Current Concepts in the Molecular Mechanisms and Management of Diabetic Neuropathy by Pharmacotherapeutics and Natural Compounds.

One of the most crippling effects of diabetes mellitus is diabetic neuropathy, which can cause discomfort, loss of movement, and even amputation. Diabetic neuropathy manifests in a variety of ways, ranging from pain to death. Diagnosing diabetic neuropathy can be challenging since it often goes unnoticed for many years following the onset of diabetes. In addition to oxidative stress in neurons, hyperglycemia activates a number of metabolic pathways that are important sources of damage and possible targets for treatment in diabetic neuropathy. Downstream metabolic cascades caused by prolonged hyperglycemia include activation of protein kinase C, increased production of advanced glycation end products, excessive release of cytokines, increased oxidative stress, and injury to peripheral nerves. Despite the fact that these metabolic anomalies are considered the main cause of diabetes-related microvascular issues, the diverse mechanistic processes of neuropathy are characterized by organ-specific histological and biochemical features. Although the symptoms of diabetic neuropathy can be treated, there are few options to correct the underlying problem. Diabetic neuropathy exerts a tremendous financial, psychological, and physical burden on society, emphasizing the need for efficient and focused treatment. The major goal of this review is to shed light on the multiple mechanisms and pathways that contribute to the onset of diabetic neuropathy and to provide readers with a comprehensive understanding of emerging therapeutic strategies to postpone or reverse various forms of diabetic neuropathy. The article discusses available medications and provides the latest guidelines for the treatment of pain and distal symmetric polyneuropathy, including diabetic autonomic neuropathy, which may help the patients control pain well and assess alternatives for treatment that might be more successful in preventing or delaying the course of a disease.

Neuroprotective Effects of Isolated Mangiferin from Swertia chirayita Leaves Regulating Oxidative Pathway on Streptozotocin-Induced Diabetic Neuropathy in Experimental Rats.

BACKGROUND: Oxidative stress has an important role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complication of diabetes mellitus. Swertia chirayita is a rich source of phenolic constituents and has hypoglycemic, anti-inflammatory, and antioxidant properties. AIMS: This study was performed to evaluate the neuroprotective effect in diabetes by enhancing antioxidant defense against oxidative stress, which exhibits a neuroprotective effect in streptozotocin- induced diabetic rats. OBJECTIVES: The objective of this study was to elucidate the therapeutic potential of bioactive compounds of Swertia chirayita for diabetic complications. METHODS: The present work focused on isolating the bioactive from the leaves of Swertia absinthe for acute toxicity studies, assessing its protective effects against diabetes and diabetic neuropathy as well as its mode of action in STZ-induced Wistar rats. The local area of Moradabad is the place from where the leaves of Swertia chirayita were gathered. Mangiferin was isolated and identified using spectroscopic techniques, such as UV, HPLC, 1H NMR, C13 NMR, MAS, and FTIR. Mangiferin was administered in doses of 15 and 30 mg/kg to test its effect on experimentally induced diabetes. The sciatic nerves of all groups were examined histopathologically. The protective effect of the drug against diabetes and diabetic neuropathy was demonstrated by measures, such as blood glucose level, body weight, food intake, thermal hyperalgesia, grip strength, spontaneous locomotor test, and lipid profile analysis. Sciatic nerve cells of the treated groups showed less inflammation, degeneration, and necrosis. RESULTS: The results of this study confirmed that mangiferin alleviated diabetic neuropathic pain, possibly by reducing inflammatory cytokines (TNF-α, TGF-ß1, IL-1ß, and IL-6), strong antioxidant activity, and NGF in sciatic nerves. It may be a therapeutic agent. CONCLUSION: Our results suggested that active phytochemicals of Swertia chirayita showed preventive and curative effects against STZ-induced diabetic neuropathy in rats, which might be due to its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Review on In-vitro Techniques and In-vivo Animals Models for Screening Diabetes and Diabetic Complications.

Diabetes mellitus is a type of metabolic disorders. Various pharmaceutical interventions and animal models have been used to investigate the genetic, environmental, and etiological aspects of diabetes and its effects. In recent years for the development of ant-diabetic remedies, numerous novel genetically modified animals, pharmaceutical substances, medical techniques, viruses, and hormones have been developed to screen diabetic complications. A unique disease-treating drug with new properties is still being sought after. The current review tried to include all published models and cutting-edge techniques. Experimental induction of diabetes mellitus in animal models and in vitro methods are essential for advancing our knowledge, a thorough grasp of pathophysiology, and the creation of novel therapeutics. Animal models and in vitro techniques are necessary to develop innovative diabetic medications. New approaches and additional animal models are required for diabetes research to advance. This is particularly true for models produced via dietary modifications, which have various macronutrient compositions. In this article, we review the rodent models of diet-induced diabetic peripheral neuropathy, diabetic retinopathy, and diabetic nephropathy and critically compare the key characteristics of these micro-vascular complications in humans and the diagnostic criteria with the parameters used in preclinical research using rodent models, taking into consideration the potential need for factors that can accelerate or aggravate these conditions.

