Effect of Vitamin D3 in combination with Omega-3 Polyunsaturated Fatty Acids on NETosis in Type 2 Diabetes Mellitus Patients.

An understanding of the consequences of oxidative/halogenative stress triggered by neutrophil activation is impossible without considering NETosis. NETosis, formation of neutrophil extracellular traps (NETs), is known to promote microthrombus formation and impair wound healing in type 2 diabetes mellitus (T2DM) patients. Therefore, there is a need to search for drugs and treatment approaches that could prevent excessive NET formation. We aimed to evaluate the effect of vitamin D3 in combination with omega-3 polyunsaturated fatty acids (vitamin D3/omega-3 PUFAs) on NETosis in T2DM patients with purulent necrotizing lesions of the lower extremities. Patients and healthy subjects had vitamin D3 deficiency. Patients received, beyond standard treatment, 6000 IU of vitamin D3 and 480 mg of omega-3 PUFAs, and healthy subjects 1000 IU of vitamin D3 and 240 mg of omega-3 PUFAs daily for seven days. Neutrophil activation in ex vivo blood by phorbol-12-myristate-13-acetate (PMA) was used as a NETosis model. The percentage of blood NETs relative to leukocytes (NETbackground) before vitamin D3/omega-3 PUFA supplementation was 3.2%-4.9% in healthy subjects and 1.7%-10.8% in patients. These values rose, respectively, to 7.7%-9.1% and 4.0%-17.9% upon PMA-induced NETosis. In addition, the leukocyte count decreased by 700-1300 per 1 µL in healthy subjects and 700-4000 per 1 µL in patients. For both patients and healthy subjects, taking vitamin D3/omega-3 PUFAs had no effect on NETbackground but completely inhibited PMA-induced NET formation, though neutrophils exhibited morphological features of activation. Also, leukocyte loss was reduced (to 500 per 1 µL). For patients on standard treatment alone, changes occurred neither in background NETs and leukocytes nor in their amount after PMA stimulation. The decreased ability of neutrophils to generate NETs, which can be achieved by vitamin D3/omega-3 PUFA supplementation, could have a positive effect on wound healing in T2DM patients and reduce the incidence and severity of complications.

Correlation between vitamin D levels and hard-to-heal wounds: a systematic review.

OBJECTIVE: Hard-to-heal wounds are a major biological, psychological, social and financial burden on both individual patients and the broader health system. They are associated with a variety of comorbidities and have a complex aetiology, but are typically associated with nutritional deficiencies, such as low vitamin D levels. This systematic literature review evaluates the current research regarding the connection between inadequate vitamin D status and wound healing. METHOD: PubMed and EBSCO databases were searched following PRISMA guidelines for primary research studies relating to pressure ulcers, diabetic ulcers or venous ulcers and vitamin D status. RESULTS: A total of 10 studies, involving 2359 participants, met the inclusion criteria. There was a strong correlation between low levels of 25-hydroxyvitamin D and the presence of all three types of hard-to-heal wounds. CONCLUSION: Research suggests a correlation between low vitamin D levels and hard-to-heal wounds. However, it is not clear if the relationship is causal or only correlational. There is also emerging evidence on the use of vitamin D supplementation for the treatment of hard-to-heal wounds. More research is needed to understand the correlation between vitamin D and hard-to-heal wounds.

Critical Reviews: How we treat sickle cell patients with leg ulcers.

The past five decades have seen an improvement in the mortality and morbidity of sickle cell disease (SCD) because of prophylaxis against infectious complications, improved and expanded red cell transfusions, implementation of hydroxyurea therapy, and advances in supportive care. Now that the majority of patients in the western hemisphere reaches adulthood, end organ diseases are frequent, which include vasculopathic complications such as chronic leg ulcers. The management of patients with leg ulcers requires the hematologist to lead a team of health care professionals, and investigates the presence of associated, but potentially still occult signs of vasculopathy, such as pulmonary hypertension, renal disease, priapism and retinopathy. These complications may be asynchronous, and long term careful screening is indicated, in order to ensure early diagnosis and intervention. It is crucial to address both the immediate consequences of pain, infection and disability, and long term effects on quality of life, employment and stigma associated with chronic ulceration. Recent insights into their pathophysiology may have practical implications. We propose a holistic approach to the management of patients' physical and emotional problems and mechanisms of ulcers formation and delayed healing. An overview of topical and systemic therapies for chronic ulcers is given, with the understanding that wound care therapy is best left to the wound specialists, medical and surgical, with whom the hematologist must keep an open line of communication. In the absence of evidence-based guidelines, our opinion is based on both a critical review of the literature and our personal clinical and research experience.

