Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents.

Vascular aging in obesity and type 2 diabetes (T2D) is associated with progressive vascular calcification, an independent predictor of morbidity and mortality. Pathways for vascular calcification modulate bone matrix deposition, thus regulating calcium deposits. We investigated the association between biomarkers of vascular calcification and vasodilator function in obesity or T2D, and whether antidiabetic therapies favorably impact those markers. Circulating levels of proteins involved in vascular calcification, such as osteopontin (OPN), osteoprotegerin (OPG), regulated on activation, normal T cell expressed and secreted (RANTES), and fetuin-A were measured in lean subjects, individuals with metabolically healthy obesity (MHO), and patients with metabolically unhealthy obesity (MUO) or T2D. Vasodilator function was assessed by infusion of ACh and sodium nitroprusside (SNP). Circulating levels of OPN were higher in the MUO/T2D group than in lean subjects (P < 0.05); OPG and RANTES were higher in MUO/T2D group than in the other groups (both P < 0.001); fetuin-A was not different between groups (P > 0.05); vasodilator responses to either ACh or SNP were impaired in both MUO/T2D and MHO compared with lean subjects (all P < 0.001). In patients with T2D who were enrolled in the intervention trial, antidiabetic treatment with glyburide, metformin, or pioglitazone resulted in a significant reduction of circulating OPG (P = 0.001), without changes in the other biomarkers and vasodilator responses (all P > 0.05). In conclusion, obese patients with MUO/T2D have elevated circulating OPN, OPG, and RANTES; in these patients, antidiabetic treatment reduces only circulating OPG. Further study is needed to better understand the mechanisms of vascular calcifications in obesity and diabetes.

Polyvinylidene Fluoride Mesh (PVDF, DynaMesh®-IPOM) in The Laparoscopic Treatment of Incisional Hernia: A Prospective Comparative Trial versus Gore® ePTFE DUALMESH® Plus.

BACKGROUND: Laparoscopic approach is now generally accepted for the treatment of incisional hernia. The ideal mesh is still to be found. The aim of this study is to compare the well-known Gore® DUALMESH® Plus (WL Gore & Associates, Flagstaff, AZ) to a new prosthesis, the DynaMesh®-IPOM (FEG Textiltechnik GmbH, Aachen, Germany), to clinically verify its potential benefits in the laparoscopic treatment of incisional hernia. MATERIALS AND METHODS: Comparing the results of the laparoscopic treatment of two groups of patients affected by incisional hernia using Gore® DUALMESH® Plus and DynaMesh®-IPOM. RESULTS: There were 45 females and 31 males, with age variable from 21 to 84 years of age. The two groups were well matched for age (median age 60 years for group A and 57.6 years for group B-p=0.44) and sex (28F and 17M group A and 13 F and 18 M group B-p=0.008), while median BMI resulted slightly higher in group B (26.12 group A and 29.74 group B-p=0.001). The median size of the defect was similar in the two groups (87.5 mm group A and 83.4 mm for group B-p=0.83), while the median operating time was slightly longer in group A (77 min group A and 67 min group B-p=0.44). No difference in the length of hospital stay was evidenced between the two groups (3.19 days for group A and 3 days for group B-p=0.74). Time to return to physical activity was similar between the two groups (13.46 days for group A and 12.7 days for group B-p=0.32). Minor complications occurred in 15 cases (19.7%): seromas (7 cases), prolonged ileus (6 cases), and hemoperitoneum (2 cases), without significant difference in the incidence of such complications in the two groups. Five recurrences (6.5% of cases) occurred. No differences in the recurrence rate was noted between the two groups (3 cases/7% for group A and 2 cases/6% for group B-p=00.7). CONCLUSIONS: DynaMesh®-IPOM proved to be a safe and effective mesh for the laparoscopic repair of incisional hernia even when compared to DUALMESH® Plus.

