Canagliflozin: A New Therapeutic Option in Patients That Present Postprandial Hyperinsulinemic Hypoglycemia after Roux-en-Y Gastric Bypass: A Pilot Study.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is the most common surgical procedure for morbid obesity. However, it can present serious late complications, like postprandial hyperinsulinemic hypoglycemia (PHH). Recent data suggested an increase in intestinal SGLT-1 after RYGB. However, there is no data on the inhibition of SGLT-1 to prevent PHH in patients with prior RYBG. On this basis, we aimed to evaluate (a) the effect of canagliflozin 300 mg on the response to 100 g glucose overload (oral glucose tolerance test [OGTT]); (b) the pancreatic response after intra-arterial calcium stimulation in the context of PHH after RYGB. MATERIALS AND METHODS: This is a prospective pilot study including patients (n = 21) with PHH after RYGB, matched by age and gender with healthy controls (n = 5). Basal OGTT and after 2 weeks of daily 300 mg of canagliflozin was performed in all cases. In addition, venous sampling after intra-arterial calcium stimulation of the pancreas was performed in 10 cases. RESULTS: OGTT after canagliflozin showed a significant reduction of plasma glucose levels (minute 30: 161.5 ± 36.22 vs. 215.9 ± 58.11 mg/dL; minute 60: 187.46 ± 65.88 vs. 225.9 ± 85.60 mg/dL, p < 0.01) and insulinemia (minute 30: 95.6 ± 27.31 vs. 216.35 ± 94.86 mg/dL, p = 0.03; minute 60: 120.85 ± 94.86 vs. 342.64 ± 113.32 mIU/L, p < 0.001). At minute 180, a significant reduction (85.7%) of the rate of hypoglycemia was observed after treatment with canagliflozin (p < 0.00001). All cases presented normal pancreatic response after intra-arterial calcium administration. CONCLUSION: Canagliflozin (300 mg) significantly decreased glucose absorption and prevented PHH after 100 g OGTT in patients with RYGB. Our results suggest that canagliflozin could be a new therapeutic option for patients that present PHH after RYGB.

AMH in combination with SHBG for the diagnosis of polycystic ovary syndrome.

Serum Anti-Müllerian hormone (AMH) level could be useful for the diagnosis of polycystic ovary syndrome (PCOS). We evaluated the hormonal status in women for the diagnosis of PCOS. A total of 77 PCOS women and 106 healthy women were enrolled in this study. Serum AMH, gonadotropins [luteinising hormone (LH) and follicle-stimulating hormone (FSH)], oestradiol, testosterone (total and free), 4-androstenedione (ANDST), dehydroepiandrosterone sulphate, sex hormone binding globulin (SHBG), prolactin, thyroid-stimulating hormone and insulin levels were measured in all enrolled women. Our data showed that insulin, LH, testosterone, ANDST and AHM levels were significantly higher in the PCOS group and FSH and SHBG levels were lower in the PCOS group. In Receiver operating characteristic analysis, the combination of AMH with SHBG showed higher area under curves (AUC) for PCOS diagnosis with an AUC of 0.843 and a specificity of 81.1% and a sensitivity of 72.7%. Our results suggest that a combination of serum AMH and SHBG levels could be used as a diagnostic biomarker of PCOS. Impact statement What is already known on this subject? Women with PCOS have an increased risk of hypertension, altered glucose metabolism and probably an increased lifetime risk of cardiovascular diseases. There is no consensus on the diagnostic criteria for PCOS. This leads to many patients with PCOS are being undiagnosed. It is known that AMH plays a role in the follicular status of PCOS and serum AMH level is increased significantly in women with PCOS compared with normo-ovulatory women. This is why several studies have suggested the inclusion of AMH as a diagnostic criterion in PCOS. What do the results of this study add? Extensive epidemiological data is available which demonstrates an association between higher AMH levels and PCOS, but there was no information available about the combination of AMH level with other hormones and PCOS. This is the first study that has investigated the association of AMH and SHBG, together, with PCOS. Our results suggest that serum AMH and SHBG level in combination could represent a useful and practical test to screen the general population for PCOS. What are the implications of these findings for clinical practice and/or further research? Many PCOS women in the general population are undiagnosed due to lack of consensus in diagnostic criteria. Therefore, the importance of identifying women with PCOS due to the need for follow-up in short and long-term health risk.

