A systematic review of low‐level light therapy for treatment of diabetic foot ulcer

Diabetes mellitus (DM) is a significant international health concern affecting more than 387 million individuals. A diabetic person has a 25% lifetime risk of developing a diabetic foot ulcer (DFU), leading to limb amputation in up to one in six DFU patients. Low‐level light therapy (LLLT) uses low‐power lasers or light‐emitting diodes to alter cellular function and molecular pathways, and may be a promising treatment for DFU. The goal of this systematic review is to examine whether the clinical use of LLLT is effective in the healing of DFU at 12 and 20 weeks in comparison with the standard of care, and to provide evidence‐based recommendation and future clinical guidelines for the treatment of DFU using LLLT. On September 30, 2015, we searched PubMed, EMBASE, CINAHL, and Web of Science databases using the following terms: “diabetic foot” AND “low level light therapy,” OR “light emitting diode,” OR “phototherapy,” OR “laser.” The relevant articles that met the following criteria were selected for inclusion: randomized control trials (RCTs) that investigated the use of LLLT for treatment of DFU. Four RCTs involving 131 participants were suitable for inclusion based upon our criteria. The clinical trials used sham irriadiation, low dose, or nontherapeutic LLLT as placebo or control in comparison to LLLT. The endpoints included ulcer size and time to complete healing with follow‐up ranging from 2 to 16 weeks. Each article was assigned a level of evidence (LOE) and graded according to the Oxford Center for Evidence‐based Medicine Levels of Evidence Grades of Recommendation criteria. Limitations of reviewed RCTs include a small sample size (N < 100), unclear allocation concealment, lack of screening phase to exclude rapid healers, unclear inclusion/exclusion criteria, short (<30 days) follow‐up period, and unclear treatment settings (wavelength and treatment time). However, all reviewed RCTs demonstrated therapeutic outcomes with no adverse events using LLLT for treatment of DFU. This systematic review reports that LLLT has significant potential to become a portable, minimally invasive, easy‐to‐use, and cost effective modality for treatment of DFU. To enthusiastically recommend LLLT for treatment of DFU, additional studies with comparable laser parameters, screening period to exclude rapid healers, larger sample sizes and longer follow‐up periods are required. We envision future stringent RCTs may validate LLLT for treatment of DFU. Systematic review registration number: PROSPERO CRD42015029825.     

Beta-adrenergic receptor activation inhibits keratinocyte migration via a cyclic adenosine monophosphate-independent mechanism

There is increasing evidence that G-protein-coupled receptors cross-talk with growth factor receptor-mediated signal transduction in a variety of cell types. We have investigated mechanisms by which the activation of beta-adrenergic receptors, classically GTP-binding proteins coupled receptors, influence the migration of cultured human keratinocytes. We found that iso-proterenol, a beta-adrenergic receptor-selective agonist, inhibited cell migration stimulated by either epidermal growth factor, or extracellular Ca2+ in a concentration-dependent manner. This was prevented by pretreatment of the cells with the beta-adrenergic receptor-selective antagonist timolol. Interestingly, isoproterenol, at a concentration of 1 nm, did not measurably increase intracellular cyclic adenosine monophosphate concentrations yet inhibited cell migration by 50%. To test further if isoproterenol's actions were mediated via activation of adenylyl cyclase, two inhibitors of its activity, 2'5'-dideoxyadenosine and SQ22536, were used. Both compounds significantly diminished iso-proterenol-induced increases in intracellular cyclic adenosine monophosphate concentrations but did not attenuate isoproterenol-induced inhibition of cell migration. Also, forskolin (1 microm) markedly increased intracellular cyclic adenosine monophosphate concentrations but did not significantly inhibit cell migration. As mitogen-activated protein kinases are known to signal growth factor-stimulated cell migration, we examined whether beta-adrenergic receptor-mediated inhibition of keratinocyte migration might occur via inactivation of mitogen-activated protein kinases. We found that isoproterenol inhibited phosphorylation of extracellular signal-regulated kinase mitogen-activated protein kinase in a concentration-dependent manner but had no effect on the phosphorylation of the stress mitogen-activated protein kinases c-jun N-terminal kinase and stress-activated protein kinase-2. Neither forskolin nor a membrane permeable cyclic adenosine monophosphate analog inhibited phosphorylation of any of these mitogen-activated protein kinases. These findings suggest that beta-adrenergic receptor-induced inhibition of keratinocyte migration is mediated through inhibition of the extracellular signal-regulated kinase mitogen-activated protein kinase signaling in a cyclic adenosine monophosphate-independent manner.     

