Mechanistic insights into the role of vitamin D and computational identification of potential lead compounds for Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects dopaminergic neurons in the midbrain. A recent study suggests that Orphan Nuclear Receptor 1 (NURR1) impairment may contribute to PD pathogenesis. Our study found three potent agonists for NURR1 protein based on structural and ligand-based screening methods. The pharmacophore is comprised of a hydrogen bond donor, a hydrophobic group, and two aromatic rings (DHRR). The Pharmacophore screening method screened 3142 compounds, of which 3 were screened using structure-based screening. An analysis of the molecules using Molecular Mechanics-Generalized Born Surface Area (binding free energy) revealed a range of -46.77 to -59.06 Kcal/mol. After that, chemical reactivity was investigated by density functional theory, and molecular dynamics simulation was performed (protein-ligand stability). Based on the computational studies, Lifechemical_16901310, Maybridge_2815310, and NPACT_392450 are promising agonists with respect to NURR1. To confirm the potency of the identified compounds, further validation and experiments must be conducted.

Establishing Consensus of Best Practice for CEA Use in Treatment of Severe Burns: A US Burn Provider Delphi Study.

The goal of this study was to inform standards of best practice in the use of cultured epidermal autograft (CEA), manufactured in the United States, for treatment of patients with severe burns. The study was designed using the modified Delphi technique, a method for structuring group communication among experts to promote the development of consensus-based recommendations. Known areas of variability related to the stages of CEA treatment were identified by literature review prior to the study and were confirmed through qualitative interview with the experts. The areas included Preoperative Planning/Surgical Planning, Immediate Post-Operative Care, and Rehabilitation and Long-Term Care. A list of 22 questions was developed based on interviews with the experts, and a 3round Delphi technique was used to establish consensus (≥80% agreement). Following 3 rounds (quantitative, qualitative, and virtual roundtable meeting) of the Delphi study, important guidance for use of CEA treatment in severely burned patients gained consensus. Final key recommendations included minimum burn limit for CEA treatment (30%-50% TBSA), ideal biopsy timing (1-2 days), number of grafts (enough to cover; adjust 72 hours before application), use of dermal substrates (recommended) and wide meshed autograft underlay (recommended), optimal CEA drying time per day (open air >6 hours), slings used if CEA placed on extremities (recommended), dressing changes (performed every day, all at once, with all layers removed down to bridal veil), CEA backing removal (10-14 days post placement), heat lamps (can be used to aid the wound in drying, depending on clinical judgement), initial activity restrictions lifted (beginning 10 days after backing removal), compression garments (introduced at approximately 2 months post CEA surgery), lasers (CO2 laser can be introduced between 3 and 6 months post CEA surgery).

Evaluating Real-World National and Regional Trends in Definitive Closure in U.S. Burn Care: A Survey of U.S. Burn Centers.

To better understand trends in burn treatment patterns related to definitive closure, this study sought to benchmark real-world survey data with national data contained within the National Burn Repository version 8.0 (NBR v8.0) across key burn center practice patterns, resource utilization, and clinical outcomes. A survey, administered to a representative sample of U.S. burn surgeons, collected information across several domains: burn center characteristics, patient characteristics including number of patients and burn size and depth, aggregate number of procedures, resource use such as autograft procedure time and dressing changes, and costs. Survey findings were aggregated by key outcomes (number of procedures, costs) nationally and regionally. Aggregated burn center data were also compared to the NBR to identify trends relative to current treatment patterns. Benchmarking survey results against the NBR v8.0 demonstrated shifts in burn center patient mix, with more severe cases being seen in the inpatient setting and less severe burns moving to the outpatient setting. An overall reduction in the number of autograft procedures was observed compared to NBR v8.0, and time efficiencies improved as the intervention time per TBSA decreases as TBSA increases. Both nationally and regionally, an increase in costs was observed. The results suggest resource use estimates from NBR v8.0 may be higher than current practices, thus highlighting the importance of improved and timely NBR reporting and further research on burn center standard of care practices. This study demonstrates significant variations in burn center characteristics, practice patterns, and resource utilization, thus increasing our understanding of burn center operations and behavior.

