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The goal of this multicentre study was to evaluate whether circulating endothelial precursor cells and microparticles can predict diabetic foot ulcer healing by the 16th week of care. We enrolled 207 subjects, and 40.0% (28.4, 41.5) healed by the 16th week of care. Using flow cytometry analysis, several circulating endothelial precursor cells measured at the first week of care were associated with healing after adjustment for wound area and wound duration. For example, CD34+CD45dim, the univariate odds ratio was 1.19 (95% confidence interval: 0.88, 1.61) and after adjustment for wound area and wound duration, the odds ratio was (1.67 (1.16, 2.42) p = 0.006). A prognostic model using CD34+ CD45dim, wound area, and wound duration had an area under the curve of 0.75 (0.67, 0.82) and CD34+ CD45dim per initial wound area, an area under the curve of 0.72 (0.64, 0.79). Microparticles were not associated with a healed wound. Previous studies have indicated that circulating endothelial precursor cells measured at the first office visit are associated with a healed diabetic foot ulcer. In this multicentred prospective study, we confirm this finding, show the importance of adjusting circulating endothelial precursor cells measurements by wound area, and show circulating endothelial precursor cells per wound area is highly predictive of a healed diabetic foot ulcer by 16th week of care. [ABSTRACT FROM AUTHOR]

Lower extremity amputation ( LEA) is a life-altering complication of diabetes. The goal of our study was to investigate the possibility that genetic variation in neuronal nitric oxide synthase associated protein ( NOS1AP ) is associated with LEA and diabetic peripheral neuropathy ( DPN). Our work used data from the Chronic Renal Insufficiency Cohort ( CRIC) study. CRIC is a multicenter investigation undertaken to pursue the relationship between chronic renal insufficiency and cardiovascular disease. We evaluated 3,040 CRIC study subjects; 1,490 individuals were African Americans and 1,550 were whites. LEA occurred in 162 (5.3%) subjects, 93 (6.2%) of African Americans and 69 (4.4%) of whites. In whites, NOS1AP single nucleotide polymorphism rs1963645 was most strongly associated with LEA (1.73 [1.23, 2.44]). In African Americans three NOS1AP single nucleotide polymorphisms were associated with LEA: rs6659759 (1.65 [1.21, 2.24]); rs16849113 (1.58 [1.16, 2.14]); rs880296 (1.54 [1.14, 2.10]). We tested a subset of 100 CRIC participants for DPN using Semmes- Weinstein filaments. DPN in those with diabetes was associated with rs1963645 (16.97 [2.38, 120.97]) in whites and rs16849113 and rs6659759 (3.62 [1.11, 11.83] and 3.02 [0.82, 11.12], respectively) in African Americans. In conclusion, this is one of the first studies to show that NOS1AP gene variants are associated with DPN and LEA. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFU) or lower extremity amputation (LEA) are complications of diabetes. In those with diabetes, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are commonly used to prevent the progression of kidney disease. Recent studies have indicated that angiotensin may affect angiogenesis and wound repair. Our goal was to evaluate in those with diabetes the likelihood of developing a DFU or LEA among users of ACEi or ARB using a retrospective cohort design of general practices in the United Kingdom. We studied 40,342 individuals at least 35 years of age with diabetes who were first prescribed ACEi or ARB between 1995 and 2006. A total of 35,153 individuals were treated with ACEi, 12,437 individuals with ARB, and 7,310 both. The hazard ratio for DFU was 0.50 (95% confidence intervals: 0.43, 0.59), showing an increased risk of DFU for those using ACEi vs. ARB. The hazard ratio for LEA was 0.72 (0.48, 1.01). However, among those with lower extremity peripheral arterial disease the hazard ratio was 0.45 (0.22, 0.91) for the new onset of a LEA. In conclusion, among those with diabetes, exposure to ACEi as compared with ARB increases the risk of developing a DFU or LEA. [ABSTRACT FROM AUTHOR]

