The Neuro-Ischaemic Charcot Foot: Prevalence, Characteristics and Severity of Peripheral Arterial Disease in Acute Charcot Neuro-Arthropathy.

The study aimed to evaluate the prevalence, characteristics and outcomes of patients affected by Charcot neuro-arthropathy (CN) and peripheral arterial disease (PAD) compared to CN without PAD. Consecutive patients presenting with an acute CN were included. The sample size was calculated by the power analysis by adopting the two-tailed tests of the null hypothesis with alfa = 0.05 and a value of beta = 0.10 as the second type error and, therefore, a test power equal to 90%. Seventy-six patients were identified. Twenty-four patients (31.6%) had neuro-ischaemic CN; they were older (66 vs. 57yrs), p = 0.03, had a longer diabetes duration (19 vs. 14yrs), p < 0.001, and more cases of end-stage-renal-disease (12.5 vs. 0%), p = 0.04 and ischaemic heart disease (58.3 vs. 15.4%), p < 0.0001 than neuropathic CN. Fifty patients (65.8%) had concomitant foot ulcers, 62.5% and 67.3% (p = 0.3), respectively, in CN with and without PAD. Neuro-ischaemic CN show arterial lesions of 2.9 vessels, and PAD was located predominantly below-the-knee (75%) but not below-the-ankle (16.7%). The outcomes for neuro-ischaemic and neuropathic CN patients were, respectively: wound healing (86.7 vs. 94.3%), p = 0.08; minor amputation (25 vs. 7.7%), p = 0.003; major amputation (8.3 vs. 1.9%), p = 0.001; hospitalization (75 vs. 23%), p = 0.0001. The study showed a frequent association between CN and PAD, leading to a neuro-ischaemic Charcot foot type. Neuro-ischaemic CN leaded to an increased risk of minor and major amputation and hospitalization, compared to neuropathic CN.

Photodynamic Topical Antimicrobial Therapy for Infected Diabetic Foot Ulcers in Patients With Diabetes: A Case Series.

Diabetic foot ulcers (DFUs) are common, complex, costly complications, associated with frequent recurrences and increased morbidity and mortality. DFUs can be prevented and their healing can be mostly influenced by appropriately and aggressively managing any infection, but the role of antiseptic therapies in reducing healing time lacks sufficient evidence. Several therapeutic interventions have been developed based on the principles of photomedicine to overcome the issue of poor drug circulation in infected areas, with the aim of killing microbial agents while leaving the surrounding host cells unharmed. Such techniques use absorption of photons by specific chromophores. Among these, RLP068 is a tetracationic Zn(II) phthalocyanine derivative activated by exposure to red light, used as a topical treatment for superficial bacterial and fungal infections. The photoactivation of RLP068 results in the production of singlet oxygen and other reactive oxygen species, able to affect a range of cellular targets, including cell membrane and/or wall, cytoplasm, and cellular components, resulting in a rapid, broad range, bactericidal and fungicidal effect. The phase IIa study showed that photoactivated RPL068 is capable of inducing a dose-dependent reduction in total and pathogen microbial load in infected diabetic foot ulcers. In this article, a case series of 22 DFU treated with photoactivated RLP068 at 5 different centers in Italy is presented. Considering microbial agents reduction, ulcer healing facilitation, healing rate (9 DFUs out of 22), and amputation rate (only 1 case over 22), the decrease in the cost of DFU seems to be a point in favor of RLP068 and its cost-effectiveness.

What COVID-19 taught us: New opportunities and pathways from telemedicine and novel antiseptics in wound healing.

The COVID-19 pandemic deeply impacted the capacity of the health systems to maintain preventive and curative services, especially for the most vulnerable populations. During the pandemic, the wound healing centres in Italy assisted a significant reduction of the frequency of their hospital admission, since only urgencies, such as severe infections or wound haemorrhagic complications, were allowed to the hospital. The aim of this multidisciplinary work is to highlight the importance of a new pathway of wound care with patient-based therapeutic approach, tailored treatments based on the characteristics of the wound and fast tracks focused on the outpatient management, reserving hospital assessment only for patients with complicated or complex wounds. This analysis highlights the point that patients with chronic wounds need to be critically evaluated in order to find the best and most appropriate care pathway, which should vary according to the patient and, especially, to the characteristics of the wound. Moreover, the most adequate topic antiseptic should be started as soon as possible. An appropriate and correct management of the wound care will allow to link the knowledge based on years of clinical practice with the new challenges and the need to visit patients remotely, when possible.