Microneedles for painless transdermal immunotherapeutic applications.

Immunotherapy has recently garnered plenty of attention to improve the clinical outcomes in the treatment of various diseases. However, owing to the dynamic nature of the immune system, this approach has often been challenged by concerns regarding the lack of adequate long-term responses in patients. The development of microneedles (MNs) has resulted in the improvement and expansion of immuno-reprogramming strategies due to the housing of high accumulation of dendritic cells, macrophages, lymphocytes, and mast cells in the dermis layer of the skin. In addition, MNs possess many outstanding properties, such as the ability for the painless traverse of the stratum corneum, minimal invasiveness, facile fabrication, excellent biocompatibility, convenient administration, and bypassing the first pass metabolism that allows direct translocation of therapeutics into the systematic circulation. These advantages make MNs excellent candidates for the delivery of immunological biomolecules to the dermal antigen-presenting cells in the skin with the aim of vaccinating or treating different diseases, such as cancer and autoimmune disorders, with minimal invasiveness and side effects. This review discusses the recent advances in engineered MNs and tackles limitations relevant to traditional immunotherapy of various hard-to-treat diseases.

Combination Therapy of Killing Diseases by Injectable Hydrogels: From Concept to Medical Applications.

The complexity of hard-to-treat diseases strongly undermines the therapeutic potential of available treatment options. Therefore, a paradigm shift from monotherapy toward combination therapy has been observed in clinical research to improve the efficiency of available treatment options. The advantages of combination therapy include the possibility of synchronous alteration of different biological pathways, reducing the required effective therapeutic dose, reducing drug resistance, and lowering the overall costs of treatment. The tunable physical properties, excellent biocompatibility, facile preparation, and ease of administration with minimal invasiveness of injectable hydrogels (IHs) have made them excellent candidates to solve the clinical and pharmacological limitations of present systems for multitherapy by direct delivery of therapeutic payloads and improving therapeutic responses through the formation of depots containing drugs, genes, cells, or a combination of them in the body after a single injection. In this review, currently available methods for the design and fabrication of IHs are systematically discussed in the first section. Next, as a step toward establishing IHs for future multimodal synergistic therapies, recent advances in cancer combination therapy, wound healing, and tissue engineering are addressed in detail in the following sections. Finally, opportunities and challenges associated with IHs for multitherapy are listed and further discussed.

Tailoring synthetic polymeric biomaterials towards nerve tissue engineering: a review.

The nervous system is known as a crucial part of the body and derangement in this system can cause potentially lethal consequences or serious side effects. Unfortunately, the nervous system is unable to rehabilitate damaged regions following seriously debilitating disorders such as stroke, spinal cord injury and brain trauma which, in turn, lead to the reduction of quality of life for the patient. Major challenges in restoring the damaged nervous system are low regenerative capacity and the complexity of physiology system. Synthetic polymeric biomaterials with outstanding properties such as excellent biocompatibility and non-immunogenicity find a wide range of applications in biomedical fields especially neural implants and nerve tissue engineering scaffolds. Despite these advancements, tailoring polymeric biomaterials for design of a desired scaffold is fundamental issue that needs tremendous attention to promote the therapeutic benefits and minimize adverse effects. This review aims to (i) describe the nervous system and related injuries. Then, (ii) nerve tissue engineering strategies are discussed and (iii) physiochemical properties of synthetic polymeric biomaterials systematically highlighted. Moreover, tailoring synthetic polymeric biomaterials for nerve tissue engineering is reviewed.

Three-Dimensional Graphene Foams: Synthesis, Properties, Biocompatibility, Biodegradability, and Applications in Tissue Engineering.

