Validation of the Fast-Track Model: A Simple Tool to Assess the Severity of Diabetic Foot Ulcers.

This study aimed to validate the association between the grades of severity of diabetic foot ulcers (DFUs) identified by the fast-tack model and specific outcomes. Three hundred and sixty-seven patients with new DFUs who were referred to a tertiary level diabetic foot service serving Rome, Italy, were included. The fast-track model identifies three levels of DFUs' severity: uncomplicated DFUs, including superficial wounds, not-infected wounds, and not-ischemic wounds; complicated DFUs, including ischemic wounds, infected wounds, and deep ulcers involving the muscles, tendons, or bones, and any kind of ulcers in patients on dialysis and/or with heart failure; and severely complicated DFUs, including abscesses, wet gangrene, necrotizing fasciitis, fever, or clinical signs of sepsis. Healing, minor and major amputation, hospitalization, and survival after 24 weeks of follow-up were considered. Among the included patients, 35 (9.6%) had uncomplicated DFUs, 210 (57.2%) had complicated DFUs, and 122 (33.2%) had severely complicated DFUs. The outcomes for patients with uncomplicated, complicated, and severely complicated DFUs were as follows, respectively: healing, 97.1%, 86.2%, and 69.8%; minor amputation, 2.9%, 20%, and 66.4%; major amputation, 0%, 2.9%, and 16.4%; hospitalization, 14.3%, 55.7%, and 89.3%; survival, 100%, 96.7%, and 89.3%. DFU severity was an independent predictor of healing, amputation, hospitalization, and survival. The current study shows an association between the grade of severity of DFUs identified by the fast-track model and the considered outcomes. The fast-track model may be a useful tool for assessing the severity and prognosis of DFUs.

Clinical scoring systems for the risk of cardiovascular autonomic neuropathy in type 1 and type 2 diabetes: A simple tool.

This study was aimed at developing a clinical risk score for cardiovascular autonomic neuropathy (CAN) for type 1 and type 2 diabetes. In a retrospective cross-sectional one-centre study in an unselected population, 115 participants with type 1 diabetes (age 41.1 ± 12.2 years) and 161 with type 2 diabetes (age 63.1 ± 8.9 years), well-characterized for clinical variables, underwent standard cardiovascular reflex tests (CARTs). Strength of associations of confirmed CAN (based on 2 abnormal CARTs) with clinical variables was used to build a CAN risk score. CAN risk score was based on resting heart rate, HbA1c, retinopathy, nephropathy, cardiovascular disease in both type 1 and type 2 diabetes, and on HDL cholesterol, systolic blood pressure, and smoking in type 1 diabetes or insulin treatment and physical activity in type 2 diabetes (range 0-10). In type 1 diabetes, CAN risk score showed an area under the ROC curve (AUC) of 0.890 ± 0.034, and at cut-off of 4 sensitivity of 88%, specificity of 74.4%, and negative predictive value (NPV) of 95.7% for confirmed CAN. In type 2 diabetes, CAN risk score showed an AUC of 0.830 ± 0.051 and at the cut-off of 4 sensitivity and specificity of 78.6% and 73.5%, respectively, and NPV of 97.3% for confirmed CAN. These newly developed CAN risk scores are accessible in clinical practice and, if confirmed in a validation study, they might identify asymptomatic individuals with diabetes at greater risk of CAN to be referred to CARTs, thus limiting the burden of a universal screening.

Macrophage Activation and M2 Polarization in Wound Bed of Diabetic Patients Treated by Dermal/Epidermal Substitute Nevelia.