Toxicological Assessment and Anti-diabetic Effects of Combined Extract of Chirata, Fenugreek and Sesame on Regulating TNF-α, TGF-ß and Oxidative Stress in Streptozotocin Induced Diabetic Rats.

BACKGROUND: Swertia chirayita, Trigonella foenum-gracum and Sesamum indicum are used as traditional medicines to treat diabetes mellitus. A collection of metabolic illnesses known as diabetes mellitus (DM) involves chronic hyperglycemia caused by flaws in insulin secretion, function, or both. Innate immunity and inflammation both play important roles in the etiology of diabetes-related microvascular problems. OBJECTIVE: This study aims to examine the anti-diabetic effects and the acute toxicity of combined extract (1:1:1) of Swertia chirayita, Trigonella foenum-gracum and Sesamum indicum. To address the demand for higher effectiveness and safety, the current effort aims to construct anti-diabetic preparations containing methanolic extract from herbal medications. METHODS: The OECD 423 method was used to investigate acute toxicity in rats. Rats were used as test subjects, and rats were given a 35 mg/kg BW injection of streptozotocin to develop diabetes. The diabetic control group was given Glibenclamide 25 mg/kg BW, while the experimental group's diabetic rats received 125 mg/kg BW and 250 mg/kg BW of a combined methanolic extract of all plants. Among the measurements looked at were acute oral toxicity, behavioral changes, body weight, serum glucose levels, lipid profiles, oxidative stress, renal function tests, and inflammatory mediators. All the rat groups' histopathologies of the kidney, liver, and stomach were compared. The data were evaluated using analysis of variance, and a post hoc test was then carried out. RESULTS: The combined extracts' medium lethal doses (LD50) were higher than 2000 mg/kg, indicating that they are not poisonous under the conditions that can be observed. Streptozotocin-induced diabetic rats' elevated blood glucose was found to be considerably lower (p 0.01) in the treated group of rats. In the treated group of rats, it was discovered that the damage and disarray in the cells typical of Streptozotocin-induced DM had been repaired. The treated group of rats returned to normal levels of the lipid profile, hyperglycemia, decreased serum protein and liver glycogen, increased liver function, and kidney function markers seen in the rats of the DM control group. CONCLUSION: The evaluated combined methanolic extract can be considered safe for use in rats. Combining methanolic extract from all selected medicinal plants (Swertia chirayita, Trigonella foenum-gracum and Sesamum indicum) has a potential anti-diabetic effect and can be safely developed as an alternative medicine.

Dual-NIR wavelength (pulsed 810 nm and superpulsed 904 nm lasers) photobiomodulation therapy synergistically augments full-thickness burn wound healing: A non-invasive approach.

A thermal burn is the most frequent, distressing form of trauma. Globally, there is a critical necessity to explore novel therapeutic strategies for burn wound care. Combination therapy has marked therapeutic efficacy in positively regulating various phases of wound repair. Photobiomodulation (PBM) is a biophysical, non-thermal therapeutic healing modality to treat chronic non-healing wounds. It hypothesized that PBM using combined NIR wavelengths may absorb through different cellular photoacceptors with varying degrees of tissue penetration, which can potentially regulate the pace of healing. Therefore, the current study investigates the efficacy of dual-NIR wavelength treatment employing pulsed 810 nm and superpulsed 904 nm lasers PBM on transdermal burn repair in rats and unveils the associated molecular mechanistic insights. Rats were randomized into five groups: uninjured skin, burn control (sham-exposed), standalone treatment with pulsed 810 nm laser, superpulsed 904 nm laser, and dual combination groups. The present findings revealed that PBM with dual-NIR wavelength synergistically augmented burn wound healing compared to control and standalone treatments. The efficacy of combined treatment was exhibited by significantly enhanced wound area contraction (α-smooth muscle actin), proliferation (PCNA, cytokeratin-14, TGF-ß2), angiogenesis (HIF-1α, CD31), ECM accumulation/ organization (collagen type 3, fibronectin), dermal hydration (AQP3), calcium homeostasis (TRPV3, calmodulin), and bioenergetics activation (CCO, AMPK-α, ATP). Collectively, PBM with dual-NIR wavelength (pulsed/ superpulsed-mode) treatment accelerates full-thickness burn wound healing, which could be used as a non-invasive translational approach in clinical significance in conjunction with existing burn wound care management.

