Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin.

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.

Prognostic values of anti-Ro52 antibodies in anti-MDA5-positive clinically amyopathic dermatomyositis associated with interstitial lung disease.

OBJECTIVE: Anti-Ro52 antibody often co-occurs with anti-Jo1 antibody in antisynthetase syndrome and their co-occurrence correlates with a more aggressive clinical phenotype and poorer prognosis. The strong association of anti-Ro52 antibody with anti-melanoma differentiation-associated protein-5 (anti-MDA5) antibody has been indicated in juvenile myositis. The aim of this study was to assess the clinical significance of anti-Ro52 antibody in a cohort of adult patients with anti-MDA5-positive clinically amyopathic dermatomyositis with interstitial lung disease (CADM-ILD). METHODS: We assessed a cohort of 83 consecutive patients with anti-MDA5-positive CADM-ILD. Anti-MDA5 antibodies and anti-Ro52 antibodies were detected in immunoblotting and semi-quantitatively analysed by densitometry. Clinical features and the 24 month survival were compared between anti-MDA5-positive patients with and without anti-Ro52 antibodies. RESULTS: Anti-Ro52 antibodies were found in 74.7% of anti-MDA5-positive CADM-ILD patients and were associated with an increased frequency of rapidly progressive interstitial lung disease (RP-ILD; 54.8% vs 23.8%; P = 0.014) and cutaneous ulcerations (27.4% vs 4.8%; P = 0.033). The cumulative 24 month survival rate tended to be lower in patients with anti-Ro52 antibodies than patients without (59.9% vs 85.7%; P = 0.051). The combination of anti-Ro52 antibody status and anti-MDA5 antibody levels further stratified patients' survival rates, showing that the survival rate of patients who were dual positive for anti-MDA5 antibody and anti-Ro52 antibody was significantly lower than patients with mild positive anti-MDA5 antibody alone (59.9% vs 100%; P = 0.019). CONCLUSION: Anti-Ro52 antibody is highly prevalent in anti-MDA5-positive CADM-ILD patients and their coexistence correlates with a subgroup of patients with more aggressive phenotypes. The combination of anti-MDA5 antibody levels and anti-Ro52 antibody status could help to predict patients' prognosis and guide risk-based therapy.

Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan.

Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.

Current and Future Outlook on Disease Modification and Defining Low Disease Activity in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with heterogeneous clinical manifestations and a variable course in which the severity of the pathology dictates the disease prognosis and course. Among autoimmune rheumatic diseases, SSc has the highest mortality rate among all rheumatic diseases, though there are exciting new therapeutic targets that appear to halt the progression of SSc manifestations such as skin or lung fibrosis. In selected patients, high-intensity regimens with autologous stem cell transplantation can favorably modify the course. In what was once thought to be an untreatable disease, targeted therapies have now changed the outlook of SSc to a treatable disorder. Herein, we discuss the targeted therapies modifying the outlook on selected organ involvement and creating opportunities for future treatment. We also present a framework for defining low disease activity in SSc.

Congenital insensitivity to pain with anhidrosis syndrome: A series from Jordan.

OBJECTIVES: To present the clinical picture, the associated complications and the genetic findings of Jordanian patients diagnosed with Congenital insensitivity to pain with anhidrosis (CIPA). PATIENTS AND METHODS: This is a retrospective study including 7 patients diagnosed with CIPA presenting to Jordan University Hospital neurology clinic between 2001 and 2017. RESULTS: Among five families, seven patients were diagnose with CIPA and followed for a period ranging from one month to 6 years. The initial symptom observed in all patients was high fever in the first few days after birth, decreased sensation to pain and decreased sweating were later noted. Poor weight gain, microcephaly and global developmental delay were present in most cases. All patients had tongue ulcerations. Fingers/toes ulcerations were present in 6/7 (86.0 %), hip joint dislocation in 3/7 (43.0 %), chronic arthritis and joint swelling in 6/7 (86.0 %), corneal ulcers in 4/7 (57.1 %) and kidney amyloidosis in 1/7 (13.0 %) of all patients. Death occurred in 4/7 (57.1 %) patients. Consanguinity was present in all families. Mutation analysis revealed three variants in NTRK1 gene. The frameshift (c.1860_1861insT; p.Pro621fs) mutation was common in our series. One patient carried a novel missense mutation (c.2170 G > A; p.Gly724Ser). The third missense mutation (C2125 G > T; p.Val709Leu) was reported in a previous study in one patient. CONCLUSION: This cohort reveals a severe CIPA phenotype necessitating thorough multidisciplinary care and follow up.

Potential prognostic factors for delayed healing of common, non-traumatic skin ulcers: A scoping review.