Improvement of ischemic non-healing wounds following hyperoxygenation: the experience at Rambam-Elisha Hyperbaric Center in Israel, 1998-2007.

BACKGROUND: Wounds of the lower extremities are a significant public health problem, being severe and costly to treat. Adjunctive treatment with hyperbaric oxygenation (HBOT) has proven to be a useful and cost-effective means of treating ischemic wounds, mainly in diabetic patients. OBJECTIVES: To describe patients with ischemic wounds treated at the Rambam and Elisha Hyperbaric Medical Center and their wound improvement following HBOT. METHODS: We conducted a retrospective cohort study of all patients (N = 385) treated in the center during 1998-2007 for ischemic non-healing wounds in the lower extremities. RESULTS: The mean age of the patients was 61.9 years (SD 13.97). Most of them were diabetic (69.6%) and male (68.8%). Half of the subjects had a wound for more than 3 months prior to undergoing pre-HBOT transcutaneous oximetry (TcPO2) testing. Most of the wounds were classified as Wagner degree 1 or 2 (39.1% and 46.2% respectively). The median number of treatments per patient was 29. Only 63.1% of patients had continuous treatments. Approximately 20% of patients experienced mild side effects. An improvement occurred in 282 patients (77.7%) following HBOT: 15.2% fully recovered, 42.7% showed a significant improvement (and were expected to heal spontaneously), and 19.8% a slight improvement. CONCLUSIONS: HBOT can benefit the treatment of non-healing ischemic wounds (especially when aided by pretreatment TcPO2 evaluation; data not shown). Our experience shows that this procedure is safe and contributes to wound healing.

Selenium, zinc, iron and copper levels in serum of patients with arterial and venous leg ulcers.

The total serum concentrations of selenium, zinc, iron and copper were determined in geriatric patients with and without leg ulcers. The levels of selenium, zinc and iron were significantly lower and the copper/zinc ratio was significantly higher in the leg ulcer group compared with control patients. The serum-copper level and the serum-copper/zinc ratio were raised in patients with poor ulcer healing.

Zinc and acute tropical ulcers in Gambian children and adolescents.

28 Gambian children and adolescents with acute tropical leg ulcers entered a double blind trial of oral zinc supplements as an adjunct to standard treatment. Analysis of the area healing of the ulcers resulted in a mathematical expression which showed that for each subject re-epithelialization reduced the ulcer radius at a constant healing rate (k). k was derived from the equation At = pi X (r - k X t)2, where At = residual ulcer area at time "t", r = initial ulcer radius and t = time from start of treatment. In the zinc treated group k was 0.55 +/- 0.39 mm/day, and 0.51 +/- 0.25 mm/day in the placebo group. The initial low plasma zinc of 6.5 +/- 1.9 mumol/L in the ulcerated subjects was not significantly lower than that of 7.5 +/- 3.6 mumol/L in the nonulcerated controls. Oral zinc supplements significantly elevated plasma zinc concentrations by 5.8 +/- 4.8 mumol/L compared to the placebo group's change of 0.4 +/- 2.0 mumol/L (p less than 0.001). Plasma alkaline phosphatase activities and fatty acid profiles did not change with zinc supplementation. Thus unequivocal clinical and biochemical evidence of zinc deficiency in these ulcerated subjects was not established, despite changes in plasma zinc. This study does not indicate any role for zinc supplementation in the management of acute tropical ulcers.