Clinical evidences have shown good results using dermal/epidermal substitutes (DESs) to treat diabetic foot ulcers. Recent studies suggest that, in addition to their scaffold action, DESs may favor wound healing by influencing wound bed inflammatory cells. This study aims to investigate whether DES may influence the inflammatory infiltrate and macrophages polarization toward a reparative phenotype. Fifteen diabetic patients with chronic foot ulcers have been randomly enrolled: 5 treated only by standard of care, served as control group (CG), and 10 treated with DES composed of type 1 bovin collagen (Nevelia, SYMATESE) considered as test group (TG). A biopsy was taken at baseline (T0) and after 30 days (T1). From bioptic paraffin specimen histological, immunohistochemical, and immunofluorescence analysis was performed. Immunohistochemistry reactions evaluated the number of M1 macrophage (CD38+) and M2 macrophage (CD163+). TG patients displayed general macrophage activation and their greater polarization toward M2 subpopulation 30 days after DES implant, compared with CG. From T0 to T1 there was a significant decrease of CD38+ (230 ± 42 and 135 ± 48 mm2, respectively; P < .001) and significant increase of CD163+ (102 ± 21 positive cells/mm2 and 366 ± 42 positive cells/mm2, respectively; P < .001). Confocal microscopy confirmed an increase of M2 cells as expressed by the reduced CD68+/CD163+ ratio. After 6 months of observation 6 patients (60%) of the TG completely healed, while only 1 patient (20%) healed in the CG (P < .01). The tested DES makes possible to treat diabetic foot ulcers inducing tissue reparative processes through macrophage activation and M2 reparative polarization.

Peripheral arterial disease in patients with renal-diabetic foot ulcers.

OBJECTIVE: To describe the angiographic characteristics of peripheral arterial disease (PAD) in persons with diabetic foot ulcers (DFUs) on dialysis treatment. METHOD: The study is a retrospective analysis of patients with DFUs and PAD who had been referred to our diabetic foot clinic. All patients had been managed by a pre-set limb salvage protocol including revascularisation of the affected limb. Arterial lesions (stenosis between 50-99% and occlusions) were retrospectively evaluated through angiogram analysis. According to the presence or not of dialysis, patients were divided into two patient groups: renal-diabetic foot (RDF) and diabetic foot (DF). Distribution of PAD and immediate revascularisation outcome (technical revascularisation outcome) for RDF and DF were separately reported and compared. RESULTS: The sample included 239 patients: mean age was 71.8 years; 72.4% were male; 87.4% had type 2 diabetes; mean diabetes duration was 21.4 years; and the mean HbA1c was 63±22mmol/mol. The RDF group compared with the DF group reported higher numbers of vessels affected (n=5±1.6 versus 3.9±1.5, respectively, p<0.0001), greater involvement of the superficial femoral artery (90.2% versus 75.8%, respectively, p=0.003), the tibial-peroneal trunk (53.7% versus 25.5%, respectively, p=0.01), the anterior tibial artery (93.9% versus 80.9%, respectively, p=0.03) and below-the-ankle (BTA) arteries (70.7% versus 35.7%, respectively, p=0.0001). The RDF group showed a higher rate of revascularisation failure in comparison to DF patients (43.9% versus 15.3%, respectively, p<0.0001). BTA arterial disease (odds ratio 9.5; 95% Confidence Interval: 3.5-25.4; p=0.0001) resulted as the only independent predictor of revascularisation failure. CONCLUSION: In this study, RDF patients showed a widespread distribution of arterial lesions with a higher involvement of foot arteries in comparison with DF patients. BTA arterial disease was found to be an independent predictor of revascularisation failure.

Effectiveness of fast-track pathway for diabetic foot ulcerations.

AIM: To investigate the effectiveness of fast-track pathway (FTP) in the management of diabetic foot ulceration (DFU) after 2 years of implementation. METHODS: The study group was composed of patients who referred to a specialized DF centre due to DFUs. Those were divided in two groups: early referral (ER) and late referral (LR) patients. According to FTP, ER were considered patients who referred after 2 weeks in the case of uncomplicated non-healing ulcers (superficial, not infected, not ischemic), within 4 days in the case of complicated ulcers (ischemic, deep, mild infection) and within 24 h in the case of severely complicated ulcers (abscess, wet gangrene, fever). Healing, healing time, minor and major amputation, hospitalization, and survival were evaluated. The follow-up was 6 months. RESULTS: Two hundred patients were recruited. The mean age was 70 ± 13 years, 62.5% were male, 91% were affected by type 2 diabetes with a mean duration of 18 ± 11 years. Within the group, 79.5% had ER while 20.5% had LR. ER patients showed increased rates of healing (89.9 vs. 41.5%, p = 0.001), reduced healing time (10 vs. 16 weeks, p = 0.0002), lower rates of minor (17.6 vs. 75.6%, p < 0.0001) and major amputation (0.6 vs. 36.6%, p < 0.0001), hospitalization (47.1 vs. 82.9%, p = 0.001), and mortality (4.4 vs. 19.5%, p = 0.02) in comparison to LR. At multivariate analysis, ER was an independent predictor of healing, while LR was an independent predictor for minor and major amputation and hospitalization. CONCLUSION: After the FTP implementation, less cases of LR were reported in comparison to ER. ER was an independent predictor of positive outcomes such as healing, healing time, limb salvage, hospitalization, and survival.

