Cutaneous blood flow in type 2 diabetic individuals after an acute bout of maximal exercise

OBJECTIVE: We previously demonstrated a positive association between chronic aerobic exercise and dorsal foot skin blood flow during local heating in type 2 diabetic individuals. Thus, we hypothesized that a prior acute bout of maximal exercise would also have positive effects on postexercise blood flow. RESEARCH DESIGN AND METHODS: Subjects consisted of 32 individuals with type 2 diabetes and 26 nondiabetic control subjects further subdivided based on their physical activity status: diabetic exerciser (DE), diabetic sedentary (DS), control exerciser (CE), or control sedentary. Dorsal foot cutaneous blood flow was measured noninvasively by continuous laser-Doppler assessment at baseline and during local heating to 44 degrees C before and after a maximal bout of cycle exercise. Interstitial nitric oxide (NO) levels were measured concurrently in the foot dorsum. RESULTS: Increases in blood flow and its responsiveness to local heating to 44 degrees C were significantly lower in both diabetic groups compared with CE before maximal exercise, but perfusion responsiveness remained lower in DS subjects only after exercise (P < 0.05). Baseline skin blood flow was not different among groups preexercise, but it was significantly increased postexercise in DE subjects only. Interstitial NO levels were not significantly different at either time. At baseline, groups differed only in HbA(1c), fasting serum glucose, HDL cholesterol, and insulin resistance (homeostasis model assessment method). CONCLUSIONS: All diabetic individuals exhibit a blunted responsiveness of cutaneous blood flow with local heating to 44 degrees C before maximal exercise compared with active nondiabetic individuals, but after an exercise bout, it remains significantly blunted only in diabetic individuals who are sedentary. These findings occur independently of changes in interstitial NO levels.     

Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway

Introduction  

Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite.     

Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity

We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied. Arachidonic acid (AA; 100 microM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ29548). Diabetes did not affect prostaglandin (PG)E(1)-induced relaxation, but it reduced relaxation induced by the PGE(1) metabolite PGE(0). This effect was related to an interaction of PGE(0) with TP receptors. Diabetic tissues had reduced endothelium-dependent relaxation, which was partially improved by SQ29548 and completely normalized by the PKC inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X; 1 microM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 microM) significantly attenuated endothelium-dependent relaxation, an effect prevented by coadministration of GF109203X. Tissues from diabetic patients had enhanced sensitivity to the contractile effects of the TP receptor agonist 9,11-dideoxy-9alpha,11alpha-epoxymethano PGF(2alpha) (U46619) (EC(50) = 0.65 +/- 0.42 and 6.01 +/- 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 microM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC(50) = 8.55 +/- 3.12 microM). Overactivity of PKC in diabetes is responsible for enhanced contraction and reduced endothelium-dependent relaxation of HCC smooth muscle. Such alterations can result in erectile dysfunction.     

脐血干细胞移植2型糖尿病下肢血管病变患者内皮依赖性血管舒张的变化

背景：研究表明,干细胞在一定诱导条件下可分化成为血管性内皮细胞,促进局部血管再生,生成新的毛细血管网,建立丰富的侧支循环,以达到改善和治疗下肢缺血的目的。目的：观察脐血干细胞对2型糖尿病合并血管病变患者内皮依赖性血管舒张功能的影响。方法：100例2型糖尿病下肢血管病变患者分为两组,试验组60例,对照组40例,试验组静脉输注脐血干细胞,对照组输注生理盐水,4周后比较两组基础指标及内皮依赖性血管舒张功能。结果与结论：试验组治疗后空腹血糖、餐后2 h血糖、糖化血红蛋白、胆固醇、三酰甘油水平较治疗前均明显下降（P〈0.05）,空腹胰岛素、餐后2 h胰岛素、血管内皮舒张功能较治疗前均明显升高（P〈0.05）。对照组空腹血糖、餐后2 h血糖、糖化血红蛋白、胆固醇、三酰甘油、血管内皮舒张功能治疗前后差异无显著性意义（P〉0.05）。结果表明脐血干细胞移植可以改善2型糖尿病下肢血管病变患者的内皮功能,促进侧支循环,避免糖尿病足的发生。     

The addition of blood flow restriction to resistance exercise in individuals with knee pain: a systematic review and meta-analysis

