Role of endogenous GLP-1 on arterial stiffness and renal haemodynamics following bariatric surgery.

BACKGROUND: Cardiovascular trials have revealed the positive impact of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes (T2D). However, the specific effects of endogenous GLP-1 on arterial stiffness and renal function remain understudied. This study aimed to explore the influence of endogenous GLP-1 response post-bariatric surgery on arterial stiffness and renal haemodynamic. METHODS: Thirty individuals with morbid obesity and without T2D, scheduled for Roux-en-Y Gastric Bypass (RYGB), were included. Clinical parameters, 3-hour oral glucose tolerance test (OGTT) with serial sampling for glycaemia, GLP-1 and insulin, carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient (carotid-DC) and renal resistive index (RRI) measurements were conducted pre-surgery and 1-year post-surgery. Participants were categorized into high-response and low-response groups based on their post-surgery increase in GLP-1 (median increase of 104% and 1%, respectively, pre- vs. post-surgery). RESULTS: Post-surgery, high-response group demonstrated a greater reduction in cf-PWV (p = .033) and a greater increase (p = .043) in carotid DC compared to low-response group. These enhancements were observed independently of weight loss or blood pressure changes. High-response group exhibited a reduction in RRI (p = .034), although this association was influenced by improvement in pulse pressure. Finally, a multivariate stepwise regression analysis indicated that the percentage increase of GLP1, Δ-GLP1(AUC)%, was the best predictor of percentage decrease in cf-PWV (p = .014). CONCLUSIONS: Elevated endogenous GLP-1 response following RYGB was associated with improved arterial stiffness and renal resistances, suggesting potential cardio-renal benefits. The findings underscore the potential role of endogenous GLP-1 in influencing vascular and renal haemodynamics independent of traditional weight loss.

Should treatment of low-level rifampicin mono-resistant tuberculosis be different?

BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation. METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates. FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%. INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB. FUNDING: None.

[Endovascular treatment of intracranial venous sinus stenosis in intracranial hypertension: three case reports and a discussion of the literature]. / Tratamiento endovascular de la estenosis de los senos venosos intracraneales en la hipertensión intracraneal: descripción de tres casos y discusión de la bibliografía.

INTRODUCTION: Idiopathic intracranial hypertension is an entity with an incidence of approximately 1.2: 100,000 inhabitants/year. It affects in a greater proportion obese women and women of childbearing age. Headache is the most characteristic symptom, followed by visual disturbances. In recent years, the diagnosis of dural sinus stenosis has increased in cases of intracranial hypertension resistant to conventional treatment. For this reason, the development of endovascular therapy as a therapeutic option in selected patients is booming. CASE REPORTS: We present three cases of intracranial hypertension secondary to dural sinus stenosis, diagnosed and treated in our hospital. Despite the establishment of adequate diuretic treatment and the performance of invasive procedures to bypass the cerebrospinal fluid, they persisted with neurological symptoms and visual deficits. After verifying that they fulfilled the requirements described in the literature, they underwent intracranial stenting, with satisfactory results in all of them, achieving the disappearance of the headache and recovery of visual acuity. CONCLUSION: Stenting of dural sinus stenosis as a cause of intracranial hypertension is an increasingly used technique, which has presented favorable results. Studies are necessary to know its long-term impact.

TITLE: Tratamiento endovascular de la estenosis de los senos venosos intracraneales en la hipertensión intracraneal: descripción de tres casos y discusión de la bibliografía.Introducción. La hipertensión intracraneal idiopática es una entidad con una incidencia anual aproximada de 1,2 por cada 100.000 habitantes. Afecta en mayor proporción a mujeres obesas y en edad fértil. La cefalea es el síntoma más característico, seguido de las alteraciones visuales. En los últimos años, se ha incrementado el diagnóstico de la estenosis de los senos durales en los casos de hipertensión intracraneal resistentes al tratamiento convencional. Por ello, se encuentra en auge el desarrollo de la terapia endovascular como opción terapéutica en pacientes seleccionados. Casos clínicos. Se presentan tres casos de hipertensión intracraneal secundaria a estenosis de los senos durales, diagnosticados y tratados en nuestro hospital. A pesar de la instauración del adecuado tratamiento diurético y de la realización de procedimientos invasivos de derivación del líquido cefalorraquídeo, persistían la clínica neurológica y el déficit visual. Tras comprobar que cumplían los requisitos descritos en la bibliografía, se sometieron a la implantación de stent intracraneal (stenting), con resultado satisfactorio en todos ellos, logrando la desaparición de la cefalea y la recuperación de la agudeza visual. Conclusión. El stenting de la estenosis de los senos durales como causa de hipertensión intracraneal es una técnica cada vez más utilizada que ha presentado resultados favorables. Es necesaria la realización de estudios para conocer su impacto a largo plazo.

Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man.

Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications.

Pulmonary functionality among workers of a Central Italy waste-to-energy plant: a retrospective study.

BACKGROUND: We are observing a growing trend towards the use of waste incineration in waste-to-energy (WTE) plants in Italy. Various authors started to investigate their potential health effects, but without univocal outcomes. The aim of this study is to assess whether or not main pulmonary function indexes could be decreased in a group of workers employed in a municipal solid WTE plant located in Central Italy, and if there's a correlation between the levels of exposure to airborne pollutants and alterations in the pulmonary apparatus. METHODS: The study was conducted with a retrospective cohort approach. We reviewed data from clinical records of 58 waste-to-energy plant workers undergoing annual health surveillance in the period 2010-2015. We considered the exposure to airborne dust and the main parameters of respiratory function (FVC, FEV1, Tiffeneau Index and FEF 25-75%) at time zero and after a period of 5 years. We divided our study population into two groups: low (< 1 mg/m3) and high (> 1 mg/m3) exposure. We estimated odds ratios (OR) with 95% confidence interval (95% CI) adjusted for potential confounders. RESULTS: We observed a decrease in lung function parameters both in high and in low exposure group after a five-years exposure period. FEV1, FEV1/VC ratio and FEF 25-75% were worst in more exposed group, even if this difference resulted not significant at Wilcoxon test. CONCLUSIONS: Active employee in WTE plants is associated to a non-significant worsening in the main parameters of lung function after 5 years exposure. Clinical significant of these variations need to be assessed.

A short-term increase in dietary cholesterol and fat intake affects high-density lipoprotein composition in healthy subjects.

BACKGROUND AND AIMS: High-cholesterol and high-fat diets alter biochemical composition and anti-oxidant properties of high-density lipoproteins (HDL) in animals. Whether this occurs in humans is unknown. Therefore, we examined the effect of a short-term elevation in dietary cholesterol and fat intake on HDL composition in healthy subjects. METHODS AND RESULTS: In a randomized, crossover clinical trial, 14 healthy young volunteers followed a 14-day low-cholesterol/low-fat diet (LChF) and a 14-day isocaloric high-cholesterol/high-fat diet (HChF) in a random order. After each diet, we measured HDL concentrations of hydroxyeicosatetraenoic acids (HETE), hydroxyoctadecadienoic acids (HODE), and haptoglobin, as well as serum amyloid A (SAA) and paroxonase-1 activity (PON-1). HDL concentrations of 15-HETE (+254%, p = 0.002), 5-HETE (+116%, p = 0.004), 13-HODE (+102%, p = 0.049), and SAA levels (+75%, p = 0.007) were significantly higher after the HChF than after the LChF. Furthermore, haptoglobin was marginally increased (+32%, p = 0.091) while PON-1 activity was unaffected (-16%, p = 0.366) by the HChF. CONCLUSION: In healthy subjects, a short-term elevation in dietary cholesterol and fat intake increases HDL lipid hydroperoxide content (15-HETE, 5-HETE, 13-HODE) and SAA levels, which are key features of dysfunctional HDL. This is the first study showing that a physiologic manipulation of dietary cholesterol and fat intake affects HDL lipidome and proteome in healthy subjects independently of weight changes. CLINICAL TRIAL REGISTRATION: NCT02549144.

Sustained effects of a protein and lipid preload on glucose tolerance in type 2 diabetes patients.

BACKGROUND: Small amounts of nutrients given as a 'preload' can reduce post-meal hyperglycaemic peaks in type 2 diabetes (T2D) patients by activating a number of mechanisms involved in glucose homoeostasis. This study was undertaken to ascertain whether this positive effect extends to the late absorptive phase and to identify the main mechanisms involved. MATERIAL AND METHODS: Eight well-controlled T2D patients, aged 40-70 years, were randomized to consume a 'preload' of either water or non-glucidic nutrients (50g of Parmesan cheese, one boiled egg) 30min before a 300-min oral glucose tolerance test. RESULTS: After the nutrient preload, significant reductions were observed in peak glucose (-49%; P<0.02), total plasma glucose (iAUC: -28%; P<0.03), exogenous glucose (iAUC: -30%; P<0.03) and insulin clearance (-28%; P<0.04), with enhancement of insulin secretion (iAUC: +22%; P<0.003). These effects were associated with higher plasma levels of GLP-1 (iAUC: +463%; P<0.002), GIP (iAUC: +152%; P<0.0003) and glucagon (iAUC: +144%; P<0.0002). CONCLUSION: In T2D patients, a protein and lipid preload improves glucose tolerance throughout the whole post-absorptive phase mainly by reducing the appearance of oral glucose, and improving both beta-cell function and insulin bioavailability.

