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Objective In this retrospective, single-center observational study, we investigated whether discontinuing metformin for at least 48 h prevents metformin-induced [18F]fluorodeoxyglucose (FDG) uptake in all segments of the colon. Methods Patients with type 2 diabetes who were using metformin before undergoing an FDG PET/CT scan were included. Two groups were created: patients who discontinued metformin for less than 48 h ( Results Colonic FDG uptake in the ≥ 48 h group (n = 23) was higher than uptake in the control group (n = 96) in the colon descendens [odds ratio (OR) 14.0; 95% confidence interval (CI) 4.8–40.9; p value: 0.001] and rectosigmoid (OR 11.3; 95% CI 4.0–31.9; p value: 0.001), and there was no difference in the colon ascendens and transversum. Colonic FDG uptake in the n = 25) was higher than uptake in the ≥ 48 h group (n = 23) in the colon transversum (OR 4.8; 95% CI 1.3–18.5; p value: 0.022) and rectosigmoid (p value: 0.023), and there was no difference in the colon ascendens and descendens. Conclusions Discontinuing metformin for 48 h before undergoing an FDG PET/CT still gives a high uptake in the distal parts of the colon when compared with non-diabetic patients who are not using metformin. Discontinuing metformin for 48 h seems to be useful for scanning the more proximal segments of the colon.

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. beta 2-Microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study Design: Study of diagnostic test accuracy.Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFRmeasured as the urinary clearance of iothalamate, plasmaclearanceof iohexol, orplasma clearance of [Cr-51]EDTA.Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m(2), and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1-P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1-P-30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

SUMMARY OBJECTIVE: This study aims to evaluate the relationship between periodontal health status and coronary slow flow phenomenon. METHODS: One hundred and two patients who underwent coronary angiography with the diagnosis of stable angina pectoris were included in the study. Patients were divided into two groups: patients with coronary slow flow (Test group) (n=51), and patients with normal coronary angiography (Control group) (n=51). Diagnosis of slow coronary flow was made according to Beltrame criteria by coronary angiography. Demographic characteristics of the participants were recorded. The periodontal health was assessed by clinical periodontal parameters such as probing depth, clinical attachment level, gingival index, plaque index, and bleeding on probing. RESULTS: There were no significant differences between groups as regards the frequencies of hypertension, smoking (p>0.05). As for the periodontal parameters of the study groups, probing depth, gingival index, plaque index, bleeding on probing, and clinical attachment level values were statistically higher in the test group compared to the control group (p

Purpose Neoadjuvant chemotherapy is the standard front-line treatment modality in locally advanced breast cancer. Achieving pathological complete response (pCR) is a significant prognostic factor for prolonged disease-free and overall survival. Insulin resistance is defined as a pathological condition in which insulin effect is impaired in peripheral target tissues such as the skeletal muscle, liver, and adipose tissue. The relationship between breast cancer and insulin resistance is controversial. In this study, our aim is to evaluate the role of insulin resistance, body mass index (BMI), metabolic syndrome, and inflammation markers to predict complete response in breast cancer patients who underwent neoadjuvant treatment. Methods Data from 55 locally advanced non-diabetic breast cancer patients, treated with neoadjuvant chemotherapy between 2015 and 2017, were retrospectively evaluated. Homeostatic model assessment, IR = insulin resistance (HOMA-IR) was calculated by using the obtained insulin and fasting blood glucose values before neoadjuvant chemotherapy (fasting insulin × fasting glucose/405). We considered a cut-off of 2.5 for insulin resistance. The systemic inflammatory index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. Results Twenty-five patients had no insulin resistance. The most common pathologic subtype (56%) was hormone receptor (HR) positive and human epidermal growth factor receptor-2 (Her-2)-negative invasive ductal carcinoma. Sixteen (29%) patients had a pathological complete response (pCR). We found that the probability of pCR in patients with insulin resistance was 4.7 times lower than that in patients without insulin resistance [OR: 4.7 (95%CI 1.7–17.2), p = 0.01]. Conclusion Our results revealed that insulin resistance may have a negative effect on pathological complete response (pCR) following neoadjuvant therapy particularly with hormone-positive and Her-2-negative cases of non-diabetic breast cancer.

Background Advanced glycation end products (AGEs) are associated with aging, diabetes mellitus (DM), and other chronic diseases. Recently, the accumulation of AGEs can be evaluated by skin autofluorescence (SAF). However, the relationship between SAF levels and exercise capacity in patients with cardiovascular disease (CVD) remains unclear. This study aimed to investigate the association between the tissue accumulation of AGEs and clinical characteristics, including exercise capacity, in patients with CVD. Methods We enrolled 319 consecutive CVD patients aged ≥40 years who underwent early phase II cardiac rehabilitation (CR) at our university hospital between November 2015 and September 2017. Patient background, clinical data, and the accumulation of AGEs assessed by SAF were recorded at the beginning of CR. Characteristics were compared between two patient groups divided according to the median SAF level (High SAF and Low SAF). Results The High SAF group was significantly older and exhibited a higher prevalence of DM than the Low SAF group. The sex ratio did not differ between the two groups. AGE levels showed significant negative correlations with peak oxygen uptake and ventilator efficiency (both P P P = 0.02). Conclusion High levels of tissue accumulated AGEs, as assessed by SAF, were significantly and independently associated with reduced exercise capacity. These data suggest that measuring the tissue accumulation of AGEs may be useful in patients who have undergone CR, irrespective of whether they have DM.

