Impact of microvascular complications on the outcomes of diabetic foot in type 2 diabetic patients with documented peripheral artery disease.

PURPOSE: Microvascular disease (MVD) is associated with amputation linked to peripheral artery disease (PAD) in the general population. No study evaluated the impact of diabetic microvascular complications on the outcomes of vascular diabetic foot ulcers (DFU). The aim of the study was to investigate whether retinopathy, nephropathy, and polyneuropathy can predict the outcomes of DFU in type 2 diabetic patients with PAD. METHODS: Three hundred and thirty-one consecutive patients with vascular DFU were enrolled and followed up for 44.1 ± 23.9 months. RESULTS: The prevalence of retinopathy was significantly higher in subjects with ulcer persistence (45.2%; p < 0.01), minor amputation (48.9%; p < 0.001), and major amputation (57.9%; p < 0.001) than in healed patients (23.3%), and in non-survivors than in survivors (64.9 versus 20.5%; p < 0.001). The prevalence of nephropathy was significantly greater in subjects with ulcer persistence (83.9%; p < 0.01), minor amputation (86.7%; p < 0.001), and major amputation (94.7%; p < 0.001) than in those with healed DFU (64.4%), and in non-survivors than in survivors (88.3 versus 65.7%; p < 0.001). The prevalence of polyneuropathy was significantly higher in non-survivors than in survivors (76.6 versus 61.0%; p = 0.012). Multivariate analysis showed that absence of retinopathy (OR: 0.451; 95% CI: 0.250-0.815; p < 0.001) and nephropathy (OR: 0.450; 95% CI: 0.212-0.951; p = 0.036) were independently associated with healing. Moreover, retinopathy was a predictor both of minor amputation (OR: 2.291; 95% CI: 1.061-4.949; p = 0.034) and mortality (OR: 5.274; 95% CI: 2.524-11.020; p < 0.001). Polyneuropathy never entered the regression model. CONCLUSIONS: Diabetic microvascular complications, in particular retinopathy, may predict the outcomes of vascular DFU. Longitudinal studies should confirm this finding.

Association of erectile dysfunction with diabetic foot and its outcomes in type 2 diabetic men.

PURPOSE: Erectile dysfunction (ED) and diabetic foot (DF) are common complications in patients with diabetes. However, the relationship between ED and DF has been little studied. In particular, no study has evaluated whether ED is associated with the outcomes of DF. The aim of this retrospective cohort study was to investigate whether ED is a predictor of the outcomes of DF in a large population of men with DF. METHODS: Three hundred and twenty-six consecutive men with type 2 diabetes and a recent and single DF ulcer were recruited and followed up for 41.7 ± 22.7 months. RESULTS: Among men with DF, 56.1% had ED (ED group) and 43.9% did not (NO ED group). Wound healing rate was significantly higher in the NO ED than in the ED group (90.2 versus 73.3%; p = 0.0001). Minor amputation rate (13.7 versus 4.8%; p = 0.007) and mortality (25.7 versus 0.7%; p < 0.001) were significantly greater in the ED than in the NO ED group. Among 263 patients with healed ulcers, recurrence rate was significantly higher in the ED than in the NO ED group (51.5 versus 26.3%; p < 0.001). Multivariate analysis showed that the absence of ED was associated with wound healing (OR: 0.459; 95% CI: 0.213-0.993; p = 0.048), while the presence of ED predicted mortality (OR: 22.644; 95% CI: 2.976-34.271; p = 0.002) and DF recurrence (OR: 3.498; 95% CI: 1.882-6.499; p < 0.001). CONCLUSIONS: Our data show that among men with DF the prevalence of ED is very high. Moreover, ED may be a strong predictor of wound healing, mortality, and ulcer recurrence.

A Comprehensive Therapeutic Patient Education May Improve Wound Healing and Reduce Ulcer Recurrence and Mortality in Persons With Type 2 Diabetes.

