A randomized, open-label, controlled trial to evaluate the antimicrobial and surgical effect of CO2 laser treatment in diabetic infected foot ulcers: DULCIS (diabetic ulcer, CO2 laser, and infections) study.

AIM: Debridement of fibrin and necrotic tissue from the ulcer surface is an important component of the treatment of diabetic ulcers. A possible alternative to standard lancets is represented by CO2 laser, which vaporizes necrotic tissues together with any pathogen. The present trial is aimed at verifying the effect of a CO2 laser on bacterial load in the debridement of infected diabetic foot ulcers. METHODS: In this open-label randomized controlled trial (NCT02677779), patients with diabetes and an infected foot ulcers were randomized to either CO2 laser or traditional debridement. RESULTS: The reduction (%) of bacterial load with CO2 laser was significantly greater than in control group [-99.9 (-100.0; -90.0) vs. -50.0 (-96.0; -75.0), p = 0.049]. Similarly, a significantly greater reduction (%) of the fraction of ulcer area covered by fibrin was obtained in the intervention group [-84.1 (-95.0; -72.2) vs. -46.9 (-69.5; -40.8), p = 0.038]. CONCLUSIONS: Debridement of ulcers with CO2 laser significantly reduces bacterial load and fibrin-covered areas, and could be of help in the treatment of diabetic foot ulcer.

CO2 laser for the treatment of diabetic foot ulcers with exposed bone. A consecutive series of type 2 diabetic patients.

AIM: The treatment of foot ulcers with exposed bone is challenging, because of the risk of infection and of difficulties in the development of granulation tissue. A CO2 laser beam could be used to produce discontinuities in periosteum, allowing the exposure of blood containing multipotent stem cells, capable of initiating the healing process. The local application of platelet-rich plasma (PRP) has been proposed as a therapeutic tool for accelerating healing in foot ulcers, including those in patients with diabetes. Aim of the present pilot, proof-of-concept study is the assessment of the therapeutic potential of CO2 laser treatment, either alone or combined with PRP, in the treatment of diabetic foot ulcers with exposed bone. METHODS: We performed a pilot, uncontrolled 3-month observation study on a consecutive series of 9 type two diabetic patients and foot ulcers with exposed bone. A CO2-laser was used for producing nine discontinuities on periosteum for each cm2, by directing the focused laser beam on the bone until bleeding. The procedure was repeated up to 6 times, at a distance of 1 week and ulcers assessed weekly until the end of the study (3 months). In the last 5 of the 14 patients, the treatment described above was associated with PRP. RESULTS: Of the nine patients treated, four healed, and one more patient developed granulation tissue covering entirely bone surface. Out of the four patients who did not heal, one underwent minor amputation. Among the five patients treated with a combination of CO2 laser and PRP, two healed within 3 months, and two more patients developed granulation tissue covering entirely bone surface; the fifth patient did not show any improvement and underwent amputation. CONCLUSIONS: The present pilot experience represents a novelty in this field showing a possible use of CO2-laser in the treatment of diabetic foot ulcers.

A meta-analysis of the hypoglycaemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes.

AIM: To assess hypoglycaemic risk with sulphonylureas in comparison with other drugs in randomized controlled trials. METHODS: Randomized trials with a duration ≥ 24 weeks, enrolling patients with type 2 diabetes, comparing sulphonylureas with placebo or active drugs different from other sulphonylureas. The principal outcome was the effect of sulphonylureas on the incidence of any or severe hypoglycaemia. Cumulative incidence of hypoglycaemia was estimated combining sulphonylurea groups of different trials with a random effect model and used for meta-regression analyses. RESULTS: The incidence of severe hypoglycaemia in patients treated with sulphonylureas was 1.2 [1.0-1.6]%. The overall risk of severe hypoglycaemia was increased more than threefold with sulphonylureas than with comparators. The proportion of patients with at least one hypoglycaemia while on sulphonylureas was 17.4 [14.5-20.8]%. The overall risk (Mantel-Haenszel Odds Ratio) of any hypoglycaemia with sulphonylureas versus comparators was 3.69 [3.47-3.93] (p < 0.001). Meta-regression analysis suggested that the incidence of any hypoglycaemia was higher in trials enrolling patients with higher body mass index (BMI) and lower haemoglobin A1c (HbA1c). CONCLUSIONS: In conclusion, hypoglycaemia, including severe hypoglycaemia, is frequent in patients treated with sulphonylureas, particularly when baseline HbA1c levels are lower and BMI levels higher. Further studies are needed to characterize predictors for the identification of patients at higher risk.