Antimicrobial Resistance Patterns in Diabetic Foot Infections, an Epidemiological Study in Northeastern Italy.

This study is a retrospective epidemiological assessment of bacterial species isolated from a cohort of out-patients with diabetic foot infections referred to our "Diabetic Foot Unit" over one year, with particular attention to index pathogens, as identified by the EARS Network. Staphylococcus aureus and Pseudomonas aeruginosa accounted for 33.5% and 11.9% of cases, respectively. MRSA was isolated in 27.1% of patients, with 14.06% showing additional resistance to three antimicrobial classes. Pseudomonas aeruginosa presented extensive resistance to fluoroquinolones (57.3%), which was associated with resistance to piperacillin in 17.6% or to carbapenems in 23.5% of cases. Other pathogens, such as methicillin resistantStaphylococcus epidermidis, Escherichia coli and Morganella morganii ESBL and Enterococcus faecium VRE, were also found.

Foot Revascularization Avoids Major Amputation in Persons with Diabetes and Ischaemic Foot Ulcers.

The study aims to evaluate the effectiveness of foot revascularization in persons with diabetic foot ulcers (DFUs) and below-the-ankle (BTA) arterial disease. Consecutive patients referred for a new active ischaemic DFU requiring lower limb revascularization were considered. Among those, only patients with a BTA arterial disease were included. Revascularization procedures were retrospectively analysed: in the case of successful foot revascularization (recanalization of pedal artery, or plantar arteries or both) or not, patients were respectively divided in two groups, successful foot perfusion (SFP) and failed foot perfusion (FFP). Healing, minor and major amputation at 12 months of follow-up were evaluated and compared. Eighty patients (80) were included. The mean age was 70.5 ± 10.9 years, 55 (68.7%) were male, 72 (90%) were affected by type 2 diabetes with a mean duration of 22.7 ± 11.3 years. Overall 45 (56.2%) patients healed, 47 (58.7%) had minor amputation and 13 (16.2%) major amputation. Outcomes for SFP and FFP were respectively: healing (89.3 vs. 9.1%, p < 0.0001), minor amputation (44.7 vs. 78.8%, p = 0.0001), major amputation (2.1 vs. 36.3%, p < 0.0001). Failed foot revascularization resulted an independent predictor of non-healing, minor amputation, and major amputation. Foot revascularization is mandatory to achieve healing and avoid major amputation in persons with ischaemic DFU and BTA arterial disease.

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.

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.

Multidisciplinary Approach for the Management and Treatment of Diabetic Foot Infections with a Resorbable, Gentamicin-Loaded Bone Graft Substitute.

Diabetic patients are at increased risk of developing foot ulcers which may cause bone infections associated with a high probability of both amputation and mortality. Therefore, prompt diagnosis and adequate treatment are of key importance. In our Diabetic Foot Unit, effective multidisciplinary treatment of osteomyelitis secondary to diabetes involves the application of a gentamicin-eluting calcium sulphate/hydroxyapatite bone graft substitute to fill residual bone voids after debridement. The data of all patients treated with the gentamicin-eluting calcium sulphate/hydroxyapatite bone graft substitute for diabetic foot infections with ulcer formation and osteomyelitis at metatarsals, calcaneus and hindfoot at our institute from July 2013 to September 2016 were retrospectively collected and evaluated. A total of 35 patients were included in this retrospective single-arm case series and were either continuously followed up for at least one year or until healing was confirmed. Nineteen lesions affected the distal row of tarsus/talus, ten the calcaneus and a further six were located at the metatarsals. While all of the metatarsal lesions had healed at 1-year follow-up, the healing rate in the hindfoot region was lower with 62.5% at the calcaneus and 72.2% at the distal tarsus and talus at 12 months, respectively. The overall cure rate for ulcerous bone infection was 81.3%. In two calcaneal lesions (25%) and two lesions of distal tarsus/talus (11.1%) amputation was considered clinically necessary. Promising results were achieved in the treatment of diabetic foot infections with soft tissue ulcers by a multidisciplinary approach involving extensive debridement followed by adequate dead space management with a resorbable gentamicin-eluting bone graft substitute.

