Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial.

Bone marrow-derived cells contribute to tissue repair, but traffic of hematopoietic stem/progenitor cells (HSPCs) is impaired in diabetes. We therefore tested whether HSPC mobilization with the CXCR4 antagonist plerixafor improved healing of ischemic diabetic wounds. This was a pilot, phase IIa, double-blind, randomized, placebo-controlled trial (NCT02790957). Patients with diabetes with ischemic wounds were randomized to receive a single subcutaneous injection of plerixafor or saline on top of standard medical and surgical therapy. The primary endpoint was complete healing at 6 months. Secondary endpoints were wound size, transcutaneous oxygen tension (TcO2 ), ankle-brachial index (ABI), amputations, and HSPC mobilization. Twenty-six patients were enrolled: 13 received plerixafor and 13 received placebo. Patients were 84.6% males, with a mean age of 69 years. HSPC mobilization was successful in all patients who received plerixafor. The trial was terminated after a preplanned interim analysis of 50% of the target population showed a significantly lower healing rate in the plerixafor vs the placebo group. In the final analysis data set, the rate of complete healing was 38.5% in the plerixafor group vs 69.2% in the placebo group (chi-square P = .115). Wound size tended to be larger in the plerixafor group for the entire duration of observation. No significant difference was noted for the change in TcO2 and ABI or in amputation rates. No other safety concern emerged. In conclusion, successful HSPC mobilization with plerixafor did not improve healing of ischemic diabetic wounds. Contrary to what was expected, outside the context of hematological disorders, mobilization of diabetic HSPCs might exert adverse effects on wound healing.

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.

The clinical management of diabetic foot in the elderly and medico-legal implications.

Diabetic foot is a complex and challenging pathological state, characterized by high complexity of management, morbidity and mortality. The elderly present peculiar problems which interfere on one hand with the patient's compliance and on the other with their diagnostic-therapeutic management. Difficult clinical management may result in medico-legal problems, with criminal and civil consequences. In this context, the authors present a review of the literature, analysing aspects concerning the diagnosis and treatment of diabetic foot in the elderly which may turn out to be a source of professional responsibility. Analysis of these aspects provides an opportunity to discuss elements important not only for clinicians and medical workers but also experts (judges, lawyers, medico-legal experts) who must evaluate hypotheses of professional responsibility concerning diabetic foot in the elderly.

Ethical and medico-legal implications of capacity of patients in geriatric surgery.

OBJECTIVES: The aim of this study was to assess the decision-making capacity of elderly patients hospitalized in a geriatric surgery division, and the clinician's ability to assess that capacity. SUBJECTS AND METHODS: The study was conducted on patients (aged >66 years) undergoing surgical procedures. Exclusion criteria were a diagnosis of psychogeriatric disorders interfering with decision-making capacity; hearing or visual impairment; and inability to communicate. Patients previously declared legally incompetent were also excluded. The methodological approach consisted of additional interviews to collect data on patients' awareness of the reasons for their hospitalization, their informed consent, and their ability to sign a consent form. The interview was integrated with a clinical-behavioral assessment by means of the Mini-Mental State Examination and the Clock Drawing Test. Data were collected anonymously. RESULTS: The inclusion criteria were met by 123 patients, with a mean age ± SD of 77.65 ± 7.91 years (range 67-98). Their mean (±SD) Mini-Mental State Examination and the Clock Drawing Test scores were 24.53 ± 4.29 and 5.36 ± 2.41, respectively. Mild-to-severe cognitive impairment was identified in 39 patients (31.7%). The consent form was signed by 111 patients (90.25%), including 33 patients (29.72%) with mild-severe cognitive impairment; 18 patients (16.21%) were unaware of the reason for their admission to hospital. DISCUSSION: Many factors may interfere with elderly patients' ability to give their valid consent to treatment, and this study reveals that clinicians may overestimate their patients' decision-making capacity. Physicians should be aware of this problem, and intellectual capacity assessments and/or enhanced consent procedures should be considered when treating elderly patients.

Analysis of suicide in the elderly in Italy. Risk factors and prevention of suicidal behavior.

The authors describe the nationwide scale of suicides among the elderly in Italy for the period 1993-2010. The data are derived from the Italian Institute for Statistics (ISTAT) and the World Health Organization (WHO). The elderly turned out to represent the highest risk category for suicide, with risk increasing with age (suicide rates, per 100,000, in men aged 75 or over and aged 65-74 were respectively 28.3 and 15.7 in 2007). The rates for men were three times higher than those for women. The north-east and north-west regions of Italy had the highest rates of suicide in the elderly. Education was inversely related to the risk of suicide. Hanging was the most frequent method of suicide in men, and precipitation in women. The reasons for suicide, as inferred from available data, were predominantly mental-physical illnesses. The risk factors emerging from our analysis are discussed from the preventive point of view, in relation to the Italian situation and a review of the literature.