OBJECTIVES: The impact of a comprehensive therapeutic patient education (TPE) on the prognosis of diabetic foot ulcer (DFU) has not yet been evaluated in the literature. The purpose of this study was to determine whether TPE is a predictor of outcome in type 2 diabetes patients with DFU. METHODS: We evaluated 583 consecutive individuals with a recent and single DFU. They were treated and followed for 42.8±23.3 months. Patients were divided into 2 groups. The TPE group included subjects who had been receiving regular sessions of a comprehensive TPE, including a specific foot care education (FCE), for at least 12 months before DFU occurred (n=129). The non-TPE group comprised the remaining subjects (n=454). All 583 patients received intensive FCE during the treatment period. RESULTS: We identified a significantly higher percentage of healed DFUs (96.0% vs 74.9%; p<0.0001) and a lower percentage of major amputations (0.8% vs 4.4%; p=0.0511), minor amputations (1.6% vs 12.3%; p=0.0003), DFU persistence (1.6% vs 8.4%; p=0.0069) and deaths (1.6% vs 21.4%; p<0.0001) in the TPE group than in the non-TPE group. Among 464 patients with healed ulcers, the proportion of subjects with re-ulceration was greater in the non-TPE group than in the TPE group (48.8% vs 6.5%; p<0.0001). Multivariate analysis showed that TPE can predict healing (odds ratio [OR], 4.202; 95% confidence interval [CI], 1.604 to 11.004; p=0.0035) and may significantly reduce DFU recurrence (OR, 0.093; 95% CI, 0.043 to 0.201; p<0.0001) and mortality (OR, 0.096; 95% CI, 0.022 to 0.410; p=0.0016). CONCLUSION: A comprehensive TPE may have a positive impact on wound healing, ulcer recurrence and mortality in people with DFU.

Buprenorphine may be effective for treatment of paramyotonia congenita.

INTRODUCTION/AIMS: Paramyotonia congenita (PMC) is a skeletal muscle sodium channelopathy characterized by paradoxical myotonia, cold sensitivity, and exercise/cold-induced paralysis. Treatment with sodium-channel-blocking antiarrhythmic agents may expose patients to a risk of arrhythmia or may be poorly tolerated or ineffective. In this study we explored the effectiveness of non-antiarrhythmic sodium-channel blockers in two patients with PMC. METHODS: Earlier treatment with mexiletine was discontinued for gastrointestinal side effects in one of the patients and lack of clinical benefit in the other. One patient received lacosamide, ranolazine, and buprenorphine, and the other was given buprenorphine only. Drug efficacy was assessed by clinical scores, timed tests, and by long and short exercise tests. RESULTS: In both patients, buprenorphine improved pain scores by at least 50%, stiffness and weakness levels, and handgrip/eyelid-opening times. The fall in compound muscle action potential (CMAP) during short exercise normalized in both patients at baseline, and improved after cooling. During long exercise, one patient showed an earlier recovery of CMAP, and the other patient had a less severe decrease (<60%). With buprenorphine, the fall in CMAP induced by cooling normalized in one patient (from -72% to -4%) and improved (from -49% to -37%) in the other patient. DISCUSSION: Buprenorphine showed promising results for the treatment of exercise-induced paralysis and cold intolerance in the two patients assessed. The exercise test may be useful for quantitative assessment of treatment response. Further studies on a larger number of patients, under carefully controlled conditions, should be considered to address the effectiveness and long-term tolerability of this therapeutic option.

Predictors of healing, ulcer recurrence and persistence, amputation and mortality in type 2 diabetic patients with diabetic foot: a 10-year retrospective cohort study.

