MiR-21 and miR-205 are induced in invasive cutaneous squamous cell carcinomas.

Cutaneous squamous cell carcinoma (cSCC) is a malignant proliferation of keratinocytes with an uncertain molecular basis causing significant morbidity. MicroRNAs (miRs) are small RNA molecules that regulate gene expression on post- transcriptional level. MiRs are critical to various biological processes. To determine if miRs play a role in pathogenesis of invasive cSCC, we collected patients' specimens from in situ and invasive cSCC (n = 19) and examined miRs expression levels using qPCR. Specifically, we evaluated miR-21, miR-103a, miR-186, miR-200b, miR-203, and miR-205 expression levels due to their role in skin biology and epithelial to mesenchymal transition. MiR levels were compared between in situ and invasive cSCCs. We found statistically significant (p ≤ 0.05) upregulation of miR-21 and miR-205 in invasive cSCC compared to cSCC in situ. We concluded that miR-21 and miR-205 may have diagnostic value in determining the invasive properties of cSCCs and that each cSCC displays unique miR profile, underscoring the possibility of personalized medicine approach in developing potential novel, less invasive treatments.

Chronic unilateral ureteral obstruction in the neonatal mouse delays maturation of both kidneys and leads to late formation of atubular glomeruli.

Unilateral ureteral obstruction (UUO) in the adult mouse is the most widely used model of progressive renal disease: the proximal tubule is the nephron segment most severely affected and atubular glomeruli are formed after only 7 days of UUO. To determine the proximal nephron response to UUO in the maturing kidney, neonatal mice were examined 7 to 28 days following complete UUO under general anesthesia. Proximal tubular mass and maturation were determined by staining with Lotus tetragolonobus lectin. Superoxide was localized by nitroblue tetrazolium and collagen by Sirius red. Cell proliferation, cell death, PAX-2, megalin, α-smooth muscle actin (α-SMA), renin, and fibronectin were identified by immunohistochemistry. During the first 14 days of ipsilateral UUO, despite oxidative stress (4-hydroxynonenal staining), glomerulotubular continuity was maintained and mitochondrial superoxide production persisted. However, from 14 to 28 days, papillary growth was impaired and proximal tubules collapsed with increased apoptosis, autophagy, mitochondrial loss, and formation of atubular glomeruli. Fibronectin, α-SMA, and collagen increased in the obstructed kidney. Oxidative stress was present also in the contralateral kidney: renin was decreased, glomerulotubular maturation and papillary growth were delayed, followed by increased cortical and medullary growth. We conclude that neonatal UUO initially delays renal maturation and results in oxidative stress in both kidneys. In contrast to the adult, proximal tubular injury in the neonatal obstructed kidney is delayed at 14 days, followed only later by the formation of atubular glomeruli. Antioxidant therapies directed at proximal tubular mitochondria during early renal maturation may slow progression of congenital obstructive nephropathy.

Quality assessment of tissue specimens for studies of diabetic foot ulcers.

Diabetic foot ulcers (DFUs) represent an important clinical problem resulting in significant morbidity and mortality. Ongoing translational research studies strive to better understand molecular/cellular basis of DFU pathology that may lead to identification of novel treatment protocols. Tissue at the non-healing wound edge has been identified as one of major contributors to the DFU pathophysiology that provides important tool for translational and clinical investigations. To evaluate quality of tissue specimens and their potential use, we obtained 81 DFU specimens from 25 patients and performed histological analyses, immunohistochemistry and RNA quality assessments. We found that depth of the collected specimen is important determinant of research utility, and only specimens containing a full-thickness epidermis could be utilized for immunohistochemistry and RNA isolation. We showed that only two-thirds of collected specimens could be utilized in translational studies. This attrition rate is important for designs of future studies involving tissue specimen collection from DFU.

Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis.

Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, α-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential "fight-or-flight" responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis.

The role of surgical debridement in healing of diabetic foot ulcers.

A critical question in the treatment of chronic wounds is whether and when debridement is needed. The three most common chronic wounds are the diabetic foot ulcer (DFU), the venous leg ulcer, and the pressure or decubitus ulcer. Surgical debridement, aimed at removing necrotic, devitalized wound bed and wound edge tissue that inhibits healing, is a longstanding standard of care for the treatment of chronic, nonhealing wounds. Debridement encourages healing by converting a chronic nonhealing wound environment into a more responsive acute healing environment. While the rationale for debridement seems logical, the evidence to support its use in enhancing healing is scarce. Currently, there is more evidence in the literature for debridement for DFUs than for venous ulcers and pressure ulcers; however, the studies on which clinicians have based their rationale for debridement in DFUs possess methodologic flaws, small sample sizes, and bias. Thus, further studies are needed to develop clinical evidence for its inclusion in treatment protocols for chronic wounds. Here, the authors review the scientific evidence for debridement of DFUs, the rationale for debridement of DFUs, and the insufficient data supporting debridement for venous ulcers and pressure ulcers.