HbA1c levels and all-cause mortality in type 2 diabetic patients: epidemiological evidence of the need for personalised therapeutic targets.

BACKGROUND AND AIM: The aim of the present case-control study is to explore the effect of case mix on the relationship between glycated haemoglobin (HbA1c) and mortality in type 2 diabetic patients. METHODS AND RESULTS: A nested case-control study data set was generated from the cohort-study data set (n = 4140 type 2 diabetic outpatients) by sampling controls from the risk sets. Cases (n = 427) were compared with an equal number of controls chosen from those members of the cohort who were at risk for the same follow-up time of the case, matched for age (±3 years), sex, body mass index (BMI) (±2 kg m(-2)), duration of diabetes (±5 years), and Charlson's Comorbidity Score (CCS) (±1). The main predefined analysis was the comparison of cases and controls for proportion of patients with each HbA1c class (<6.5%, 6.5-7.4%, 7.5-8.4% and ≥8.5%). During a mean follow-up of 5.7 ± 3.5 years, 427 deaths were recorded. The lowest risk of death was observed in the HbA1c 6.5-7.4% category; a lower HbA1c was associated with a non-significant trend towards a higher risk. The risk associated with a low (<6.5%) HbA1c was significantly greater in patients who were insulin-treated than in the rest of the sample. CONCLUSIONS: The present study suggests that glycaemic targets should be individualised on the basis of the characteristics of each patient, considering age, co-morbidity and duration of diabetes. Caution should be used in prescribing insulin to reach near-normoglycaemia, particularly in older, frail patients.

Effects of antihypertensive treatments on incidence of diabetes: a case-control study.

AIMS: Aim of this case-control study is the assessment of the relationship between antihypertensive treatment and incidence of diabetes in an unselected cohort of subjects participating in a screening program for diabetes. METHODS: A case-control study nested within a cohort of nondiabetic subjects with a mean follow-up of 27.7 ± 11.3 months was performed, comparing 40 cases of incident diabetes and 160 controls matched for age, sex, body mass index, fasting plasma glucose, 2-h post-load glycemia, smoking and alcohol abuse. RESULTS: When considering antihypertensive treatment at enrolment, a lower proportion of cases was exposed to ACE-inhibitors/angiotensin receptor blockers (ACE-i/ARB) in comparison with controls. A non-significant trend toward a higher exposure to diuretics, which were mainly represented by thiazide diuretics, was observed in cases. In a multivariate analysis, including both ACE-i/ARB and diuretics, a protective effect of ACEi/ARB, and an increased risk with diuretics were observed. Similar results were obtained in alternative models, after adjusting for systolic and diastolic blood pressure at enrolment, diagnosis of hypertension, concurrent treatment with ß-blockers or calcium-channel blockers, and number of antihypertensive medications. CONCLUSIONS: Diuretics seem to be associated with a higher incidence of diabetes, whereas treatment with ACEi/ARB could have a protective effect.

The importance of subcapsular anesthesia in the anesthesiological management for thyroid radiofrequency ablation.