PURPOSE: Predictors of outcome of diabetic foot ulcer (DFU) are important to improve the management of patients. Aim of the study was to find these predictors in type 2 diabetic patients with DFU. METHODS: We recruited 583 patients. They were followed-up by a multidisciplinary team. A holistic and conservative approach was used and all risk factors and co-morbidities were aggressively treated. RESULTS: During the follow-up period, 79.6% of patients healed in a mean time of 7.6 ± 3.8 months, 6.9% showed DFU persistence, 9.9% had minor amputations, and 3.6% experienced major amputation. Seventeen percent of the patients died. Among patients who healed, 37.1% of them showed DFU recurrence. Impairment of renal function was associated to DFU persistence, amputation, and mortality. Previous cardiovascular disease predicted DFU persistence, DFU recurrence, and mortality. Lower BMI predicted DFU persistence and mortality. Osteomyelitis was a predictor of amputation and death. Markers of peripheral artery disease (PAD) predicted minor amputation and DFU recurrence. Our study shows a relatively low incidence of complications of DFU. CONCLUSIONS: Some predictors of outcome of DFU were confirmed and new predictors, like BMI and markers of PAD, were found. Our new findings suggest future strategies for nutrition support and revascularization. In addition, a holistic and conservative approach may improve the prognosis.

Lupus anticoagulant and mortality in patients hospitalized for COVID-19.

Coronavirus disease 2019 (COVID-19) is characterized by a procoagulant state that can lead to fatal thromboembolic events. Several studies have documented a high prevalence of lupus anticoagulant that may at least partially explain the procoagulant profile of COVID-19. However, the association between lupus anticoagulant and thrombotic complications in COVID-19 is controversial and no study has specifically evaluated the impact of lupus anticoagulant on mortality. The aim of our study was to investigate the association between lupus anticoagulant and mortality in a large group of 192 consecutive patients hospitalized for COVID-19. Lupus anticoagulant was found in 95 patients (49.5%). No difference in the percentage of patients with lupus anticoagulant was observed between 130 survivors and 62 non-survivors (47.7 versus 53,2%; p = 0.4745). When the combined outcome of death or need for mechanical ventilation in survivors was taken into account, the difference in the prevalence of patients with lupus anticoagulant between the patients with the combined outcome (n = 76) and survivors who did not require mechanical ventilation (n = 116) was not significant (52.6% versus 47.4%; p = 0.4806). In multivariate analysis predictors of mortality or need for mechanical ventilation in survivors were obesity, low oxygen saturation and elevated troponin levels measured on admission. In conclusion, our study did not show any association of lupus anticoagulant with mortality and with need for mechanical ventilation in survivors. The role of obesity, low SaO2 and elevated troponin levels as predictors of a worse prognosis in patients hospitalized for COVID-19 was confirmed.

Association between antithrombin and mortality in patients with COVID-19. A possible link with obesity.

BACKGROUND AND AIMS: Despite anticoagulation, usually with heparin, mortality for thromboembolic events in COVID-19 remains high. Clinical efficacy of heparin is due to its interaction with antithrombin (AT) that may be decreased in COVID-19. Therefore, we correlated AT levels with outcomes of COVID-19. METHODS AND RESULTS: We recruited 49 consecutive patients hospitalized for COVID-19. AT levels were significantly lower in 16 non-survivors than in 33 survivors (72.2 ± 23.4 versus 94.6 ± 19.5%; p = 0.0010). A multivariate Cox regression analysis showed that low AT (levels below 80%) was a predictor of mortality (HR:3.97; 95%CI:1.38 to 11.43; p = 0.0103). BMI was the only variable that showed a significant difference between patients with low and those with normal AT levels (32.9 ± 7.9 versus 27.5 ± 5.9%; p = 0.0104). AT levels were significantly lower in obese patients than in subjects with normal weight or overweight (77.9 ± 26.9 versus 91.4 ± 26.9 versus 91.4 ± 17.1%; p = 0.025). An inverse correlation between AT levels and BMI was documented (r:-0.33; p = 0.0179). CONCLUSIONS: Our data first suggest that AT is strongly associated with mortality in COVID-19. In addition, AT may be the link between obesity and a poorer prognosis in patients with COVID-19. Other studies should confirm whether AT may become a prognostic marker and a therapeutic target in COVID-19.

Association between clitoral tissue perfusion and female sexual dysfunction in healthy women of reproductive age: a pilot study.