Characteristics and Outcome for Persons with Diabetic Foot Ulcer and No-Option Critical Limb Ischemia.

The study aimed to evaluate clinical and vascular characteristics, as well as outcomes, for diabetic persons with foot ulceration and no-option critical limb ischemia (CLI). The study group included a sample of patients admitted to our diabetic foot unit because of a new diabetic foot ulcer and CLI. All subjects were managed using a limb salvage protocol which includes lower-limb revascularization. According to whether or not the revascularization procedure was a success, patients were respectively divided into two groups: successfully treated CLI patients (ST-CLI) and no-option CLI patients (NO-CLI). Failed revascularization was considered in the case of technical recanalization failure of occluded vessels (inability to overcome the obstruction) and/or absence of arterial flow to the foot. Limb salvage, major amputation, and death after 1 year of follow-up were evaluated and compared between the two groups. Overall, 239 patients were included, 74.9% belonging to ST-CLI and 25.1% to NO-CLI. NO-CLI patients reported more cases of ischemic heart disease (80 vs. 62.1, p = 0.008), heart failure (63.3 vs. 32.4%, p < 0.0001), and end-stage renal disease (ESRD) (60 vs. 25.7%) than ST-CLI patients. In addition, more vessels were affected in the NO-CLI group (5.2 ± 1.6 vs. 4 ± 1.5, p < 0.0001), and there was more involvement of tibio-peroneal trunk (50 vs. 30.2%, p = 0.006), anterior tibial (93.3 vs. 82.7, p = 0.03), posterior tibial (93.3 vs. 73.7%, p = 0.0005), peroneal (70 vs. 48%, p = 0.002), and below-the-ankle arteries (73.3 vs. 39.1%, p < 0.0001) than ST-CLI. The 1 year outcomes for the whole population were 69.9% limb salvage, 10.9% major amputation, and 19.2% death. The outcomes for NO-CLI and ST-CLI were, respectively, as follows: limb salvage (13.8 vs. 73.4%, p < 0.0001), amputation (30 vs. 4.5%, p = 0.0001), and mortality (50 vs. 8.9%, p < 0.0001). NO-CLI patients showed a more severe pattern of peripheral arterial disease (PAD) with distal arterial lesions and worse outcomes than ST-CLI.

Prevalence, Clinical Aspects and Outcomes in a Large Cohort of Persons with Diabetic Foot Disease: Comparison between Neuropathic and Ischemic Ulcers.

This study aims to evaluate clinical and ulcer characteristics as well the outcomes of patients with diabetic foot ulcers (DFUs). The study group was composed of DFUs patients managed by a limb salvage protocol according to guidance. Clinical and ulcers findings were described, and 1-year outcomes defined as limb salvage, healing, healing time, major amputation and death were compared between neuropathic and ischemic DFUs. One thousand, one hundred and ninety-eight subjects were included; 386 (32.2%) neuropathic and 812 (67.8%) ischemic DFUs. Neuropathic patients were younger (69.5 ± 11.5 vs. 74.5 ± 11.5, p < 0.0001) and reported less cases of nephropathy (22.8 vs. 39.6%, p < 0.0001), ischemic heart disease (22.8 vs. 36.9, p = 0.0004), cerebrovascular disease (8.3 vs. 17.2%, p = 0.002), heart failure (10.1 vs. 24.7%, p = 0.0002) and end-stage-renal-disease (ESRD) (5.4 vs. 27%, p = 0.0001) than ischemic patients; they also showed less cases of large (>5 cm2) (10.3 vs. 22.9%, p = 0.0007), infected (40.4 vs. 55.7%, p = 0.0005) and deep to the bone (22.3 vs. 39.2, p = 0.0002) ulcers, as well less multiple ulcerations (21.8 vs. 32.8%, p = 0.006) than patients with ischemic DFUs. The outcomes for neuropathic and ischemic DFUs were limb salvage (98.4 vs. 82.3%, p < 0.0001), healing (97.3 vs. 79.6%, p < 0.0001), healing time (34.9 vs. 35.6 weeks, p = 0.8), major amputation (0.5 vs. 6.6%, p = 0.0001), death (1.1 vs. 11%, p < 0.0001) respectively. Revascularization failure and ESRD were independent predictors of major amputation, while heart failure and number of co-morbidities (³5) were independent predictors of death. Ischemic DFUs patients showed more severe clinical and ulcers features as well worse outcomes than neuropathic DFUs patients.

