Large primary Intradural extramedullary spinal tumors: A case report.

Intradural extramedullary spinal tumors occured in 80 % of intradural tumor. Pain and motor disturbance are the most common symptomps. We present a case of 50 years-old man with intradural extramedullary spinal tumors. Patient complained radiating back pain, which getting worse with activity. There was history of antituberculosis treatment, no history of trauma and tumor. Physical examination revealed lack of flexion, extension, lateral bending and rotation, lack of patellar and achilees tendon reflexes, hypoesthesia at level L2 and L3. Magnetic resonance imaging showed "dumbbell shaped" mass, suggesting schwannoma. Lateral incision, extended to posterior combining with posterior approach was performed. Patient had improved ROM and no pain nor instability. In this report, we performed surgical procedure as a treatment for intradural extramedullary spinal tumor.

Blood-Borne Microparticles Are an Inflammatory Stimulus in Type 2 Diabetes Mellitus.

The proinflammatory state associated with diabetes mellitus (DM) remains poorly understood. We found patients with DM have 3- to 14-fold elevations of blood-borne microparticles (MPs) that bind phalloidin (Ph; Ph positive [+] MPs), indicating the presence of F-actin on their surface. We hypothesized that F-actin-coated MPs were an unrecognized cause for DM-associated proinflammatory status. Ph+MPs, but not Ph-negative MPs, activate human and murine (Mus musculus) neutrophils through biophysical attributes of F-actin and membrane expression of phosphatidylserine (PS). Neutrophils respond to Ph+MPs via a linked membrane array, including the receptor for advanced glycation end products and CD36, PS-binding membrane receptors. These proteins in conjunction with TLR4 are coupled to NO synthase 1 adaptor protein (NOS1AP). Neutrophil activation occurs because of Ph+MPs causing elevations of NF-κB and Src kinase (SrcK) via a concurrent increased association of NO synthase 2 and SrcK with NOS1AP, resulting in SrcK S-nitrosylation. We conclude that NOS1AP links PS-binding receptors with intracellular regulatory proteins. Ph+MPs are alarmins present in normal human plasma and are increased in those with DM and especially those with DM and a lower-extremity ulcer.

Circulating endothelial precursor cells are associated with a healed diabetic foot ulcer evaluated in a prospective cohort study.

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

Further evidence that wound size and duration are strong prognostic markers of diabetic foot ulcer healing.

Diabetic foot ulcers (DFU) are a critical problem for those with diabetes mellitus. Predicting the healing likelihood of a DFU is important to implementing appropriate care, allocating resources, having access to advanced therapies, having successful clinical trials, calibrating clinical trial results, and providing information to administrative entities on patient and provider outcomes. Prognostic modelling can also be important when attempting to compare results across trials or care centres. In a prospective cohort study, we demonstrate and replicate that simple wound characteristics like wound area and wound duration can be used to predict wound healing by the 16th week of care. The models were based on previous literature and replicated using a machine learning algorithm. The use of wound duration and wound area in a prognostic model continues to be important when comparing study results, centre-based outcomes, as well as designing clinical trials.

Advanced Wound Diagnostics: Toward Transforming Wound Care into Precision Medicine.

Significance: Nonhealing wounds are an ever-growing global pandemic, with mortality rates and management costs exceeding many common cancers. Although our understanding of the molecular and cellular factors driving wound healing continues to grow, standards for diagnosing and evaluating wounds remain largely subjective and experiential, whereas therapeutic strategies fail to consistently achieve closure and clinicians are challenged to deliver individualized care protocols. There is a need to apply precision medicine practices to wound care by developing evidence-based approaches, which are predictive, prescriptive, and personalized. Recent Advances: Recent developments in "advanced" wound diagnostics, namely biomarkers (proteases, acute phase reactants, volatile emissions, and more) and imaging systems (ultrasound, autofluorescence, spectral imaging, and optical coherence tomography), have begun to revolutionize our understanding of the molecular wound landscape and usher in a modern age of therapeutic strategies. Herein, biomarkers and imaging systems with the greatest evidence to support their potential clinical utility are reviewed. Critical Issues: Although many potential biomarkers have been identified and several imaging systems have been or are being developed, more high-quality randomized controlled trials are necessary to elucidate the currently questionable role that these tools are playing in altering healing dynamics or predicting wound closure within the clinical setting. Future Directions: The literature supports the need for the development of effective point-of-care wound assessment tools, such as a platform diagnostic array that is capable of measuring multiple biomarkers at once. These, along with advances in telemedicine, synthetic biology, and "smart" wearables, will pave the way for the transformation of wound care into a precision medicine. Clinical Trial Registration number: NCT03148977.

