Spirulina extract improves age-induced vascular dysfunction.

CONTEXT: Vascular dysfunction is considered a hallmark of ageing that has been associated with altered vasomotor responses, in which nitric oxide (NO) and reactive oxygen species participate. The consumption of Spirulina extracts, with antioxidant properties, increased recently. OBJECTIVE: This study investigates the effect of Spirulina aqueous extract (SAE) on the vascular function of the aorta from aged rats. MATERIALS AND METHODS: Aortic segments from aged male Sprague-Dawley rats (20-22 months old) were exposed to SAE (0.1% w/v, for 3 h) to analyse: (i) the vasodilator response induced by acetylcholine (ACh), by the NO donor sodium nitroprusside (SNP), by the carbon monoxide releasing molecule (CORM) and by the KATP channel opener, cromakalim (CK); (ii) the vasoconstrictor response induced by KCl and noradrenaline (NA); (iii) the production of NO and superoxide anion, and (iv) the expression of the p-eNOS and HO-1 proteins. RESULTS: Incubation with SAE increased the expression of p-eNOS (1.6-fold) and HO-1 (2.0-fold), enhanced NO release (1.4-fold in basal and 1.9-fold in ACh-stimulated conditions) while decreased the production of superoxide (0.7-fold). SAE also increased the sensitivity (measured as pEC50) to ACh (control: -7.06 ± 0.11; SAE: -8.16 ± 0.21), SNP (control: -7.96 ± 0.16; SAE: -9.11 ± 0.14) and CK (control: -7.05 ± 0.39; SAE: -8.29 ± 0.53), and potentiated the response to KCl (1.3-fold) and to NA (1.7-fold). CONCLUSION: The antioxidant properties of SAE improved the vasomotor responses of aorta from aged rats. These results may support the use of Spirulina as a protection against vascular dysfunction.

Effect of CLA supplementation on factors related to vascular dysfunction in arteries of orchidectomized rats.

The vascular endothelium is a monolayer of flat epithelial cells located between the circulating blood and the underlying connective tissue. It conveys key functions that when impaired, lead to endothelial dysfunction. This condition is responsible for the pathogenesis of vascular diseases. The cardioprotective effect of sex hormones is widely known; hence, a murine orchidectomized model has been employed to study the effects caused by their deficiency. In the search for approaches to maintain vascular health, the effect of dietary fatty acids as CLA on cardiovascular diseases has been studied. Some proven beneficial properties of CLA are antioxidant, antiatherogenic and anti-inflammatory. Our objective was to evaluate the effect of a diet supplemented with 1.8 % (w/w) of CLA, administered during eight weeks, on the amount of cholesterol oxidation products (COPs) produced by orchidectomy and on factors related to vascular dysfunction in the aorta and the mesenteric arteries. The diet with CLA prevented the increase in prostanoids formation and maintained the normal physiological conditions of NO and antioxidant activity. In addition, it prevented the increase in cholesterol and COPs at the vascular wall. CLA-supplemented diet prevented the orchidectomy-induced alterations on prostanoids, NO and COPs and also improved the antioxidant activity. These findings could contribute to understand the mechanisms of actions of CLA involved in the prevention of cardiovascular diseases.

Gonadal function protects against organ culture-induced vascular damage. Involvement of prostanoids.