Intragastric gastric band migration: erosion: an analysis of multicenter experience on 177 patients.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has proven to be a safe and effective surgical treatment for morbid obesity. It can be a simple, fast, reversible, anatomy-preserving procedure. Despite these advantages, its long-term efficacy came into question by the occurrence of complications such as intragastric band migration. Consistent information regarding this complication is still lacking. Treatment for migration is still being debated as well. Most of the inconsistencies of these data stem from the very low number of patients reported in single-center experiences or case reports. Lack of multicenter experience is evident. The aim of this study was to perform a retrospective analysis of data on intragastric migration in a large multicenter cohort of patients who underwent LAGB. METHODS: A retrospective multicenter study on LAGB patients was performed. Data had been entered into a prospective database of the Italian Group for LapBand(®) (GILB) since January 1997. Pars flaccida and perigastric positioning were considered along with different kinds of gastric bands by the same manufacturer. Time of diagnosis, mean body mass index (BMI), presentation symptoms, and conservative and surgical therapy of intragastric migration were considered. RESULTS: From January 1997 to December 2009, a total of 6,839 patients underwent LAGB and their data were recorded [5,660 females, 1,179 males; mean age 38.5 ± 18.2 years (range 21-62 years); mean BMI = 46.7 ± 7.7 kg/m(2) (range 37.3-68.3); excess weight (EW) 61.8 ± 25.4 kg (range 36-130); %EW 91.1 ± 32.4 % (range 21-112 %)]. A total of 177 of 6,839 (2.5 %) intragastric erosions were observed. According to the postoperative time of follow-up, the diagnosis of intragastric migration was made in 74 (41.8 %), 14 (7.9 %), 38 (21.4 %), 40 (22.6 %), 6 (3.4 %), and 4 (2.2 %) banded patients at 6-12, 24, 36, 48, 60, and 72 months after banding, respectively. Most of intragastric band migration during the first 2 years occurred in bands with no or a few milliliters of filling. In patients with late erosion, the bands were adjusted several times; no band was overfilled but one was filled to the maximum or submaximum with a maximum of two adjustments. Erosions diagnosed during the first 24 months were related to the experience of the surgical staff, while late erosions were not. CONCLUSIONS: Intragastric band migration or band erosion is a rare, disturbing, and usually not life-threatening complication of gastric banding. Its pathogenesis is probably linked to different mechanisms in early (technical failure in retrogastric passage) or late (band management) presentation. It is usually asymptomatic and there is no pathognomonic presentation. A wide range of therapeutic options are available, from simple endoscopic or laparoscopic removal to early or late band replacement or other bariatric procedure. More experience and more studies are needed to lower its presentation rate and definitively clarify its pathogenesis to address the right therapeutic option.

Laparoscopic adjustable gastric banding via pars flaccida versus perigastric positioning: technique, complications, and results in 2,549 patients.

AIM: Retrospective multicenter analysis of the results of two different approaches for band positioning: perigastric and pars flaccida. METHODS: Data were collected from the database of the Italian Group for LapBand (GILB). Patients operated from January 2001 to December 2004 were selected according to criteria of case-control studies to compare two different band positioning techniques: perigastric (PG group) and pars flaccida (PF group). Demographics, laparotomic conversion, postoperative complications, and weight loss parameters were considered. Data are expressed as mean +/- standard deviation. RESULTS: 2,549 patients underwent the LapBand System procedure [age: 40 +/- 11.7 years; sex: 2,130 female, 419 male; body mass index (BMI): 46.4 +/- 6.9 kg/m(2); excess weight (EW): 60.1 +/- 23.6 kg; %EW: 90.1 +/- 32.4]. During this period 1,343/2,549 (52.7%) were operated via the pars flaccida (PF group) and 1,206/2,549 (47.3%) via the perigastric approach (PG group). Demographics for both groups were similar. Thirty-day mortality was absent in both groups. Operative time was significantly longer in the PG group (80 +/- 20 min versus 60 +/- 40 min; p < 0.05). Hospital stay was similar in the two groups (2 +/- 2 days). Laparotomic conversion was significantly higher in the PG group (6 versus 2 patients; p < 0.001). Overall postoperative complication rate was 172/2,549 (6.7%) and was linked to gastric pouch dilation/slippage (67/172), intragastric migration/erosion (17/172), and tube/port failure (88/172). Gastric pouch dilation and intragastric migration were significantly more frequent in the PG group: 47 versus 20 (p < 0.001) and 12 versus 5 (p < 0.001), respectively. Patients eligible for minimum 3-year follow-up were 1,118/1,206 (PG group) and 1,079/1,343 (PF group). Mean BMI was 33.8 +/- 12.1 kg/m(2) (PG group) and 32.4 +/- 11.7 kg/m(2) (PF group) (p = ns), and mean percentage excess weight loss (%EWL) was 47.2 +/- 25.4 and 48.9 +/- 13.2 in PG and PF groups, respectively (p = ns). CONCLUSIONS: Significant improvement in LapBand System results with regard to laparotomic conversion and postoperative complication rate, with similar weight loss results, was observed in the pars flaccida group.

Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity.

Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow (P=0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; P>0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both P>0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) (P=0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified (P=0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; P<0.001); nitric oxide inhibition by l-N-monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) (P=0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity.

Thrombosis of the superior vena cava due to a Hickman catheter: successful management by rt-PA thrombolysis.

INTRODUCTION: Venous thrombosis is a frequent complication of long-term venous access. Its management is well defined in most cases, but some specific clinical situations have not yet been definitively standardized.Thrombosis may occur at the catheter tip and involve the superior vena cava (SVC) and/or the right atrium (RA). In such cases, while the need for a rapid intervention to relieve the venous obstruction and avoid embolism is obvious, the best management is still to be established. CASE DESCRIPTION: We report the case of a 25-year-old woman with symptomatic thrombosis of SVC and RA, associated with a Hickman catheter, which was successfully treated by recombinant tissue plasminogen activator (rt-PA). CONCLUSIONS: According to the literature, thrombolytic therapy with rt-PA may be considered the treatment of choice in symptomatic thrombosis of SVC secondary to long-term catheter, uncertainty still exists about dosage, optimal rate of infusion, and optimal duration of treatment, as well as the criteria for choosing local versus systemic infusion.

Vascular Effects of Obestatin in Lean and Obese Subjects.

Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both P < 0.001). This vasodilation was predominantly mediated by enhanced NO activity, because NG-monomethyl-l-arginine markedly blunted the flow response to obestatin in both groups (both P < 0.05 vs. saline). In obese subjects, antagonism of ETA receptors by BQ-123 increased forearm flow during saline (P < 0.001) but did not induce additional vasodilation (P > 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (P = 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.

Beneficial Effects of Apelin on Vascular Function in Patients With Central Obesity.

Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)-dependent vasodilator and a counter-regulator of AT1 (angiotensin [Ang] II type 1) receptor-induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr1)apelin on NO-mediated vasodilation and Ang II- or ET-1-dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both P>0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both P<0.05). Interestingly, the vasodilator effect of concurrent blockade of AT1 (telmisartan) and AT2 (PD 123,319) receptors was blunted by apelin (3±5% versus 32±9%; P<0.05). Similarly, during apelin administration, blockade of ETA receptors (BQ-123) resulted in lower vasodilator response than during saline (23±10% versus 65±12%; P<0.05). NO synthase inhibition by L-NMMA (l-N-monometylarginine) during the concurrent blockade of either Ang II or ETA receptors resulted in similar vasoconstriction in the absence or presence of apelin (P>0.05). In conclusion, in patients with central obesity, apelin has favorable effects not only to improve insulin-stimulated endothelium-dependent and endothelium-independent vasodilator responses but also to blunt Ang II- and ET-1-dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the apelin system might favorably impact some hemodynamic abnormalities of insulin-resistant states like obesity.

Short-term Effects of Laparoscopic Adjustable Gastric Banding Versus Roux-en-Y Gastric Bypass.

