CIRCULATING PROGENITOR CELLS: A NOVEL BIOMARKER OF MICROVASCULAR AND MACROVASCULAR DISEASE IN TYPE 2 DIABETIC PATIENTS

Objective. We evaluated the ability of circulating stem cell levels to predict future micro and macrovascular complications in patients with type 2 diabetes. We further investigate the prognostic value of stem cells in a wide and heterogeneous cohort of patients, using a meta-analytic approach. Research design and methods. A cohort of 187 patients with type 2 diabetes was followed-up for a median of 3.3 years and 6.1 years for the evaluation of microvascular and macrovascular outcomes, respectively. The primary outcomes were onset or progression of any microangiopathy, and time to a first cardiovascular event. In addition, we meta-analysed all studies reporting the prognostic role of the CPC/EPC measure on cardiovascular outcomes and death in a heterogeneous population of 4451 patients at high cardiovascular risk. Results. New onset or progression of microangiopathy occurred in 70 patients (9.5% per year). After controlling the false discovery rate (FDR), baseline CD34+ CPCs and EPCs were significantly lower in patients with onset/progression of microalbuminuria and any microangiopathy. Patients with baseline CD34+ CPC or CD133+KDR+ EPC levels below median were more likely to experience worsening microangiopathy than those with high cell levels. In FDR-fully-adjusted analysis, CD34+ cells predicted onset/progression of microalbuminuria, retinopathy, and any microangiopathy. A first cardiovascular event occurred in 48 patients (4.5% per year). Patients with incident cardiovascular events had significantly lower CD34+ and CD34+CD133+ cells than those without. Patients with below median levels of CD34+ and CD34+CD133+ cells experienced higher rates of cardiovascular events. In Cox proportional hazard regression analyses, a reduced CD34+ and CD34+CD133+ cell count independently predicted future events. Addition of the CD34+ cell count to the UKPDS risk engine model improved C-statistics, continuous NRI and/or IDI. In the meta-analysis, reduced CPC/EPC levels were associated with a ~2 fold increased risk of future cardiovascular events and cardiovascular death and the most predictive phenotypes were CD34+ and CD34+CD133+. Conclusions. In patients with type 2 diabetes, a reduced baseline level of circulating CD34+ stem cells predicts worsening of microangiopathy and cardiovascular events up to 6 years later, and improves risk stratification. The meta-analysis suggests that prognostic impact of reduced stem cell levels was similar in diabetic and non-diabetic patients

The Stockouts Study: an Examination of the Extent and the Causes in the São Paulo Supermarket Sector

Stockouts remain a significant retail problem. Progress has been limited, as estimates of stockout rates in the past forty years have consistently averaged above 8 percent. The purpose of this study is to investigate the importance and extent of the stockout problem in the supermarket sector in the state of São Paulo, Brazil, from the perspective of the supermarket managers themselves. Results suggest that the level of stockouts is high. Generally, the suppliers are mentioned as being the ones mainly responsible for stockouts. These results suggest that managers have significant opportunities to reduce retail stockouts by taking preventative actions