The amino acid response to a mixed meal in patients with type 2 diabetes: effect of sitagliptin treatment.

AIMS: Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment. METHODS: Forty-seven T2D patients [56 ± 7 years, body mass index (BMI) 29.9 ± 4.2 kg/m(2) ] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). RESULTS: During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l · h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l · h, p = 0.05]. Fasting α-HB was higher [7.5(2.7) vs. 5.9(1.3) µg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) µg/ml · h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 ± 16 vs. 35 ± 10 mEq/l · h, p = 0.005). Compared to placebo, both BCAA [-6.4(21.1) vs. 0.0(48.0) mmol/l · h, p = 0.01] and α-HB increments [-114(250) vs. 114(428) µg/ml · h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and α-HB were reciprocally related to changes in insulin sensitivity (ρ = -0.37 and -0.43, p ≤ 0.01). CONCLUSIONS: T2D is associated with a hyperaminoacidaemic response to MTT, which circulating α-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and α-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that α-HB is a readout of metabolic overload.

HDL lipid composition is profoundly altered in patients with type 2 diabetes and atherosclerotic vascular disease.

BACKGROUND AND AIMS: We have previously shown that the anti-inflammatory and anti-oxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD). METHODS AND RESULTS: HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (D⁺CVD⁻) and 38 T2D with known history of CVD (D⁺CVD⁺). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC). Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from D⁺CVD⁺ when compared to D⁺CVD⁻ and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100. CONCLUSION: Patients with D⁺CVD⁻ and D⁺CVD⁺ are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. In the present study, a loss of HDL function (as estimated by the HDL oxidant index) is observed only in patients with more advanced atherosclerosis.

Impact of mild to moderate reductions of glomerular filtration rate on coronary artery disease severity.

BACKGROUND & AIMS: The bases of the link between reduced glomerular filtration rate (GFR) and coronary artery disease (CAD) are complex and to some extent still unclear. We performed this observational, single referral center, cohort study to evaluate whether mild to moderate GFR reduction is associated with more severe CAD and/or with a worse cardiac prognosis independently of proteinuria, diabetes and traditional risk factors. METHODS AND RESULTS: In 1752 consecutive non-diabetic patients without proteinuria or moderate/severe kidney disease undergoing a clinically driven coronary angiography, coronary arteries lesions, myocardial function and hypertrophy and 10-yrs incidence of cardiac events and death were evaluated in relation to classes of estimated GFR defined according the lowest eGFR value (105+, 90+, 75+, 60+, 45+). A reduced eGFR was independently associated with hypertension, myocardial hypertrophy and stress induced ischemia, while the excess coronary lesions and the worse myocardial systolic function were both largely explained by age and cardiovascular risk factors. When compared to subjects 75+, both the risk of cardiac death (1.67[1.10-2.57] and 3.06[1.85-5.10]) and non-fatal myocardial infarction (2.58[1.12-6.49] and 2.73[1.31-6.41]) adjusted for age and comorbidities were higher in eGFR 60+ and 45+ patients. CONCLUSIONS: A mild-moderate reduction of eGFR is closely associated to higher rates of stress-induced ischemia, myocardial hypertrophy and higher risk of fatal and non-fatal cardiac events. The associations of reduced eGFR with coronary atherosclerosis and myocardial systolic dysfunction are both largely explained by age and traditional risk factors.

Ex vivo lung perfusion increases the pool of lung grafts: analysis of its potential and real impact on a lung transplant program.

BACKGROUND: Among the strategies to increase the number of lung transplants, ex vivo lung perfusion (EVLP) represents a novel technique to expand the donor pool. METHODS: Data from donors referred to our center were retrospectively analyzed to identify grafts that could potentially be potentially reconditioned by EVLP and for comparison with those obtained by clinical application of EVLP program in our center. RESULTS: Among 75 rejected lungs, 23 organs have been identified as potentially treatable with EVLP with a hypothetic increase of lung transplant activity of 53%. After the introduction of the EVLP program in our center, lung transplantation with reconditioned grafts was performed in 7 (23%) patients with a 30% increase in transplant procedures. CONCLUSION: Although less than expected, EVLP increased the number of lungs suitable for transplantation.