Non-pharmacologic approaches for hidradenitis suppurativa - a systematic review.

Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition presenting with painful nodules and sinus tracts primarily in intertriginous regions. The persistent nature of HS and challenges in symptom management lead many patients to seek non-pharmacologic approaches due to the paucity and limited efficacy of conventional HS therapeutic options.Objective: To evaluate the existing evidence for non-pharmacologic modalities in treatment of HS.Findings: Discussed in this review are non-pharmacologic modalities with evidence of efficacy in HS treatment, including weight loss, vitamin B12, vitamin D and zinc supplementation, and dietary avoidance of brewer's yeast. Limitations of the available data on non-pharmacologic therapies in HS include the predominance of pilot and single-armed studies, as well as heterogeneity in study design, subject disease severity, concomitant treatment and comorbid conditions.Conclusions and relevance: HS patients are becoming increasingly interested in the use of non-pharmacologic approaches to augment conventional treatments. Strength of evidence for non-pharmacologic therapies in HS is limited by small study size and lack of randomized controlled trials. Future large-scale investigations should be pursued to better establish efficacy and dosing regimens for the use of non-pharmacologic treatments in HS.

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3+ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3+ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3+ T cell dose cutoff of 14 × 107 cells/kg identified MSD/low CD3+ (n = 223) and MSD/high CD3+ (n = 1214), and a dose of 15 × 107 cells/kg identified MUD/low CD3+ (n = 197) and MUD/high CD3+ (n = 1102). On univariate analysis, the MSD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3+ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3+ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3+ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3+ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4+ and CD8+ T cell doses were not possible given our small sample size.

Wound odor: current methods of treatment and need for objective measures.

Chronic wounds are an enormous burden to society, costing billions of dollars annually in the USA alone. Despite the extensive research into methods to heal chronic wounds, many remain unhealed for months to years. There is a need to focus on patient reported outcomes to improve quality of life in patients with non-healing wounds. Wound odor has a significant impact on patient quality of life; however, relatively little information is available on the management of wound odor. We review the current data available on wound odor and discuss the need for standardized objective measures of odor to improve research quality. An independent search of the PubMed and Embase databases was conducted using combinations of the following words or phrases: "wounds," "chronic wounds," "diabetic ulcers," "venous leg ulcers (VLUs)," "malignant ulcers," "odor," "odour," "smell," "malodor," "artificial olfaction," "electronic nose," and "e-nose." Article references were also searched for significance. There are few overall studies on wound odor, and fewer randomized controlled trials. Current trials on odor have consistent weaknesses such as subjective measures and poor methodology. No single odor treatment modality has been demonstrated to be widely effective for wound odor or superior to other methods. Future research should incorporate objective measures of odor such as electronic noses into clinical trials.

SIRT1, miR-132 and miR-212 link human longevity to Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common cause of dementia in the elderly. Centenarians - reaching the age of >100 years while maintaining good cognitive skills - seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56-82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.

The Role of Polyphenols in Rosacea Treatment: A Systematic Review.