Effect of combination of photobiomodulation 904 nm superpulsed laser therapy and Hippophae rhamnoides L. on third-degree burn wound healing.

BACKGROUND: Burn is a traumatic injury and aesthetic scarless repair poses a great challenge in area of cosmetic dermatology. Focus on multimode therapeutic strategies to promote healing of burns by regulating various stages of healing is warranted. Photobiomodulation therapy (PBMT), a non-invasive modality grabs the attention to repair impaired wounds. Seabuckthorn extract (SBTL-ALE) is known to possess antioxidant, anti-inflammation, and tissue-repair abilities. Current study aims to assess the effect of combination treatment of PBM 904 nm superpulsed laser and SBTL-ALE (2.5%) on repair of third-degree burn in rats. METHODS: Rats were randomized into five groups: uninjured, control, SBTL-ALE, 904 nm PBMT, and combination. A transdermal burn wound was induced on the dorsal side of rats of all groups except the uninjured group and respective treatment was applied for 7 days postwounding. RESULTS: Dual treatment increased wound area contraction compared to control and either treatment alone. Immunohistochemical analyses exhibited increased angiogenesis, dermal hydration, collagen synthesis, and maintained redox homeostasis as evidenced by enhanced expression (p < 0.05) of CD31, aquaporin3, collagen type 3, Nrf2, and HO1 in combination group compared with control. Conversely, pro-inflammatory and oxidative stress markers exhibited reduced (p < 0.05) TNF-α, IL-6, IL-1ß, NOS-2, ROS levels, and increased catalase activity in combined treatment. Furthermore, energy metabolizing enzymes viz. citrate synthase, CCO, and ATP contents were substantially (p < 0.05) increased, and LDH activity was reduced in the combination group. CONCLUSIONS: Dual treatment (PBMT + SBTL-ALE) prominently accelerates third-degree burn wound healing in rats, which could pave the path for multimode therapeutic strategies for the management of burns and dermal cosmetic care.

Surgical Track and Scalp Implantation Following Intraventricular Meningiomas Excision: A Report with Review of Literature.

Meningiomas are benign intracranial neoplasms arising from arachnoid cap cells. High grade meningiomas are uncommon and metastasis from these is an extremely rare event. Commonest sites of metastasis from high grade meningiomas include lung, liver, lymph nodes and bone. It is unusual for meningiomas to recur in the surgical track following excision. More so, it is even the rarest phenomenon for a meningioma to implant in subgaleal location. Various mechanisms have been proposed for the scalp implantation vis-à-vis CSF dissemination, direct surgical implantation etc., It may apply to all histological grades of meningiomas. Even the benign tumors have been shown to seed at postoperative scar. This seems to have provoked our interest to review the literature regarding this scalp implantation. We have reviewed all the cases where surgical excision of intracranial meningiomas has led to seeding of surgical track as well as scalp. We have discussed the various genetic aberrations that can guide us regarding the progression of the tumor and prognosis. We also report a case of surgical track and scalp implantation of an atypical intraventricular meningioma following excision.

Effects of Microwave 10 GHz Radiation Exposure in the Skin of Rats: An Insight on Molecular Responses.

Microwave (MW) radiation poses the risk of potential hazards on human health. The present study investigated the effects of MW 10 GHz exposure for 3 h/day for 30 days at power densities of 5.23 ± 0.25 and 10.01 ± 0.15 mW/cm2 in the skin of rats. The animals exposed to 10 mW/cm2 (corresponded to twice the ICNIRP-2020 occupational reference level of MW exposure for humans) exhibited significant biophysical, biochemical, molecular and histological alterations compared to sham-irradiated animals. Infrared thermography revealed an increase in average skin surface temperature by 1.8°C and standard deviation of 0.3°C after 30 days of 10 mW/cm2 MW exposure compared to the sham-irradiated animals. MW exposure also led to oxidative stress (ROS, 4-HNE, LPO, AOPP), inflammatory responses (NFkB, iNOS/NOS2, COX-2) and metabolic alterations [hexokinase (HK), lactate dehydrogenase (LDH), citrate synthase (CS) and glucose-6-phospahte dehydrogenase (G6PD)] in 10 mW/cm2 irradiated rat skin. A significant alteration in expression of markers associated with cell survival (Akt/PKB) and HSP27/p38MAPK-related stress-response signaling cascade was observed in 10 mW/cm2 irradiated rat skin compared to sham-irradiated rat skin. However, MW-irradiated groups did not show apoptosis, evident by unchanged caspase-3 levels. Histopathological analysis revealed a mild cytoarchitectural alteration in epidermal layer and slight aggregation of leukocytes in 10 mW/cm2 irradiated rat skin. Altogether, the present findings demonstrated that 10 GHz exposure in continuous-wave mode at 10 mW/cm2 (3 h/day, 30 days) led to significant alterations in molecular markers associated with adaptive stress-response in rat skin. Furthermore, systematic scientific studies on more prevalent pulsed-mode of MW-radiation exposure for prolonged duration are warranted.