Androgen deprivation induces vascular dysfunction in which altered release and action of prostanoids has been extensively studied. On the other hand, the vascular organ-culture system has been reported as a valid model for phenotypic changes that occur in several cardiovascular pathologies. Since there are no studies analyzing the impact of androgenic loss on vascular vulnerability during induced vascular damage, the objective of this study was to analyze the possible preventive role of male sex hormones on the organ culture-induced vascular damage in rat aorta. The link to possible changes in gross structure was also analyzed. For this purpose, fresh and 20 h-cultured aortic arterial segments from intact and orchidectomized rats were used to analyze: (i) the release and vasomotor effect of the thromboxane A2 (TXA2), prostaglandin (PG) E2, PGF2α and PGI2; (ii) the vasodilator response induced by acetylcholine (ACh) as well as the involvement of prostanoids, in particular TXA2, in the ACh-induced response; (iii) the effect of activation of thromboxane/prostaglandin (TP) receptors on the ACh-induced response; and (iv) the vascular structure. The results showed that organ culture: i) increased production of prostanoids; ii) increased prostanoids-induced vasomotor responses; iii) decreased ACh-induced relaxation after incubation with indomethacin, a blocker of cyclooxygenases; iv) increased the ACh-induced relaxation after incubation with the TXA2 synthase inhibitor, furegrelate, more in arteries from orchidectomized rats than in those of intact rats; v) diminished ACh-induced relaxation after U-46619 incubation only in arteries from orchidectomized rats; and vi) preserved the integrity of the different vascular layers. These results showed the protective role of male sex hormones against the induced vascular damage, since a decreased deleterious effect of prostanoids, in particular that of TXA2, was observed in arteries from rats with intact gonadal function.

RISK FACTORS FOR HYPOGLYCEMIA IN INPATIENTS WITH TOTAL PARENTERAL NUTRITION AND TYPE 2 DIABETES: A POST HOC ANALYSIS OF THE INSUPAR STUDY.

Objective: Treatment of hyperglycemia with insulin is associated with increased risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients receiving total parenteral nutrition (TPN). The aim of this study was to determine the predictors of hypoglycemia in hospitalized T2DM patients receiving TPN. Methods: Post hoc analysis of the INSUPAR study, which is a prospective, open-label, multicenter clinical trial of adult inpatients with T2DM in a noncritical setting with indication for TPN. Results: The study included 161 patients; 31 patients (19.3%) had hypoglycemic events, but none of them was severe. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes with end-organ damage, duration of diabetes, use of insulin prior to admission, glycemic variability (GV), belonging to the glargine insulin group in the INSUPAR trial, mean daily grams of lipids in TPN, mean insulin per 10 grams of carbohydrates, duration of TPN, and increase in urea during TPN. Multiple logistic regression analysis showed that the presence of diabetes with end-organ damage, GV, use of glargine insulin, and TPN duration were risk factors for hypoglycemia. Conclusion: The presence of T2DM with end-organ damage complications, longer TPN duration, belonging to the glargine insulin group, and greater GV are factors associated with the risk of hypoglycemia in diabetic noncritically ill inpatients with parenteral nutrition. Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CV% = coefficient of variation; DM = diabetes mellitus; GI = glargine insulin; GV = glycemic variability; ICU = intensive care unit; RI = regular insulin; T2DM = type 2 diabetes mellitus; TPN = total parenteral nutrition.

Defective p27 phosphorylation at serine 10 affects vascular reactivity and increases abdominal aortic aneurysm development via Cox-2 activation.

Phosphorylation at serine 10 (S10) is the major posttranslational modification of the tumor suppressor p27, and is reduced in both human and mouse atherosclerosis. Moreover, a lack of p27-phospho-S10 in apolipoprotein E-null mice (apoE-/-) leads to increased high-fat diet-induced atherosclerosis associated with endothelial dysfunction and augmented leukocyte recruitment. In this study, we analyzed whether p27-phospho-S10 modulates additional endothelial functions and associated pathologies. Defective p27-phospho-S10 increases COX-2 activity in mouse aortic endothelial cells without affecting other key regulators of vascular reactivity, reduces endothelium-dependent dilation, and increases arterial contractility. Lack of p27-phospho-S10 also elevates aortic COX-2 expression and thromboxane A2 production, increases aortic lumen diameter, and aggravates angiotensin II-induced abdominal aortic aneurysm development in apoE-/- mice. All these abnormal responses linked to defective p27-phospho-S10 are blunted by pharmacological inhibition of COX-2. These results demonstrate that defective p27-phospho-S10 modifies endothelial behavior and promotes aneurysm formation via COX-2 activation.