Management of diabetic persons with foot ulceration during COVID-19 health care emergency: Effectiveness of a new triage pathway.

AIM: To define the outcomes of persons with diabetes and foot ulcers (DFUs) managed through a specific triage pathway during the COVID-19 crisis. METHODS: Patients who had an active DFU during the COVID-19 emergency were included. All participants were managed using a specific triage system driven both by ulcer'severity and concomitant co-diseases. Subjects with severely complicated DFUs were urgently referred to hospital regardless of the concomitant comorbidities. Subjects with complicated DFUs received outpatient evaluation (within 48-72 h) and were admitted to hospital if required (revascularization, surgical intervention, intravenous antibiotic therapy); after the first outpatient visit or hospitalization, patients were followed according to the number of comorbidities (in the case of 3 or more comorbidities patients were followed up by telemedicine). Patients with uncomplicated DFUs were managed by telemedicine after outpatient evaluation. Healing, major amputation, death and rate of COVID-19 infection were evaluated. The minimum follow-up was 1 month. RESULTS: The study group included 151 patients. The mean age was 69.9 ± 14.2 years, 58.9% were male and 91.4% had type 2 diabetes; 58.7% had severely complicated, 21% complicated and 20.3% uncomplicated DFUs. Among those, 78.8% presented with 3 or more comorbidities. One hundred and six patients had regular clinical follow-ups, while 45 were managed through telemedicine. Forty-one (27.1%) patients healed, 3 (1.9%) had major amputations and 3 (1.9%) died. One patient (0.6%) reported COVID-19 positivity due to infection acquired at home. CONCLUSION: The triage pathway adopted during the COVID-19 pandemic showed adequate management of DFUs and no cases of hospital virus exposure.

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy.

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One-hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 µS and/or feet ESC <70 µS) in 47.4%. Both the patterns-COMPASS 31+ESC and COMPASS 31 and/or ESC-were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality.

Use of Nevelia Dermal-Epidermal Regenerative Template in the Management of Ischemic Diabetic Foot Postsurgical Wounds.

The purpose of this cross-sectional study is evaluate the effectiveness of a dermal-epidermal substitute (DES) composed of 3-dimensional porous matrix of type 1, purified, stabilized, bovin-origin collagen (Nevelia, SYMATESE, Chaponost, France) without a subsequent skin graft in the treatment ischemic postsurgical diabetic foot ulcers. This study group was composed of a sample of consecutive diabetic patients with critical limb ischemia and postsurgical wounds. All patients received a preset limb salvage protocol including the application of the DES, but none received a skin graft. Patients were closely followed until wound healing or different outcome. The outcome measures were healing, nonhealing, major amputation, and death evaluated at 1 and 2 years of follow-up. Forty-one patients were included. The average postsurgical wound area was 69.6 ± 50 cm2. Twenty-one patients (51%) healed; 10 patients (24%) did not heal after 1 year of follow-up; however, all of them achieved a mean ulcer size reduction >50%; 7 patients (17%) were amputees; 3 patients (7.3%) died. In a later follow-up (2 years), wounds in 8 additional patients healed. Successful revascularization was an independent predictor of healing (hazard ratio = 5.1, 95% confidence interval [CI] = 2.5-14-9; P = .0001), the postsurgical ulcer size (>50 cm2) was an independent predictor of nonhealing (hazard ratio = 6.2, 95% CI = 2.1-38.4; P = .0001) while recurrence of critical limb ischemia was an independent predictor of major amputation (odds ratio = 3.4, 95% CI = 1.1-4.5; P = .002). The DES composed of type 1 bovin-origin collagen is useful in the treatment of large postsurgical diabetic foot ulcers, even when the skin graft is not a suitable therapeutic option.

Limb Salvage in Diabetic Patients With Ischemic Heel Ulcers.

