal-derived nitric oxide has not been examined. Thus, the aim was to investigate effects of the calpain inhibitor A-705253, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethyl-aminomethylphenyl)ethen-1-yl]benzamide, on nitrergic neurovascular function in diabetic mice. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention A-705253 treatment (30 mg/kg/day) was given for 2 weeks following 4 weeks of untreated diabetes. After 6 weeks of diabetes, corpus cavernosa were isolated in organ baths for measurement of agonist- and electrical stimulation-evoked smooth muscle tensions. Adrenergic nerve- and phenylephrine-mediated contractions were not altered by diabetes or calpain inhibition. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 29% reduced by diabetes (P<0.001). This neurological deficit was 66% corrected by A-705253 treatment (P<0.05). Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 39% by diabetes (P<0.01). Similarly, maximum endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside, was blunted approximately 23% by diabetes (P<0.001). A-705253 treatment partially improved endothelium-dependent relaxation to acetylcholine but had no effect on the deficit in response to nitroprusside. The data suggest that calpain contributes to the aetiology of diabetic nitrergic autonomic neuropathy and endothelial dysfunction, which may provide a novel therapeutic target for neurovascular complications.


Assuntos
Benzamidas/farmacologia , Calpaína/antagonistas & inibidores , Diabetes Mellitus Experimental/fisiopatologia , Neurônios Nitrérgicos/efeitos dos fármacos , Pênis/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Camundongos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Neurônios Nitrérgicos/fisiologia , Nitroprussiato/farmacologia , Tamanho do Órgão , Pênis/inervação , Pênis/fisiopatologia , Fenilefrina/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
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