Tailored cytomegalovirus management in lung transplant recipient: a single-center experience.

INTRODUCTION: Among solid organ recipients lung transplant recipients are at highest risk to be affected by cytomegalovirus infection (CMV) or to die from CMV disease. Two strategies are usually adopted in the clinical management of transplant recipients: antiviral prophylaxis and pre-emptive therapy. METHODS: In our center we adopted from 2007 a combined prophylaxis with anti-CMV immunoglobulins in the first post-transplant year and antiviral therapy (gancyclovir or valgancyclovir) from post-transplant day 15 for 3 weeks and in case of CMV bronchoalveolar lavage specimen positivity (polymerase chain reaction or shell vial). Moreover, we studied specific cellular immune response by an Elispot assay to define responder patients by the number of spot forming units (<5 nonresponders, 5-20 weeks, 20-100 good, >100 very good responders). RESULTS: We reduced acute rejections (from 17% to 6%, odds ratio 3.25), lymphocytic bronchitis bronchiolitis (from 11% to 2%), and first-year CMV pneumonia after the first post-transplant month (from 6.4% to 1%). We showed in nonresponders an earlier onset (68 vs 204 post-transplant days) and a longer duration (>14 days vs <14 days) of infection (P < .05 for all referred data). DISCUSSION: The morbility reduction has been obtained by antiviral therapy, increasing costs and risk of side effects. Our more recent studies show a population with a good immune response that probably doesn't need a pharmacological intervention but just a strict follow-up. CONCLUSION: Our proposed strategy is now tailoring the therapy on immune response clinical application, limiting to the specimen positivity in nonresponders.

Evaluation of Epstein-Barr virus-specific immunologic response in solid organ transplant recipients with an enzyme-linked ImmunoSpot assay.

Epstein-Barr virus (EBV) is a γ-herpes virus, responsible for infectious mononucleosis in immunocompetent hosts. Cellular immunity appears rapidly during EBV primary infection, keeping it silent despite long-life persistence in B lymphocytes. Defects of the EBV-specific cellular immunity are supposed to be the basis of post-transplantation lymphoproliferative disorders, promoted by high levels of immunosuppression. We retrospectively reviewed 197 solid organ transplant recipients to investigate EBV-specific lymphocyte responsiveness using Enzyme-linked ImmunoSpot assay (EliSpot), which assesses the EBV-specific interferon (IFN)-γ producing peripheral blood mononuclear cells, and kinetics of EBV infection/reactivation post-transplantation using quantitative real-time polymerase chain reaction (PCR) on whole blood. Overall, 102 of the 197 patients (51.8%) showed EBV responsiveness at the EBV-EliSpot assay: 68 (66.6%) showed a persistently positive EBV response in 3 or more determinations and 34 (33.3%) had transient episodes of nonresponsiveness. Ninety-five (48.2%) patients were persistently EBV nonresponders. EBV-DNAemia data were available for 58 patients: 27.6% presented at least one episode of EBV-DNA occurrence. No differences were found in EBV-EliSpot response stratification between the groups of patients who experienced episodes of EBV reactivation and those without EBV-DNAemia. However, EBV DNAemia peak values tended to be higher in the first year post-transplantation in the group of patients with a persistent positive EBV-specific immune response. EBV viral load quantitation in blood and EliSpot EBV-specific immune response determination may represent a powerful tool for monitoring solid organ transplant recipients, guiding immunosuppression modulation in patients with active EBV replication.

Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones.

CONTEXT: In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control. OBJECTIVE: The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. PATIENTS, SETTING, AND INTERVENTION: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG). MAIN OUTCOME MEASURES: Insulin sensitivity, ß-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured. RESULTS: T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, ß-cell glucose sensitivity improved both early and long term (P < .005), whereas insulin sensitivity improved long term only (P < .006), in proportion to body mass index changes (P < .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P = .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery ß-cell glucose sensitivity (positive, P < .0001) and meal-stimulated GLP-1 response (negative, P = .004) were the only predictors of remission. CONCLUSIONS: RYGB and SLG have a similar impact on diabetes remission, of which baseline ß-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion.

AIMS/HYPOTHESIS: Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. METHODS: Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 µg min⁻¹ kg⁻¹) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 µg min⁻¹ kg⁻¹) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. RESULTS: Compared with saline, L-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (-12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, L-NAME raised 2 h plasma glucose by 1.8 mmol/l (p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. CONCLUSIONS/INTERPRETATION: In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.

Lung volume reduction surgery 10 years later.