Role of 904 nm superpulsed laser-mediated photobiomodulation on nitroxidative stress and redox homeostasis in burn wound healing.

BACKGROUND: Burn wound healing is delayed due to several critical factors such as sustained inflammation, vascular disorder, neuropathy, enhanced proteolysis, infection, and oxidative stress. Burn wounds have limited oxygen supply owing to compromised blood circulation. Hypoxic burn milieu leads to free radicals overproduction incurring oxidative injury, which impedes repair process causing damage to cell membranes, proteins, lipids, and DNA. Photobiomodulation (PBM) with 904 nm superpulsed laser had shown potent healing efficacy via attenuating inflammation while enhancing proliferation, angiogenesis, collagen accumulation, and bioenergetic activation in burn wounds. METHODS: This study investigated the effects of 904 nm superpulsed laser at 0.4 mW/cm2 average power density, 0.2 J/cm2 total energy density, 100 Hz frequency, and 200 ns pulse width for 10 min daily for seven days postburn injury on nitroxidative stress, endogenous antioxidants status, and redox homeostasis. RESULTS: Photobiomodulation treatment significantly decreased reactive oxygen species, nitric oxide, and lipid peroxidation levels as compared to non-irradiated control. Further, protective action of PBM against protein oxidative damage was evidenced by reduced protein carbonylation and advanced oxidation protein product levels along with significantly enhanced endogenous antioxidants levels of SOD, catalase, GPx, GST, reduced glutathione, and thiol (T-SH, Np-SH, P-SH). Biochemical changes aid in reduction of oxidative stress and maintenance of redox homeostasis, which further well corroborated by significantly up-regulated protein expression of Nrf 2, hemeoxygenase (HO-1), and thioredoxin reductase 2 (Txnrd2). CONCLUSION: Photobiomodulation with 904 nm superpulsed laser led to reduction of nitroxidative stress, induction of endogenous antioxidants, and maintenance of redox homeostasis that could play a vital role in augmentation of burn wound healing.

Identifying the Most Successful Procedures in Hip Arthroscopy.

Hip arthroscopy for femoral and acetabular pathologies has increased dramatically. However, there is little literature analyzing procedures as predictors of revision arthroscopy or arthroplasty. From February 2008 to November 2015, patients undergoing hip arthroscopy for a labral tear with minimum 2-year follow-up and between 18 and 60 years old were retrospectively reviewed. Those with previous surgeries, Tönnis grade greater than 1, and previous hip conditions were excluded. Follow-up was obtained for 1118 patients (1249 hips; 81.7%) with a mean age of 38.7 years (range, 18.0-60.0 years), mean body mass index of 26.4 kg/m2 (range, 16.3-48.9 kg/m2), and mean follow-up of 50.2 months (range, 24.0-111.9 months). A total of 122 (9.8%) patients converted to total hip arthroplasty (mean, 35.3 months; range, 1.4-95.2 months). Multivariate analysis for predictors of total hip arthroplasty found age at surgery (hazard ratio, 1.064/y; P<.05), body mass index (nonlinear; P<.05), labral debridement (HR, 1.558; P=.03), and notchplasty (HR, 2.128; P<.05), with trochanteric bursectomy (HR, 0.367; P<.05) identified as associated with higher survivorship. A total of 124 (9.9%) patients underwent revision hip arthroscopy at a mean of 21.7 months (range, 0.10-83.3 months). Multivariate analysis for predictors of revision surgery found workers' compensation (HR, 3.352; P<.05), capsular repair (HR, 1.950; P<.05), and femoral head microfracture (HR, 2.844; P=.04) to be significant, with age at date of surgery (HR, 0.973/y; P<.05) and femoral head chondroplasty (HR, 0.241; P=.05) associated with higher survivorship. Understanding risk factors for conversion to total hip arthroplasty or revision is paramount during discussions with patients. [Orthopedics. 2020;43(3):173-181.].

Effects of Pulsed 810 nm Al-Ga-As Diode Laser on Wound Healing Under Immunosuppression: A Molecular Insight.