The Complexity of Diabetic Foot Management: From Common Care to Best Practice. The Italian Expert Opinion by Delphi Survey.

Diabetic foot is a major public health issue, driven by diabetes complications (neuropathy, peripheral vascular disease, foot deformity, and abnormal leucocyte function), which may lead to leg amputation, thus resulting in severe disability, reduced quality of life, and high health costs. The prevention of diabetes complications and the early detection and proper management of diabetic foot wounds are the milestones to avoid major amputations. Unfortunately, in many areas, the prevention of diabetic foot lesions is inadequate and wounds may proceed toward infection and chronicity, with limb- and life-threatening results. Using the Delphi method, we conducted a survey on diabetic foot among Italian experts, selected across different Italian clinical centers. This method was used to achieve a consensus on current opinion and clinical leanings on the diagnosis and management of diabetic foot ulcers. Specifically, the aim of the survey was to evaluate the current management of the diabetic foot syndrome; highlight the differences in the approach among a group of experts; evaluate the role of wound bed preparation and antisepsis; and discuss any areas of disagreement in which evidences are sparse and the clinical judgment plays a crucial role in the decision-making process.

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.

Diabetic foot management: multidisciplinary approach for advanced lesion rescue.

The diabetic foot is a complication of diabetes affecting 15% of diabetics in their lives. It is associated to diabetic neuropathy and peripheral vascular disease and its incidence has increased. The ulceration is the initial cause of a dramatic process leading, if not correctly treated, to amputations. Both neuropathy, neuro-ischemia and infections have a role in determining healing or worsening of the lesions and 85% of all amputations in diabetic patients are preceded by a foot ulceration deteriorating to a severe gangrene or infection. The different causative agents and the different clinical presentations of diabetic foot ask a multidisciplinary approach in order to address treatments to the final goals, the prevention of the amputations and the maintenance of a functional foot able with weight-bearing ability. Many professional figures, diabetologists, surgeons (both general and vascular and orthopedics), interventional radiologists, infectious diseases specialists, specialized nurses, podiatrists, orthotic technicians, are called to apply their knowledges to the diabetic patients affected by diabetic foot in a virtuous circle leading to reach the goals, with the imperative action of the multidisciplinary team. The so organized center will allow both a correct and rapid diagnosis, the use in ambulatorial environments of modern tools, or the hospitalization in multitasking wards, in which all the complications and the necessary treatments are possible, both in emergencies or in elective way, considering both revascularizations and surgery.

Drug-coated balloon angioplasty for the management of recurring infrapopliteal disease in diabetic patients with critical limb ischemia.

OBJECTIVE: To describe the 1-year outcomes of recurring infrapopliteal disease after endovascular revascularization with the Lutonix drug-coated balloons (LDCB) in diabetic patients with critical limb ischemia (CLI), and to benchmark our findings with previously published objective performance goals (OPG) addressing safety and efficacy of new catheter-based therapies for CLI. METHODS: The present study was a retrospective, single-center, and single-arm trial of symptomatic diabetic patients with CLI, who underwent LDCB-angioplasty for recurring infrapopliteal disease. Acute procedural and technical success were recorded. TcPO2 metrics variations at baseline and follow up were analyzed. Freedom from clinically driven target lesion revascularization (CD-TLR) was calculated using Kaplan-Meier analysis, and outcomes compared with previously published OPG for infrapopliteal interventions. RESULTS: 21 patients (15 men; mean age 66,6±11,2 years) were followed-up for 356.5±159.2 days and 90.47% had 12-months follow up data available for analysis. TcPO2 increased (14.3±11.6mmHg to 53.8±11.7mmHg; p<0.05). Limb salvage rate was 100%, and 90.4% of patients achieved the combined endpoint of reduction in ulcer size/depth or complete healing. LDCB had superior efficacy (MALE+post-operative death, amputation free survival, freedom from re-intervention, limb salvage and survival rates), while attaining superior or equivalent safety (Major Adverse Limb Events, major adverse cardiovascular events and Amputation) endpoints for the overall, modified clinical and anatomical high-risk groups. CONCLUSIONS: Lutonix DCB is safe and effective for recurring infrapopliteal disease. It outperforms the OPG for CLI patients with clinical and anatomical high-risk features.