ABSTRACT The adherence by patients to diabetic foot ulcer therapy is often difficult. The goal of this study was to begin to understand how a patient's health literacy affects their foot ulcer management decisions. Initially using a cross-sectional study design, we evaluated diabetics with foot ulcers within 4 weeks of being asked to participate in a longitudinal study. We assessed health literacy using measures of general health literacy, diabetes health literacy, diabetes self-efficacy, and diabetes numeracy. Individuals enrolled in the study had higher health literacy based on the Short Test of Functional Health Literacy in Adults [33.8 (SD 2.3) versus 27.3 (SD 9.6); p = 0.009] as compared to individuals who previously declined an invitation to enroll in the study. Furthermore, patients with lower Short Test of Functional Health Literacy in Adults scores had larger ( p = 0.04) and older ( p = 0.125) wounds (markers for poorer prognosis). Other measures of literacy showed similar results. In conclusion, those with diminished health literacy were less likely to enroll in an investigational study and had wounds that were less likely to heal. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association of different contraceptive methods on the incidence and severity of acne.Methods: Using a de-identified commercial claims database, we performed a retrospective cohort study evaluating the incidence of clinical encounters for acne in the first year after initiation of contraception among female patients aged 12-40 years who were new contraceptive users. To evaluate the association of contraception class with acne severity, a subgroup analysis was performed among a cohort of patients with a history of acne examining the incidence of treatment escalation from topical acne medications to an oral tetracycline-class antibiotic in the year after initiation of contraception.Results: Among new contraceptive users with no history of acne (N=336,738), compared with combined oral contraceptives (OCs), the copper intrauterine device (IUD) (hazard ratio [HR] 1.14; 95% CI 1.01-1.29) and levonorgestrel IUDs (HR 1.09; 95% CI 1.03-1.16) were associated with increased risk of clinical encounters with acne. Among those with a history of acne (n=21,178), compared with combined OCs, the copper IUD (HR 1.44; 95% CI 1.00-2.06) and levonorgestrel IUDs (HR 1.34; 95% CI 1.10-1.64) were associated with increased risk of treatment escalation from topical acne medications to an oral tetracycline class antibiotic.Conclusion: Combined OCs appear to be associated with a modest (or small) protective effect with respect to incident acne and treatment escalation compared with other contraceptive methods. However, absolute differences between contraceptive methods were small. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated endothelial progenitor cell (EPC) mobilization following wound injury. Blood samples were taken from subjects that were enrolled from the dermatologic surgical practice at the University of Pennsylvania (UPenn). The researchers found that a change occurred in the peripheral EPC pool within a 1- to 2-hour time frame.

Importance: Disease burden data helps guide research prioritization. Objective: To determine the extent to which grants issued by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reflect disease burden, measured by disability-adjusted life years (DALYs) from Global Burden of Disease (GBD) 2010 project. Design: Two investigators independently assessed 15 skin conditions studied by GBD 2010 in the NIAMS database for grants issued in 2013. The 15 skin diseases were matched to their respective DALYs from GBD 2010. Setting: The United States NIAMS database and GBD 2010 skin condition disability data. Main Outcome(s) and Measure(s): Relationship of NIAMS grant database topic funding with percent total GBD 2010 DALY and DALY rank for 15 skin conditions. Results: During fiscal year 2013, 1,443 NIAMS grants were issued at a total value of $424 million. Of these grants, 17.7% covered skin topics. Of the total skin disease funding, 82% (91 grants) were categorized as “general cutaneous research.” Psoriasis, leprosy, and “other skin and subcutaneous diseases” (ie; immunobullous disorders, vitiligo, and hidradenitis suppurativa) were over-represented when funding was compared with disability. Conversely, cellulitis, decubitus ulcer, urticaria, acne vulgaris, viral skin diseases, fungal skin diseases, scabies, and melanoma were under-represented. Conditions for which disability and funding appeared well-matched were dermatitis, squamous and basal cell carcinoma, pruritus, bacterial skin diseases, and alopecia areata. Conclusions and Relevance: Degree of representation in NIAMS is partly correlated with DALY metrics. Grant funding was well-matched with disability metrics for five of the 15 studied skin diseases, while two skin diseases were over-represented and seven were under-represented. Global burden estimates provide increasingly transparent and important information for investigating and prioritizing national research funding allocations. [ABSTRACT FROM AUTHOR]

Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer's disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect-depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer's disease and other tauopathies. [ABSTRACT FROM AUTHOR]

Diabetes is the major risk factor for nontraumatic lower extremity amputation (LEA). The role of genetic polymorphisms in predisposing diabetics to impaired wound healing leading to LEA has not been sufficiently explored. We investigated the association between a set of genes belonging to the angiogenesis/wound repair pathway with LEA in the Chronic Renal Insufficiency Cohort, a study of adults with chronic kidney disease (CKD) that includes a subgroup with diabetes. This study was performed on 3,772 Chronic Renal Insufficiency Cohort participants who were genotyped on the ITMAT-Broad-CARe array chip. A total of 1,017 single-nucleotide polymorphisms (SNPs) in 22 genes belonging to the angiogenesis/would repair pathway were investigated. LEA was determined from patient self-report. The association between genetic variants and LEA status was examined using logistic regression and additive genetic models after stratifying the cohort by race/ethnicity and diabetic status. Unadjusted analyses as well as analyses adjusted for age, sex, estimated glomerular filtration rate, body mass index, peripheral vascular disease, hemoglobin A1c, and population stratification were performed. In non-Hispanic white participants with diabetes, rs11938826 and rs1960669, both intronic SNPs in the gene basic fibroblast growth factor-2 (FGF2), were significantly associated with LEA in covariate-adjusted analysis (OR: 2.83 (95% CI: 1.73, 4.62); p-value: 0.000034; Bonferroni adjusted p-value: 0.0006) and (OR: 2.61 (95% CI: 1.48, 4.61); p-value: 0.00095; Bonferroni adjusted p-value: 0.02). In the same subgroup, rs10883688, an FGF8 SNP of unknown functional effect, was also associated with LEA (OR: 1.72 (95% Confidence Interval: 1.14, 2.6); p-value: 0.00999; Bonferroni adjusted p-value: 0.04). No statistically significant associations were identified in the other ethnic groups. In conclusion, variant/s in FGF2 and FGF8 may predispose diabetics with CKD to LEA. Dysregulation of the FGF2 gene represents an opportunity to understand further, and possibly intervene upon, mechanisms of wound healing in diabetics with CKD. [ABSTRACT FROM AUTHOR]

Management of neuropathic foot ulcers in patients with diabetes (DFUs) has changed little over the past decade, and there is currently no objective method to gauge probability of successful healing. We hypothesized that studies of stem/progenitor cells (SPCs) in the early weeks of standard wound management could predict who will heal within 16 weeks. Blood and debrided wound margins were collected for 8 weeks from 100 patients undergoing weekly evaluations and treatment. SPC number and intracellular content of hypoxia-inducible factors (HIFs) were evaluated by flow cytometry and immunohistochemistry. More SPCs entered the bloodstream in the first 2 weeks of care in patients who healed (n = 37) than in those who did not (n = 63). Logistic regression demonstrated that the number of blood-borne SPCs and the cellular content of HIFs at study entry and the first-week follow-up visit predicted healing. Strong correlations were found among week-to-week assessments of blood-borne SPC HIF factors. We conclude that assays of SPCs during the first weeks of care in patients with DFUs can provide insight into how well wounds will respond and may aid with decisions on the use of adjunctive measures. [ABSTRACT FROM AUTHOR]