BACKGROUND AND OBJECTIVES: Dysregulated inflammation is one of the major contributing factors for the prevalence of non-healing chronic wound in immunosuppressed subjects. Photobiomodulation (PBM) has emerged as a potential non-thermal, light-based therapeutic healing intervention for the treatment of impaired wounds. STUDY DESIGN/MATERIALS AND METHODS: The present study delineates the underlying molecular mechanisms of PBM 810 nm laser-induced full-thickness cutaneous wound repair in immunosuppressed rats at continuous and pulsed wave-mode with power-density of 40 mW/cm 2 , fluence 22.6 J/cm 2 for 10 minutes daily for 7 post-wounding days. Molecular markers were assessed using biochemical, enzyme-linked immunosorbent assay quantification, enzyme kinetics and immunoblots analyses pertaining to inflammation, oxidative stress, cell survival, calcium signaling, and proliferation cascades. RESULTS: Results distinctly revealed that pulsed 810 nm (10 Hz) PBM potentially influenced the cell survival and proliferation signaling pathway by significantly upregulated phospho-protein kinase B(phospho-Akt), phospho-extracellular-signal-regulated kinase 1 (ERK1), transient receptor potential vanilloid-3 (TRPV3), Ca2+ , calmodulin, transforming growth factor-ß1 (TGF-ß1), TGF-ßR3, and Na + /K + -ATPase pump levels. PBM treatment resulted in reduction of exaggerated inflammatory responses evident by significantly repressed levels of interleukin-1ß (IL-1ß), IL-6, cyclooxygenase 2 (COX-2), and substance-P receptor (SPR), as well as inhibited apoptotic cell death by decreasing p53, cytochrome C, and caspase 3 levels (P < 0.05), which, in turn, effectively augment the wound repair in immunosuppressed rats. PBM treatment also lowered 4-hydroxynoneal (HNE) adduct level and NADP/NADPH ratio and upregulated the GRP78 expression, which might culminate into reduced oxidative stress and maintained the redox homeostasis. CONCLUSIONS: Taken together, these findings would be helpful in better understanding of the molecular aspects involved in pulsed 810 nm laser-mediated dermal wound healing in immunosuppressed rats through regulation of cell survival and proliferation via Ca2+ -calmodulin, Akt, ERK, and redox signaling. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Effect of Cigarette Smoking on Patient-Reported Outcomes in Hip Arthroscopic Surgery: A Matched-Pair Controlled Study With a Minimum 2-Year Follow-up.

BACKGROUND: The rate of hip arthroscopic surgery has recently increased; however, there is limited literature examining patient-reported outcomes (PROs) in cigarette smokers. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate whether smoking status for patients undergoing hip arthroscopic surgery affects clinical findings and PRO scores. We hypothesized that patients who smoke and undergo primary hip arthroscopic surgery will have similar clinical examination findings and preoperative and postoperative PRO scores compared with nonsmoking patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were collected on all patients who underwent primary hip arthroscopic surgery from February 2008 to July 2015. A retrospective analysis of the data was then conducted to identify patients who reported cigarette use at the time of the index procedure. Patients were matched 1:2 (smoking:nonsmoking) based on sex, age within 5 years, labral treatment (repair vs reconstruction vs debridement), workers' compensation status, and body mass index within 5 kg/m2. All patients were assessed preoperatively and postoperatively using 4 PRO measures: the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sport-Specific Subscale (HOS-SSS), and International Hip Outcome Tool-12 (iHOT-12). Pain was estimated using a visual analog scale. Satisfaction was measured on a scale from 0 to 10. Significance was set at P < .05. RESULTS: A total of 75 hips were included in the smoking group, and 150 hips were included in the control group. Preoperatively, the smoking group had significantly lower PRO scores compared with the control group for the mHHS, NAHS, and HOS-SSS. Both groups demonstrated significant improvement from preoperative levels. A minimum 2-year follow-up was achieved, with a mean of 42.5 months for the smoking group and 47.6 months for the control group (P = .07). At the latest follow-up, the smoking group reported inferior results for all outcome measures compared with controls. The improvement in PRO scores and rates of treatment failure, revision arthroscopic surgery, and complications was not statistically different between the groups. CONCLUSION: Patients who smoke had lower PRO scores preoperatively and at the latest follow-up compared with nonsmokers. Both groups demonstrated significant improvement in all PRO scores. These results show that while hip arthroscopic surgery may still yield clinical benefit in smokers, these patients may ultimately achieve an inferior functional status. To optimize results, physicians should advise patients to cease smoking before undergoing hip arthroscopic surgery.

Combination of medicinal honey and 904 nm superpulsed laser-mediated photobiomodulation promotes healing and impedes inflammation, pain in full-thickness burn.