Vasoactive androgens: Vasorelaxing effects and their potential regulation of blood pressure.

BACKGROUND: Testosterone, 5α- and 5ß-dihydrotestosterone (-DHT) induce an acute in vitro vasorelaxation and in vivo vasodepressor, hypotensive and antihypertensive responses. Our aim was to study whether androgen-induced blood pressure (BP) reduction is involved with a blockade of Ca2+ influx through L-type voltage-operated calcium channels (L-VOCCs) and/or the signaling pathways of α1-adrenoceptors to induce vasoconstriction, which are one of the major mechanisms of BP maintenance. MATERIALS AND METHODS: The relaxing potency and efficacy of each androgen in large conduit (thoracic aorta) and resistance (mesenteric) arteries from male hypertensive (SHR) and normotensive (WKY) rats were established. Blood vessels were isometrically recorded and precontracted with KCl or phenylephrine (Phe). RESULTS: Androgens induced concentration-dependent vasorelaxation in precontracted arteries from SHR and WKY rats. 5ß-DHT was always the most potent vasorelaxant in arteries from SHR. The KCl-induced contraction resulted significantly more sensitive to androgen-induced vasorelaxation than the Phe-induced contraction. On Phe-induced contraction, 5ß-DHT was more potent in the mesenteric artery than in the thoracic aorta. CONCLUSIONS: The vasorelaxation induced by androgens is mainly mediated by blocking L-VOCCs and in lesser extent by the blockade of multiple signaling pathways operative during α-adrenoceptor-induced vasoconstriction. 5ß-DHT regulates vascular resistance and BP by mainly acting in the mesenteric arterial bed, which may explain its outstanding antihypertensive response previously reported.

Prevalence of diabetes, prediabetes, and stress hyperglycemia: insulin therapy and metabolic control in patients on total parenteral nutrition (prospective multicenter study).

OBJECTIVE: The prevalence of carbohydrate metabolism disorders in patients who receive total parenteral nutrition (TPN) is not well known. These disorders can affect the treatment, metabolic control, and prognosis of affected patients. The aims of this study were to determine the prevalence in noncritically ill patients on TPN of diabetes, prediabetes, and stress hyperglycemia; the factors affecting hyperglycemia during TPN; and the insulin therapy provided and the metabolic control achieved. METHODS: We undertook a prospective multicenter study involving 19 Spanish hospitals. Noncritically ill patients who were prescribed TPN were included, and data were collected on demographic, clinical, and laboratory variables (glycated hemoglobin, C-reactive protein [CRP], capillary blood glucose) as well as insulin treatment. RESULTS: The study included 605 patients. Before initiation of TPN, the prevalence of known diabetes was 17.4%, unknown diabetes 4.3%, stress hyperglycemia 7.1%, and prediabetes 27.8%. During TPN therapy, 50.9% of patients had at least one capillary blood glucose of >180 mg/dL. Predisposing factors were age, levels of CRP and glycated hemoglobin, the presence of diabetes, infectious complications, the number of grams of carbohydrates infused, and the administration of glucose-elevating drugs. Most (71.6%) patients were treated with insulin. The mean capillary blood glucose levels during TPN were: known diabetes (178.6 ± 46.5 mg/dL), unknown diabetes (173.9 ± 51.9), prediabetes (136.0 ± 25.4), stress hyperglycemia (146.0 ± 29.3), and normal (123.2 ± 19.9) (P<.001). CONCLUSION: The prevalence of carbohydrate metabolism disorders is very high in noncritically ill patients on TPN. These disorders affect insulin treatment and the degree of metabolic control achieved.

Testosterone and ß-oestradiol prevent inward remodelling of rat small mesenteric arteries: role of NO and transglutaminase.