CIRCULATING PROGENITOR CELLS: A NOVEL BIOMARKER OF MICROVASCULAR AND MACROVASCULAR DISEASE IN TYPE 2 DIABETIC PATIENTS

Objective. We evaluated the ability of circulating stem cell levels to predict future micro and macrovascular complications in patients with type 2 diabetes. We further investigate the prognostic value of stem cells in a wide and heterogeneous cohort of patients, using a meta-analytic approach. Research design and methods. A cohort of 187 patients with type 2 diabetes was followed-up for a median of 3.3 years and 6.1 years for the evaluation of microvascular and macrovascular outcomes, respectively. The primary outcomes were onset or progression of any microangiopathy, and time to a first cardiovascular event. In addition, we meta-analysed all studies reporting the prognostic role of the CPC/EPC measure on cardiovascular outcomes and death in a heterogeneous population of 4451 patients at high cardiovascular risk. Results. New onset or progression of microangiopathy occurred in 70 patients (9.5% per year). After controlling the false discovery rate (FDR), baseline CD34+ CPCs and EPCs were significantly lower in patients with onset/progression of microalbuminuria and any microangiopathy. Patients with baseline CD34+ CPC or CD133+KDR+ EPC levels below median were more likely to experience worsening microangiopathy than those with high cell levels. In FDR-fully-adjusted analysis, CD34+ cells predicted onset/progression of microalbuminuria, retinopathy, and any microangiopathy. A first cardiovascular event occurred in 48 patients (4.5% per year). Patients with incident cardiovascular events had significantly lower CD34+ and CD34+CD133+ cells than those without. Patients with below median levels of CD34+ and CD34+CD133+ cells experienced higher rates of cardiovascular events. In Cox proportional hazard regression analyses, a reduced CD34+ and CD34+CD133+ cell count independently predicted future events. Addition of the CD34+ cell count to the UKPDS risk engine model improved C-statistics, continuous NRI and/or IDI. In the meta-analysis, reduced CPC/EPC levels were associated with a ~2 fold increased risk of future cardiovascular events and cardiovascular death and the most predictive phenotypes were CD34+ and CD34+CD133+. Conclusions. In patients with type 2 diabetes, a reduced baseline level of circulating CD34+ stem cells predicts worsening of microangiopathy and cardiovascular events up to 6 years later, and improves risk stratification. The meta-analysis suggests that prognostic impact of reduced stem cell levels was similar in diabetic and non-diabetic patients.Obiettivi. Il presente studio è stato finalizzato a valutare l’abilità delle cellule progenitrici endoteliali nel predire le complicanze croniche micro a macro-vascolari dei pazienti affetti da diabete mellito di tipo 2. Metodi. Una coorte di 187 pazienti affetti da diabete di tipo 2 è stata seguita durante un follow-up mediano di 3.3 e 6.1 anni per la valutazione delle complicanze micro e macro-vascolari, rispettivamente. L’outcome primario era rappresentato dalla nuova insorgenza o dalla progressione di una qualsiasi forma di microangiopatia o dal tempo al primo evento cardiovascolare (CV). Inoltre, abbiamo meta-analizzato tutti gli studi che riportavano il ruolo prognostico dei livelli di CPC/EPC nel predire lo sviluppo di eventi CV o la morte, in una coorte eterogenea di 4451 pazienti ad alto rischio CV. Risultati. Settanta pazienti hanno sperimentato l’insorgenza o la progressione della microangiopatia (9.5% per anno). Dopo l’aggiustamento per il false discovery rate (FDR), il livello basale di CD34+ CPCs e di EPCs era significativamente inferiore nei pazienti che andavano incontro ad insorgenza o progressione di microalbuminuria o dell’end point composito di una qualsiasi forma di microangiopatia. I pazienti con valori basali di CD34+ CPC o CD133+KDR+ EPC inferiori alla mediana presentavano un rischio più elevato di peggioramento della microangiopatia, rispetto a quelli con valori più elevati di cellule. Nell’analisi statistica multivariata, i livelli di CD34+ erano in grado di predire lo sviluppo/progressione di microalbuminuria, retinopatia e dell’end point costituito da una qualsiasi forma di microangiopatia. Quarantotto pazienti hanno sviluppato un evento CV durante il periodo di follow-up (4.5% per anno). I pazienti con evento CV avevano livelli di cellule CD34+ e CD34+CD133+ significativamente più bassi rispetto ai pazienti senza eventi. I pazienti con livelli basali di CD34+ e CD34+CD133+ inferiori al valore mediano, presentavano un maggior rischio di eventi CV. Nell’analisi di sopravvivenza di Cox, un ridotto numero di CD34+ e CD34+CD133+ rappresentava un predittore indipendente di futuri eventi CV. L’inserimento dei livelli di CD34+ all’interno dell’UKPDS risk engine model, migliorava significativamente la capacità predittiva del modello. Nella meta-analisi, un ridotto livello di CPC/EPC era associato ad un raddoppio del rischio di sviluppare futuri eventi CV e di morte CV, e i fenotipi cellulari maggiormente predittivi erano il CD34+ e il CD34+CD133+. Conclusioni. Nei pazienti con diabete mellito di tipo 2, un ridotto livello basale di cellule progenitrici CD34+, è in grado di predire a lungo termine la progressione della microangiopatia e lo sviluppo di eventi CV. La meta-analisi suggerisce che l’impatto prognostico del ridotto numero di cellule progenitrici sembra essere simile nei pazienti diabetici e non diabetici