Burn wound is a complex multi-factorial pathophysiology producing excruciating pain and psychological discomfort among patients, which imposes a major burden on the healthcare system. Multi-target therapy focuses on augmented healing by regulating different phases of tissue repair. Recently, photobiomodulation (PBM)-induced wound healing has achieved profound impetus as a non-invasive, drug-free biophysical therapeutic approach. On the other hand, medicinal honey known to possess antibacterial and immunomodulatory properties and is being used as an effective treatment option for infected wounds. The present study aimed to determine whether the combination of medicinal honey and PBM using superpulsed 904 nm laser treatment could additively accelerate full-thickness burn wound repair in rats. Animals were randomly allocated into 4 experimental groups: control (C), PBM superpulsed 904 nm laser treated (PBMT), honey treated (HT) and combined treatment (CT). The dual treatment exhibited an enhanced wound area contraction and hexosamine content as compared to the other groups. Histopathological analysis revealed increased cellular proliferation, extracellular matrix accumulation and decreased inflammation in the CT group. Further, the CT group demonstrated synergistically attenuated inflammation, pain and enhanced cell adhesion, migration as evidenced by significantly reduced protein expression of TNF-α, NF-κB, IL-1ß, COX-2, substance-P receptor and up-regulation of fibronectin, respectively as compared with the other groups. Thus, the findings of present study signify that the combination of medicinal honey and PBMT accelerates the repair process of burn wounds. The study showed that therapeutic efficacy of 904 nm superpulsed laser-mediated PBM augments in the presence of medicinal honey by enhancing cellular proliferation and attenuation of inflammation and pain in burn wound healing.

Glucose-6-phosphate dehydrogenase is critical for suppression of cardiac hypertrophy by H2S.

Hydrogen Sulfide (H2S), recently identified as the third endogenously produced gaseous messenger, is a promising therapeutic prospect for multiple cardio-pathological states, including myocardial hypertrophy. The molecular niche of H2S in normal or diseased cardiac cells is, however, sparsely understood. Here, we show that ß-adrenergic receptor (ß-AR) overstimulation, known to produce hypertrophic effects in cardiomyocytes, rapidly decreased endogenous H2S levels. The preservation of intracellular H2S levels under these conditions strongly suppressed hypertrophic responses to adrenergic overstimulation, thus suggesting its intrinsic role in this process. Interestingly, unbiased global transcriptome sequencing analysis revealed an integrated metabolic circuitry, centrally linked by NADPH homeostasis, as the direct target of intracellular H2S augmentation. Within these gene networks, glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme (producing NADPH) in pentose phosphate pathway, emerged as the critical node regulating cellular effects of H2S. Utilizing both cellular and animal model systems, we show that H2S-induced elevated G6PD activity is critical for the suppression of cardiac hypertrophy in response to adrenergic overstimulation. We also describe experimental evidences suggesting multiple processes/pathways involved in regulation of G6PD activity, sustained over extended duration of time, in response to endogenous H2S augmentation. Our data, thus, revealed H2S as a critical endogenous regulator of cardiac metabolic circuitry, and also mechanistic basis for its anti-hypertrophic effects.

What Factors Predict Conversion to THA After Arthroscopy?

BACKGROUND: Failure of hip preservation to alleviate symptoms potentially subjects the patient to reoperation or conversion surgery to THA, adding recovery time, risk, and cost. A risk calculator using an algorithm that can predict the likelihood that a patient who undergoes arthroscopic hip surgery will undergo THA within 2 years would be helpful, but to our knowledge, no such tool exists. QUESTIONS: (1) Are there preoperative and intraoperative variables at the time of hip arthroscopy associated with subsequent conversion to THA? (2) Can these variables be used to develop a predictive tool for conversion to THA? MATERIALS AND METHODS: All patients undergoing arthroscopy from January 2009 through December 2011 were registered in our longitudinal database. Inclusion criteria for the study group were patients undergoing hip arthroscopy for a labral tear, who eventually had conversion surgery to THA. Patients were compared with a control group of patients who underwent hip arthroscopy for a labral tear but who did not undergo conversion surgery to THA during the same study period. Of the 893 who underwent surgery during that time, 792 (88.7%) were available for followup at a minimum of 2 years (mean, 31.1 ± 8.1 years) and so were considered in this analysis. Multivariate regression analyses of 41 preoperative and intraoperative variables were performed. Using the results of the multivariate regression, we developed a simplified calculator that may be helpful in counseling a patient regarding the risk of conversion to THA after hip arthroscopy. RESULTS: Variables simultaneously associated with conversion to THA in this model were older age (rate ratio, 1.06; 95% CI, 1.03-1.08; p < 0.0001), lower preoperative modified Harris hip score (rate ratio [RR], 0.98; 95% CI, 0.96-0.99; p = 0.0003), decreased femoral anteversion (RR, 0.97; 95% CI, 0.94-0.99; p = 0.0111), revision surgery (RR, 2.4; 95% CI, 1.15-5.01; p = 0.0193), femoral Outerbridge Grades II to IV (Grade II: RR, 2.23 [95% CI, 1.11-4.46], p = 0.023; Grade III: RR, 2.17, [95% CI, 1.11-4.23], p = 0.024; Grade IV: RR, 2.96 [95% CI, 1.34-6.52], p = 0.007), performance of acetabuloplasty (RR, 1.83; 95% CI, 1.03-3.24; p = 0.038), and lack of performance of femoral osteoplasty (RR, 0.62; 95% CI, 0.36-1.06; p = 0.081). Using the results of the multivariate regression, we developed a simplified calculator that may be helpful in counseling a patient regarding the risk of conversion surgery to THA after hip arthroscopy. CONCLUSION: Multiple risk factors have been identified as possible risk factors for conversion to THA after hip arthroscopy. A weighted calculator based on our data is presented here and may be useful for predicting failure after hip arthroscopy for labral treatment. Determining the best candidates for hip preservation remains challenging; careful attention to long-term followup and identifying characteristics associated with successful outcomes should be the focus of further study. LEVEL OF EVIDENCE: Level III, therapeutic study.