Hospitalization for Charcot neuroarthropathy in diabetes: A population study in Italy.

AIMS: To provide data on hospitalization and incidence rates of Charcot neuroarthropathy (CN) and its relation to lower limbs' amputations/revascularizations in population with diabetes of Italy as well as of one of its regions (Tuscany). METHODS: Hospitalizations with CN diagnosis (codes ICD-9-CM: 7130, 7135, 7138) have been recorded in people with diabetes over years 2003-2013 in Italy and 2008-2015 in Tuscany. Amputations, peripheral vascular disease, revascularizations and infections were likewise evaluated. RESULTS: Between 2003 and 2013 CN hospitalizations were very infrequent in Italy ranging between 14×100,000 and 11×100,000 patients with diabetes. In Tuscany they declined to a minimum of 7×100,000 patients in 2015, after a previous increase to a maximum of 22×100,000 (p=NS for both). Yearly CN incidence remained constant in Italy, declining in Tuscany to a minimum of 3.4×100,000 diabetic patients in 2015 (p=0.047). CN patients were younger and with longer length of hospital stay than those with non-Charcot diabetic foot (p<0.05 for both). Amputation and infection rates were manifold higher in CN patients than in those with non-Charcot diabetic foot, while the revascularization rate was similar in both. CONCLUSIONS: Over last decade, in Italy and Tuscany yearly CN incidence and hospitalization rates concerned only a small percentage of patients, remaining constant over years and declining in Tuscany in the last couple of years. CN was significantly associated to younger age, longer hospital stay and greater risk of amputations and infections while the need of revascularization was similar to that of non-Charcot diabetic foot.

Feasibility and 1-Year outcomes of subintimal revascularization with supera® stenting of long femoropopliteal occlusions in critical limb ischemia: The "Supersub" Study.

BACKGROUND: Stent-based revascularization of long femoro-popliteal (FP) lesions has been mainly studied in claudicants and compromised by restenosis and stent fractures. The Supera® stent's biomimetic design allows enhanced fracture resistance. Data for Supera® stenting to treat long chronic total occlusions (CTOs) in patients with critical limb ischemia (CLI), are scarce. OBJECTIVE: To assess long-term outcomes of subintimal revascularization with Supera® stenting, for long FP CTOs in patients with CLI. METHODS: Prospective, single-center, single-arm study of 34 consecutive CLI patients with FP TASC C and D CTOs, who underwent Supera® stenting after subintimal crossing. Primary efficacy endpoint was 1-year patency and freedom from target lesion revascularization (TLR). Primary safety endpoint was the composite rate of freedom from death from any cause, major amputations, and TLR at a year. Secondary endpoints were stent integrity, clinical improvement, amputation free-survival, quality of life, and cost-efficiency. RESULTS: Mean lesion length was 27.9 ± 10.2 cm. Acute technical success was 100%. Primary patency was 94.1%. Freedom from TLR was 97.1%. Limb salvage was 100%. Clinical improvement was observed in 100% of patients: TC PO2 increased from 12.7 ± 6.2 to 54.8 ± 8.4 mm Hg (p < 0,0001); and 100% of patients experienced a shift in Rutherford to class 0 (p < 0.0001). There were no stents fractures. Amputation free-survival was 82.4%. CONCLUSIONS: Subintimal revascularization with Supera® stenting in CLI patients with long FP occlusions, is feasible and superior to validated efficacy performance goals. Larger multicenter studies are needed to validate the safety and efficacy of this novel alternative approach. © 2016 Wiley Periodicals, Inc.