Background: The incidence and potential factors influencing deep sternal wound infection (DSWI) in a cohort of patients undergoing coronary artery bypass grafting (CABG) using skeletonized bilateral internal thoracic artery (BITA) was explored. Furthermore, we studied influence of DSWI on long-term survival, major adverse cardiac events (MACEs) and repeat coronary revascularization (RCR).Methods: The study cohort consisted of 1,325 consecutive patients who were divided in two groups: patients experiencing DSWI (n=33, group 1) and those who did not have sternal infection (n=1,292, group 2). A logistic regression model was employed to find predictors of DSWI whereas Cox regression and a competing risk models were carried out to test predictors of late death, MACE and RCR, respectively. Follow up was 100% complete and ranged from 1 to 245 months. Median follow-up was 103 months (IQR, 61 to 189 months). Cumulative follow-up was 16,430 patient years.Results: The incidence of DSWI was 2.4%. Multivariable logistic regression analysis found any single independent predictor of DSWI. However, the association of peripheral vascular disease (PVD) and diabetes increased the risk by 1.4 and 1.6 times. When DM was associated with obesity the risk increased by 2.1 and 2.6 times compared to the single factors, respectively. Obese female patients were at a 1.6-fold higher risk when compared to the association of DM with obesity. DSWI was not an independent predictor of long-term survival (HR, 2.31; 95% CI: 0.59–9.12), RCR (SHR, 2.89; 95% CI: 0.65–10.12), or MACE (SHR, 1.98; 95% CI: 0.44–8.56).Conclusions: With an accurate patient selection (i.e., exclusion of obese diabetic females) and strict DM control BITA represents a first choice for most of CABG patients, even at high risk for DSWI. The occurrence of DSWI does not influence long-term survival and late outcomes. Our findings should be confirmed by further larger research.

BackgroundMyocardial infarction (MI) is associated with mental health disorders, in which neuroinflammation and cerebral microvascular dysfunction may play a role. Previously, we have shown that the proinflammatory factors Nε-(carboxymethyl)lysine (CML) and NADPH oxidase 2 (NOX2) are increased in the human infarcted heart microvasculature. The aim of this study was to analyse the presence of CML and NOX2 in the cerebral microvasculature of patients with MI.MethodsBrain tissue was obtained at autopsy from 24 patients with MI and nine control patients. According to their infarct age, patients with MI were divided into three groups: 3–6 hours old (phase I), 6 hours–5 days old (phase II) and 5–14 days old (phase III). CML and NOX2 in the microvasculature were studied through immunohistochemical analysis.ResultsWe observed a 2.5-fold increase in cerebral microvascular CML in patients with phase II and phase III MI (phase II: 21.39±7.91, p=0.004; phase III: 24.21±10.37, p=0.0007) compared with non-MI controls (8.55±2.98). NOX2 was increased in microvessels in patients with phase II MI (p=0.002) and phase III MI (p=0.04) compared with controls. No correlation was found between CML and NOX2 (r=0.58, p=0.13).ConclusionsMI coincides with an increased presence of CML and NOX2 in the brain microvasculature. These data point to proinflammatory alterations in the brain microvasculature that may underlie MI-associated mental health disorders.

Postprandial responses predict cardiovascular disease risk. However, only a few studies have compared acute postprandial effects of a low-fat, high-carbohydrate (LF) meal with a high-fat, low-carbohydrate (HF) meal. Furthermore, theobromine has favorably affected fasting lipids, but postprandial effects are unknown. Because both fat and theobromine have been reported to increase fasting apolipoprotein A-I (apoA-I) concentrations, the main hypothesis of this randomized, double-blind crossover study was that acute consumption of an HF meal and a theobromine meal increased postprandial apoA-I concentrations, when compared with an LF meal. Theobromine was added to the LF meal. Nine healthy men completed the study. After meal intake, blood was sampled frequently for 4 hours. Postprandial apoA-I concentrations were comparable after intake of the 3 meals. Apolipoprotein B48 curves, however, were significantly lower and those of triacylglycerol were significantly higher after HF as compared with LF consumption. Postprandial free fatty acid concentrations decreased less, and glucose and insulin concentrations increased less after HF meal consumption. Except for an increase in the incremental area under the curve for insulin, theobromine did not modify responses of the LF meal. These data show that acute HF and theobromine consumption does not change postprandial apoA-I concentrations. Furthermore, acute HF consumption had divergent effects on postprandial apolipoprotein B48 and triacylglycerol responses, suggesting the formation of less, but larger chylomicrons after HF intake. Finally, except for an increase in the incremental area under the curve for insulin, acute theobromine consumption did not modify the postprandial responses of the LF meal. (C) 2017 Elsevier Inc. All rights reserved.

Background Cardiac evaluation before kidney transplantation is recommended, but no unequivocal screening strategy has yet been identified. We investigated if coronary artery calcium score (CACS) can replace cardiovascular risk factor assessment in selection of kidney transplantation candidates for cardiac evaluation and the choice of noninvasive modality for diagnosing obstructive coronary artery disease (CAD). Methods We conducted a prospective study of 167 patients referred for pretransplantation cardiac evaluation. Patients underwent risk factor assessment, CACS, coronary computed tomography angiography (CCTA), single-photon emission computed tomography (SPECT), and invasive coronary angiography. In total, 138 patients completed all diagnostic tests. Results In patients with CAD (22%), the number of risk factors and CACS score were higher than that in patients without CAD. The accuracy evaluated by the receiver-operating characteristic curve was higher for CACS than for risk factors, 0.85 versus 0.71 (P = 0.01). Adding CACS to the risk factor increased correct categorical net reclassification (0.58, P < 0.0001). Combining risk factors (≥3) with SPECT to identify patients with obstructive CAD resulted in less sensitivity (47% vs 80%) and higher specificity (94% vs 74%), compared with CCTA. In patients with low CACS (