Long-term effects of an intensive intervention in HIV-infected patients with moderate-high atherosclerotic cardiovascular risk.

OBJECTIVES: To evaluate the 5 year effects of an intensive intervention versus the standard-of-care intervention on cardiovascular risk factors in HIV-infected patients on antiretroviral therapy (ART). METHODS: This was a longitudinal study including virologically suppressed patients with at least two cardiovascular risk factors or a Framingham risk score ≥10%. Intensive and standard-of-care interventions aimed for low-density lipoprotein cholesterol (LDL-C) <100 and <130 mg/dL, respectively, by using lipid-lowering drugs. In the intensive group, switching ART when needed to achieve the LDL-C target and low-dose aspirin were used. Achievement of LDL-C targets and changes in carotid intima-media thickness (cIMT) and cardiovascular biomarkers were compared between groups at different timepoints through a 5 year period. RESULTS: Twenty-two and 25 patients in the intensive and standard intervention groups, respectively, were followed up. At 5 years, pre-specified LDL-C targets were achieved in 82% (intensive) and 81% (standard of care) of patients. The median (IQR) change in LDL-C in the intensive and standard intervention groups was -78 (-96/-39.7) and -49 (-72/-3) mg/dL, respectively (P = 0.04), and in the Framingham score was -4% (-8%/-1%) and 0% (-4%/6.5%), respectively (P = 0.01). There were no significant intra- or between-group changes in cIMT measurements. A significant decrease was observed in the intensive and standard groups in interleukin 6 (P = 0.001 and P = 0.002, respectively) and in tumour necrosis factor α (P = 0.023 and P = 0.052, respectively). Asymptomatic creatine phosphokinase elevations were observed in two patients assigned to the standard intervention group. CONCLUSIONS: An intensive intervention on cardiovascular risk factors in HIV-infected patients on ART was feasible, safe and capable of achieving LDL-C targets in the long term. Both intensive and standard interventions were accompanied by antiatherosclerotic changes in inflammatory cytokines and lack of cIMT progression.

Cellular characterization of wound exudate as a predictor of wound healing phases.

UNLABELLED: This study was designed to characterize the cell populations present in wound exudate, to examine the validity of these populations in identifying the wound phase to find possible predictors of healing, and to anticipate events in favor of a more rapid recovery. METHODS: Fourteen patients who presented with postsurgical wounds with negative pressure therapy were included in the study. The authors collected samples from 51 wounds in the inflammatory phase and 29 in the proliferative phase. RESULTS: The number of neutrophils and platelets in the exudate collected from wounds in the inflammatory phase was significantly higher (P < 0.05), while the number of lymphocytes, eosinophils, and basophils was significantly higher in exudate from wounds in the proliferative phase. The receiver operating characteristic analysis gives an area under curve of 0.815 for neutrophils (P < 0.001, CI: 0.698-0.933) and 0.760 for platelets (P < 0.001, CI: 0.647-0.873). The results showed 45.8% of neutrophils have a sensitivity of 84.4% and a specificity of 66.7% for detecting the inflammatory phase. For platelets, a level of 135.000 has a sensitivity of 71.1% and a specificity of 61.1%. The percentage of neutrophils and the platelet levels remained significant predictors of the inflammatory phase. CONCLUSION: The study results suggest that platelets and neutrophils in wound exudate might be useful prognostic indicators of the inflammatory or proliferative phase of wound healing.

Increased carotid intima-media thickness associated with antibody responses to varicella-zoster virus and cytomegalovirus in HIV-infected patients.