Increasing evidence shows that sex hormones exert a protective effect on the vasculature, especially in the regulation of the active vasomotor responses. However, whether sex hormones affect vascular remodelling is currently unclear. In the present study, we tested the hypothesis that testosterone in males and ß-oestradiol in females prevent inward remodelling, possibly through inhibition of cross-linking activity induced by enzymes of the TG (transglutaminase) family. Small mesenteric arteries were isolated from male and female Wistar rats. Dose-dependent relaxation to testosterone and ß-oestradiol was inhibited by the NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester), confirming that these hormones induce NO release. When arteries were cannulated, pressurized and kept in organ culture with ET-1 (endothelin-1) for 3 days we observed strong vasoconstriction and inward remodelling. Remodelling was significantly inhibited by testosterone in males, and by ß-oestradiol in females. This preventive effect of sex hormones was not observed in the presence of L-NAME. Inward remodelling was also reduced by the inhibitor of TG L682.777, both in males and females. In arteries from female rats, ET-1 increased TG activity, and this effect was prevented by ß-oestradiol. L-NAME induced a significant increase in TG activity in the presence of sex hormones in arteries from both genders. We conclude that testosterone and ß-oestradiol prevent constriction-induced inward remodelling. Inward remodelling, both in males and females, depends on NO and TG activity. In females, inhibition of inward remodelling could be mediated by NO-mediated inhibition of TG activity.

Dietary modulation of gut microbiota in patients with colorectal cancer undergoing surgery: A review.

Colorectal cancer (CRC) is the third most frequent malignancy and the second cause of cancer death worldwide. Several factors have been postulated to be involved in CRC pathophysiology, including physical inactivity, unhealthy dietary habits, obesity, and the gut microbiota. Emerging data suggest that the microbiome may play a key role in CRC prognosis and derived complications in patients undergoing colorectal surgery. On the other hand, dietary intervention has been demonstrated to be able to induce significant changes in the gut microbiota and related metabolites in different conditions; therefore, the manipulation of gut microbiota through dietary intervention may constitute a useful approach to improve perioperative dysbiosis and post-surgical outcomes in patients with CRC. In this article, we review the role of the gut microbiota in CRC surgery complications and the potential therapeutic modulation of gut microbiome through nutritional intervention in patients with CRC undergoing surgery.

Visceral larva migrans in immigrants from latin america.

To determine whether increased migration is associated with an increase in incidence of toxocariasis (visceral larva migrans), we analyzed clinical data obtained from immigrants from Latin America. Although infection with Toxocara sp. roundworm larvae is distributed worldwide, seroprevalence is highest in tropical and subtropical areas.

Vasomotor action of androgens in the mesenteric artery of hypertensive rats. Role of perivascular innervation.

Androgens may exert cardiovascular protective actions by regulating the release and function of different vascular factors. In addition, testosterone (TES) and its 5-reduced metabolites, 5α- and 5ß-dihydrotestosterone (5α- and 5ß-DHT) induce vasorelaxant and hypotensive effects. Furthermore, hypertension has been reported to alter the release and function of the neurotransmitters nitric oxide (NO), calcitonin gene-related peptide (CGRP) and noradrenaline (NA). Since the mesenteric arteries possess a dense perivascular innervation and significantly regulate total peripheral vascular resistance, the objective of this study was to analyze the effect of TES, 5α- and 5ß-DHT on the neurogenic release and vasomotor function of NO, CGRP and NA. For this purpose, the superior mesenteric artery from male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to analyze: (i) the effect of androgens (10 nM, incubated for 30 min) on the neurogenic release of NO, CGRP and NA and (ii) the vasoconstrictor-response to NA and the vasodilator responses to the NO donor, sodium nitroprusside (SNP) and exogenous CGRP. The results showed that TES, 5α- or 5ß-DHT did not modify the release of NO, CGRP or NA induced by electrical field stimulation (EFS) in the arteries of SHR; however, in the arteries of WKY rats androgens only caused an increase in EFS-induced NO release. Moreover, TES, and especially 5ß-DHT, increased the vasodilator response induced by SNP and CGRP in the arteries of SHR. These findings could be contributing to the hypotensive/antihypertensive efficacy of 5ß-DHT previously described in conscious SHR and WKY rats, pointing to 5ß- DHT as a potential drug for the treatment of hypertension.