The impact of abnormalities in the vascular bed of the external genitalia and vagina on female sexuality is not well defined because of some methodological difficulties in correctly assessing vascular changes of genitalia in women. Transmucosal oxygen tension (TmPO2) represents a precise measure of oxygen partial pressure at the clitoris surface and is expression of clitoral tissue perfusion. Aim of the study was to correlate TmPO2 with female sexual dysfunction (FSD) in healthy women in order to evaluate the impact of clitoral vascularization on female sexual health. Twenty-seven healthy, heterosexual, and sexually active women of reproductive age (mean age: 31.18 ± 4.71) were enrolled in the study. TmPO2 was assessed in every woman. In addition, all the women filled out the Female sexual function index (FSFI). After adjustment for some covariates (age, BMI, and smoking), TmPO2 significantly correlated with FSFI total score (r = 0.4261; p = 0.0379) and with arousal (r = 0.3239; p = 0.0390), lubrication (r = 0.4345; p = 0.0339), orgasm (r = 0.4092; p = 0.0471), and satisfaction (r = 0.4456; p = 0.0291) scores. In addition, TmPO2 was significantly lower in the FSD than in the NO FSD group (28.4 ± 14.5 versus 48.1 ± 25.1 mmHg; p = 0.0416). This study first shows that in healthy women of reproductive age clitoral tissue perfusion, as assessed by TmPO2, correlates very well with FSD and in particular with arousal, lubrication, orgasm, and satisfaction. Further studies should confirm our data and test TmPO2 as potential predictor for cardiovascular disease and metabolic conditions in women.

Evaluation of circulating sRAGE in osteoporosis according to BMI, adipokines and fracture risk: a pilot observational study.

BACKGROUND: Osteoporosis is a systemic metabolic disease based on age-dependent imbalance between the rates of bone formation and bone resorption. Recent studies on the pathogenesis of this disease identified that bone remodelling impairment, at the base of osteoporotic bone fragility, could be related to protein glycation, in association to oxidative stress. The glycation reactions lead to the generation of glycation end products (AGEs) which, in turn, accumulates into bone, where they binds to the receptor for AGE (RAGE). The aim of this study is to investigate the potential role of circulating sRAGE in osteoporosis, in particular evaluating the correlation of sRAGE with the fracture risk, in association with bone mineral density, the fracture risk marker FGF23, and lipid metabolism. RESULTS: Circulating level of soluble RAGE correlate with osteopenia and osteoporosis level. Serum sRAGE resulted clearly associated on the one hand to bone fragility and, on the other hand, with BMI and leptin. sRAGE is particularly informative because serum sRAGE is able to provide, as a single marker, information about both the aspects of osteoporotic disease, represented by bone fragility and lipid metabolism. CONCLUSIONS: The measure serum level of sRAGE could have a potential diagnostic role in the monitoring of osteoporosis progression, in particular in the evaluation of fracture risk, starting from the prevention and screening stage, to the osteopenic level to osteoporosis.

Proinsulin C-peptide modulates the expression of ERK1/2, type I collagen and RANKL in human osteoblast-like cells (Saos-2).

A lower bone mass accompanied by a higher bone fragility with increased risk of fracture are observed in individuals with type 1 diabetes mellitus. Low C-peptide levels are associated with low lumbar mineral density in postmenopausal woman. In this work, we investigated the role of C-peptide on the osteoblast cell biology in vitro. We examined intracellular pathways and we found that C peptide activates ERK1/2 in human osteoblast-like cells (Saos-2). We also observed that proinsulin C-peptide prevents a reduction of type I collagen expression and decreases, in combination with insulin, receptor activator of nuclear factor-κB (RANKL) levels. In this work we show for the first time that Cpeptide activates a specific intracellular pathway in osteoblasts and it modulates the expression of protein involved in bone remodeling. Our results suggest that both C-peptide may have a role in bone metabolism. Further studies are needing to fully clarify its role.