OBJECTIVE: We investigated the relationship of the Herpesviridiae with inflammation and subclinical atherosclerosis in HIV-infected patients. METHODS: Prospective study including virologically suppressed HIV-infected patients. IgG antibodies against herpesviruses, carotid intima-media thickness (cIMT), endothelial function through flow-mediated dilatation (FMD) of the brachial artery, and blood atherosclerosis biomarkers (hsCRP, TNF-α, IL-6, MCP-1, MDA, sCD14, sCD163, VCAM-1, ICAM-1, D-dimer, and PAI-1) were measured. RESULTS: 136 patients with HIV viral load <200 copies/ml were included. 93.4% patients were infected with herpes simplex virus type-1, 55.9% with herpes simplex virus type-2, 97.1% with varicella-zoster virus, 65.4% with human herpesvirus-6, 91.2% with cytomegalovirus, and 99.3% with Epstein-Barr virus. Previous AIDS diagnosis was associated with higher cytomegalovirus IgG titers (23,000 vs 17,000 AU, P = 0.011) and higher varicella-zoster virus IgG titers (3.19 vs 2.88 AU, P = 0.047), and there was a positive correlation of the Framingham risk score with IgG levels against cytomegalovirus (Spearman's Rho 0.216, P = 0.016) and Herpes simplex virus-2 (Spearman's Rho 0.293, P = 0.001). IgG antibodies against cytomegalovirus correlated in adjusted analysis with the cIMT (P = 0.030). High seropositivity for varicella-zoster virus (OR 2.91, 95% CI 1.05-8.01, P = 0.039), and for cytomegalovirus (OR 3.79, 95% CI 1.20-11.97, P = 0.023) were predictors for the highest quartile of the cIMT in adjusted analyses. PAI-1 levels were independently associated with cytomegalovirus IgG titers (P = 0.041), IL-6 and ICAM-1 levels with varicella-zoster virus IgG (P = 0.046 and P = 0.035 respectively), and hsCRP levels with Herpes simplex virus-2 IgG (P = 0.035). CONCLUSION: In virologically suppressed HIV-infected patients, antibody responses against herpesviruses are associated with subclinical atherosclerosis, and with increased inflammation and coagulation biomarkers.

Oxidative stress in Alzheimer's disease and mild cognitive impairment with high sensitivity and specificity.

Some studies have determined that oxidative stress is a decisive factor in Alzheimer's disease (AD) and even suggested that it is present in the initial phase of mild cognitive impairment (MCI). The aim of our study was to investigate the process of oxidative stress by measuring the level of malondialdehyde (MDA), the specific activity of two peripheral antioxidant defenses (superoxide dismutase (SOD) and ceruloplasmin), and the level of copper in AD and MCI patients and compare those results with healthy subjects. The sample group consisted of 36 patients with AD, 18 patients with MCI, and 33 healthy aged subjects. Blood samples were obtained from each subject. A significantly higher copper level was found in patients with AD and MCI compared to the control group. The levels of MDA showed a similar trend and were higher in patients from the AD and MCI groups than in the control group. It was found that both studied parameters had positive correlation in the whole studied population (r = 0.340; p = 0.001). A stepwise logistic regression analysis was used to identify an optimal combination of these biomarkers. The optimal biomarker combinations were MDA and SOD with area under the curve of 0.803 (0.691-0.915, CI 95%, p < 0.001) for the diagnosis of AD. The optimal cutpoint yielded 88.0% Sensitivity and 70.0% Specificity. The biomarker combinations predicted AD and were markedly superior to individual biomarkers. Our findings support the hypothesis that oxidative stress might represent a sign of AD pathology and could be an early event in the progression of MCI to AD.

Tratamiento percutáneo del síndrome de vena cava superior tras implantación de electrodos y/o cirugía de cardiopatías congénitas / Percutaneous treatment of superior vena cava syndrome after pacemakers electrodes implantation and/or surgical correction of congenital heart disease

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Early changes in parathyroid hormone concentrations in HIV-infected patients initiating antiretroviral therapy with tenofovir.

Initiation of combined antiretroviral therapy (cART) is associated with bone loss, which may be more intense with regimens including tenofovir. The underlying mechanisms are not well understood. Cross-sectional data have linked tenofovir with higher parathyroid hormone (PTH) concentrations in patients with vitamin D deficiency. We performed a longitudinal study with a 48-week follow-up to evaluate sequential changes in PTH and 25-hydroxyvitamin D [25(OH)D] levels in patients starting cART with either tenofovir/emtricitabine or abacavir/lamivudine. Fifty-seven patients were included, 31 initiating tenofovir/emtricitabine and 26 initiating abacavir/lamivudine. Median PTH levels turned out to be significantly higher among tenofovir/emtricitabine users at week 4 (p=0.01), week 24 (p=0.008), and week 36 (p=0.02), and were above the upper limits of normal values (ULN) at weeks 24, 36, and 48 only in patients receiving tenofovir/emtricitabine. 25(OH)D, serum and urine calcium and phosphate, and renal-tubular maximum reabsorption of phosphate to the glomerular filtration rate (TmP/GFR) levels did not differ between the two treatment arms over the study period. Among tenofovir/emtricitabine users, median (interquartile range) PTH concentrations were significantly higher in patients with suboptimal 25(OH)D levels (<30 µg/liter) at week 24 [63 (57.8-82.4) ng/liter vs. 54.3 (34.4-63.067.5) ng/liter, p=0.05] and week 48 [67.5 (59.6-86.0) ng/liter vs. 41.9 (37.3-68.8) ng/liter, p=0.03]. A multivariable logistic regression model showed that tenofovir/emtricitabine use was an independent predictor of high PTH levels (≥53 ng/liter). Starting cART with tenofovir regimens is associated with an elevation in PTH plasma concentrations soon after introducing the drug. Suboptimal baseline 25(OH)D levels increase the risk of developing secondary hyperparathyroidism among tenofovir users.