AIM: The purpose of this study was to evaluate whether favorable short-term results in term of functional outcome and survival following lung volume reduction surgery persist for longer periods. Composite preoperative and early postoperative variables were analysed. METHODS: This study was conducted on 52 emphysematous patients who underwent lung volume reduction surgery (LVRS) from 1993 to 2000, through a delayed retrospective analysis that has allowed us to evaluate a long-term follow-up (10 years or more); lung function and other variables were considered with respect to survival; 11 patients submitted to lung transplantation were also evaluated. RESULTS: Upper lobe distribution of emphysema (P=0.02, HR:2.43) and systolic PAP (P=0.04, HR=2.11) were significantly correlated to survival in a multivariate analysis; these variables seem to identify a small subgroup of 14 patients with longer survival (more than 10 years). Lung transplantation performed in some worsening patients (mean FEV1%:17±4) showed a trend of better survival when we compared the observed survival (55±47 months) with expected survival (39.5±15 months) (P=ns). CONCLUSION: We conclude that LVRS can lead to a very long survival (10 years or more) in a small subgroup of patients, with improvement of pulmonary functional data. Some preoperative data (upper lobe distribution of emphysema and pulmonary arterial pressure) appear to predict survival. Lung transplantation can be offered to these patients, showing a trend to improved life expectancy.

Lung volume reduction surgery 10 years later.

AIM:The purpose of this study was to evaluate whether favorable short-term results in term of functional outcome and survival following lung volume reduction surgery persist for longer periods. Composite preoperative and early postoperative variables were analysed. METHODS: This study was conducted on 52 emphysematous patients who underwent lung volume reduction surgery (LVRS) from 1993 to 2000, through a delayed retrospective analysis that has allowed us to evaluate a long-term follow-up (10 years or more); lung function and other variables were considered with respect to survival; 11 patients submitted to lung transplantation were also evaluated. RESULTS:Upper lobe distribution of emphysema (P=0.02, HR:2.43) and systolic PAP (P=0.04, HR=2.11) were significantly correlated to survival in a multivariate analysis; these variables seem to identify a small subgroup of 14 patients with longer survival (more than 10 years). Lung transplantation performed in some worsening patients (mean FEV1%:17±4) showed a trend of better survival when we compared the observed survival (55±47 months) with expected survival (39.5±15 months) (P=ns). CONCLUSION: We conclude that LVRS can lead to a very long survival (10 years or more) in a small subgroup of patients, with improvement of pulmonary functional data. Some preoperative data (upper lobe distribution of emphysema and pulmonary arterial pressure) appear to predict survival. Lung transplantation can be offered to these patients, showing a trend to improved life expectancy.

Effects of short and prolonged mild intracellular nitric oxide manipulations on various aspects of insulin secretion in INS-1E ß-cells.

OBJECTIVE: We aimed at evaluating the impact of short and prolonged mild manipulations of intracellular nitric oxide (NO) bioavailability on the main features of insulin secretion and whether NO promotes mitochondrial biogenesis in isolated ß-cells. MATERIALS/METHODS: INS-1E ß-cells were exposed to either the intracellular NO donor, hydroxylamine (HA), or the NO synthase inhibitor, L-nitro-arginine-methyl-ester (L-NAME), at concentrations lower than 2.0 mM. Glucose and arginine-induced insulin secretion (GIIS and AIIS) were measured after short (1 h) or prolonged (48 h) exposure to L-NAME 1.0 and 2.0 mM or HA 0.4 and 0.8 mM, lower concentrations were also evaluated for the 1 h effects. Basal insulin secretion (BIS), with either HA or L-NAME added to culture media, and peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor-1 (NRF-1), and mitochondrial DNA transcription factor-A (Tfam) gene expression during chronic HA supplementation were also measured. RESULTS: Neither L-NAME nor HA affected insulin release at glucose 3.3 mM or in cell culture (BIS). Both short and prolonged cell exposure to L-NAME potentiated GIIS though with a flat dose-response curve while HA inhibited GIIS only at the highest concentration. AIIS was prevented by short exposure to L-NAME and potentiated by HA, while it did not respond to prolonged incubations. Prolonged cell exposure to HA had no effect on PGC-1α, NRF-1 or Tfam gene expression. CONCLUSION: In INS1E cells an intact NO synthesis is necessary to limit insulin release in response to acute glucose gradients and to fully respond to arginine while intracellular NO enrichment above the physiologic levels further inhibits GIIS and potentiate AIIS only when excessive. Prolonged NO manipulations do not affect AIIS, BIS or mitochondrial biogenesis.