Presently, clinical nanomedicine and nanobiotechnology have impressively demanded the generation of new organic/inorganic analogues of graphene (as one of the intriguing biomedical research targets) for stem-cell-based tissue engineering. Among different shapes of graphene, three-dimensional (3D) graphene foams (GFs) are highly promising candidates to provide conditions for mimicking in vivo environments, affording effective cell attachment, proliferation,and differentiation due to their unique properties. These include the highest biocompatibility among nanostructures, high surface-to-volume ratio, 3D porous structure (to provide a homogeneous/isotropic growth of tissues), highly favorable mechanical characteristics, and rapid mass and electron transport kinetics (which are required for chemical/physical stimulation of differentiated cells). This review aims to describe recent and rapid advances in the fabrication of 3D GFs, together with their use in tissue engineering and regenerative nanomedicine applications. Moreover, we have summarized a broad range of recent studies about the behaviors, biocompatibility/toxicity,and biodegradability of these materials, both in vitro and in vivo. Finally, the highlights and challenges of these 3D porous structures, compared to the current polymeric scaffold competitors, are discussed.

Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling.

Ischemic cerebral stroke is a major cause of death and morbidity. Currently, no neuroprotective agents have been shown to impact the clinical outcomes in cerebral stroke cases. Here, we report therapeutic effects of Se nanoparticles on ischemic stroke in a murine model. Anti-transferrin receptor monoclonal antibody (OX26)-PEGylated Se nanoparticles (OX26-PEG-Se NPs) were designed and synthesized and their neuroprotective effects were measured using in vitro and in vivo approaches. We demonstrate that administration of the biodegradable nanoparticles leads to resolution of brain edema, protection of axons in hippocampus region, and myelination of hippocampal area after cerebral ischemic stroke. Our nanoparticle design ensures efficient targeting and minimal side effects. Hematological and biochemical analyses revealed no undesired NP-induced changes. To gain mechanistic insights into the therapeutic effects of these particles, we characterized the changes to the relevant inflammatory and metabolic signaling pathways. We assessed metabolic regulator mTOR and related signaling pathways such as hippo, Ubiquitin-proteasome system (ERK5), Tsc1/Tsc2 complex, FoxO1, wnt/ß-catenine signaling pathway. Moreover, we examined the activity of jak2/stat3 signaling pathways and Adamts1, which are critically involved in inflammation. Together, our study provides a promising treatment strategy for cerebral stroke based on Se NP induced suppression of excessive inflammation and oxidative metabolism.

Would Colloidal Gold Nanocarriers Present An Effective Diagnosis Or Treatment For Ischemic Stroke?

INTRODUCTION: This study was conducted to evaluate OX26-PEG-coated gold nanoparticles (GNPs) (OX26@GNPs) as a novel targeted nanoparticulate system on cell survival after ischemic stroke. MATERIALS AND METHODS: Dynamic light scattering (DLS), zeta sizer, and transmission electron microscopy (TEM) were performed to characterize the OX26@GNPs. The effect of OX26@GNPs on infarct volume, neuronal loss, and necroptosis was evaluated 24 h after reperfusion using 2, 3,5-Triphenyltetrazolium chloride (TTC) staining, Nissl staining and Western blot assay, respectively. RESULTS: Conjugation of OX26-PEG to the surface of the 25 nm colloidal gold particles increased their size to 32±2 nm, while a zeta potential change of -40.4 to 3.40 mV remarkably increased the stability of the nanoparticles. Most importantly, OX26@GNPs significantly increased the infarcted brain tissue, while bare GNPs and PEGylated GNPs had no effect on the infarct volume. However, our results indicated an extension of necroptotic cell death, followed by cell membrane damage. CONCLUSION: Collectively, our results showed that the presently formulated OX26@GNPs are not suitable nanocarriers nor contrast agents under oxidative stress for the diagnosis and treatment of ischemic stroke. Moreover, our findings suggest that the cytotoxicity of GNPs in the brain is significantly associated with their surface charge.