Diabetic foot complicated by vertebral osteomyelitis and epidural abscess.

UNLABELLED: Vertebral osteomyelitis (or spondylodiscitis) is steadily increasing in Western countries and often results from hematogenous seeding, direct inoculation during spinal surgery, or contiguous spread from an infection in the adjacent soft tissue. We present the case of a 67-year-old white patient with type 2 diabetes who went to Hospital for high fever, back pain, and worsening of known infected ulcers in the left foot. Despite intravenous antibiotic treatment and surgical debridement of the foot infection, high fever and lower back pain continued. Bone biopsy and two consecutive blood cultures were positive for Staphylococcus aureus. A spinal magnetic resonance imaging (MRI) was performed, revealing serious osteomyelitis in L4 and L5 complicated by an epidural abscess. Contiguous or other distant focuses of infection were not identified. In this case, diabetic foot could be considered as a primary distant focus for vertebral osteomyelitis. Clinicians should consider vertebral osteomyelitis as a 'possible' diagnosis in patients with type 2 diabetes complicated by foot infection that is associated with fever and lower back pain. LEARNING POINTS: Vertebral osteomyelitis is increasing in Western countries, especially in patients with type 2 diabetes.The primary focus of infection is the genitourinary tract followed by skin, soft tissue, endocarditis, bursitis, septic arthritis, and intravascular access.Diabetic foot could be a rare primary focus of infection for vertebral osteomyelitis, and, however, vertebral osteomyelitis could be a serious, albeit rare, complication of diabetic foot.Clinicians should keep in mind the many potential complications of diabetic foot ulcerations and consider vertebral osteomyelitis as a "possible" diagnosis in patients with type 2 diabetes and foot ulcers associated with nonspecific symptoms such as lower back pain.Early diagnosis and correct management of vertebral osteomyelitis are crucial to improve clinical outcomes.

NETosis Delays Diabetic Wound Healing in Mice and Humans.

Upon activation, neutrophils undergo histone citrullination by protein arginine deiminase (PAD)4, exocytosis of chromatin and enzymes as neutrophil extracellular traps (NETs), and death. In diabetes, neutrophils are primed to release NETs and die by NETosis. Although this process is a defense against infection, NETosis can damage tissue. Therefore, we examined the effect of NETosis on the healing of diabetic foot ulcers (DFUs). Using proteomics, we found that NET components were enriched in nonhealing human DFUs. In an independent validation cohort, a high concentration of neutrophil elastase in the wound was associated with infection and a subsequent worsening of the ulcer. NET components (elastase, histones, neutrophil gelatinase-associated lipocalin, and proteinase-3) were elevated in the blood of patients with DFUs. Circulating elastase and proteinase-3 were associated with infection, and serum elastase predicted delayed healing. Neutrophils isolated from the blood of DFU patients showed an increased spontaneous NETosis but an impaired inducible NETosis. In mice, skin PAD4 activity was increased by diabetes, and FACS detection of histone citrullination, together with intravital microscopy, showed that NETosis occurred in the bed of excisional wounds. PAD4 inhibition by Cl-amidine reduced NETting neutrophils and rescued wound healing in diabetic mice. Cumulatively, these data suggest that NETosis delays DFU healing.

Cognitive functioning among patients with diabetic foot.