BackgroundBlood flow restriction (BFR) is an effective clinical intervention used to increase strength in healthy individuals. However, its effects on pain and function in individuals with knee pain are unknown.ObjectiveTo determine the effectiveness of adding BFR to resistance exercise for pain relief and improvement of function in patients with knee pain.MethodsSystematic review with meta-analysis of randomized clinical trials. Medline, Central, Embase, PEDro, Lilacs, CINAHL, SPORTDiscus, and Web of Science databases were searched from inception to May 2019. Randomized clinical trials that compared resistance exercise with or without BFR to treat knee pain and function in individuals older than 18 years of age with knee pain were included.ResultsEight randomized clinical trials met the eligibility criteria and for the quantitative synthesis, five studies were included. The pooled standardized mean difference (SMD) estimate showed that resistance exercises with BFR was not more effective than resistance exercises for reducing pain (SMD: −0.37 cm, 95% CI = −0.93, 0.19) and improving knee function (SMD = −0.23 points, 95% CI = −0.71, 0.26) in patients with knee pain.ConclusionIn the short term, there is low quality of evidence that resistance exercise with BFR does not provide significant differences in pain relief and knee function compared to resistance exercises in patients with knee pain.PROSPERO registration number: CRD42018102839.     

Diabetic retinopathy is related to both endothelium-dependent and -independent responses of skin microvascular flow

OBJECTIVE

Endothelial dysfunction has been hypothesized as a possible pathogenic factor in the development of diabetic retinopathy (DR). We examined the relationship of DR to endothelium-dependent and endothelium-independent responses in skin microvascular flow.

RESEARCH DESIGN AND METHODS

Participants consisted of 224 individuals with diabetes: 85 with type 1 diabetes and 139 with type 2 diabetes. Sodium nitroprusside (SNP) and acetylcholine (ACh) were delivered across the skin by iontophoresis. Laser Doppler flowmetry was used to assess the skin microcirculation response to SNP (endothelium-independent response) and ACh (endothelium-dependent response). The presence and severity of DR were graded from retinal photographs using a standard protocol.

RESULTS

Of 224 participants, 64.3% had DR. After multivariable adjustment, participants with reduced responses to SNP or ACh were more likely to have DR, with an odds ratio (OR) of 2.33 (95% CI 1.09–5.01) for SNP and 2.20 (1.05–4.61) for ACh, comparing participants with responses below and above the median values. Participants with reduced responses (below the median) to both SNP and ACh were nearly four times more likely to have DR (OR 3.86 [1.45–10.3]) than those with SNP and ACh both above the median values.

CONCLUSIONS

The presence of DR was associated with a reduction in skin microcirculation responses to iontophoresis of both SNP and ACh, suggesting that vascular processes associated with both endothelial dysfunction and endothelial function-independent mechanisms may be pathogenically related to DR.Diabetes affects 285 million individuals worldwide (1), and diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in most developed countries (2). Although it has been suggested that endothelial dysfunction may underlie the pathogenesis of DR (3), the few clinical and epidemiologic studies to date have found inconsistent associations of DR with indirect serum markers of endothelial function (e.g., soluble vascular adhesion molecule-1) (4–9) or brachial flow–mediated dilation (FMD) (10–13), a more direct measurement of endothelial dysfunction (14).Drug delivery to the skin by iontophoresis, accompanied by laser Doppler technology to measure microvascular flow, has been validated as a measure of endothelial function in the skin microcirculation (15). Responses of the skin microcirculation to sodium nitroprusside (SNP) and acetylcholine (ACh) are measures of endothelium-independent and endothelium-dependent responses, respectively. Studies have shown a strong correlation between endothelial function assessed by FMD of the brachial artery and ACh increase in skin blood flow (r = 0.92, P < 0.0001) (16). Further study has shown that impaired skin microvascular response is associated with a range of cardiovascular risk factors and diseases (15).In this study, we examined the relationship of DR with skin microvascular dysfunction as measured by iontophoresis and laser Doppler flowmetry in a clinical sample of patients with diabetes. Our aim was to establish whether DR was associated with systemic microvascular dysfunction evidenced in the skin and whether this was primarily driven by endothelial dysfunction.     

Human arterial responses to isometric exercise: the role of the muscle metaboreflex

The effects of exercise on the distensibility of large and medium-sized arteries are poorly understood, but can be attributed to a combination of local vasodilator effects of exercise opposed by sympathetic vasoconstrictor tone. We sought to examine this relationship at the conduit artery level, with particular reference to the role of the sympatho-excitatory muscle metaboreflex. The effect of maintained muscle metaboreflex activation on a previously passive or exercised limb femoral artery was investigated. A total of ten healthy volunteers performed 2 min of isometric ankle plantar-flexion at 40% MVC (maximal voluntary force), in conjunction with 2 min of either non-ischaemic isometric HG (handgrip; control condition) or IHG (ischaemic HG) at 40% MVC. IHG was followed by 2 min of PECO (post-exercise circulatory occlusion) to maintain muscle metaboreflex activation. FTPWV [femoral-tibial PWV (pulse wave velocity)] was measured in the exercised or contralateral limb at baseline and immediately following calf exercise. BP (blood pressure) and HR (heart rate) were measured continuously throughout. In the HG condition, BP and HR returned promptly to baseline post-exercise, whereas exercised leg FTPWV was decreased (less stiff) by 0.6 m/s (P<0.05) and the non-exercised leg PWV was not changed from baseline. PECO caused a sustained increase in BP, but not HR, in the IHG condition. Contralateral leg PWV increased (stiffened) during PECO by 0.9 m/s (P<0.05), whereas exercised limb FTPWV was not changed from baseline. In conclusion, muscle metaboreflex activation causes a systemic stiffening of the arterial tree, which can overcome local exercise-induced decreases in arterial PWV.     