Multiregional Utilization of a Mobile Device App for Triage and Transfer of Burn Patients.

Technology and telehealth have the potential to optimize burn care in areas limited by lack of expertise and geographic distance from a Burn Center. This study reports a multicenter, multiregional experience using a mobile phone app to facilitate triage of patients by allowing referring providers to send encrypted photos, thus enhancing the telephone consultation process. A retrospective review was conducted on referrals from August 2016 to July 2017 at three regional Burn Centers that utilize the same mobile phone app. Centers studied are located in the Western, Northeastern, and Southern regions of the United States. Data on numbers of admissions, consults, referral facilities, type of wounds, disposition, and distance from the Burn Centers were recorded. A total of 2011 consults were placed using the mobile phone app from 294 different referring facilities spanning seven states. Utilization of the mobile phone app ranged from 20.4% to 84% among centers. All three centers demonstrated a similar range of consult distances (0-289 miles). Overall, the top three referral diagnoses were scald, contact, and flame burns. Regional differences included a higher percentage of frostbite in the Western region (P < 0.001) and a higher percentage of scald burns in the Northeastern and Southern regions (P < 0.001). The majority of patients at all centers were referred to outpatient clinics for ongoing burn care. Utilization of a mobile phone app appears to be a useful tool in the triage of patients, but further studies are warranted to assess the impact on accuracy of triage, patient outcomes, and reduction of costs.

Antioxidant nanomaterials in advanced diagnoses and treatments of ischemia reperfusion injuries.

Organ ischemia with inadequate oxygen supply followed by reperfusion (which initiates a complex of inflammatory responses and oxidative stress) occurs in different clinical conditions and surgical procedures including stroke, myocardial infarction, limb ischemia, renal failure, organ transplantation, free-tissue-transfer, cardiopulmonary bypass, and vascular surgery. Even though pharmacological treatments protect against experimental ischemia reperfusion (I/R) injury, there has not been enough success in their application for patient benefits. The main hurdles in the treatment of I/R injury are the lack of diagnosis tools for understanding the complicated chains of I/R-induced signaling events, especially in the acute phase after ischemia, determining the affected regions of the tissue over time, and then, targeting and safe delivery of antioxidants, drugs, peptides, genes and cells to the areas requiring treatment. Besides the innate antioxidant and free radical scavenging properties, some nanoparticles also show higher flexibility in drug delivery and imaging. This review highlights three main approaches in nanoparticle-mediated targeting of I/R injury: nanoparticles (1) as antioxidants for reducing tissue oxidative stress, (2) for targeted delivery of therapeutic agents to the ischemic regions or cells, and (3) for imaging I/R injury at the molecular, cellular or tissue level and monitoring its evolution using contrasts induced by nanoparticles. These approaches can also be combined to realize so called theranostics for providing simultaneous diagnosis of ischemic regions and treatments by targeted delivery.

Therapeutic role of sirtuins in neurodegenerative disease and their modulation by polyphenols.

Searching for effective therapeutic agents to prevent neurodegeneration is a challenging task due to the growing list of neurodegenerative disorders associated with a multitude of inter-related pathways. The induction and inhibition of several different signaling pathways has been shown to slow down and/or attenuate neurodegeneration and decline in cognition and locomotor function. Among these signaling pathways, a new class of enzymes known as sirtuins or silent information regulators of gene transcription has been shown to play important regulatory roles in the ageing process. SIRT1, a nuclear sirtuin, has received particular interest due to its role as a deacetylase for several metabolic and signaling proteins involved in stress response, apoptosis, mitochondrial function, self-renewal, and neuroprotection. A new strategy to treat neurodegenerative diseases is targeted therapy. In this paper, we reviewed up-to-date findings regarding the targeting of SIRT1 by polyphenolic compounds, as a new approach in the search for novel, safe and effective treatments for neurodegenerative diseases. .

Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants.