Dyskeratosis Congenita Associated with Elevated Fetal Hemoglobin, X-Linked Ocular Albinism, and Juvenile-Onset Diabetes Mellitus

An 11-year-old boy had dyskeratosis congenita, elevated fetal hemoglobin level, X-linked ocular albinism, and juvenile-onset diabetes mellitus. A review of the international literature revealed that elevated fetal hemoglobin has been noted in 15 reported cases of dyskeratosis congenita. It is a previously unrecognized, commonly associated finding in dyskeratosis congenita that may provide insight into the location and function of the gene for dyskeratosis congenita.     

Melanocytes do not migrate directionally in physiological DC electric fields

Wounding skin generates an endogenous electric field of 100-200 mV/mm in the immediate vicinity of the wound. When keratinocytes are exposed to direct current electric fields of this magnitude, they exhibit galvanotaxis, or directional migration toward the cathode, suggesting that wound-generated electric fields provide migrational cues that contribute to wound healing. Because melanocytes must also migrate into the healing wound to repigment it, their motility in response to electric fields of physiologic magnitude was examined. Human skin-derived melanocytes, either exposed to 100 mV/mm direct current electric fields or nonexposed controls, both exhibited motility rates of 9 micro m/hour, significantly (three- to five-fold) lower than the motility rates of keratinocytes under identical conditions. However, in sharp contrast to keratinocytes, melanocytes exhibited no directional migration in the electric field. Additionally, neither the number of primary dendrites per cell, nor the orientation of the dendrites with respect to the field vector, nor the average length of the dendrites was significantly different in melanocytes exposed to the electric field as compared to nonexposed controls. Thus, in marked contrast to keratinocytes, human skin-derived melanocytes do not respond to direct current electric fields of physiologic magnitude with either directional migration or reorientation of dendrites. This may account for the delay in repigmentation that often accompanies wound reepithelialization.     

Serial Diaphragm Ultrasonography to Predict Successful Discontinuation of Mechanical Ventilation

Introduction

Diaphragm excursion and contraction velocity measured using ultrasonography have been used to assess diaphragm function. We aimed to evaluate the performance of diaphragm ultrasonography during weaning from mechanical ventilation (MV).

Methods

Diaphragm ultrasonography was performed on 73 mechanically ventilated patients who were being considered for extubation on three separate occasions: (1) on assist control mode (A/C) during consistent patient triggered ventilation, (2) following 30 min during a spontaneous breathing trial (SBT), (3) 4–24 h following extubation. Right hemidiaphragm excursion and contraction velocity were measured on A/C, during SBT, and following extubation. These measurements were correlated with the outcome of extubation.

Results

Twenty patients failed extubation: 6 of whom required re-intubation and 14 of whom required non-invasive ventilatory support. During SBT, the mean diaphragm excursions were 1.7?±?0.82 cm in the group who failed extubation compared to 2.1?±?0.9 cm in the group who were successfully extubated (p?=?0.06). To predict successful extubation, a decrease in diaphragm excursion of <?16.4% between A/C and SBT had a sensitivity of 84.9% and a specificity of 65%. The area under curve (AUC) for receiver operative characteristics for above cut-off was 0.75. Diaphragm contraction velocity performed poorly in predicting weaning outcome.

Conclusions

Diaphragm excursion measured during SBT is an imperfect predictor of the outcome of extubation. Maintenance of diaphragm excursion between A/C and SBT has good performance characteristics by AUC analysis. Diaphragm contraction velocity has poor ability to predict outcome of extubation.

     

Does Inflammation Have a Role in the Pathogenesis of Venous Ulcers?: A Critical Review of the Evidence

Chronic venous disease, a disorder involving venous return from the legs, is a growing epidemic in the developed world. Numerous studies have been conducted in the past two decades in an attempt to elucidate its underlying pathophysiology. Many theories have been proposed to address the profound inflammatory dysregulation, with the majority focusing on fibrin trap, inflammatory trap, cytokines, growth factors, and matrix metalloproteinases. Although many of these theories have obtained great momentum, much of the data are contradictory. Moreover, many treatments built on these theories have claimed overwhelming success despite insufficient evidence. At the same time, there are few reviews that critically analyze and evaluate these data. Therefore, in this paper, we will provide summaries of the background data and evolution of these theories and examine their supporting evidence.     

Beta adrenergic receptors in keratinocytes

Beta2 adrenergic receptors were identified in keratinocytes more than 30 years ago, but their function in the epidermis continues to be elucidated. Abnormalities in their expression, signaling pathway, or in the generation of endogenous catecholamine agonists by keratinocytes have been implicated in the pathogenesis of cutaneous diseases such as atopic dermatitis, vitiligo, and psoriasis. New studies also indicate that the beta2AR also modulates keratinocyte migration, and thus can function to regulate wound reepithelialization. This review focuses on the function of these receptors in keratinocytes and their contribution to cutaneous physiology and disease.