Healing of non-traumatic skin ulcers is often suboptimal. Prognostic tools that identify people at high risk of delayed healing within the context of routine ulcer assessments may improve this, but robust evidence on which factors to include is lacking. Therefore, we scoped the literature to identify which potentially prognostic factors may warrant future systematic reviews and meta-analyses. We conducted electronic searches in MEDLINE and Embase to identify studies in English published between 1997 and 2017 that tested the association between healing of the three most common non-traumatic skin ulcers encountered by health care professionals (venous leg, diabetic foot, and pressure ulcers) and patient characteristics, ulcer characteristics, and results from clinical investigations. We included 42 studies that investigated factors which may be associated with the healing of venous leg ulcers (n = 17), diabetic foot ulcers (n = 15), and pressure ulcers (n = 10). Across ulcer types, ulcer characteristics were most commonly reported as potential prognostic factors for healing (n = 37), including the size of the ulcer area (n = 29) and ulcer duration at first assessment (n = 16). A total of 35 studies investigated the prognostic value of patient characteristics (n = 35), including age (n = 31), gender (n = 30), diabetes (n = 22), smoking status (n = 15), and history of deep vein thrombosis (DVT) (n = 13). Of these studies, 23 reported results from clinical investigations as potential prognostic factors, with the majority regarding vessel quality. Age, gender, diabetes, smoking status, history of DVT, ulcer area, and ulcer duration at time of first assessment warrant a systematic review and meta-analysis to quantify their prognostic value for delayed ulcer healing.

The association of sociodemographic and disease variables with hand function: a Scleroderma Patient-centered Intervention Network cohort study.

OBJECTIVES: Impaired hand function in systemic sclerosis (SSc) is a primary cause of disability and contributes diminished health-related quality of life. The objective of the present study was to evaluate sociodemographic, lifestyle, and disease-related factors independently associated with hand function in SSc. METHODS: Patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort who completed baseline study questionnaires between March 2014 and September 2017 were included. Hand function was measured using the Cochin Hand Function Scale (CHFS). Multiple linear regression analysis was used to identify independent correlates of impaired hand function. RESULTS: Among 1193 participants (88% female), the mean CHFS score was 13.3 (SD=16.1). Female sex (standardised regression coefficient, beta (ß)=.05), current smoking (ß=.07), higher BMI (ß=.06), diffuse SSc (ß=0.14), more severe Raynaud's scores (ß=.23), more severe finger ulcer scores (ß=.23), moderate (ß=0.19) or severe small joint contractures (ß=.20), rheumatoid arthritis (ß=0.07), and idiopathic inflammatory myositis (ß=0.06) were significantly associated with higher CHFS scores (more impaired hand function). Consumption of 1-7 alcoholic drinks per week (ß=-0.07) was associated with lower CHFS scores (less impaired hand function) compared to no drinking. CONCLUSIONS: Multiple factors are associated with hand function in SSc. The presence of moderate or severe small joint contractures, the presence of digital ulcers, and severity of Raynaud's phenomenon had the largest associations. Effective interventions are needed to improve the management of hand function in patients with SSc.

Advances in Upper Extremity Scleroderma Wound Care.

GENERAL PURPOSE: To provide information about the pathophysiology, diagnosis, and treatment options for systemic sclerosis. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Describe the pathophysiology, signs, symptoms, and diagnosis of systemic sclerosis.2. Outline the evidence-based medical and surgical management of systemic sclerosis. ABSTRACT: OBJECTIVE:: To perform a targeted review of systemic sclerosis, including epidemiology, pathophysiology, diagnosis, signs and symptoms, and medical and surgical management of upper extremity manifestations. DATA SOURCES AND STUDY SELECTION: An electronic literature review was conducted using PubMed for all publication dates through October 2017. Searches were performed using combinations of terms including "systemic sclerosis," "scleroderma," "management," "upper extremity," "hypercalcinosis," "Raynaud's phenomenon," "sympathectomy," and "digital ulcers." Only full-length articles written in English that discussed the management of upper extremity scleroderma were used. DATA EXTRACTION AND SYNTHESIS: The epidemiology, pathophysiology, diagnosis, upper extremity manifestations, and medical and surgical management of systemic sclerosis were reviewed. The case described in this article reports the utility of microsurgical interventions in the treatment of medically refractory upper extremity systemic sclerosis. CONCLUSIONS: Systemic sclerosis is a rare rheumatologic disease that greatly impacts quality of life. Medical management is the mainstay of treatment, propelling an improvement in the dismal 10-year cumulative survival rate from 54% in the 1970s to 66% in the 1990s. However, the pathophysiology of this disease is still poorly understood, and when medical management fails and the disease inevitably progresses, surgical approaches are critical.

Parasympathetic activity increases with digital microvascular damage and vascular endothelial growth factor in systemic sclerosis.