Over the course of the last three decades, a large body of evidence has shown that polyphenols, the secondary metabolites occurring in plant foods and beverages, exert protective effects due to their antioxidant activity mediated through different mechanisms ranging from direct radical scavenging and metal chelating activities, to the capacity to inhibit pro-oxidant enzymes and to target specific cell-signalling pathways. In the last decade, dietary components, and polyphenols in particular have gained considerable attention as chemopreventive agents against different types of cancer. The signal transducers and activators of transcription (STAT) family is a group of cytoplasmic transcription factors which interact with specific sequences of DNA, inducing the expression of specific genes which in turn give rise to adaptive and highly specific biological responses. Growing evidence suggests that, of the seven STAT members identified, STAT3 is over-expressed in many human tumors (i.e. solid tumors and hematological malignancies) promoting the onset and development of cancer in humans by inhibiting apoptosis or by inducing cell proliferation, angiogenesis, invasion, and metastasis. This review article aims to assess the most recent studies on the role of STATs, with focus on STAT3, in oncogenesis, and the promising effects of some polyphenols on STAT expression. Moreover, the mechanisms behind the anti-inflammatory and antioxidant activities of polyphenols which have an influence on STAT expression are discussed, with a focus on their ability to target specific cell-signalling pathways.

Use of Transcyte and dermabrasion to treat burns reduces length of stay in burns of all size and etiology.

BACKGROUND: With the cost of healthcare increasing, greater emphasis is placed on finding better ways to manage burn patients by increasing the quality of care while reducing length of hospital stay (LOS), thereby reducing overall cost. To date, this is the largest study to determine if Transcyte reduces LOS for partial thickness burns of any size or etiology. METHODS: All consecutive patients with deep partial thickness burns from April 2002 to December 2002 were reviewed (n=110) with IRB approval. Ninety-two patients were treated with dermabrasion and Transcyte only. Eighteen patients were treated with a combination of STSG and dermabrasion and Transcyte where appropriate. Our data was compared to the American Burn Association Patient Registry, as reported by Saffle et al. 1995. RESULTS: The data for percent TBSA and LOS are reported as mean+/-S.E.M. One-tailed t-test was used to analyze the data. Significant difference was found in patients who were treated with dermabrasion and Transcyte compared to the population reported by Saffle et al. Patients with 0-19.9% TBSA burn treated with dermabrasion and Transcyte had LOS of 6.1 days versus 9.0 days (p<0.001). Those with 20-39.9% TBSA burn had length of stay of 17.5 days versus 25.5 days. Patients treated with STSG and Transcyte who had 40-59.9% TBSA burn had length of stay of 39.7 days versus 44.6 days. Those treated with dermabrasion and Transcyte alone had length of stay of 31 days. CONCLUSION: This is the first study comparing burns of all sizes treated with dermabrasion and Transcyte with a known population receiving standard therapy. The authors found this new method of managing patients with partial thickness burns to be more efficacious and significantly reduces length of stay compared to traditional management.

Targeting mTOR signaling by polyphenols: A new therapeutic target for ageing.

Current ageing research is aimed not only at the promotion of longevity, but also at improving health span through the discovery and development of new therapeutic strategies by investigating molecular and cellular pathways involved in cellular senescence. Understanding the mechanism of action of polyphenolic compounds targeting mTOR (mechanistic target of rapamycin) and related pathways opens up new directions to revolutionize ways to slow down the onset and development of age-dependent degeneration. Herein, we will discuss the mechanisms by which polyphenols can delay the molecular pathogenesis of ageing via manipulation or more specifically inhibition of mTOR-signaling pathways. We will also discuss the implications of polyphenols in targeting mTOR and its related pathways on health life span extension and longevity. .

The first reported case of ureteral perforation in a patient with severe toxic epidermal necrolysis syndrome.