Androgen Deprivation Therapy in Patients With Prostate Cancer Increases Serum Levels of Thromboxane A2: Cardiovascular Implications.

Introduction: Androgens have been described as important players in the regulation of vascular function/structure through their action on the release and effect of vasoactive factors, such as prostanoids. Patients with prostate cancer (PCa) under androgen deprivation therapies (ADTs) present increased risk of cardiovascular mortality. Since thromboxane A2 (TXA2) is one of the most studied prostanoids and its involvement in different cardiovascular diseases has been described, the aim of this study was to investigate: (i) the effect of ADT on the serum levels of TXA2 in PCa patients and its possible link to the redox status and (ii) the effect of the non-hydrolyzable TXA2 analog U-46619 on the function of the aorta of male rats. Methods: The levels of TXA2 and total antioxidant status in 50 healthy subjects, 54 PCa patients, and 57 PCa under ADT were evaluated. These determinations were accompanied by levels of testosterone and C-reactive protein as an inflammation marker. In aortic segments from male rats, the U46619-induced effects on: (i) the vasomotor responses to acetylcholine (ACh), to the NO donor sodium nitroprusside (SNP), to the carbon monoxide-releasing molecule-3 (CORM-3), and to noradrenaline (NA) and (ii) the expression of cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), and phosphorylated ERK1/2 were analyzed. Results: The serum level of TXA2 in patients with PCa was increased with respect to healthy subjects, which was further increased by ADT. There was no modification in the total antioxidant status among the three experimental groups. In aortic segments from male rats, the TXA2 analog decreased the endothelium-dependent relaxation and the sensitivity of smooth muscle cells to NO, while it increased the vasoconstriction induced by NA; the expression of COX-2, HO-1, and pERK1/2 was also increased. Conclusions: ADT increased, along with other inflammatory/oxidative markers, the serum levels of TXA2. The fact that TXA2 negatively impacts the vascular function of the aorta of healthy male rats suggests that inhibition of TXA2-mediated events could be considered a potential strategy to protect the cardiovascular system.

Long-term antibiotic therapy in patients with surgery-indicated not undergoing surgery infective endocarditis.

BACKGROUND: To date, there is little information regarding management of patients with infective endocarditis (IE) that did not undergo an indicated surgery. Therefore, we aimed to evaluate prognosis of these patients treated with a long-term antibiotic treatment strategy, including oral long term suppressive antibiotic treatment in five referral centres with a multidisciplinary endocarditis team. METHODS: This retrospective, multicenter study retrieved individual patient-level data from five referral centres in Spain. Among a total of 1797, 32 consecutive patients with IE were examined (median age 72 years; 78% males) who had not undergone an indicated surgery, but received long-term antibiotic treatment (LTAT) and were followed by a multidisciplinary endocarditis team, between 2011 and 2019. Primary outcomes were infection relapse and mortality during follow-up. RESULTS: Among 32 patients, 21 had IE associated with prostheses. Of the latter, 8 had an ascending aorta prosthetic graft. In 24 patients, a switch to long-term oral suppressive antibiotic treatment (LOSAT) was considered. The median duration of LOSAT was 277 days. Four patients experienced a relapse during follow-up. One patient died within 60 days, and 12 patients died between 60 days and 3 years. However, only 4 deaths were related to IE. CONCLUSIONS: The present study results suggest that a LTAT strategy, including LOSAT, might be considered for patients with IE that cannot undergo an indicated surgery. After hospitalization, they should be followed by a multidisciplinary endocarditis team.