Treatment for hepatitis C virus with pegylated interferon-α plus ribavirin induces anti-atherogenic effects on cardiovascular risk biomarkers in HIV-infected and -uninfected patients.

OBJECTIVES: We investigated the influence of hepatitis C virus (HCV) therapy with pegylated interferon-α plus ribavirin on cardiovascular disease risk through the serial measurement of several laboratory markers in HCV-monoinfected and HCV/HIV-coinfected patients. METHODS: In a longitudinal study, biomarkers of inflammation, coagulation and oxidative stress were measured during and after therapy. RESULTS: A total of 56 patients were included; 32 (57.1%) were HCV/HIV coinfected and 24 (42.9%) were HCV monoinfected. Compared with baseline, during HCV therapy there was a significant decrease in the concentrations of matrix metalloproteinase-9 (P < 0.001), intercellular cell adhesion molecule-1 (ICAM-1) (P ≤ 0.01) and oxidized low-density lipoproteins (P = 0.002). In contrast, levels of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 and fibrinogen increased during treatment. After treatment discontinuation, levels of ICAM-1, VCAM-1 and tumour necrosis factor-α were significantly lower compared with baseline, a change restricted to patients with sustained virological response. Decreases in transaminases and HCV-RNA from baseline correlated positively with the decrease in ICAM-1 concentration 6 months after treatment discontinuation. Changes in biomarkers were similar in HIV-infected and -uninfected patients. CONCLUSIONS: Treatment for HCV induces different changes in several cardiovascular risk biomarkers, most being anti-atherogenic effects, although only the anti-atherogenic effects remain after treatment discontinuation in patients with sustained virological response.

Endothelial function is impaired in HIV-infected patients with lipodystrophy.

BACKGROUND: Data supporting a link between body-fat distribution changes and cardiovascular disease risk in HIV-infected patients are scarce and contradictory. We evaluated endothelial dysfunction, an early event in the development of atherosclerosis, and pro-atherosclerotic plasma biomarkers in HIV-infected patients with lipodystrophy. METHODS: HIV-infected patients with and without lipodystrophy were prospectively enrolled. Endothelial function was measured through flow-mediated dilatation (FMD) of the brachial artery. Plasma levels of several biomarkers of inflammation, endothelial activation and coagulation associated with adipose tissue and endothelial dysfunction were determined. RESULTS: The study included 110 patients, 55 of them with lipodystrophy. FMD was significantly lower in patients with lipodystrophy than in those without lipodystrophy (median [IQR] 3.1% [0.4-8.9] versus 6.3% [3.3-10.7]; P=0.004). Patients with isolated lipoatrophy exhibited the lowest FMD (2.6% [0-6.6]; P(Kruskal-Wallis)=0.02). Lipodystrophy was associated with significantly higher plasma levels of interleukin 6 (IL-6) and plasminogen activator inhibitor 1 (PAI-1) and lower levels of adiponectin; severe lipodystrophy was associated with higher concentrations of vascular cell adhesion molecule 1 (sVCAM-1). There was an inverse correlation between FMD and IL-6 (Spearman's rho =-0.26; P=0.007). In a multivariate regression model with the lowest quartile of FMD as the dependent variable and lipodystrophy, traditional cardiovascular risk factors, 10-year Framingham risk score, pro-atherosclerotic biomarkers and HIV-related variables as predictors, the only independent predictor of endothelial dysfunction was lipodystrophy (odds ratio 5.22, 95% confidence interval 1.76-15.46; P=0.003). CONCLUSIONS: Lipodystrophy is associated with endothelial dysfunction, independently of the presence of traditional cardiovascular risk factors. This finding and the accompanying profile of pro-atherosclerotic biomarkers support an increased cardiovascular risk in HIV-infected patients with lipodystrophy.