OBJECTIVE: Bariatric surgery has been shown to have important long-term metabolic effects resulting in enhanced insulin sensitivity and improved glucose tolerance in patients with type 2 diabetes. The contribution of reduced caloric intake to these beneficial effects of surgery remains unclear. The aim of this study was to compare the short-term effects (1 week) of bariatric surgical procedures with a very low caloric intake (VLCI) on insulin sensitivity (IS) and insulin secretion (ISR) in nondiabetic obese subjects. RESEARCH DESIGN AND METHODS: Twenty obese patients without diabetes (BMI 44.2 ± 0.7 kg/m2) were admitted to the clinic for 1 week. At baseline and 1 week after VLCI (600 kcal/day), subjects received a hyperinsulinemic-euglycemic clamp with tracer infusion to quantify endogenous glucose production (EGP), lipolysis (rate of appearance of glycerol [RaGlycerol]), peripheral insulin sensitivity (insulin-stimulated glucose disposal [M value] divided by the steady-state plasma insulin concentration [M/I]), hepatic insulin sensitivity (Hep-IS [= 1/(EGP ⋅ insulin)]), and adipose insulin sensitivity (Adipo-IS [= 1/(RaGlycerol ⋅ insulin)]). An intravenous glucose bolus was administered at the end of the insulin clamp to measure ISR and ß-cell function (disposition index [DI]). Approximately 3 months later, patients were admitted for laparoscopic adjustable gastric banding (LAGB) (n = 10) or Roux-en-Y gastric bypass (RYGB) (n = 10), and were restudied 1 week after surgery under the same caloric regimen (600 kcal/day). RESULTS: After 1 week of VLCI, patients lost 2.1 kg without significant changes in Hep-IS, Adipo-IS, M/I, or DI. RYGB and LAGB led to greater weight loss (5.5 and 5.2 kg, respectively) and to significant improvement in Hep-IS, EGP, and lipolysis. Only RYGB improved Adipo-IS and M/I. No change in ISR or DI was observed in either surgical group. CONCLUSIONS: Bariatric surgery improves IS within 1 week. These metabolic effects were independent of caloric intake and more pronounced after RYGB compared with LAGB.

99mTc-EDDA/HYNIC-TOC in the management of medullary thyroid carcinoma.

An early diagnosis of distant metastases or local recurrences of medullary thyroid carcinoma (MTC) can be achieved by several conventional radiological modalities (e.g., ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI] as well as by radioisotopic procedures, such as positron emission tomography (PET), scintigraphy with different types of radiopharmaceuticals, and radiolabeled receptor-ligands in particular. The aim of this study was to evaluate the clinical utility of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative, to detect recurrences of disease or distant metastases in MTC. Images obtained of 5 patients with high levels of serum calcitonin were compared to findings obtained with other diagnostic procedures: 111In-octreotide, 99mTc-DMSA-V, 18F-flouro-D-deoxyglucose-PET, and CT/MRI. 99mTc-EDDA/HYNIC-TOC was positive in all patients and showed 15 areas of pathological uptake in the cervical and mediastinal regions. 111In-octreotide was positive in 3 of 3 patients and showed 4 areas, compared to 8 of 99mTc-EDDA/HYNIC-TOC. 99mTc-V-DMSA was positive in 3 of 4 patients but showed 6 pathological areas, compared to 13 of 99mTc-EDDA/HYNIC-TOC. 18F-FDG-PET was positive in 5 of 5 patients but showed only 11 areas, compared to 15 of 99mTc-EDDA/HYNIC-TOC. The CT scan was positive in only 2 patients. In conclusion, 99mTc-EDDA/HYNIC-TOC detected more sites of pathological uptake than other modalities, showed better imaging properties than 111In-octreotide, and might be the radiopharmaceutical of choice for providing a rationale for radioisotopic therapy.

Leptin stimulates both endothelin-1 and nitric oxide activity in lean subjects but not in patients with obesity-related metabolic syndrome.

CONTEXT: Leptin has nitric oxide (NO)-dependent vasodilator actions, but hyperleptinemia is an independent risk factor for cardiovascular disease. OBJECTIVE: The objective of the study was to investigate whether, in the human circulation, properties of leptin to release NO are opposed by stimulation of vasculotoxic substances, such as endothelin (ET)-1, and whether this mechanism might contribute to vascular damage in hyperleptinemic states like obesity. METHODS: Forearm blood flow responses (plethysmography) to ETA receptor antagonism (BQ-123, 10 nmol/min) and NO synthase inhibition [N(G)-monomethyl L-arginine (L-NMMA), 4 µmol/min] were assessed before and after intraarterial administration of leptin (2 µg/min) in lean controls (n = 8) and patients with obesity-related metabolic syndrome (MetS; n = 8). RESULTS: Baseline plasma leptin was higher in patients than in controls (P < .001). Before infusion of leptin, the vasodilator response to BQ-123 was greater in patients than in controls (P < .001), whereas infusion of L-NMMA induced higher vasoconstriction in controls than in patients (P = .04). In lean subjects, hyperleptinemia resulted in increased vasodilator response to ETA receptor antagonism (P < .001 vs before) and enhanced vasoconstrictor effect of L-NMMA during ETA receptor blockade (P = .015 vs before). In patients with the MetS, by contrast, vascular responses to both BQ-123 and L-NMMA were not modified by exogenous leptin (both P > .05 vs before). CONCLUSIONS: These findings indicate that, under physiological conditions, leptin stimulates both ET-1 and NO activity in the human circulation. This effect is absent in hyperleptinemic patients with the MetS who are unresponsive to additional leptin. In these patients, therefore, hyperleptinemia may be a biomarker of vascular dysfunction, rather than a mediator of vascular damage.