Cerebral myogenic reactivity and blood flow in type 2 diabetic rats: role of peroxynitrite in hypoxia-mediated loss of myogenic tone

Dysregulation of cerebral vascular function and, ultimately, cerebral blood flow (CBF) may contribute to complications such as stroke and cognitive decline in diabetes. We hypothesized that 1) diabetes-mediated neurovascular and myogenic dysfunction impairs CBF and 2) under hypoxic conditions, cerebral vessels from diabetic rats lose myogenic properties because of peroxynitrite (ONOO(-))-mediated nitration of vascular smooth muscle (VSM) actin. Functional hyperemia, the ability of blood vessels to dilate upon neuronal stimulation, and myogenic tone of isolated middle cerebral arteries (MCAs) were assessed as indices of neurovascular and myogenic function, respectively, in 10- to 12-week control and type 2 diabetic Goto-Kakizaki rats. In addition, myogenic behavior of MCAs, nitrotyrosine (NY) levels, and VSM actin content were measured under normoxic and hypoxic [oxygen glucose deprivation (OGD)] conditions with and without the ONOO(-) decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl) prophyrinato iron (III), chloride (FeTPPs). The percentage of myogenic tone was higher in diabetes, and forced dilation occurred at higher pressures. Functional hyperemia was impaired. Consistent with these findings, baseline CBF was lower in diabetes. OGD reduced the percentage of myogenic tone in both groups, and FeTPPs restored it only in diabetes. OGD increased VSM NY in both groups, and although FeTPPs restored basal levels, it did not correct the reduced filamentous/globular (F/G) actin ratio. Acute alterations in VSM ONOO(-) levels may contribute to hypoxic myogenic dysfunction, but this cannot be solely explained by the decreased F/G actin ratio due to actin nitration, and mechanisms may differ between control and diabetic animals. Our findings also demonstrate that diabetes alters the ability of cerebral vessels to regulate CBF under basal and hypoxic conditions.     

Stiffness and impaired blood flow in lower-leg arteries are associated with severity of coronary artery calcification among asymptomatic type 2 diabetic patients

OBJECTIVE: To clarify whether stiffness and impaired blood flow in lower-leg arteries are associated with severity of coronary artery calcification among asymptomatic diabetic patients. RESEARCH DESIGN AND METHODS: We enrolled 102 asymptomatic type 2 diabetic patients with no history of cardiovascular complications consecutively admitted to our hospital. Agatston coronary artery calcium (CAC) score, as a marker of coronary artery calcification, was obtained using electron-beam computed tomography. Total flow volume and resistive index, as an index of vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial-ankle pulse-wave velocity (PWV), as an index of distensibility in the lower-extremity arteries, was also measured using an automatic device. RESULTS: When the patients were grouped according to CAC scores of 0-10 (n = 54), 11-100 (n = 25), and > 100 (n = 23), those with the highest scores, which is considered to show possible coronary artery disease, showed the highest brachial-ankle PWV (P < 0.001) and resistive index (P < 0.001) and the lowest total flow volume (P < 0.001) among the groups. Simple linear regression analyses showed that both brachial-ankle PWV (r = 0.508, P < 0.001) and resistive index (r = 0.500, P < 0.001) were positively correlated and total flow volume (r = -0.528, P < 0.001) was negatively correlated with the log-transformed CAC score. Receiver operator characteristic curve analyses indicated that 1,800 cm/s for brachial-ankle PWV, 1.03 for resistive index, and 70 ml/min for total flow volume were diagnostic values for identifying patients with the highest scores. CONCLUSIONS: Quantitatively assessed stiffness and impaired blood flow in lower-leg arteries may help identify diabetic patients with possible coronary artery disease.     

Management of blood donors and blood donations from individuals found to have a positive direct antiglobulin test

The medical literature is replete with articles addressing the diagnosis and management of patients with a positive direct antiglobulin test (DAT). However, there is scant information addressing the management of blood donors and blood donations found to have a positive DAT. Practices vary considerably between countries and blood suppliers within countries, and there is no standardized approach to the management of these blood donors or the blood products prepared from their donations. Recent evidence from Israel suggests that the finding of a positive DAT in a blood donor may not be as benign as previously thought. Therefore, it may be prudent for blood collection agencies to periodically reexamine their approach to the management of blood donors with a positive DAT and their donations. This article reviews the available literature and explores options for the management of DAT-positive blood donors and their blood donations.     