The purpose of this study is to investigate the outcomes of diabetic individuals with ischemic heel ulcers. The study group was composed of a consecutive sample of persons with diabetic ischemic foot ulcers managed by a preset multidisciplinary limb salvage protocol, including revascularization through endovascular technique. The outcome measures were healing, major amputation (above the ankle), and death at 1-year of follow-up. The outcomes between patients with heel ulcers (HUs) and without (NHUs) were compared. A total of 254 patients were recruited. There were 50/254 (19.7%) HUs and 204/254 (79.3%) NHUs. Overall, 190/254 (74.8%) patients healed. The rate of healing for HUs and NHUs was 30/50 (60%) and 160/204 (78.4%); P = .03, respectively. Major amputation occurred in 24/254 (9.4%) patients. The rates of major amputation for HUs and NHUs were 10/50 (20%) and 14/204 (6.9%; P = .002), respectively; 40/254 (15.7%) patients died, unhealed. The rates of mortality for HUs and NHUs were 10/50 (20%) and 30/204 (14.7%; P = .07), respectively. In HUs patients, absence of infection [95% CI = 3.1 (1.6-5.5); P = .002] and superficial ulcers [95% CI = 4.4 (2.2-9.3); P = .0001] were independent predictors of healing, whereas revascularization failure [95% CI = 8.1 (1.5.0-19.4); P = .0001], involvement of the plantar arch [95% CI = 6.3 (2.0-15.4); P = .0001], and dialysis [95% CI = 2.2 (1.3-4.5); P = .006] were independent predictors of major amputation. A multidisciplinary approach achieves good rate of limb salvage in people with diabetic ischemic heel ulcers.

Procalcitonin Is a Prognostic Marker of Hospital Outcomes in Patients with Critical Limb Ischemia and Diabetic Foot Infection.

AIM: To evaluate the prognostic role of procalcitonin (PCT) in patients with diabetic foot infection (DFI) and critical limb ischemia (CLI). MATERIALS AND METHODS: The study group was composed of diabetic patients with DFI and CLI. All patients were treated according to a preset limb salvage protocol which includes revascularization, wound debridement, antibiotic therapy, and offloading. Inflammatory markers, including PCT, were evaluated at admission. Only positive values of PCT, greater than 0.5 ng/ml, were considered. Hospital outcomes were categorized as limb salvage (discharge with preserved limb), major amputation (amputation above the ankle), and mortality. RESULTS: Eighty-six patients were included. The mean age was 67.3 ± 11.4 years, 80.7% were male, 95.1% had type 2 diabetes, and the mean diabetes duration was 20.5 ± 11.1 with a mean HbA1c of 67 ± 16 mmol/mol. 66/86 (76.8%) of patients had limb salvage, 7/86 (8.1%) had major amputation, and 13/86 (15.1%) died. Patients with positive PCT baseline values in comparison to those with normal values showed a lower rate of limb salvage (30.4 versus 93.6%, p = 0.0001), a higher rate of major amputation (13 versus 6.3%, p = 0.3), and a higher rate of hospital mortality (56.5 versus 0%, p < 0.0001). At the multivariate analysis of independent predictors found at univariate analysis, positive PCT was an independent predictor of major amputation [OR 3.3 (CI 95% 2.0-5.3), p = 0.0001] and mortality [OR 4.1 (CI 95% 2.2-8.3), p < 0.0001]. DISCUSSION: Positive PCT at admission increased the risk of major amputation and mortality in hospital patients with DFI and CLI.

α-Ketoglutarate inhibits autophagy.

The metabolite α-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl -ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG) and octyl α-ketoglutarate (O-KG). Once these compounds cross the plasma membrane, they are hydrolyzed by esterases to generate α-ketoglutarate, which remains trapped within cells. Here, we systematically compared DMKG, TFMKG and O-KG for their metabolic and functional effects. All three compounds similarly increased the intracellular levels of α-ketoglutarate, yet each of them had multiple effects on other metabolites that were not shared among the three agents, as determined by mass spectrometric metabolomics. While all three compounds reduced autophagy induced by culture in nutrient-free conditions, TFMKG and O-KG (but not DMKG) caused an increase in baseline autophagy in cells cultured in complete medium. O-KG (but neither DMKG nor TFMK) inhibited oxidative phosphorylation and exhibited cellular toxicity. Altogether, these results support the idea that intracellular α-ketoglutarate inhibits starvation-induced autophagy and that it has no direct respiration-inhibitory effect.