OBJECTIVES: The imbalance between angiogenic and angiostatic factors with derangement of the microvasculature are hallmarks of systemic sclerosis (SSc). Raynaud's phenomenon in SSc probably is due to the impaired neuroendothelial control mechanisms between vasoconstriction and vasodilatation. The aim of this study is to evaluate autonomic nervous system function using heart rate variability (HRV) analysis and to correlate with vascular endothelial growth factor (VEGF). METHODS: Twenty-seven SSc patients were enrolled. HRV was measured and markers of global sympathetic and parasympathetic system, respectively standard deviation of normal-to-normal RR intervals (SDNN) and square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) were evaluated. Serum VEGF levels and nailfold videocapillaroscopy (NVC) were performed. RESULTS: A linear positive correlation was observed between RMSSD and VEGF (p<0.01, r=0.55), and RMSSD and disease duration (p< 0.01, r=0.54). The RMSSD median value was significantly increased (p< 0.05) with NVC damage progression. The RMSSD median value was significantly (p<0.05) higher in SSc patients with digital ulcers (DUs) than in SSc patients without DUs [44 (39.4-60.2) vs 24.6 (23-37.1)]. CONCLUSIONS: In our study parasympathetic modulation increases in relation to VEGF. When microcirculation is modified with capillaroscopic pattern progression and DUs, autonomic system seems to stimulate vasodilatation trough parasympathetic system. We can conclude that parasympathetic activity increases with digital microvascular damage and promotes VEGF release.

Skin-resident stem cells and wound healing.

CD271 is common stem cell marker for the epidermis and dermis. We assessed a kinetic movement of epidermal and dermal CD271+ cells in the wound healing process to elucidate the possible involvement with chronic skin ulcers. Epidermal CD271+ cells were proliferated and migrated from 3 days after wounding. Purified epidermal CD271+ cells expressed higher TGFß2 and VEGFα transcripts than CD271- cells. Delayed wound healing was observed in the aged mice compared with young mice. During the wound healing process, the peak of dermal CD271+ cell accumulation was delayed in aged mice compared with young mice. The expression levels of collagen-1, -3, -5, F4-80, EGF, FGF2, TGFß1, and IL-1α were significantly increased in young mice compared with aged mice. Furthermore, purified dermal CD271+ cells expressed higher FGF2, EGF, PDGFB, and TGFß1 gene transcripts than CD271- cells. These results suggested that epidermal and dermal CD271+ cells were closely associated with wound healing process by producing various growth factors. Epidermal and dermal CD271+ cells in chronic skin ulcer patients were significantly reduced compared with healthy controls. Thus, both epidermal and dermal stem cells can play an important role in wound healing process.

Inhibition of cyclooxygenase-1 and -2 activity in keratinocytes inhibits PGE2 formation and impairs vascular endothelial growth factor release and neovascularisation in skin wounds.

Inhibition of cyclooxygenase (Cox) enzymatic activity by non-steroidal anti-inflammatory drugs (NSAIDs) provides the molecular basis of analgesia following wounding or surgery. This study investigated the role of Cox activity in the regulation of vascular endothelial growth factor (VEGF) expression in keratinocytes and the formation of new blood vessels in acute wounds in mice. To this end, human HaCaT keratinocytes were stimulated with epidermal growth factor (EGF). EGF increased Cox-1 mRNA in the presence of the constitutively expressed Cox-1 protein in keratinocytes. EGF coinduced Cox-2 and VEGF165 mRNA and protein expression and an accumulation of prostaglandin E2 (PGE2 ) in cell culture supernatants. Inhibition of Cox isozyme activity by Cox-1 and -2 siRNA or ibuprofen reduced PGE2 and VEGF165 release from keratinocytes. In a mouse model of excisional wound healing, Cox-2 and VEGF165 expression were colocalized in the granulation tissue of acute wounds. Oral treatment of mice with the Cox-1 and -2 inhibitor diclofenac was associated with reduced levels of VEGF165 protein and an impaired blood vessel formation in acute wound tissue. In summary, our data suggest that a reduction of PGE2 -triggered VEGF165 protein expression in wound keratinocytes is likely to contribute to the observed impairment of wound neovascularisation upon Cox inhibition.

Digital ulcers in systemic sclerosis.

Digital ulcers (DUs) are a common visible manifestation of the progressive vascular disease that characterizes the SSc disease process. DUs not only impact significantly on patients' quality of life and hand function, but are also a biomarker of internal organ involvement and of disease severity. The aetiology of (digital) vascular disease in SSc is multifactorial, and many of these factors are potentially amenable to therapeutic intervention. The management of DU disease in SSc is multifaceted. Patient education and non-pharmacological interventions (e.g. smoking cessation) should not be neglected. There are a number of drug therapies available to prevent (e.g. phosphodiesterase type-5 inhibitors and ET receptor-1 antagonists) and treat (e.g. i.v. iloprost) DUs. DUs are also important for two other reasons: firstly, as a primary end point in SSc-related clinical trials; and secondly, DUs are included in the ACR/EULAR SSc classification criteria. However, the reliability of rheumatologists to grade DUs is poor to moderate at best, and this poses challenges in both clinical practice and research. The purpose of this review is to provide the reader with a description of the spectrum of DU disease in SSc including pathophysiology, epidemiology and clinical burden, all of which inform the multifaceted approach to management.