Androgens modulate osteocalcin release by human visceral adipose tissue.

OBJECTIVE: Androgens inhibit adipogenic differentiation through an androgen receptor (AR)-mediated pathway, increase lipolysis and reduce lipid accumulation in adipocytes. Undercarboxylated osteocalcin (ucOCN) regulates insulin and adiponectin secretion and is released by adipose tissue (AT). Our objective was to investigate, ex vivo and in vivo, the role of androgens on osteocalcin (OCN) modulation in human AT. DesiGN, PATIENTS, SETTING: Omental AT (OAT) for in vitro study and blood samples from 91 male patients of Padova University Hospital were used. MEASUREMENTS: Omental AT was treated with dihydrotestosterone (DHT) in presence and in absence of flutamide. cOCN and ucOCN release by AT in a simple growth medium was evaluated by ELISA. OCN, both undercarboxylated (ucOCN) and carboxylated (cOCN) forms, was measured in serum by ELISA. RESULTS: After 24-h DHT stimulation, the release of both cOCN and ucOCN by OAT was statistically increased (P < 0·05). Co-incubation with flutamide blunted OCN production. Overweight and obese patients had lower total and free testosterone (T), associated with lower ucOCN and ucOCN/OCN ratio. Free T was negatively correlated to BMI (ρ = -0·706, P < 0·05) and positively correlated to ucOCN/OCN ratio (ρ = 0·223, P < 0·05). CONCLUSIONS: Our data suggest that androgens modulate OCN release by OAT in vitro. In addition to the anti-adipogenic role of androgens, they support a novel mechanism by which androgens could exert a protective effect in energy metabolism. This hypothesis appears even more significant considering that sexual hormones' levels are greatly altered in obesity and that AT is both highly involved in their clearance and able to produce OCN.

5-fluorouracil and weekly oxaliplatin combined with radiotherapy for locally advanced rectal cancer: surgical complications and long-term results.

BACKGROUND: We undertook this study to evaluate early surgical complications and long-term results after preoperative radiotherapy and chemotherapy (RCT) using 5-fluorouracil (5-FU) and oxaliplatin (OXA) for rectal cancer. METHODS: Forty six TNM stage II-III rectal cancer patients were studied, who were given preoperative RT (50.4 Gy/28 fractions) combined with 5-FU (200-225 mg/m(2)/day by continuous venous infusion) and weekly OXA (25-60 mg/m(2)). Major complications and reoperations were recorded overall, whereas outcome analyses were performed only for patients who received the recommended regimen dosage. RESULTS: Forty three patients (M:F, 25:18; median age 59 years) were available for analysis. All patients received the planned RT dose. There were no postoperative deaths; seven patients had early major surgical complications, four requiring re-operation. One additional patient had a second surgical procedure due to a duodenal fistula complicating the resection of an aortic aneurysm performed concomitantly with rectal cancer surgery. At a median follow-up of 49 months, two of the 23 patients treated at the recommended doses developed recurrence (one local, and one local and distant), and two died of cancer progression. Following the Kaplan-Meier method, the estimated 5-year overall and disease-free survival rates were 92 and 89%, respectively. CONCLUSIONS: The preoperative RCT regimen used in the present study incurs a low rate of recurrence with an acceptable surgical morbidity.

Pathophysiology of giant incisional hernias with loss of abdominal wall substance.

Incisional hernia represents the most common wound complication after abdominal surgery. The repair of large incisional hernias requires an accurate knowledge of the interactions between the tissues of the abdominal wall, the prosthetic materials and the bowel. At the same time a careful attention must be placed on the physiopathology of abdominal hypertension. Repair of giant incisional hernias with heavy loss of substance may take to a sudden increase of intra-abdominal pressure and, sometimes, to Abdominal Compartment Syndrome (ACS). The aim of preventing recurrences very often requires the use of a prosthesis, which must be placed on a low-tension environment to avoid early failures and excessive increase of intra-abdominal pressure. It is also necessary to employ as much parietal tissues as possible to prevent visceral adhesions and lesions and to pay attention to an appropriate employment of prosthesis. Utilization of composite materials, absorbable prosthesis or of combinations of mesh and flaps looks promising in preventing endoabdominal hypertension without increasing the rate of recurrences, infections and adhesive complications.