// Giada Poli 1, * , Giulia Cantini 1, * , Roberta Armignacco 1, * , Rossella Fucci 1 , Raffaella Santi 2 , Letizia Canu 1 , Gabriella Nesi 2 , Massimo Mannelli 1 , Michaela Luconi 1 1 Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence Italy 2 Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence Italy * These authors contributed equally to this work Correspondence to: Michaela Luconi, email: michaela.luconi@unifi.it Keywords: metformin, H295R, IGF-1R, apoptosis, tumor proliferation Received: March 24, 2016 Accepted: June 09, 2016 Published: July 06, 2016 ABSTRACT Adrenocortical carcinoma (ACC) is a rare heterogeneous malignancy with poor prognosis. Since radical surgery is the only available treatment, more specific and effective drugs are urgently required. The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment. This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R. Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%. Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo . Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC.

PurposeVitreoretinal (VR) surgery is the third most common intraocular surgery after refractive and cataract surgery. The impact of statin therapy on VR surgery outcomes remains unclear, despite a potentially beneficial effect. We explored the association of preoperative statin therapy and the need for revitrectomy after primary vitrectomy. MethodsOur historical, population-based, register-based, VR surgery cohort consisted of 5709 patients operated in a tertiary, academic referral hospital in Finland, during 2008-2014, covering 6.5years. Subgroup analysis was performed as follows: eyes operated due to (i) rhegmatogenous retinal detachment (RRD), (ii) VR interface diseases (macular pucker/hole), (iii) diabetic maculopathy or proliferative retinopathy, (iv) vitreous haemorrhage, (v) lens subluxation, (vi) vitreous opacities or (vii) other VR indication. The primary end-point event was revitrectomy during a postoperative follow-up period of 1year due to retinal redetachment, vitreous rehaemorrhage, postoperative endophthalmitis, recurrent pucker or unclosed macular hole. ResultsRhegmatogenous retinal detachment (RRD) was the second most frequent indication of VR surgery, including 1916 patients, with 305 re-operations with rate 0.20 (95% CI 0.18-0.23) per person-year. Statin treatment in time of operation was associated with lower risk of re-operation according to relative scale (incidence rate ratio 0.72, 95% CI 0.53-0.97), but not in absolute scale (incidence rate difference -0.58, 95% CI -4.30 to 3.15 for 100 person-years). No association with statin therapy and vitrectomy outcome was observed in the other VR subgroups. ConclusionUse of statin treatment was associated with a 28% lower risk of revitrectomy in patients operated due to RRD. Further randomized clinical trials are highly warranted.

IntroductionDiastolic dysfunction is an important predictor of poor outcome after myocardial infarction. Metformin treatment improved diastolic function in animal models and patients with diabetes. Whether metformin improves diastolic function in patients presenting with ST-segment elevation myocardial infarction (STEMI) is unknown.MethodsThe GIPS-III trial randomized STEMI patients, without known diabetes, to metformin or placebo initiated directly after PCI. The previously reported primary endpoint was left ventricular ejection fraction at 4 months, which was unaffected by metformin treatment. This is a predefined substudy to determine an effect of metformin on diastolic function. For this substudy trans-thoracic echocardiography was performed during hospitalization and after 4 months. Diastolic dysfunction was defined as having the combination of a functional alteration (i.e. decreased tissue velocity: mean of septal e' and lateral e') and a structural alteration (i.e. increased left atrial volume index (LAVI)). In addition, left ventricular mass index and transmitral flow velocity (E) to mean e' ratio (E/e') were measured to determine an effect of metformin on individual echocardiographic markers of diastolic function.ResultsIn 237 (63%) patients included in the GIPS-III trial diastolic function was measured during hospitalization as well as at 4 months. Diastolic dysfunction was present in 11 (9%) of patients on metformin and 11 (9%) patients on placebo treatment (P = 0.98) during hospitalization. After 4 months 22 (19%) of patients with metformin and 18 (15%) patients with placebo (P = 0.47) had diastolic dysfunction. In addition, metformin did not improve any of the individual echocardiographic markers of diastolic function.ConclusionsIn contrast to experimental and observational data, our randomized placebo controlled trial did not suggest a beneficial effect of short-term metformin treatment on diastolic function in STEMI patients.

Objective: The aim of this study was to identify the pre-treatment subject characteristics and weight loss changes as determinants of weight loss and attrition during a 10-week dietary intervention study. Methods: A total of 771 obese subjects (BMI 35.6 kg/m2) of both genders were included from 8 clinical centres in 7 European countries, who underwent a 10-week dietary intervention study comparing two hypo-energetic (–600 kcal/day) diets varying in fat content. Results: The multiple regression model showed that weight loss at week 10 was predicted by: 6.55 + 1.27 × early weight loss (kg) at week 1 + 1.35 × gender (R2 = 0.28, p < 0.001). When performing the corresponding model with half-way weight loss (week 5) as covariate, the regression equation was: weight loss (kg) at week 10 = 1.88 + 1.38 × half-way weight loss (kg) (week 5) + 0.42 × gender (R2 = 0.77, p < 0.001). A cut-off target of ≥ 4 kg weight loss at week 5 emerged as an optimal predictor for reaching at least 10% weight loss at week 10. Greater attrition likelihood was predicted by high-fat diet, decreased early and half-way weight losses. Conclusion: Early and half-way weight losses are associated with and could contribute to prediction of the final weight loss and attrition.