OBJECTIVES: Various treatment options are available for the management of rosacea symptoms such as facial erythema, telangiectasia, papules and pustules, burning, stinging, and itching. Botanical therapies are commonly used to treat the symptoms. The objective of this review is to evaluate the use of polyphenols in rosacea treatment. DESIGN: PubMed, Embase, Biosis, Web of Knowledge, and Scopus databases were systematically searched for clinical studies evaluating polyphenols in the management of rosacea. RESULTS: Of 814 citations, 6 met the inclusion criteria. The studies evaluated licochalcone (n = 2), silymarin (n = 2), Crysanthellum indicum extract (n = 1), and quassia extract (n = 1). The studies only evaluated topical formations of stated polyphenols. Main results were summarized. CONCLUSIONS: There is evidence that polyphenols may be beneficial for the treatment of rosacea symptoms. Polyphenols appear to be most effective at reducing facial erythema and papule and pustule counts. However, studies included have significant methodological limitations and therefore large-scale, randomized, placebo-controlled trials are warranted to further assess the efficacy and safety of polyphenols in the treatment of rosacea.

RGS2 expression predicts amyloid-ß sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining.

Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-ß (Aß) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aß in AD pathology have been raised as Aß is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aß neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aß plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aß. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aß sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aß sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.

Benchmark of Schemes for Multiscale Molecular Dynamics Simulations.

In multiscale molecular dynamics simulations the accuracy of detailed models is combined with the efficiency of a reduced representation. For several applications - namely those of sampling enhancement - it is desirable to combine fine-grained (FG) and coarse-grained (CG) approaches into a single hybrid approach with an adjustable mixing parameter. We present a benchmark of three algorithms that use a mixing of the two representation layers using a Lagrangian formalism. The three algorithms use three different approaches for keeping the particles at the FG level of representation together: 1) addition of forces, 2) mass scaling, and 3) temperature scaling. The benchmark is applied to liquid hexadecane and includes an evaluation of the average configurational entropy of the FG and CG subsystems. The temperature-scaling scheme achieved a 3-fold sampling speedup with little deviation of FG properties. The addition-of-forces scheme kept FG properties the best but provided little sampling speedup. The mass-scaling scheme yielded a 5-fold speedup but deviated the most from FG properties.

Phytochemical and Botanical Therapies for Rosacea: A Systematic Review.

Botanical and cosmeceutical therapies are commonly used to treat symptoms of rosacea such as facial erythema, papules/pustule counts, and telangiectasia. These products may contain plant extracts, phytochemicals, and herbal formulations. The objective of this study was to review clinical studies evaluating the use of botanical agents for the treatment of rosacea. MEDLINE and Embase databases were searched for clinical studies evaluating botanical therapies for rosacea. Major results were summarized, and study methodology was analyzed. Several botanical therapies may be promising for rosacea symptoms, but few studies are methodologically rigorous. Several plant extract and phytochemicals effectively improved facial erythema and papule/pustule counts caused by rosacea. Many studies are not methodologically rigorous. Further research is critical, as many botanicals have been evaluated in only one study. Botanical agents may reduce facial erythema and effectively improve papule/pustule counts associated with rosacea. Although promising, further research in the area is imperative.

Botanical and phytochemical therapy of acne: a systematic review.

Acne is prevalent among adolescents and adults with significant psychological effects. Standard oral and topical therapies can have significant side effects including skin irritation, gastrointestinal upset, and the development of drug-resistant bacteria. The use of botanicals and phytochemicals in dermatological products is increasingly popular, and many patients are turning to these alternative therapies for treatment of acne. This study aimed to systematically review clinical studies that have investigated the use of botanical agents in the treatment of acne. PubMed and Embase databases were searched in March 2013 for trials assessing botanical therapies in the treatment of acne vulgaris. Data from these trials are presented, and methodology of each study is assessed. Twenty-three trials met inclusion criteria. Interventions included plant extracts, herbal formulations, and phytochemicals. All studies reported favorable results, and several showed equal or superior treatment to standard therapies. No serious adverse events were reported. Few studies were methodologically rigorous. Each botanical was studied in only one or two trials. Botanicals are promising therapies for acne vulgaris although further research is warranted, especially with regard to severe acne and acne resistant to conventional therapy. There is a need for standardized methods for grading acne and assessing therapeutic effects.

Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes.

Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrenergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression levels of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine-N-methyltransferase were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, tyrosine hydroxylase, and phenylethanolamine-N-methyltransferase expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR-binding affinity remained depressed even after its expression returned to prewounding levels. Keratinocyte-derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR-selective antagonist ICI-118,551 but not with B1AR-selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound-edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine-related effects in the wound are warranted.

The use of botanically derived agents for hyperpigmentation: a systematic review.

BACKGROUND: Hyperpigmentation disorders are common among those seeking care from dermatologists and primary care physicians. The cosmeceutical and natural product industries are rapidly growing and many botanical agents are purported to improve hyperpigmentation disorders. OBJECTIVE: We sought to review clinical evidence for the use of botanical agents in the treatment of hyperpigmentation. METHODS: We searched MEDLINE and Embase databases and a total of 26 articles met inclusion criteria. Study methodology was analyzed and the reproducibility of the studies was graded. RESULTS: Several botanical agents appear promising as treatment options but few studies were methodologically rigorous. Several plant extract and phytochemicals effectively lighten signs of epidermal melasma and hyperpigmentation induced by ultraviolet radiation exposure. Results were mixed for treatment of solar lentigines or dermal hyperpigmentation. LIMITATIONS: There were few rigorously designed studies; future research will be critical to further ascertain the discussed results. CONCLUSIONS: The subtype of hyperpigmentation is important for treatment prognosis, with dermal hyperpigmentation less responsive to treatment. Botanical extracts may play an integrative role in the treatment of hyperpigmentation and further studies that integrate them with standard therapies are needed. Side effects, including worsened hyperpigmentation, need to be discussed when considering these therapies.

Density embedded VB/MM: a hybrid ab initio VB/MM with electrostatic embedding.

A hybrid QM/MM method that combines ab initio valence-bond (VB) with molecular mechanics (MM) is presented. The method utilizes the ab initio VB approach to describe the reactive fragments and MM to describe the environment thus allows VB calculations of reactions in large biological systems. The method, termed density embedded VB/MM (DE-VB/MM), is an extension of the recently developed VB/MM method. It involves calculation of the electrostatic interaction between the reactive fragments and their environment using the electrostatic embedding scheme. Namely, the electrostatic interactions are represented as one-electron integrals in the ab initio VB Hamiltonian, hence taking into account the wave function polarization of the reactive fragments due to the environment. Moreover, the assumptions that were utilized in an earlier version of the method, VB/MM, to formulate the electrostatic interactions effect on the off-diagonal matrix elements are no longer required in the DE-VB/MM methodology. Using DE-VB/MM, one can calculate, in addition to the adiabatic ground state reaction profile, the energy of the diabatic VB configurations as well as the VB state correlation diagram for the reaction. The abilities of the method are exemplified on the identity SN2 reaction of a chloride anion with methyl chloride in aqueous solution. Both the VB configurations diagram and the state correlation diagram are presented. The results are shown to be in very good agreement with both experimental and other computational data, suggesting that DE-VB/MM is a proper method for application to different reactivity problems in biological systems.

Hybrid ab initio VB/MM method--a valence bond ride through classical landscapes.

The development of a new hybrid (QM/MM) method, where the QM part is treated by ab initio valence bond (VB) theory is presented. This VB/MM method has the advantages of empirical VB (EVB) methodology but does not rely on empirical parameterization for the quantum part. The method implements embedding of the quantum region of each diabatic state separately, by treating the electrostatic interactions between QM and MM regions classically. Additionally, it assumes that changes of the off diagonal matrix element due to different environments are such that the overall resonance integral does not change. These assumptions are discussed in detail and the validity of the method is shown to be successful in three different bond dissociation processes, where bond dissociation as well as solvation energies compare very well with the experimental data.