Objectives To identify care-related factors associated with hospital-acquired pressure ulcers ( HAPUs). Design Prospective cohort study. Setting Nine hospitals in Baltimore Hip Studies network. Participants Six hundred fifty-eight individuals aged 65 and older who underwent surgery for hip fracture. Measurements Skin examinations at baseline and on alternating days until hospital discharge. Participants were deemed to have a HAPU if they developed one or more new Stage 2 or higher pressure ulcers ( PUs) during the hospital stay. Results Longer emergency department stays were associated with lower HAPU incidence (>4-6 hours: adjusted incidence rate ratio ( aIRR) = 0.68, 95% confidence interval (CI) = 0.48-0.96; >6 hours: aIRR = 0.68, 95% CI = 0.46-0.99, both vs ≤ 4 hours). Participants with 24 hours or longer between admission and surgery had a higher postsurgery HAPU rate than those with less than 24 hours ( aIRR = 1.62, 95% CI = 1.24-2.11). Surgery with general anesthesia had a lower postsurgery HAPU rate than surgery with other types of anesthesia ( aIRR = 0.66, 95% CI = 0.49-0.88). There was no significant association between HAPU incidence and timing of transport to the hospital, type of transport to the hospital, or surgery duration. Conclusion Most of the factors hypothesized to be associated with higher PU incidence were associated with lower incidence or were not significantly associated, suggesting that HAPU development may not be as sensitive to care-related factors as commonly believed. Rigorous studies of innovative preventive interventions are needed to inform policy and practice. [ABSTRACT FROM AUTHOR]

To evaluate the association between pressure-redistributing support surface (PRSS) use and incident pressure ulcers in older adults with hip fracture. Secondary analysis of data from prospective cohort with assessments performed as soon as possible after hospital admission and on alternating days for 21 days. Nine hospitals in the Baltimore Hip Studies network and 105 postacute facilities to which participants were discharged. Six hundred fifty-eight people aged 65 and older who underwent surgery for hip fracture. Full-body examination for pressure ulcers; bedbound status; and PRSS use, recorded as none, powered (alternating pressure mattresses, low-air-loss mattresses, and alternating pressure overlays), or nonpowered (high-density foam, static air, or gel-filled mattresses or pressure-redistributing overlays except for alternating pressure overlays). Incident pressure ulcers (IPUs), Stage 2 or higher, were observed at 4.2% (195/4,638) of visits after no PRSS use, 4.5% (28/623) of visits after powered PRSS use, and 3.6% (54/1,496) of visits after nonpowered PRSS use. The rate of IPU per person-day of follow-up did not differ significantly between participants using powered PRSSs and those not using PRSSs. The rate also did not differ significantly between participants using nonpowered PRSSs and those not using PRSSs, except in the subset of bedbound participants (incidence rate ratio=0.3, 95% confidence interval=0.1-0.7). PRSS use was not associated with a lower IPU rate. Clinical guidelines may need revision for the limited effect of PRSS use, and it may be appropriate to target PRSS use to bedbound patients at risk of pressure ulcers. [ABSTRACT FROM AUTHOR]

Diabetic patients undergoing hyperbaric oxygen therapies (HBOT) for refractory lower extremity neuropathic ulcers exhibit more than a twofold elevation ( p=0.004) in circulating stem cells after treatments and the post-HBOT CD34 cell population contains two- to threefold higher levels of hypoxia inducible factors-1, -2, and -3, as well as thioredoxin-1 ( p<0.003), than cells present in blood before HBOT. Skin margins obtained from 2-day-old abdominal wounds exhibit higher expression of CD133, CD34, hypoxia inducible factor-1, and Trx-1 vs. margins from refractory lower extremity wounds and expression of these proteins in all wounds is increased due to HBOT ( p<0.003). HBOT is known to mobilize bone marrow stem cells by stimulating nitric oxide synthase. We found that nitric oxide synthase activity is acutely increased in patients' platelets following HBOT and remains elevated for at least 20 hours. We conclude that HBOT stimulates vasculogenic stem cell mobilization from bone marrow of diabetics and more cells are recruited to skin wounds. [ABSTRACT FROM AUTHOR]