The first Injection Technique workshop brought together endocrinologists and injection experts from around the world in Strasbourg in 1997. From its work came groundbreaking recommendations which advanced best practices in areas such as the use of a skin fold when injecting. The second Injection Technique workshop, with an expanded format including nurses and diabetes educators, took place in Barcelona in 2000. The initial stimulus to use shorter injecting needles can be said to date from this meeting. The third Injection Technique workshop was held in Athens in September 2009 and involved 127 experts from across the globe. After a comprehensive review of all publications since 2000 as well as several unpublished studies, the attendees divided into smaller groups to debate and draft new injecting recommendations based on the new data and their collective experience. This paper summarizes all the formal presentations given at this practical consensus workshop. (C) 2010 Elsevier Masson SAS. All rights reserved.

Recognition of the link between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has boosted research in this area. The main objective of this paper is to review the literature on NAFLD in the context of CVD, focussing on underlying mechanisms and treatment. Besides excessive fatty acid influx, etiologic factors may include components of the metabolic syndrome, cytokines and mitochondrial dysfunction. NAFLD is associated with both hepatic and systemic insulin resistance. In the case of NAFLD, the liver overproduces several atherogenic factors, notably inflammatory cytokines, glucose, lipoproteins and coagulation factors, and factors increasing blood pressure. Intervention studies on diet and laparoscopic surgery revealed improvements of hepatic fat content and CVD risk profile. Pharmacological approaches with potential benefit have been developed as well, but effects are often confounded by weight change. NAFLD is associated with an increased CVD risk profile (and hepatic risk). In order to improve CVD risk profile, prevention and treatment of NAFLD seem advisable. However, well-designed intervention studies, randomized clinical trials and long-term follow-up studies are scarce.

OBJECTIVE: Local capillary permeability in patients with SSc has been reported increased when assessed by nail-fold capillaroscopy. We measured capillary permeability at a clinically less affected site by using large-window fluorescein videodensitometry of the ankle. We hypothesized that increased capillary permeability or leakage is a generalized phenomenon in SSc.METHODS: Large-window videodensitometry with sodium fluorescein was performed in 38 SSc patients and 20 healthy controls. Capillary permeability was expressed as the average relative light intensity over the first 7 min [I(av)(7)] after appearance of fluorescein in skin capillaries.RESULTS: Capillary permeability, expressed as I(av)(7) was significantly decreased in patients with SSc (47.3 +/- 15.0% vs 57.6 +/- 9.4% in controls, P = 0.007), as was capillary density (12 +/- 6/mm(2) vs 26 +/- 11/mm(2), P < 0.001). Adjustment for capillary density in multivariate regression analysis demonstrated that differences in I(av)(7) between SSc patients and controls were related to differences in capillary density, BMI and high density lipoprotein cholesterol.CONCLUSION: At the level of the ankle decreased capillary permeability was found in SSc patients, related to decreased capillary density. Microvascular involvement in SSc is widespread, but no evidence was established for increased capillary permeability at the level of individual capillaries as a generalized phenomenon.

Purpose Underlying mechanisms of the beneficial health effects of low glycemic index starchy foods are not fully elucidated yet. We varied the wheat particle size to obtain fiber-rich breads with a high and low glycemic response and investigated the differences in postprandial glucose kinetics and metabolic response after their consumption. Methods Ten healthy male volunteers participated in a randomized, crossover study, consuming 13C-enriched breads with different structures; a control bread (CB) made from wheat flour combined with wheat bran, and a kernel bread (KB) where 85 % of flour was substituted with broken wheat kernels. The structure of the breads was characterized extensively. The use of stable isotopes enabled calculation of glucose kinetics: rate of appearance of exogenous glucose, endogenous glucose production, and glucose clearance rate. Additionally, postprandial plasma concentrations of glucose, insulin, glucagon, incretins, cholecystokinin, and bile acids were analyzed. Results Despite the attempt to obtain a bread with a low glycemic response by replacing flour by broken kernels, the glycemic response and glucose kinetics were quite similar after consumption of CB and KB. Interestingly, the glucagon-like peptide-1 (GLP-1) response was much lower after KB compared to CB (iAUC, P

The concept of glycaemic index (GI) was developed 25 years ago by Jenkins and co-workers in 1981 and first studied to help diabetic patients with blood glucose control. In 1997 two epidemiological studies were published showing that high GI food consumption is associated with an increased risk of type 2 diabetes. At the same time the concept of the glycaemic load (GL) was introduced, based on GI and total carbohydrate intake. Since then, many studies have been conducted to investigate the role of dietary GI and GL in the prevention and management of type 2 diabetes, cardiovascular disease, obesity and other chronic diseases such as cancer. The current review will focus on the epidemiological evidence obtained so far. In addition, several key methodological issues will be addressed, such as the dietary assessment method used, the application of the international GI and GL table, and the correlated dietary patterns.International Journal of Obesity (2006) 30, S66-S71. doi:10.1038/sj.ijo.0803495.