Outcomes of heterotopic ossification excision following revision hip arthroscopy.

This study reviewed pain and outcome scores of patients undergoing revision surgery with heterotopic ossification (HO) excision following previous hip arthroscopy. The aim was to determine if performing the excision arthroscopically improved clinical outcomes. Data were prospectively collected and retrospectively reviewed in patients who had HO removed arthroscopically between February 2008 and 2014. Four patient-reported outcome (PRO) measures were collected: Modified Harris Hip Score (mHHS), Non-Arthritis Hip Score (NAHS), Hip Outcome Score-Activity of Daily Living (HOS-ADL) and Sport-Specific (HOS-SS) subscales. Minimum 1.5 year follow-up from index procedure was available for 23 patients (mean age = 38.6 years). Of the 23 patients who had revision surgery and HO removal, 19 (83%) were available for follow-up. Prior to revision, the average mHHS was 53.4, HOS-ADL 51.4, HOS-SS 24.5, NAHS 50.3 and VAS 6.7. Following revision with HO excision, each score had improved with an average mHHS of 73.62, HOS-ADL of 68.88, HOS SS of 58.51, NAHS of 70.83 and VAS of 4.33. Overall, mHHS increased by 20.26 points (P < 0.001), HOS-ADL increased by 17.48 points (P = 0.023), HOS-SS increased by 34.03 points (P < 0.001), NAHS increased by 20.55 points (P = 0.001) and VAS decreased by 2.38 points (P < 0.001). Patients undergoing revision hip surgery with HO excision demonstrated improved outcome scores and pain resolution; however, few patients achieved a good or excellent result. Revision hip surgery with HO excision should be approached cautiously because of the modest results in this patient group.

Does Bony Regrowth Occur After Arthroscopic Femoroplasty in a Group of Young Adolescents?

PURPOSE: To evaluate femoral head-neck bone regrowth and PROs in skeletally immature patients that underwent arthroscopic femoroplasties over a minimum 2-year period. METHODS: Eleven skeletally immature hips (10 patients) with open femoral head physes underwent femoroplasty between October 2008 and November 2013. Inclusion criteria were minimum 2-year follow-up with patient-reported outcomes (PROs) and radiographs preoperatively, at 2 weeks, and at a minimum of 2 years postoperatively. Exclusion criteria were >16 years of age, preoperative Tönnis grade >1 and previous hip conditions. Preoperative radiographs were used to assess skeletal immaturity, which was indicated by a Risser score ≤4 and femoral head physis >1 mm. Alpha angles were measured preoperatively, at 2 weeks, and at a minimum of 2 years postoperatively. PROs, including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale (HOS-SSS), and visual analog scale (VAS) score, were measured preoperatively and at the latest follow-up. RESULTS: Mean age at surgery was 14.7 years (range: 13.2-15.9). Mean follow-up was 35.7 months (range: 23.3-61.4). All hips tested positive for anterior impingement preoperatively. The mean preoperative alpha angle was 61.8°, which decreased to 41.5° postoperatively (P < .0001) and was 40.7° at a minimum of 2 years postoperatively. No bony regrowth was documented at the latest follow-up. Mean improvements in scores were as follows: mHHS = 58.5 to 79.8 (P < .0001), NAHS = 56.8 to 87.1 (P = .008), HOS-SSS = 34.3 to 78.3 (P = .004), and VAS score = 7.5 to 1.3 (P < .0001). Mean patient satisfaction was 8.7 ± 1.7. One hip (9.0%) required revision arthroscopy at 31.1 months. No postoperative complications were reported. CONCLUSIONS: Bony regrowth of the femoral head-neck region did not occur in this study of skeletally immature females who underwent arthroscopic femoroplasty. In this group of patients, hip arthroscopic treatment of FAI and labral tears is a safe and favorable intervention because of its high patient satisfaction and outcome scores and absence of postoperative complications. LEVEL OF EVIDENCE: Level IV, prognostic study.