Musculoskeletal responses of spinal cord injured individuals to functional neuromuscular stimulation-induced knee extension exercise training

This study was conducted to evaluate a newly designed functional neuromuscular stimulation (FNS)-induced knee extension (KE) exercise system that incorporates the most desired features of previously described systems by determining the musculoskeletal responses of spinal cord injured (SCI) individuals to training. A specially designed chair and electrical stimulator were fabricated for FNS-induced KE resistance exercise. Surface electrodes were placed over motor points of the quadriceps muscles, and KE was alternated between legs at an average rate of 6 KE/min/leg. KE testing protocols were developed for pre- and post-training evaluations of performance, and 12 SCI subjects exercise-trained up to three times per week for 36 sessions using a progressive resistance load at ankle level. Pre- and post-training evaluation data were statistically compared using a 0.05 level for significance. Quadriceps muscle performance (strength x repetitions) improved for both legs in all subjects as indicated by significant increases in load resistance and repetitions over the 36-session training period (right leg mean = 1156.0 versus 1624.8 kg.reps, left leg mean = 1127.3 versus 1721.1 kg.reps). In addition, knee range of motion significantly increased (right leg mean = 134 versus 146 degrees, left leg mean = 133 versus 144 degrees). Thigh skinfold, thigh girth, body weight and bone density were not significantly changed. The lack of decrease in bone density in some subjects suggests that the training may retard the rate of bone loss which typically occurs with SCI. No injuries or problems were encountered during testing and training.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic responses of spinal cord injured individuals to functional neuromuscular stimulation-induced knee extension exercise

The purpose of this study was to determine and compare acute hemodynamic responses of spinal cord injured (SCI) quadriplegics (quads), and paraplegics (paras) during a graded-intensity knee extension (KE) exercise test utilizing functional neuromuscular stimulation (FNS) of paralyzed quadriceps muscles. Seven quads and seven paras (N = 14) performed a series of 4-minute stages of bilateral alternating FNS-KE exercise (approximately zero to 70 degree range of motion at the knee and 6 KE/min/leg) at ankle loads of 0, 5, 10, and 15 kg/leg. Physiologic responses were determined with open-circuit spirometry, impedance cardiography, and auscultation. Comparing rest with peak FNS-KE for both groups combined, FNS-KE exercise elicited significant (p less than 0.05) increases in oxygen uptake (130 percent), pulmonary ventilation (120 percent), respiratory exchange ratio (37 percent), arteriovenous oxygen difference (57 percent), cardiac output (32 percent), stroke volume (41 percent), mean arterial pressure (18 percent), and rate-pressure product (23 percent). Heart rate increased significantly by 11 percent from the 5- to the 15-kg/leg stages. Physiologic responses of quads and paras were very similar, except for lower (p less than 0.05) arterial pressures, rate-pressure product, and peripheral vascular resistance in quads. This graded FNS-KE exercise up to the 15-kg/leg load induced relatively small but appropriate increases in aerobic metabolism and cardiopulmonary responses that appear to be safe and easily tolerated by quads and paras. Arterial pressure needs to be monitored carefully in quads to prevent excessive hypertension or hypotension. Although FNS-KE exercise has been shown to elicit peripheral adaptations to improve muscle strength and endurance, it is probably not an effective central cardiovascular training tool for all but the least fit SCI individuals. This information is important for understanding the effects of FNS use during more complex activities such as cycling and ambulation.     

Short-term variability of cerebral blood flow velocity responses to arterial blood pressure transients

The time course of mean beat-to-beat changes in cerebral blood flow velocity changes induced by spontaneous transients in mean arterial blood pressure was studied in a group of 39 healthy subjects, ages 40 +/- 15 (SD) years. Continuous 10-min noninvasive recordings of cerebral blood flow velocity (CBFV) from both middle cerebral arteries (MCA) with Doppler ultrasound (US) and simultaneous beat-to-beat arterial blood pressure (ABP) were made. A total of 522 spontaneous positive transients of ABP and CBFV were extracted with a maximum of 15 transients for each subject. The CBFV transient amplitude was normalized by the corresponding ABP change and the area-under-the-curve (AUC) of the falling phase was used to classify the CBFV regulatory response as either weak, moderate or strong. The coherent average of ABP and CBFV of each category confirmed the consistency of this classification, reinforced by the agreement of separate averages for recordings from the right and left MCA. All 39 subjects showed at least two categories of transients, with all three categories present in 33 subjects (right MCA) and 29 subjects (left MCA), respectively. These results indicate a significant short-term variability of CBFV responses in healthy subjects whose origin remains unexplained.