Analysis of Quality of Life and Nutritional Status in Elderly Patients with Dysphagia in Order to Prevent Hospital Admissions in a COVID-19 Pandemic.

(1) Background: Oropharyngeal dysphagia (OD) is currently recognized as one of the geriatric syndromes due to its high frequency in older people and its associated complications, which have a direct impact on quality of life. The main objective is to determine the effectiveness of telehealth consultation for the re-evaluation of nutritional status and quality of life assessment in older people diagnosed with OD associated with active use of thickeners to prevent hospital admissions in a COVID-19 pandemic. (2) Methods: an observational, descriptive, and longitudinal study that included a sample of 33 subjects with age equal or superior to 65 years diagnosed with OD with conserved cognitive capacity. The nutritional status was evaluated through the Mini-Nutritional Assessment (MNA) questionnaire and biochemical parameters and, the quality of life was determined through the Swallowing Quality of Life (SWAL-QOL) questionnaire. (3) Results: Thirty-three older patients with OD were recruited (54.5% women), with a mean age of 83.5 ± 7.6 years. The main cause of OD in the study population was neurodegenerative disease (51.5%), followed by cerebrovascular disease (33.3%), and other causes (15.2%). Sixty point six percent of patients were found to be at risk of malnutrition. The MNA score was significantly correlated to albumin (r: 0.600, p < 0.001) and total proteins (r: 0.435, p = 0.015), but not to total cholesterol (r: -0.116, p = 0.534) or lymphocytes (r: -0.056, p = 0.758). The mean total score of the SWAL-QOL was 75.1 ± 16.4 points. (4) Conclusions: the quality of life of the subjects related to the use of a thickener is good. Although the body mass index (BMI) and average biochemical, nutritional parameters of the subjects are within the range of normality, the MNA has detected a high percentage of subjects with the risk of malnutrition, which suggests the need for continuous re-evaluation in these patients, demonstrating the viability of the telematic route in this research.

Beneficial Effects of Spirulina Aqueous Extract on Vasodilator Function of Arteries from Hypertensive Rats.

Hypertension is a multifactorial disorder considered one of the major causes of premature death worldwide. This pathology is associated with vascular functional/structural alterations in which nitric oxide (NO) and oxygen reactive species participate. On the other hand, the use of microalgae extracts in the treatment of cardiovascular diseases is increasing. Based on the antioxidant and antihypertensive properties of Spirulina, this study aims to investigate the effect of an aqueous extract of Spirulina on the vasodilator function of the aorta from spontaneously hypertensive rats (SHR), analyzing the functional role of NO. For this, aortic segments from male SHR were divided into two groups, one control and the other exposed to an Spirulina aqueous extract (0.1% w/v, for 3 hours), to analyze (i) the production of NO, superoxide anion, and hydrogen peroxide; (ii) the vasodilator response induced by acetylcholine (ACh), by the NO donor and sodium nitroprusside (SNP), and by the KATP channel opener and pinacidil; and (iii) the expression of the p-Akt, p-eNOS, and HO-1 proteins. The results showed that the aqueous Spirulina extract (i) increased the production of NO, did not significantly modify that of superoxide, while decreased that of hydrogen peroxide; (ii) increased the vasodilatory responses induced by ACh, NPS, and pinacidil; and (iii) increased the expression of p-Akt and HO-1. These results suggest that incubation with the aqueous Spirulina extract improves the vascular function of arteries from SHR by increasing the release/bioavailability/function of NO. Increased KATP channel activation and expression of pAkt and HO-1 appear to be participating in these actions.

Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study.

BACKGROUND: Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia. METHODS: We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1. FINDINGS: Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51-75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2-4 days, 43% (30 of 69) with 5-7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51-2·46; p<0·0001). INTERPRETATION: We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection. FUNDING: None.

Regular insulin added to total parenteral nutrition vs subcutaneous glargine in non-critically ill diabetic inpatients, a multicenter randomized clinical trial: INSUPAR trial.