Stress-Induced Hormones Cortisol and Epinephrine Impair Wound Epithelization.

BACKGROUND: Stress-induced disruption of hormonal balance in animals and humans has a detrimental effect on wound healing. THE PROBLEM: After the injury, keratinocytes migrate over the wound bed to repair a wound. However, their nonmigratory phenotype plays a role in pathogenesis of chronic wounds. Despite many therapeutic approaches, there is a dearth of treatments targeting the molecular mechanisms mediated by stress that prevent epithelization. BASIC/CLINICAL SCIENCE ADVANCES: Recent studies show that epidermal keratinocytes synthesize stress hormones. During acute wound healing, cortisol synthesis in the epidermis is tightly controlled. Further, a key intermediate molecule in the cholesterol synthesis pathway, farnesyl pyrophosphate (FPP), can bind glucocorticoid receptor (GR) and activate GR. Additionally, keratinocytes express beta-2-adrenergic-receptor (ß2AR), a receptor for the stress hormone epinephrine. Importantly, migratory rates of keratinocytes are reduced by cortisol, FPP, epinephrine, and other ß2AR agonists, thus indicating their role in the inhibition of epithelization. Topical inhibition of local glucocorticoid and FPP synthesis, as well as treatment with ß2AR antagonists promotes wound epithelization. CLINICAL CARE RELEVANCE: Modulation of local stress hormone production may represent an important therapeutic target for wound healing disorders. Topical administration of inhibitors of cortisol synthesis, statins, ß2AR antagonists, and systemic beta-blockers can decrease cortisol synthesis, FPP, and epinephrine levels, respectively, thus restoring keratinocyte migration capacity. These treatment modalities could represent a novel therapeutic approach for wound healing disorders. CONCLUSION: Attenuation of the local stress-induced hormonal imbalance in epidermis may advance therapeutic modalities, thereby leading to enhanced epithelization and improved wound healing.

Trachyonychia: a comprehensive review.

Trachyonychia or rough nails, may present as an idiopathic disorder of the nails or it can be associated with other dermatological conditions. The dystrophic nail findings seen in trachyonychia are characterized by brittle, thin nails, with excessive longitudinal ridging. The most common histopathologic features associated with trachyonychia are spongiosis and exocytosis of inflammatory cells into the nail epithelia; typical features of lichen planus or psoriasis can also be detected. Determining the cause of trachyonychia is challenging. Treatment is often unsatisfactory, although in general it should be aimed at the underlying cause, if found. In most cases, the nail abnormalities improve spontaneously.

Alopecia: evaluation and treatment.

Hair loss is a very common complaint. Patients may describe increased shedding and diffuse or localized alopecia. The differential diagnosis of hair loss includes a number of disorders causing cicatricial or noncicatricial alopecias. This paper describes the clinical approaches and diagnostic tests that are useful in the evaluation of patients presenting with alopecia. It also reviews treatments for noncicatricial alopecias, including androgenetic alopecia, alopecia areata, and telogen effluvium, as well as cicatricial alopecias, including lichen planopilaris, its clinical variant frontal fibrosing alopecia, and discoid lupus erythematosus.

Single kidney and sports participation: perception versus reality.

OBJECTIVES: Physician opinions and practice patterns regarding the participation of children and adolescents with single, normal kidneys in contact/collision sports are widely varied. We hypothesize that limitation of participation from play based only on the presence of a single kidney is not supported by available data. We sought to determine recommendations of pediatric nephrologists regarding the participation of patients with single, normal kidneys in contact/collision sports and review the literature to determine the rate of sports-related kidney injury compared with other organs. METHODS: Members of the American Society of Pediatric Nephrology were surveyed regarding their recommendations for participation of patients with single, normal kidneys in contact/collision sports. Medical and sports literature databases were searched to determine sports-related kidney, brain, spinal cord, and cardiac injury rates and the sports associated with kidney injury. RESULTS: Sixty-two percent of respondents would not allow contact/collision sports participation. Eighty-six percent of respondents barred participation in American football, whereas only 5% barred cycling. Most cited traumatic loss of function as the reason for discouraging participation. The literature search found an incidence of catastrophic sports-related kidney injury of 0.4 per 1 million children per year from all sports. Cycling was the most common cause of sports-related kidney injury causing > 3 times the kidney injuries as football. American football alone accounted for 0.9 to 5.3 fatal brain injuries and 4.9 to 7.3 irreversible spinal cord injuries per 1 million players per year. Commotio cordis causes 2.1 to 9.2 deaths per year. CONCLUSIONS: Most pediatric nephrologists prohibit contact/collision sports participation by athletes with a single kidney, particularly football. The available evidence suggests that cycling is far more likely to cause kidney injury. In addition, kidney injury from sports is much less common than catastrophic brain, spinal cord, or cardiac injury. Restricting participation of patients with a single, normal kidney from contact/collision sports is unwarranted.