Percutaneous transluminal angioplasty for critical limb ischemia in very elderly diabetic patients.

In diabetic subjects, new less invasive therapies for critical limb ischemia (CLI) are available to obtain limb salvage. One of these is the percutaneous transluminal angioplasty (PTA), a minor surgical intervention which allows obtaining an effective revascularization, avoiding the traditional major surgery and its post-operative complications. Our case report regards a 94-year-old woman with CLI due to critical obstruction (stage IV according to Leriche's classification) of superficial femoral and popliteal arteries and infrapopliteal arteries that should have been treated by the left limb amputation considering her age, severe co-morbidities, and poor compliance. Instead of this quite common approach, our team treated the patient with PTA. This led to very good outcomes, above all in terms of pain control. PTA is able to avoid major surgery, lower intra and post-operative risks, reduce length of hospital stay, and preserve functional autonomy. Therefore, this procedure should be taken into account also for frail very elderly diabetic patients with peripheral artery disease (PAD).

Transcutaneous oxygen tension as a potential predictor of cardiovascular events in type 2 diabetes: comparison with ankle-brachial index.

OBJECTIVE: Transcutaneous oxygen tension (TcPO2) measures tissue perfusion and is important in the management of peripheral artery disease (PAD). Ankle brachial index (ABI) is used for the diagnosis of PAD and represents a predictor of major adverse cardiovascular events (MACE), even if in diabetes its diagnostic and predictive value seems to be reduced. No study has evaluated TcPO2 as a predictor of cardiovascular events. Aim of this longitudinal study was to assess whether TcPO2 is better than ABI at predicting MACE in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Among 361 consecutive patients with apparently uncomplicated diabetes, 67 MACE occurred during a follow-up period of 45.8 ± 23.2 months. RESULTS: The percentage of both subjects with low ABI (≤ 0.9) and subjects with low TcPO2 (≤ 46 mmHg as measured by a receiver operating characteristic curve) was significantly (<0.001) greater among patients with than among those without MACEs (ABI 64.2 vs. 40.8; TcPO2 58.2 vs. 34%). The Kaplan-Meier method showed that both low ABI (Mantel log-rank test, 4.087; P = 0.043) and low TcPO2 (Mantel log-rank test, 33.748; P > 0.0001) were associated with a higher rate of MACEs. Cox regression analysis showed that low TcPO2 (hazard ratio 1.78 [95% CI 1.44-2.23]; P < 0.001) was a significant predictor of MACE, while ABI did not enter the model. CONCLUSIONS: This longitudinal study showed that TcPO2 may be a potential predictor of MACE among patients with uncomplicated type 2 diabetes and that its predictive value seems to be greater than that of ABI.

Lipoprotein(a) and homocysteine as genetic risk factors for vascular and neuropathic diabetic foot in type 2 diabetes mellitus.

Neuropathy and peripheral artery disease represent the main pathophysiological conditions underlying diabetic foot. Several studies showed that Lipoprotein(a)-Lp(a)-and homocysteine (Hcy) can be associated with diabetic complications, but their relationship with diabetic foot is unclear. Aim of this study was to investigate whether Lp(a) and Hcy were associated with diabetic foot ulcerations, classified according to the presence of peripheral artery disease (PAD) or neuropathy. From among consecutive type 2 diabetic attending at the Diabetic Foot Clinic 27 subjects with vascular diabetic foot (VDF), 43 with neuropathic diabetic foot (NDF) and 52 controls without foot ulceration, neuropathy, and PAD were enrolled. Both Lp(a) (26.1 ± 22.7 vs. 14.9 ± 19.5 mg/dl; P = 0.003) and Hcy levels (15.4 ± 5.7 vs. 12.2 ± 5.1 µmol/l; P = 0.022) were significantly greater in the VDF group than in controls. Lp(a) levels were significantly lower in the NDF group than in controls (6.9 ± 8.1 versus 14.9 ± 19.5 mg/dl; P = 0.009), while no difference in Hcy levels was found. Multiple logistic regression analysis showed that Hcy was associated with VDF (OR: 1.11; 95% CI: 1.07-14.1; P = 0.048). Lp(a) did not enter the model, but its P-value was very near to the significant level (OR: 1.09; 95% CI: 0.99-12.05; P = 0.059). Moreover, low Lp(a) levels were associated with NDF (OR: 0.84; 95% CI: 0.21-0.96; P = 0.039). Our study has shown for the first time that high Lp(a) and Hcy levels are associated with the development of VDF, while low Lp(a) levels appear to be associated with delayed wound healing in patients with neuropathic foot ulcerations.