BACKGROUND: There is no established insulin regimen in T2DM patients receiving parenteral nutrition. AIMS: To compare the effectiveness (metabolic control) and safety of two insulin regimens in patients with diabetes receiving TPN. DESIGN: Prospective, open-label, multicenter, clinical trial on adult inpatients with type 2 diabetes on a non-critical setting with indication for TPN. Patients were randomized on one of these two regimens: 100% of RI on TPN or 50% of Regular insulin added to TPN bag and 50% subcutaneous GI. Data were analyzed according to intention-to-treat principle. RESULTS: 81 patients were on RI and 80 on GI. No differences were observed in neither average total daily dose of insulin, programmed or correction, nor in capillary mean blood glucose during TPN infusion (165.3 ± 35.4 in RI vs 172.5 ± 43.6 mg/dL in GI; p = 0.25). Mean capillary glucose was significantly lower in the GI group within two days after TPN interruption (160.3 ± 45.1 in RI vs 141.7 ± 43.8 mg/dL in GI; p = 0.024). The percentage of capillary glucose above 180 mg/dL was similar in both groups. The rate of capillary glucose ≤70 mg/dL, the number of hypoglycemic episodes per 100 days of TPN, and the percentage of patients with non-severe hypoglycemia were significantly higher on GI group. No severe hypoglycemia was detected. No differences were observed in length of stay, infectious complications, or hospital mortality. CONCLUSION: Effectiveness of both regimens was similar. GI group achieved better metabolic control after TPN interruption but non-severe hypoglycemia rate was higher in the GI group. CLINICAL TRIAL REGISTRY: This trial is registered at clinicaltrials.gov as NCT02706119.

Dexamethasone decreases neuronal nitric oxide release in mesenteric arteries from hypertensive rats through decreased protein kinase C activation.

Neuronal NO plays a functional role in many vascular tissues, including MAs (mesenteric arteries). Glucocorticoids alter NO release from endothelium and the CNS (central nervous system), but no results from peripheral innervation have been reported. In the present study we investigated the effects of dexamethasone on EFS (electrical field stimulation)-induced NO release in MAs from WKY (Wistar-Kyoto) rats and SHRs (spontaneously hypertensive rats) and the role of PKC (protein kinase C) in this response. In endothelium-denuded MAs, L-NAME (NG-nitro-L-arginine methyl ester) increased the contractile response to EFS only in segments from SHRs. EFS-induced contraction was reduced by 1 micromol/l dexamethasone in segments from SHRs, but not WKY rats, and this effect was abolished in the presence of dexamethasone. EFS induced a tetrodotoxin-resistant NO release in WKY rat MAs, which remained unchanged by 1 micromol/l dexamethasone. In SHR MAs, dexamethasone decreased basal and EFS-induced neuronal NO release, and this decrease was prevented by the glucocorticoid receptor antagonist mifepristone. Dexamethasone did not affect nNOS [neuronal NOS (NO synthase)] expression in either strain. In SHR MAs, incubation with calphostin C (a non-selective PKC inhibitor), Gö6983 (a classic PKC delta and zeta inhibitor), LY379196 (a PKCbeta inhibitor) or PKCzeta-PI (PKCzeta pseudosubstrate inhibitor) decreased both basal and EFS-induced neuronal NO release. Additionally, PKC activity was reduced by dexamethasone. The PKC inhibitor-induced reduction in NO release was unaffected by dexamethasone. In conclusion, results obtained in the present study indicate that PKC activity positively modulates the neuronal NO release in MAs from SHRs. They also reveal that by PKC inhibition, through activation of glucocorticoid receptors, dexamethasone reduces neuronal NO release in these arteries.

Long-term portal hypertension increases the vasodilator response to acetylcholine in rat aorta: role of prostaglandin I2.