Below-the-ankle arterial disease severely impairs the outcomes of diabetic patients with ischemic foot ulcers.

AIM: To evaluate the impact of below-the-ankle (BTA) arterial disease in people with ischemic diabetic foot ulcers (DFUs). METHODS: Patients with ischemic DFUs treated by a pre-set limb salvage protocol including peripheral revascularization were included. They were divided in two groups according to the involvement of BTA arteries (BTA+) or not (BTA-). Not healing, minor amputation, major amputation and mortality have been evaluated as primary outcome. Revascularization failure has been evaluated as secondary outcome. RESULTS: The study group was composed of 272 patients, 120 (44.1%) belonging to BTA+ group and 152 (55.9%) to BTA-. After 1 year of follow-up the outcomes for BTA+ and BTA- were respectively: not healing (40.8 vs 17.8%, p < 0.0001), minor amputation (80.8 vs 20.4%, p < 0.0001), major amputation (18.3 vs 6.6%, p = 0.002), mortality (16.7% vs 10.5%, p = 0.001). The rate of revascularization failure was respectively 38.3 vs 11.2%, p < 0.0001. At the multivariate analysis BTA arterial disease resulted an independent predictor of not healing [OR 3.5 (CI 95% 2.3-6.1) p = 0.0001], minor amputation [OR 3.1 (1.5-5.9) p < 0.0001] and revascularization failure [OR 3.5 (1.9-6.3) p = 0.0001]. BTA+ patients with successful BTA revascularization showed lower rate of not healing (37.8 vs 89.1%) p < 0.0001, minor amputation (74.3 vs 91.3%) p = 0.002 and major amputation (8.1 vs 34.8%) p = 0.0003 in comparison to patients with unsuccessful BTA revascularization. CONCLUSION: BTA arterial disease severely impairs the outcomes of diabetics with ischemic foot ulcers. BTA revascularization reduces the rate of not healing, minor and major amputation.

Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate.

Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens.

Letter Regarding "The Prostacyclin Analogue Iloprost as an Early Predictor of Successful Revascularization in Diabetic Patients Affected by Critical Limb Ischemia and Foot Ulcers".

PURPOSE: The aim of this study is to evaluate the role of Iloprost as an early predictor of successful revascularization in patients affected by ischemic diabetic foot ulcers (DFUs). METHODS: Consecutive patients with ischemic DFUs with persistent low TcPO2 (<30mmHg) one day after a technical successful Percutaneous Transluminal Angioplasty (PTA) have been included. All patients underwent Iloprost infusion and TcPO2 has been recorded at days 3, 14 and 30. According to the TcPO2 reported at day 3, patients were divided into two groups: group A (patients with TcPO2 ≥30mmHg) and group B (patients with TcPO2 <30mmHg). Baseline TcPO2 values at days 3, 14 and 30 after Iloprost infusion and needing of re-intervention (re-PTA) have been evaluated. RESULTS: Twenty-five patients have been included, 12/25 (48%) in Group A and 13/25 (52%) in Group B. There were no significant differences at the baseline and one day after PTA between the two groups while TcPO2 values recorded in Group A at days 3, 14 and 30 after Iloprost infusion were significant higher in comparison to the Group B (χ = 0.005). The rate of re-PTA were respectively 33,3% (Group A) and 53,8% (Group B) (p = 0.03). CONCLUSIONS: Iloprost may be an early predictor of successful revascularization in patients affected by critical limb ischemia (CLI) and DFUs.

Recurrence of Critical Limb Ischemia After Endovascular Intervention in Patients with Diabetic Foot Ulcers.