AIMS: Using diabetic foot (DF) as an indicator of severe diabetes, we aimed to investigate the cognitive profile of DF patients and the relations between cognitive functioning and both diabetes complications and comorbidities. METHODS: Dementia-free patients with DF aged 30-90 (n=153) were assessed through medical records and a cognitive battery. Information on diabetes complications and comorbidities was collected via interview; glycated hemoglobin (HbA1c) was tested. Data were analyzed using robust logistic or quantile regression adjusted for potential confounders. RESULTS: The mean Mini-Mental Examination (MMSE) score of patients was 24.6 (SD=3.6), and 40% had global cognitive dysfunction (MMSE ≤24). Among elderly patients (aged ≥65), MMSE impairment was related to amputation (OR 3.59, 95% CI 1.07-12.11). Episodic memory impairment was associated with foot amputation (OR 4.13, 95% CI 1.11-15.28) and microvascular complications (OR 9.68, 95% CI 1.67-56.06). Further, elderly patients with HbA1c <7% had increased odds of psychomotor slowness (OR 7.75, 95% CI 1.55-38.73) and abstract reasoning impairment (OR 4.49, 95% CI: 1.15-17.46). However, such significant associations were not shown in adult patients aged <65. CONCLUSION: Amputation, microvascular diseases and glycemic control were associated with impaired global cognitive function and its domains among patients aged ≥65.

The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker.

AIMS/HYPOTHESIS: Chronic foot ulceration is a severe complication of diabetes, driving morbidity and mortality. The mechanisms underlying delaying wound healing in diabetes are incompletely understood and tools to identify such pathways are eagerly awaited. METHODS: Wound biopsies were obtained from 75 patients with diabetic foot ulcers. Matched subgroups of rapidly healing (RH, n = 17) and non-healing (NH, n = 11) patients were selected. Proteomic analysis was performed by labelling with isobaric tag for relative and absolute quantification and mass spectrometry. Differentially expressed proteins were analysed in NH vs RH for identification of pathogenic pathways. Individual sample gene/protein validation and in vivo validation of candidate pathways in mouse models were carried out. RESULTS: Pathway analyses were conducted on 92/286 proteins that were differentially expressed in NH vs RH. The following pathways were enriched in NH vs RH patients: apoptosis, protease inhibitors, epithelial differentiation, serine endopeptidase activity, coagulation and regulation of defence response. SerpinB3 was strongly upregulated in RH vs NH wounds, validated as protein and mRNA in individual samples. To test the relevance of serpinB3 in vivo, we used a transgenic mouse model with α1-antitrypsin promoter-driven overexpression of human SERPINB3. In this model, wound healing was unaffected by SERPINB3 overexpression in non-diabetic or diabetic mice with or without hindlimb ischaemia. In an independent validation cohort of 47 patients, high serpinB3 protein content was confirmed as a biomarker of healing improvement. CONCLUSIONS/INTERPRETATION: We provide a benchmark for the unbiased discovery of novel molecular targets and biomarkers of impaired diabetic wound healing. High serpinB3 protein content was found to be a biomarker of successful healing in diabetic patients.

Vitamin D deficiency, serum leptin and osteoprotegerin levels in older diabetic patients: an input to new research avenues.

The aim of this study was to assess the effects of single oral bolus of 300,000 IU Vitamin D3 on serum levels and on bone and metabolic parameters in diabetic patients. This study is a Phase IV, randomized, double-blind, placebo-controlled, monocenter clinical trial. Thirty patients, 60 years or older, with type 2 diabetes mellitus, and diabetic foot complications, were enrolled and monitored for 24 weeks: 14 were treated with Vitamin D3 and 16 with placebo. Parameters including glucose, adiponectin, leptin, osteoprotegerin (OPG), 25-hydroxyvitamin D [25(OH)D], beta-CrossLaps, osteocalcin, bone-specific isoenzyme of alkaline phosphatase, tumor necrosis factor-α and parathyroid hormone were measured at screening and baseline and 12 and 24 weeks after treatment. Analysis of covariance was used to compare treatment groups. Analysis of the data detected a significant increase in 25(OH)D serum levels both at 12 and 24 weeks with respect to baseline values only in the treated patients. Significant variations with respect to baseline values were noted in OPG (P = 0.0085) and in leptin (P = 0.0442) levels: these were lower in the placebo group at week 24 but higher in the treated group. Vitamin D3 supplementation significantly increased serum leptin and OPG levels. Further, large-scale clinical trials are warranted to confirm these results.