Circulating stem/progenitor cells as prognostic biomarkers in macro- and microvascular disease. A narrative review of prospective observational studies

Circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) are immature cells involved in vascular repair and related to many aspects of macro and microvascular disease

Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies

none3nomixedRigato, Mauro; Monami, Matteo; Fadini, Gian PaoloRigato, Mauro; Monami, Matteo; Fadini, GIAN PAOL

Effects of dose escalating liraglutide from 1.2 to 1.8 mg in clinical practice: A case-control study

Purpose Randomized trials show that liraglutide 1.8 mg is more effective than 1.2 mg in reducing HbA1c, but dose escalation is neither routinely considered nor recommended by some guidelines. We report real world data on the effects of dose-escalating liraglutide from 1.2 to 1.8 mg. Methods In a pseudo-prospective, case-control study, patients who underwent liraglutide dose escalation to 1.8 mg for not having met individualized targets while on the 1.2 mg dose (n = 52) were compared to matched patients who remained on 1.2 mg (n = 52) for having shown good response, as defined by the patient's own diabetologist. HbA1c was recorded at <= 6-month intervals until the end of observation. Results The two groups were matched for all clinical characteristics, including baseline HbA1c (8.5 %). During a 12-month follow-up, patients who remained on liraglutide 1.2 mg showed a maximal HbA1c reduction of 1.29 +/- 0.15 %. Patients who escalated to 1.8 mg showed a lower HbA1c reduction during therapy with 1.2 mg than controls (0.58 +/- 0.16 %; p = 0.0017). Escalation to 1.8 mg resulted in a further HbA1c reduction of 0.62 +/- 0.17 %. During a total 18-month follow-up, patients who escalated to 1.8 mg showed a total maximal HbA1c reduction of 0.84 +/- A 0.22 %. At the end of the observation, HbA1c was 7.54 +/- 0.17 % in patients who remained on 1.2 mg and 7.92 +/- 0.21 in patients who escalated to 1.8 mg (p = 0.13). Escalation to 1.8 mg also helped further body weight reduction. Conclusions Escalating liraglutide dose to 1.8 mg in patients who responded less than expected to 1.2 mg helps in reducing HbA1c and reaching therapeutic targets

Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death: A Meta-Analysis of Prospective Observational Studies

Rationale: Circulating progenitor cells (CPCs), including endothelial progenitor cells (EPCs) are biologically related to many aspects of cardiovascular disease, as they promote angiogenesis and vascular repair. Objective: We herein aimed to meta-analyze studies reporting the prognostic role of the CPC/EPC measure on cardiovascular outcomes and death. Methods and Results: We screened the English-language literature for longitudinal studies reporting the association between baseline CPC/EPC levels, future cardiovascular events, and death. We retrieved 28 studies, 21 of which contained poolable data and entered the meta-analysis, for a total of 4155 patients, mostly with a high baseline cardiovascular risk. Sixty percent of the studies met at least 11 of 16 items of quality assessment. Overall, reduced CPC/EPC levels were associated with a approximate to 2-fold increased risk of future cardiovascular events and cardiovascular death. The most predictive phenotype was CD34(+)CD133(+): low versus high levels predicted cardiovascular events, restenosis after endovascular intervention, cardiovascular death, and all-cause mortality. Heterogeneity among studies and according to the CPC/EPC phenotype was generally high. Excluding studies for which the risk estimate had to be extrapolated or limiting the analyses to higher quality studies still indicated a significant risk for future cardiovascular events and death in patients with low versus high progenitor cell counts. Conclusions: This meta-analysis shows that a reduction in the levels of circulating cells putatively provided with vasculoregenerative properties represents a risk factor for adverse cardiovascular outcomes and death