Screening for asymptomatic coronary artery disease can reduce cardiovascular mortality and morbidity in type 2 diabetic patients.

The impact of the screening for asymptomatic coronary artery disease (CAD) on the cardiovascular prognosis in diabetes is controversial. The aim of the study was to investigate whether screening for asymptomatic CAD can have an impact on cardiovascular morbidity and mortality in diabetes. In this nonrandomized longitudinal study, 1,189 consecutive type 2 diabetic patients without a history of CAD were evaluated. They were subdivided into two groups according to whether they were screened (screening group, n = 921) or not (no-screening group, n = 268) for asymptomatic CAD. Among the screened patients, 386 had angiographically proven CAD (CAD group) and 535 did not have silent CAD (no-CAD group). During a mean follow-up period of 4.3 ± 1.9 years, 130 patients experienced major adverse cardiac events (MACE). The incidence of MACE was significantly greater in the no-screening than in the screening group (22.0 vs. 7.7%; p = 0.001). The Kaplan-Meier method showed that: (1) the screening was associated with a lower rate of MACE (log-rank test, 3-95; p = 0.047); (2) the no-screening group had a risk profile similar to that of CAD group (log-rank test, 2.02; p = 0.154); and (3) cardiovascular prognosis was significantly better in no-CAD than in no-screening group (log-rank test, 4.27; p = 0.039). Multivariate Cox regression analysis showed that screening for CAD (HR 0.2; 95% CI 0.2-0.3; p = 0.000) was significantly protective against the occurrence of MACE. Our data suggest that screening for asymptomatic CAD can significantly reduce cardiovascular morbidity and mortality in type 2 diabetic patients. This may be due to specific diagnostic and therapeutic interventions in diabetic patients with proven CAD at screening.

Erectile dysfunction can improve the effectiveness of the current guidelines for the screening for asymptomatic coronary artery disease in diabetes.

About 40% of diabetic patients with asymptomatic coronary artery disease (CAD) are missed on the basis of the current screening guidelines. Erectile Dysfunction (ED) is a powerful marker of asymptomatic CAD. Aim of the study is to evaluate whether ED can improve the effectiveness of the current guidelines for the screening of CAD in diabetes. From among 299 consecutive men with newly diagnosed type 2 diabetes without any apparent vascular complication, 293 (mean age 56.6±5.9 years) were enrolled. Among them, 219 did not have myocardial ischemia (NO CAD group) and 74 men had a coronary stenosis angiographically proven (CAD group). Five risk factors (RFs) of the current screening guidelines (hypertension, dyslipidemia, family history for CAD, smoking e micro/macroalbuminuria) and ED were assessed. ED was significantly more prevalent in the CAD than in the NO CAD group (37.8 versus 15.1%; P<0.001) and was a predictor of asymptomatic CAD (OR: 4.4; 95%CI: 2.1-9.0; P<0.001). If ED is added to the list of RFs, it can increase the sensitivity of the current guidelines from 62 to 89%, without a significant variation in specificity (from 60 to 57%). The negative predictive value can increase from 82 to 94%. ED can reduce from 37.84 to 10.81% the percentage of patients with silent CAD missed at the screening. This study first shows that ED can improve the effectiveness in discriminating diabetic men to screen for asymptomatic CAD, when it is added to the list of RFs of the current screening guidelines.