Background: To assess long-term survival in unselected patients with coronary artery disease in who an invasive approach is considered.Methods: All patients with significant coronary artery disease who were presented for coronary revascularisation to two tertiary centres in 1992 were included. Follow-up data were collected in September 2002. Multivariate Cox' proportional-hazards regression analysis was applied to assess the independent relation between variables and 10-year survival.Results: A total of 877 patients were included in this analysis. Mean age was 62 and the most common clinical diagnosis was chronic stable angina (60%). Diabetes was present in 12% of the patients. During the follow-up period, 233 patients (27%) died. Predictors of long-term survival were increasing age, diabetes, peripheral vascular disease and a decreased left ventricular function. Compared to medical treated patients, those treated with revascularisation (either by PCI or CABG) had a decreased long-term mortality (p Conclusions: In patients with coronary artery disease in whom an invasive approach is considered, increasing age, impaired left ventricular function and diabetes are the strongest predictors of long-term mortality. After adjustments for differences in baseline variables, invasive treatment is not associated with a lower long-term mortality. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Objective: The aim of this study was to determine whether diabetologists recognise patients' needs for additional intensive multidisciplinary care due to glycaemic and diabetes-related psychosocial difficulties. Research design and methods: We compared 114 participants in a diabetes intervention programme with 201 as yet non-referred outpatients, of whom 54 outpatients were considered eligible for the intervention by their diabetologists; thus, 147 outpatients were considered non-eligible. Results: Analysis revealed that the eligible patients had poorer glycaemic control but all other parameters were similar to non-eligible patients. Significantly, 22 (15%) of the 147 non-eligible patients clearly had diabetes distress and could potentially benefit from the intervention. Conclusion: The results suggest that in regular care, patients' needs with respect to glycaemic control are recognised by their diabetologists, but patients with high psychosocial diabetes-related distress are often overlooked, though they also may be in need of additional care. Integrated monitoring of diabetes-related distress in outpatients could improve this area of diabetes care. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE: Several somatic illnesses are associated with psychiatric comorbidity. Evidence is provided that availability of the essential amino acid tryptophan, which is the precursor of serotonin, may cause this phenomenon. METHODS: We performed a database search to find relevant articles published between 1966 and 2002. For our search strategy, we combined several diseases from the categories hormonal, gastrointestinal, and inflammatory with the search terms "tryptophan" and "serotonin." RESULTS: The catabolism of tryptophan is stimulated under the influence of stress, hormones and inflammation by the induction of the enzymes tryptophan pyrrolase (in the liver) and IDO (ubiquitous). Because of the reduction in blood levels of tryptophan under these circumstances the formation of cerebral serotonin is decreased. CONCLUSIONS: It is argued that the coupling of peripheral tryptophan levels and cerebral serotonin levels has physiological significance. The clinical implications and therapeutic consequences of changes in tryptophan and consequently serotonin metabolism are discussed.

Increased cardiovascular risk has been associated with reduced response to proerectile drugs. The Italian Society of Andrology and Sexual Medicine (SIAMS) promoted an independent, multicenter study performed in 604 men (55 ± 12 yrs) suffering from erectile dysfunction (ED) to assess multiple health outcomes and response to 6-month vardenafil challenge in a real-life setting. Overall, 30.8% men had metabolic syndrome. Cardiovascular risk stratification revealed a greater number of ED subjects with moderate risk of a major adverse cardiovascular event than the general population (P<0.01). Age-adjusted pulse pressure was positively correlated with ED severity and negatively with androgens and waist circumference (P<0.01). A decline in total testosterone was observed with increasing arterial pulse pressure (P<0.05), which was not accompanied by compensatory LH rise. Follow-up on 185 men treated with vardenafil in an nonrandomized, open, single-arm trial documented a significant rise in IIEF-5 (delta = 6.1 ± 4.8) that was maintained in men with high cardiovascular risk. Mild adverse events occurred in

BACKGROUND: This study aimed to evaluate the use of QT intervals, their diagnostic predictive value in patients with syncope and their relationship with syncope severity. METHODS: One hundred and forty nine patients with a diagnosis of syncope were admitted to Internal Medicine departments at the University of Palermo, Italy, between 2006 and 2012, and 140 control subjects hospitalised for other causes were enrolled. QT maximum, QT minimum, QTpeak, QT corrected, QT dispersion and Tpeak-to-Tend interval were compared between two groups. The paper medical records were used for scoring with San Francisco Syncope Rule (SFSR), Evaluation of Guidelines in SYncope Study (EGSYS) score and Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk score. RESULTS: Mean QTc (p < 0.0005), mean QTmax (p < 0.0005), mean QTdisp (p < 0.0005), mean QTpeak (p = 0.005) and mean TpTe (p = 0.018) were significantly longer in patients with syncope compared with control subjects. A QTc > 424.8 ms (sensibility: 81.88 - specificity: 57.86) showed the greatest predictive value for diagnosis of syncope. On the EGSYS score and on the OESIL score, QTc was significantly prolonged in high-risk patients compared with low-risk patients. On the San Francisco Syncope Rule, QTc and QTdisp were significantly prolonged in high-risk patients compared with low-risk patients. CONCLUSION: Mean QTc, mean QTdisp, mean TpTe, mean QTmax and mean QTpeak were significantly longer in patients with syncope compared with control subjects. Furthermore, prolonged QTc and QTdisp were associated with major severe syncope according to San Francisco Syncope Rule, EGSYS and OESIL risk scores.

Objective LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin–kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction. Methods Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m 2 , proteinuria 1.9 [0.9–3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na + /day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3–1.1] g/day ( P Results Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161–314] vs. 143 [113–190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline ( R = 0.399, P = 0.018) and at maximal antiproteinuric treatment ( R = 0.525, P = 0.001), but did not decrease during proteinuria reduction ( P = 0.84). Individual changes in total cholesterol ( R = 0.365, P = 0.024), non-HDL cholesterol ( R = 0.333, P = 0.041), and LDL cholesterol ( R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment ( P = 0.04). Conclusion Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects.