Bitter Melon Extract Promotes Granulation Tissue Growth and Angiogenesis in the Diabetic Wound.

OBJECTIVE: Bitter melon is a plant fruit that has been shown to exert a hypoglycemic effect when used systemically in patients with diabetes. This study was designed to investigate the topical effect of bitter melon on diabetic wounds using the wound chamber model in rats. DESIGN: Two bilateral wound chambers were implanted subcutaneously in the thoracic-lumbar region of male Sprague-Dawley rats. Diabetes was induced with streptozotocin 7 days after implantation of wound chambers. After 24 hours of induction of diabetes, aqueous extract of bitter melon was injected into 1 wound chamber, and saline (0.9% sodium chloride solution) was injected into the contralateral chamber once daily for 3 days. Wound fluid was collected on day 4 for analysis, following which rats were euthanized. The granulation tissue encapsulating the wound chamber was removed and processed for histology. Controls included diabetic rats with wound chambers injected with saline (instead of bitter melon) and nondiabetic rats with wound chambers injected with bitter melon. RESULTS: In rats with diabetes, wound granulation tissue treated with bitter melon was well formed, with distinct cellular layers, whereas the saline-treated granulation tissue showed a severe loss of tissue organization and blood vessels. Moreover, the bitter melon treatment increased angiogenesis in the diabetic granulation tissue, marked by abundant microvessels and large blood vessels. In nondiabetic rats, no differences in wound granulation tissues were observed between saline- and bitter melon-treated groups. Bitter melon treatment had no effect on systemic blood glucose levels or insulin receptor substrate 1, suggesting that its stimulatory effect on diabetic granulation tissue was not due to alteration of systemic blood glucose levels. CONCLUSIONS: When applied locally to diabetic wounds, bitter melon extract prevents regression of granulation tissue and blood vessels, thus accelerating and improving wound healing.

A Regenerative Approach with Dermal Micrografts in the Treatment of Chronic Ulcers.

BACKGROUND: The etiology of non-healing ulcers depends on both systemic and local factors. The introduction of advanced dressing, negative wound therapy and compression therapy have undoubtedly improved clinical outcomes. The principal aim of study was to demonstrate the efficacy of dermal micrografts in the treatment of ulcers with different etiologies. The second aim was to investigate in vitro the action of micrografts in the regenerative process. METHODS: The dermal micro-grafts were obtained from mechanical disaggregation of small pieces of skin tissue through a medical device called Rigeneracons. RESULTS: We observed in vivo the ability of dermal autologous micrografts to improve the healing of venous, diabetic, pressure and post-traumatic ulcers after few week of treatment accomplished in general with a better quality of life for the patients. In vitro results showed that these micrografts express mesenchymal stem cells (MSCS) marker such as CD34, CD73, CD90 and CD105, and are able to form a viable and proliferative biocomplex with collagen sponge. Finally, the site of ulcers displayed a different expression of epidermal growth factors, insulin-like growth factors, platelet-derived growth factors and their receptors and tumor necrosis factor-ß with respect to healthy skin samples. CONCLUSION: We reported a good outcome for the treatment of chronic ulcers using dermal autologous micrografts. Finally, we suggest that the positivity to MSCs markers and the ability to interact with a scaffold can play a key role in their regenerative properties.

Delayed Healing of Sickle Cell Ulcers Is due to Impaired Angiogenesis and CXCL12 Secretion in Skin Wounds.

Leg ulcers are a major complication of sickle cell disease that occur in 2.5-40% of patients. Leg ulcers are responsible for frequent complications because they are often long-lasting and are highly resistant to therapy. Although their occurrence is associated with hyperhemolysis, the mechanisms underlying sickle cell ulcers remain poorly understood. In this study, we show that skin wound healing is severely altered in old SAD sickle cell mice but is normal in young animals, consistent with reports in humans. Alterations of wound healing were associated with impaired blood and lymphatic angiogenesis in the wound beds and poor endothelial progenitor cell mobilization from the bone marrow. CXCL12 secretion by keratinocytes and inflammatory cells was low in the wounds of SAD mice. Local therapy with endothelial progenitor cells or recombinant CXCL12 injections restored wound angiogenesis and rescued the healing defect together with mobilization of circulating endothelial progenitor cells. To our knowledge, this is a previously unreported study of the cellular and molecular mechanisms of sickle cell ulcers in a murine model that provides promising therapeutic perspectives for clinical trials.