Objective: To establish the rate of clinical recurrence of critical limb ischemia (CLI) in diabetic patients with ischemic foot ulcers (DFUs) treated by percutaneous transluminal angioplasty (PTA). Approach: The study group was composed of 304 patients with ischemic DFUs treated by PTA. We evaluated the rate of clinical recurrence of CLI requiring a second PTA (repeated PTA [rePTA]), the factors related to CLI relapse, and the outcomes of rePTA patients. The follow-up was 12.5 ± 6.6 months. Results: Seventy-four of 304 patients (24.3%) needed rePTA. The mean time to rePTA was 3.5 ± 0.64 months. rePTA group in comparison with no rePTA group had lower rate of healing (28.5% vs. 71.9% p = 0.0001), higher rate of ulcer recurrence (20% vs. 10.3% p = 0.03), major amputation (24.3% vs. 4.3% p = 0.0005), and death (33.3% vs. 7.9% p = 0.002). Glycated hemoglobin, type A1C (HbA1c; 2.2 [1.9-2.7] p = 0.02) and dialysis (1.5 [1.4-3.6] p = 0.006) were independently associated to clinical recurrence of CLI after PTA. Innovation: To identify the outcomes of patients with clinical recurrence of CLI and the clinical factors involved to reduce the rate of restenosis after endovascular treatment and improve the rate of limb salvage. Conclusions: Clinical recurrence of CLI is associated with a high rate of nonhealing ulcer recurrence, major amputation, and death. Dialysis and impaired glycemic control were independent predictors of CLI relapse after endovascular treatment.

Critical limb ischemia: current challenges and future prospects.

Critical limb ischemia (CLI) is considered the most severe pattern of peripheral artery disease. It is defined by the presence of chronic ischemic rest pain, ulceration or gangrene attributable to the occlusion of peripheral arterial vessels. It is associated with a high risk of major amputation, cardiovascular events and death. In this review, we presented a complete overview about physiopathology, diagnosis and holistic management of CLI. Revascularization is the first-line treatment, but several challenging cases are not treatable by conventional techniques. Unconventional techniques for the treatment of complex below-the-knee arterial disease are described. Furthermore, the state-of-the-art on gene and cell therapy for the treatment of no-option patients is reported.

Impact of heart failure and dialysis in the prognosis of diabetic patients with ischemic foot ulcers.

AIM: To establish the role of heart failure (HF) and dialysis (D) in the prognosis of diabetic patients with critical limb ischemia and foot ulcers (FUs). METHODS: Consecutive diabetic patients with ischemic FUs who referred to our Diabetic Foot Centre were prospectively included. All patients underwent a preset limb salvage protocol including peripheral revascularization. According to the presence of HF and D, they were divided in four groups: group 1 without HF and without D defined as ischemic foot (IF); group 2 with HF and without D defined as heart ischemic foot (H-IF); group 3 without HF and with D defined as renal ischemic foot (R-IF); group 4 with HF and with dialysis defined as heart-renal foot (HR-IF). Survival with limb salvage, survival with major amputation and death were reported after 1 year of follow-up. RESULTS: 136 patient have been included: 66 with IF, 26 with H-IF, 24 with R-IF and 20 with HR-IF. The mean age was 68,9 ±â€¯9,7 years, the diabetes duration 20,7 ±â€¯11,6 years, the mean HbA1c 62,7 ±â€¯22,3 mmol/mol. 103/136 (75,7%) survived with limb salvage, 10/136 (7,4%) survived with major amputation, 23/136 (16,9%) died. The outcomes for group IF patients, H-IF, R-IF and HR-IF were respectively: survival with limb salvage (92,4%, 61,5%, 79,2% and 35%), survival with major amputation (6,1%, 7,7%, 8,3% and 10%), death (1,5%, 30,8%, 12,5% and 55%) χ = 0.0001. Heart failure was an independent predictor of death. DISCUSSION: The presence of heart failure and dialysis in diabetic patients with ischemic foot ulcers was associated to high risk of amputation and mortality.

Insulin autoimmune syndrome in an Argentine woman taking α-lipoic acid: A case report and review of the literature.

Insulin autoimmune syndrome is an unusual cause of spontaneous hypoglycaemia in non-Asian populations. In the majority of cases, this syndrome appears a few weeks after the administration of drugs containing a sulfhydryl group. A strong association between this syndrome and HLA-DR4 has been shown. Only seven cases have been described in non-Asian patients. We report the first case of insulin autoimmune syndrome in an Argentine woman taking alfa-lipoic acid. She developed hypoglycaemic symptoms approximately 1 month after starting therapy. Blood sampling collected during an episode of symptomatic hypoglycaemia showed low blood glucose level (2.39 mmol/L), high level of serum insulin (1971.55 pmol/L), inappropriately high level of C-peptide (2.36 nmol/L) and high levels of insulin antibodies (274.78 IU/mL). HLA-DNA typing identified DRB1*04:03. Due to the widespread use of alfa-lipoic acid for its antioxidant properties, clinicians should be aware that it may trigger an autoimmune hypoglycaemia in people with a genetic predisposition.