The obesity hormone leptin has been implicated in breast cancer development. Breast cancer cells express the leptin receptor and are able to synthesize leptin in response to obesity-related stimuli. Furthermore, leptin is a positive regulator of vascular endothelial growth factor (VEGF) and high levels of both proteins are associated with worse prognosis in breast cancer patients. Peroxisome proliferator-activated receptor γ (PPARγ) ligands are therapeutic agents used in patient with Type 2 diabetes and obesity which have recently been studied for their potential anti-tumor effect. Here, we studied if these compounds, ciglitazone and GW1929, can affect the expression of leptin and VEGF in breast cancer cells. In MDA-MB-231 and MCF-7 breast cancer cells, treatment with submolar concentrations of ciglitazone and GW1929 elevated the expression of leptin and VEGF mRNA and protein, and increased cell viability and migration. These effects coincided with increased recruitment of PPARγ to the proximal leptin promoter and decreased association of a transcriptional factor Sp1 with this DNA region.

PURPOSE OF REVIEW: Screening for chronic kidney disease frequently starts with assessment of estimated glomerular filtration rate (eGFR). In current approaches, further evaluation will only include measurement of albuminuria in case of eGFR less than 60 ml/min/1.73 m. We will review whether this screening approach is correct.RECENT FINDINGS: Albuminuria is an important predictor of both cardiovascular and kidney outcomes in chronic kidney disease. The predictive value of albuminuria for these endpoints is not only independent of well known risk factors, including diabetes and hypertension, but it is also independent of eGFR. Many individuals with normal eGFR have albuminuria. More research is needed to define why albuminuria adds to eGFR in predicting outcomes. After leakage through the glomerular filter, albumin is not only excreted in urine, but also reabsorbed by tubules. Albuminuria may, therefore, be a marker of both glomerular and tubular damage, whereas eGFR is merely a marker of glomerular damage.SUMMARY: As many individuals with an eGFR more than 60 ml/min/1.73 m have microalbuminuria, and albuminuria is an independent predictor of both renal and cardiovascular outcomes, screening for chronic kidney disease should at least include measurement of albuminuria. Future studies should consider whether the inclusion of (other) markers of tubular damage will further improve our ability to predict outcomes in patients with chronic kidney disease.

The prognostic impact of reduced glomerular filtration rate (GFR) in chronic heart failure (CHF) is increasingly recognised, but little is known about tubular damage in these patients.To investigate the prevalence of tubular damage, and its association with GFR, and prognosis in patients with CHF.In 90 patients with CHF, GFR and effective renal plasma flow (ERPF) were measured ([(125)I]iothalamate and [(131)I]hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as well as urinary albumin excretion were determined in 24 h urine collections. Mean GFR was 78+/-26 ml/min/1.73 m(2). Urinary NGAL (175 (70-346) microg/g creatinine (gCr)), NAG (12 (6-17) U/gCr) and KIM-1 (277 (188-537) ng/gCr) levels were increased compared with 20 healthy controls (all p0.001). Urinary NAG, but not NGAL or KIM-1 correlated with GFR (r=-0.34, p=0.001) and ERPF (r=-0.29, p=0.006). Both NAG (r=0.21, p=0.048) and KIM-1 (r=0.23, p=0.033) correlated with plasma N-terminal pro-brain natriuretic peptide levels. Both urinary KIM-1 (HR=1.15 (95% CI 1.02 to 1.30) per 100 ng/gCr increase, p=0.025) and NAG (HR=1.42 (95% CI 1.02 to 1.94) per 5 U/gCr increase, p=0.039), were associated with an increased risk of death or heart failure hospitalisations, independent of GFR.Tubular damage, as indicated by increased urinary concentrations of NGAL, NAG and KIM-1 is common in patients with CHF and mildly reduced GFR. Both urinary KIM-1 and NAG showed prognostic information additional to GFR. These findings suggest an important role for tubular damage and tubular markers in cardiorenal interaction in heart failure.

Background: Our objective was to evaluate the accuracy and safety of a real-time (RT) continuous glucose monitoring system (CGMS) in patients before and after cardiothoracic surgery and to investigate whether activation of the alarm function of the RT-CGMS had an effect on glucose control.Methods: Patients scheduled for elective cardiothoracic procedures, without a history of insulin-requiring diabetes, were perioperatively monitored with RT-CGMS for 72 h and were randomized into two groups: with or without the alarm function (set at 4 and 10 mmol/L) of the device activated. Sensor values were compared with capillary, arterial, and venous blood glucose values. Percentages of time spent in various glucose ranges were compared between groups.Results: There were no adverse effects of the RT-CGMS. Of the 1,001 sensor value comparisons with capillary or arterial measurements, 96.6% fell within Clarke Error Grid zones A and B, with relative absolute differences ranging from 15% (preoperative period) to 12% (intensive care unit period) to 14% (postoperative period on the ward). Seventeen (7.9%) arterial and 16 (2.0%) capillary comparisons fell within zone D or E. Whether or not the alarm function, as used in this pilot study, was activated did not affect time spent in different glucose ranges.Conclusions: Although the RT-CGMS is safe and accurate according to accepted standards, there are still small aberrations, which in our opinion preclude unlimited use in its present form in a clinical setting. The effect of the alarm function at different glucose levels remains to be investigated.