Noninvasive red and near-infrared wavelength-induced photobiomodulation: promoting impaired cutaneous wound healing.

The innumerable intricacies associated with chronic wounds have made the development of new painless, noninvasive, biophysical therapeutic interventions as the focus of current biomedical research. Red and near-infrared light-induced photobiomodulation therapy appears to emerge as a promising drug-free approach for promoting wound healing, reduction in inflammation, pain and restoration of function owing to penetration power in conjunction with their ability to positively modulate the biochemical and molecular responses. This review will describe the physical properties of red and near-infrared light and their interaction with skin and highlight their efficacy of wound repair and regeneration. Near-infrared (800-830 nm) was found to be the most effective and widely studied wavelength range followed by red (630-680 nm) and 904 nm superpulsed light exhibiting beneficial photobiomodulatory effects on impaired dermal wound healing.

Survey mode influence on patient-reported outcome scores in orthopaedic surgery: telephone results may be positively biased.

PURPOSE: Patient-reported outcome (PRO) scores are used to evaluate treatment modalities in orthopaedic surgery. The method of PRO collection may introduce bias to reported surgical outcomes due to the presence of an interviewer. This study evaluates post-operative PROs for variation of outcomes between survey methods-in-person, online, or telephone. METHODS: From 2008 to 2011, 456 patients underwent arthroscopic surgical treatment for acetabular labral tears. All pre-operative surveys were completed in the clinic during pre-operative visit. Two-year follow-up questionnaires were completed by 385 (84 %) patients. The PRO data were prospectively collected pre- and post-operatively using five tools: modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADLS), Hip Outcome Score Sports-Specific Subscale (HOS-SSS), Non-Arthritic Hip Score (NAHS), and visual analog scale. Patients were grouped according to method of 2-year follow-up: in-person during follow-up visit (102 patients, 26 %), online by email prompt (138 patients, 36 %), or telephone with an interviewer (145 patients, 38 %). RESULTS: Pre-operative baseline PRO scores demonstrated no statistically significant difference between groups for mHHS, HOS-ADLS, HOS-SSS, and NAHS. Two-year post-operative PRO scores obtained by telephone were statistically greater than scores obtained in-person or online for mHHS (p < 0.001), HOS-ADLS (p < 0.001), and HOS-SSS (p < 0.01). CONCLUSION: This study demonstrates higher patient-reported outcome scores and greater improvement by telephone surveys compared to in-person or online. The variation of results between collection methods is indicative of a confounding variable. Clinically, it is important to understand these confounding variables in order to assess patient responses and guide treatment. LEVEL OF EVIDENCE: IV.

Photobiomodulation with Pulsed and Continuous Wave Near-Infrared Laser (810 nm, Al-Ga-As) Augments Dermal Wound Healing in Immunosuppressed Rats.

Chronic non-healing cutaneous wounds are often vulnerable in one or more repair phases that prevent normal healing and pose challenges to the use of conventional wound care modalities. In immunosuppressed subject, the sequential stages of healing get hampered, which may be the consequences of dysregulated or stagnant wound inflammation. Photobiomodulation (PBM) or low-level laser (light) therapy (LLLT) emerges as a promising drug-free, non-invasive biophysical approach for promoting wound healing, reduction of inflammation, pain and restoration of functions. The present study was therefore undertaken to evaluate the photobiomodulatory effects of 810 nm diode laser (40 mW/cm2; 22.6 J/cm2) with pulsed (10 and 100 Hz, 50% duty cycle) and continuous wave on full-thickness excision-type dermal wound healing in hydrocortisone-induced immunosuppressed rats. Results clearly delineated that 810 nm PBM at 10 Hz was more effective over continuous and 100 Hz frequency in accelerating wound healing by attenuating the pro-inflammatory markers (NF-kB, TNF-α), augmenting wound contraction (α-SM actin), enhancing cellular proliferation, ECM deposition, neovascularization (HIF-1α, VEGF), re-epithelialization along with up-regulated protein expression of FGFR-1, Fibronectin, HSP-90 and TGF-ß2 as compared to the non-irradiated controls. Additionally, 810 nm laser irradiation significantly increased CCO activity and cellular ATP contents. Overall, the findings from this study might broaden the current biological mechanism that could be responsible for photobiomodulatory effect mediated through pulsed NIR 810 nm laser (10 Hz) for promoting dermal wound healing in immunosuppressed subjects.