The aim of this study was to briefly review toxic epidermal necrolysis syndrome (TENS) and Steven Johnson Syndrome (SJS), as well as describe the unique complication of ureteral perforation. A case of ureteral perforation in an 18-year old woman with TENS was documented and reviewed. In addition to studying this unusual presentation the authors have also provided a brief review of TENS and SJS along with several common complications of this disease process. The patient in question suffered a severe case of TENS with extensive mucocutaneous involvement. After 2 weeks of intensive therapy, she suddenly became anuric. She developed obstructive uropathy and bilateral hydronephrosis from mucosal debris and sludge. A left forniceal rupture was visualized on pyelography. SJS and TENS are two different presentations in the spectrum of the same disease process. There have been descriptions of gastrointestinal, respiratory, vaginal, and ocular mucosal involvement, including cases of corneal and colonic perforation. However, acute renal failure secondary to ureteral obstruction and perforation has never been described. Although rare, one must entertain every possibility when attempting to diagnose complications of the disease.

Burn disaster-management planning: a preparedness tool kit.

It is vital that preburn center emergency providers have the knowledge and equipment needed to treat burn-injured patients should there be an extended delay in transporting the patients to a burn center as may be the case during a mass-casualty incident or weather-related emergency. Since 2007 a collaborative effort has been underway to build an emergency-response tool kit that provides to and draws from local, state, and federal resources. This tool kit is designed to fill knowledge deficits regarding burn treatment as well as address gaps in stockpiled treatment materials. This tool kit was implemented in four modules: provide equipment, provide guidance, provide education, and provide drill. Module one ensures that equipment needed for treating burn injuries is available to emergency providers. Module two ensures that policies and procedures congruent with the practice of the regional burn center are in place. Module three ensures that preburn center providers are provided education on modern burn care. Module four is to drill. The sum of the effort by the authors is the establishment of a tool kit that enhances the capabilities of preburn center emergency providers. Implementation has led to improved collaborative relationships, increased the awareness of available resources, and reduced knowledge deficit regarding burn care among preburn center providers. This tool kit provides greater continuity of care for all burn patients affected by a delay in transport to a burn center, and its modular structure makes it adaptable to other regions as a whole or in part.

Brother, have you got a light? Assessing the need for intubation in patients sustaining burn injury secondary to home oxygen therapy.

Home oxygen therapy use has steadily increased for the past 30 years. A majority of these patients suffer from chronic obstructive pulmonary disease secondary to smoking. Although warned of the danger of smoking while on oxygen, patients continue to do so, potentially resulting in cutaneous burns and suspected inhalation injury. Those suspected of inhalation injury are intubated for airway control. In the English literature, there is a paucity of data discussing the need for intubation. To date, this is the largest study to determine whether intubated patients had inhalation injury as observed by bronchoscopy and whether intubation was necessary. All patient's charts who sustained burns while on home oxygen therapy from May 2000 to May 2010 were retrospectively reviewed (n = 86). Data collected were age, sex, TBSA, ventilator days, length of stay (LOS), and presence or absence of inhalation. Of those patients intubated, a subset analysis was performed to determine whether intubation in the "Field" or "Outside Hospital" correlated with inhalation injury compared with intubation in our Emergency Department. Eighty-six patients (mean age 64 years, mean %TBSA 2.6) were included. Before transfer to the burn unit, 32 patients (37%) were intubated and 52 patients (61%) were not intubated. Of the 32 intubated patients, bronchoscopy confirmed inhalation injury in 12 patients (39%). No significant difference was seen in %TBSA between intubated vs nonintubated patients (3.5 vs 2.0, respectively). However, there was a difference in LOS between the two groups (12.7 vs 2.8, respectively). No difference was found in incidence of inhalation injury between patients intubated in the "Field/Outside Hospital" compared with patients intubated in our Emergency Department (39% and 37.5%, respectively). Between the subgroups, no difference was found in %TBSA, ventilator days, or LOS. One patient admitted for airway observation required intubation and one patient failed extubation, postoperatively. Patients on home oxygen therapy suspected of inhalation injury should ideally be observed for signs of airway compromise before intubation is performed.