Radiofrequency ablation is a minimally invasive procedure alternative to surgery to treat benign thyroid nodules causing compressive symptoms. Tolerability of this procedure, aimed at treatment of benign conditions, is fundamental. In this study, we evaluated if local anesthesia should be enough to reduce both hospital costs and sedation-related risks for the patient, avoiding deep sedation and presence of the anesthesiologist. From July 2017 to August 2018, 14 consecutive patients (mean age 60.1 years) were treated and divided in two groups: Group A (7 patients) underwent systemic sedoanalgesia (intravenous remifentanil/fentanyl ± intravenous midazolam ± intravenous acetaminophen/nonsteroidal anti-inflammatory drugs) + subcutaneous anesthesia (lidocaine), with anesthesiologist. Group B (7 patients) underwent mild systemic sedoanalgesia (oral solution morphine sulfate + intravenous midazolam + intravenous acetaminophen) + both subcutaneous and subcapsular anesthesia (mepivacaine + bupivacaine), without anesthesiologist. Tolerability, sedation grade (Ramsay scale), total opioid dose, complications, and results at 12 months were analyzed and compared. Mean tolerability was 9.4 in group A and 8.9 in group B (p: 0.786). Mean sedation grade was 3.86 in group A and 2.71 in group B (p: 0.016). Mean total opioid dose was 70.9 mg in group A and 10 mg in group B (p:0.00015). No complications were observed. At 12 months, mean volume reduction was 56.1% in the group A and 60% in the group B. In thyroid radiofrequency ablation, subcapsular anesthesia can decrease both total opioid dose and level of patient's sedation without significant differences in tolerability, allowing to perform ablation without the anesthesiologist.

Activation of haptoglobin gene expression by cAMP involves CCAAT/enhancer-binding protein isoforms in intestinal epithelial cells.

CCAAT/enhancer-binding protein (C/EBP) isoforms are expressed in rodent intestine and in the rat intestinal epithelial cell line IEC-6 but their role remains to be determined. Treatment of IEC-6 cells with the adenylate cyclase activator forskolin led to coordinate induction of C/EBP isoforms alpha, beta and delta at the mRNA and protein levels. Transient transfection assays showed that their expression is controlled at the transcriptional level. Forskolin treatment induced haptoglobin mRNA levels. Electrophoretic mobility shift and supershift assays demonstrated an increase in DNA-binding activities of the three C/EBP isoforms to the haptoA and haptoC C/EBP DNA-binding sites of the proximal haptoglobin promoter. Site-specific mutations of both sites led to a decrease in transcriptional induction by forskolin, suggesting that C/EBP isoforms are involved in the cAMP-dependent regulation of the acute-phase protein gene haptoglobin in intestinal epithelial cells.

Negative regulation of glucocorticoid-dependent induction of c-fos by ras in intestinal epithelial cells.

In order to investigate the regulatory mechanisms involved in the expression of fos and jun family members by glucocorticoids, and the effect of ras transformation in intestinal epithelial cells, we used the rat cell line IEC-6. Dexamethasone treatment induced transiently c-jun mRNAs, in contrast to the sustained expression of c-fos, whereas its effect on junB expression resulted in a later increase. Dexamethasone-dependent stimulation of c-fos and c-jun was modulated predominantly at the level of transcription. Sustained levels of induced c-fos and c-jun proteins were observed after dexamethasone treatment. AP-1 DNA-binding capacity of c-fos, and to a smaller extent c-jun, was increased by glucocorticoids later than after serum treatment. To analyse the effect of ras on the glucocorticoid response of AP-1 components, we studied several IEC-6 cell clones transformed by the Ha-ras oncogene. In comparison to normal cells, these transformants displayed increased AP-1 DNA-binding activity with higher levels of junB and variable levels of c-jun in the AP-1 complex. Ras transformation repressed the growth-inhibitory properties of glucocorticoids. Furthermore, ras inhibited the glucocorticoid-dependent induction of c-fos protein and mRNA, leading to changes in AP-1 composition as compared to normal cells. As assessed by transient transfection luciferase assays, glucocorticoids induced significantly a minimal promoter containing 3 copies of an AP-1 DNA-binding site as well as the murine c-fos -276 to +112 promoter in non-transformed cells. In contrast, glucocorticoid addition did not induce these constructs in two ras transformed cell lines. These results suggest that ras negatively modulates specific responses of intestinal epithelial cells to glucocorticoids.