Because urinary albumin excretion (UAE) is a marker of cardiovascular (CV) risk, some have proposed screening the general population; however, it is unknown how the predictive power of a single screening value changes over time. In this study, data of 8496 individuals in a community-based, prospective cohort were used to evaluate this question. For each doubling of baseline UAE, the hazard ratio (HR) for a CV event was 1.36 (95% confidence interval [CI] 1.31 to 1.42). Baseline UAE similarly predicted events occurring >5 yr after baseline, suggesting that it remains a good predictor during at least the first 5 yr after measurement. Approximately 4 yr after baseline, UAE was measured again in 6800 individuals. Once again, high UAE (>75th percentile) predicted subsequent CV events, whether defined using the baseline UAE or follow-up UAE (HR 3.39 [95% Cl 2.58 to 4.45] and HR 2.50 [95% CI] 1.90 to 3.29, respectively; P = 0.3 for difference). Finally, compared with individuals with consistently low UAE, individuals who progressed from low to high UAE during follow-up had a significantly higher risk for CV events (HR 3.68; 95% Cl 2.45 to 5.53). In conclusion, UAE remains a good predictor of CV events during the first 5 yr after measurement, but repeating the measurement several years later also detects progression of UAE, which is also associated with increased CV risk. Future studies are required to determine the optimal interval of repeat testing and its cost-effectiveness.

Background. Increased levels of albuminuria have been recognized as a feature of obesity and the metabolic syndrome, and to be associated with an increased risk for cardiovascular and renal disease. The impact of weight change on albuminuria and its possible mechanism has not been studied yet in the general population. We investigated this issue in a cohort of the Northern European population.Methods. A total of 6894 participants of the Prevention of Renal and Vascular Endstage Disease (PREVEND) study were evaluated from baseline to a mean period of follow-up of 4.2 years for weight change (gain/loss), and its impact on albuminuria, renal function and cardiovascular risk factors. Participants were categorized into three groups based on absolute change in weight from baseline to follow-up: significant weight loss (> 10kg reduction in weight), stable weight, or significant weight gain (> 10 kg increase). Multivariate regression analysis was used to evaluate the effect of baseline characteristics and time-dependent changes in these characteristics on the relationship of weight change with urine albumin excretion (UAE).Results. At follow-up 101 subjects experienced significant weight loss (mean change = -14.2 kg), 348 had significant weight gain (mean change = +13.4 kg) and the remaining were defined stable in weight (mean change = +1.4kg). Weight loss was associated with significant improvement in systolic blood pressure (-11 +/- 15 mmHg), diastolic blood pressure (-5 +/- 8 mmHg), and cholesterol (-0.7 +/- 1.3 mmol/l), even after adjustment for the use of medications (P Conclusion. This is the first population-based longitudinal study to show that changes in weight are associated with parallel changes in albuminuria. This relationship cannot be fully explained by the association between weight and classical cardiovascular risk factors and renal function. Based on our data we hypothesize that weight-induced changes in vascular inflammation may cause changes in albuminuria.

Background Favorable clinical outcomes have been observed with glucose-insulin-potassium infusion (GIK) in acute myocardial infarction (MI). The mechanisms of this beneficial effect have not been delineated clearly. GIK has metabolic, anti-inflammatory and profibrinolytic effects and it may preserve the ischemic myocardium. We sought to assess the effect of GIK infusion on infarct size and left ventricular function, as part of a randomized controlled trial. Methods Patients (n = 940) treated for acute MI by primary percutaneous coronary intervention (PCI) were randomized to GIK infusion or no infusion. Endpoints were the creatinine kinase MB-fraction (CK-MB) and left ventricular ejection fraction (LVEF). CK-MB levels were determined 0, 2, 4, 6, 24, 48, 72 and 96 hours after admission and the LVEF was measured before discharge. Results There were no differences between the two groups in the time course or magnitude of CK-MB release: the peak CK-MB level was 249 ± 228 U/L in the GIK group and 240 ± 200 U/L in the control group (NS). The mean LVEF was 43.7 ± 11.0 % in the GIK group and 42.4 ± 11.7% in the control group (P = 0.12). A LVEF ≤ 30% was observed in 18% in the controls and in 12% of the GIK group (P = 0.01). Conclusion Treatment with GIK has no effect on myocardial function as determined by LVEF and by the pattern or magnitude of enzyme release. However, left ventricular function was preserved in GIK treated patients.

Aims/hypothesis: We explored the impact of baseline left ventricular hypertrophy (LVH) and losartan treatment on renal and cardiovascular (CV) events in 1,513 patients from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, which studied the effects of losartan on the progression of renal disease and/or death in patients with type 2 diabetes and nephropathy. Materials and methods: LVH was assessed using ECG criteria (Cornell product and/or Sokolow-Lyon voltage). The risk of renal or CV events was determined by a proportional hazards model fit with treatment allocation and presence of LVH. Covariates at baseline included age, sex, systolic BP, mean arterial pressure, pulse, proteinuria, serum creatinine, albumin and haemoglobin. Results: A total of 187 subjects (12%) had LVH at baseline. Treatment with losartan resulted in a significant decrease in the Cornell product (-6.2%) and Sokolow-Lyon voltage (-6.3%). LVH was shown to be significantly associated with the primary endpoint, which was a composite of doubling of serum creatinine (DSCR), endstage renal disease (ESRD) or death (hazard ratio [HR]=1.44, p=0.011), as well as with the composite renal endpoint of DSCR/ESRD (HR=1.42, p=0.031) and CV events (HR=1.68, p=0.001). Losartan treatment of patients with LVH decreased the CV as well as renal risk to a level similar to that of patients without LVH. Conclusions/interpretation: In patients with type 2 diabetes and nephropathy, LVH is associated with significantly increased risk of CV events and the progression of kidney disease. Importantly, in patients with LVH, losartan reduced the CV as well as the renal risk to a level similar to that seen in subjects without LVH.