ω3-PUFAs exert anti-inflammatory activity in visceral adipocytes from colorectal cancer patients.

OBJECTIVE: The aim of this study was to correlate specific fatty acid profiles of visceral white adipose tissue (WAT) with inflammatory signatures potentially associated with colorectal cancer (CRC). METHODS: Human adipocytes were isolated from biopsies of visceral WAT from 24 subjects subdivided in four groups: normal-weight (BMI 22.0-24.9 Kg/m2) and over-weight/obese (BMI 26.0-40.0 Kg/m2), affected or not by CRC. To define whether obesity and/or CRC affect the inflammatory status of WAT, the activation of the pro-inflammatory STAT3 and the anti-inflammatory PPARγ transcription factors as well as the expression of adiponectin were analyzed by immunoblotting in adipocytes isolated from each group of subjects. Furthermore, to evaluate whether differences in inflammatory WAT environment correlate with specific fatty acid profiles, gas-chromatographic analysis was carried out on WAT collected from all subject categories. Finally, the effect of the ω3 docosahexaenoic acid treatment on the balance between pro- and anti-inflammatory factors in adipocytes was also evaluated. RESULTS: We provide the first evidence for the existence of a pro-inflammatory environment in WAT of CRC patients, as assessed by the up-regulation of STAT3, and the concomitant decrease of PPARγ and adiponectin with respect to healthy subjects. WAT inflammatory status was independent of obesity degree but correlated with a decreased ω3-/ω6-polyunsaturated fatty acid ratio. These observations suggested that qualitative changes, other than quantitative ones, in WAT fatty acid may influence tissue dysfunctions potentially linked to inflammatory conditions. This hypothesis was further supported by the finding that adipocyte treatment with docosahexaenoic acid restored the equilibrium between STAT3 and PPARγ. CONCLUSION: Our results suggest that adipocyte dysfunctions occur in CRC patients creating a pro-inflammatory environment that might influence cancer development. Furthermore, the protective potential of docosahexaenoic acid in re-establishing the equilibrium between pro- and anti-inflammatory factors might represent a useful tool for preventive and therapeutic strategies.

Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome.

Obesity is associated with endothelial dysfunction related to decreased NO bioavailability, increased endothelin 1 vasoconstrictor activity, and decreased circulating ghrelin. Therefore, we tested whether exogenous ghrelin may have benefits to improve the balance between endothelin 1 and NO in patients with obesity-related metabolic syndrome. Vasoactive actions of endothelin 1 and NO were assessed in 8 patients with metabolic syndrome and 8 matched controls by evaluating forearm blood flow responses (strain-gauge plethysmography) to intra-arterial infusion of BQ-123 (endothelin A receptor antagonist; 10 nmol/min), followed by NG-monomethyl-L-arginine (NO synthase inhibitor; 4 micromol/min), before and after infusion of ghrelin (200 ng/min). In the absence of ghrelin, the vasodilator response to BQ-123 was greater in patients than in controls (P<0.001), whereas infusion of NG-monomethyl-L-arginine induced smaller vasoconstriction in patients than in controls (P=0.006). Importantly, exogenous ghrelin decreased the vasodilator response to BQ-123 (P=0.007 versus saline) and enhanced the magnitude of changes in forearm blood flow induced by NG-monomethyl-L-arginine (P=0.003) in patients but not in controls (both P>0.05). The favorable effect of ghrelin on endothelin A-dependent vasoconstriction was likely related to the stimulation of NO production, because no change in the vascular effect of BQ-123 was observed after ghrelin (P=0.44) in 5 patients with metabolic syndrome during continuous infusion of the NO donor sodium nitroprusside (0.2 microg/min). In patients with metabolic syndrome, ghrelin has benefits to normalize the balance between vasoconstrictor (endothelin 1) and vasodilating (NO) mediators, thus suggesting that this peptide has important peripheral actions to preserve vascular homeostasis in humans.