In the present study, we have analysed both the effect of long-term portal hypertension on the vasomotor response to acetylcholine in rat aorta and the mechanism involved in this response. For this purpose, sham-operated rats and rats with pre-hepatic PH (portal hypertension; triple partial portal vein ligation) were used at 21 months after surgery. The participation of NO and COX (cyclo-oxygenase) derivatives in the vasodilator response elicited by acetylcholine after incubation with L-NAME (NG-nitro-L-arginine methyl ester), indomethacin, SC-560, NS-398, tranylcypromine and furegrelate, was analysed. NO, TXB2 (thromboxane B2) and 6-keto PGF1alpha (prostaglandin F1alpha) release were measured. In addition, SNP (sodium nitroprusside), U-46619, PGI2 and forskolin vasomotor responses were analysed. COX-1 and COX-2 expression was also determined. The acetylcholine-induced vasodilating response was higher in rats with PH. TXA2 and NO release, and SNP and U-46619 sensitivity were similar in both groups. PGI2 release was not modified by portal hypertension, but vasodilator responses to this prostanoid and to forskolin were higher in rats with PH. COX-1 and COX-2 expression remained unmodified by surgery. In conclusion, increased vasodilation to acetylcholine is maintained in long-term PH. Although the participation of endothelial NO remained unmodified, the COX-2 derivative PGI2 does participate through an increased vasodilator response.

Orchidectomy increases the formation of prostanoids and modulates their role in the acetylcholine-induced relaxation in the rat aorta.

AIMS: This study examines the effect of endogenous male sex hormones on thromboxane A2 (TXA2), prostaglandin (PG) I2, PGF(2 alpha), and PGE I2 release, as well as their role in acetylcholine (ACh)-mediated relaxation in the aorta. METHODS AND RESULTS: Aortic segments from orchidectomized and control male Sprague-Dawley rats were used to measure COX-2 protein expression. ACh-induced relaxation of these segments was also determined in the absence and presence of the COX-2 inhibitor NS-398, the TXA2 synthesis inhibitor furegrelate, the PGI2 synthesis inhibitor tranylcypromine (TCP), or the thromboxane-prostanoid (TP) receptor antagonist SQ-29 548. Furthermore, TXA2, PGI2, PGF(2 alpha), and PGE2 release as well as the vasomotor effect of exogenous TXA2, PGI2, PGF(2 alpha), and PGE2 were measured. COX-2 expression was increased in aortas from orchidectomized rats. NS-398 did not modify the ACh-induced relaxation in arteries from both control or orchidectomized rats. Furegrelate did not modify the ACh-induced relaxation in aortas from control animals but, in aortas from orchidectomized rats, it increased that response. TCP decreased the ACh-induced relaxation in both groups. The TP receptor antagonist, SQ29 548 failed to modify ACh-induced relaxation in aortas from either rat group. Pre-incubating arteries from orchidectomized rats with TCP plus furegrelate did not modify the decrease in the ACh response induced by TCP alone, but this response was restored by co-incubation of TCP plus SQ29 548. ACh-induced TXA2, PGI2, PGF(2 alpha), and PGE2 release were increased by orchidectomy. The presence of furegrelate plus TCP increased the ACh-induced PGE2 release more in arteries from orchidectomized than in those from control rats. The contractile responses induced by the TXA2 mimetic U-46619 or by exogenous PGF(2 alpha) were similar in arteries from control and orchidectomized rats, while those induced by exogenous PGE2 were increased in arteries from orchidectomized rats; the vasodilator response induced by exogenous PGI2 was decreased in arteries from orchidectomized rats. CONCLUSION: These data show that endogenous male sex hormone deprivation increases COX-2 expression, the release of TXA2, PGI2, PGF(2 alpha), and PGE2 and the contractile response induced by exogenous PGE2 and TXA2, while it decreases the relaxation induced by exogenous PGI2. Despite the predominance of vasoconstrictor prostanoids derived from COX-2 in aortas from orchidectomized rats, the ACh-induced relaxation remains increased.