We initiated a worldwide collaborative study, including 455 episodes of bacteremia, to elucidate the clinical patterns of Klebsiella pneumoniae. Historically, community-acquired pneumonia has been consistently associated with K. pneumoniae. Only four cases of community-acquired bacteremic K. pneumoniae pneumonia were seen in the 2-year study period in the United States, Argentina, Europe, or Australia; none were in alcoholics. In contrast, 53 cases of bacteremic K. pneumoniae pneumonia were observed in South Africa and Taiwan, where an association with alcoholism persisted (p=0.007). Twenty-five cases of a distinctive syndrome consisting of K. pneumoniae bacteremia in conjunction with community-acquired liver abscess, meningitis, or endophthalmitis were observed. A distinctive form of K. pneumoniae infection, often causing liver abscess, was identified, almost exclusively in Taiwan.

Publication of the United Kingdom Prospective Diabetes Study (UKPDS) in 2006 [1], resulted in metformin being considered the first choice for new-onset diabetes type-2 in many international guidelines significantly increasing its use. [2,3]. The number of metformin users in the Netherlands increased with 43% between 2005 and 2009 from 27.5 to 39.4 per 1000 patients [4]. Although relatively safe, metformin has a high prevalence of gastrointestinal adverse effects. In 2009 three patients were admitted to our geriatric department for metformin-induced long-lasting disabling diarrhea. We describe one of these cases.

Blood pressure reduction initiates the antiproteinuric effect of ACE inhibition. Several observations question the role of blood pressure and renal hemodynamic changes in the long-term antiproteinuric effect of ACE inhibition. To differentiate blood pressure and renal effects in the initial antiproteinuric response, the placebo-controlled acute effects of the ACE inhibitor enalaprilat (10mg i.v.) on blood pressure, renal hemodynamics, and proteinuria were compared with those of nitroprusside in nine patients with non-diabetic proteinuria. In addition, we studied whether an exogenous angiotensin II infusion reverse the initial enalaprilat-induced antiproteinuric response. Enalaprilat and nitroprusside reduced MAP by -11.3 ± 2.4% and -14.1 ± 2.3%, respectively, whereas only enalaprilat showed renal hemodynamic effects, reflected by an increase in ERPF of 18.4 ± 5.4% and a decrease in FF of -17.1 ± 2.6%. Despite the contrasting renal hemodynamic profiles, enalaprilat (-10.6 ± 4.8%) and nitroprusside (-12.8 ± 5.1%) equally decreased proteinuria. Exogenous infusion of angiotensin II completely reversed the blood pressure reduction and renal efferent vasodilatation induced by enalaprilat. Proteinuria also increased by 13.1 ± 7.8% to placebo level, albeit statistically non-significant. We conclude that the initial antiproteinuric effect of ACE inhibition appears to be mediated by blood pressure reduction and does not require its specific renal hemodynamic effect. Further studies should clarify whether the renal efferent vasodilatation during ACE inhibition is required to gradually induce renal structural changes that prevent the abundant passage of proteins.

Current care guidelines recommend glucose control (GC) in critically ill patients. To achieve GC, many ICUs have implemented a (nurse-based) protocol on paper. However, such protocols are often complex, time-consuming, and can cause iatrogenic hypoglycaemia. Computerized glucose regulation protocols may improve patient safety, efficiency, and nurse compliance. Such computerized clinical decision support systems (CDSSs) use more complex logic to provide an insulin infusion rate based on previous blood glucose levels and other parameters. A computerized CDSS for glucose control has the potential to reduce overall workload, reduce the chance of human cognitive failure, and improve glucose control. Several computer-assisted glucose regulation programs have been published recently. In order of increasing complexity, the three main types of algorithms used are computerized flowcharts, Proportional-Integral-Derivative (PID), and Model Predictive Control (MPC). PID is essentially a closed-loop feedback system, whereas MPC models the behaviour of glucose and insulin in ICU patients. Although the best approach has not yet been determined, it should be noted that PID controllers are generally thought to be more robust than MPC systems. The computerized CDSSs that are most likely to emerge are those that are fully a part of the routine workflow, use patient-specific characteristics and apply variable sampling intervals.

Objectives. The aim of this study is to assess the influence of subintimal angioplasty (SIA) on lower limb amputation rate and level in critically ischaemic limbs. Methods. Between January 1989 and March 2004, 1268 patients were admitted for treatment of lower limb critical ischaemia. Eight hundred and twenty-nine patients underwent revascularisation (bypass 671 and angioplasty 158), while 439 patients had primary amputations. A retrospective analysis of a prospectively maintained vascular registry was performed. Patients were divided into two groups, those who were admitted prior to the availability of subintimal angioplasty and those treated post-introduction of angioplasty. The two groups were compared with regards to age, sex, diabetes mellitus, ASA grade, Rutherford classification and level of disease. Outcome was assessed by the limb salvage rate, 30-day morbidity and mortality, and length of hospital stay. Results. The average number of revascularisation increased with the introduction of subintimal angioplasty, from 53 to 96 per year (p < 0.001). The overall limb salvage rate increased significantly from 42 to 70% (p < 0.001). The cumulative limb salvage rate following revascularisation rose from 72 to 86% (p < 0.001). The level of amputation (AKA:BKA) did not vary significantly. Thirty-day morbidity, mortality and length of hospital stay were significantly lower in the post-angioplasty group. Conclusions. Technical advances have resulted in a steadying of amputation numbers despite an ageing population.