Total Solid-Phase Synthesis of Dehydroxy Fengycin Derivatives.

A rapid and efficient solid-phase strategy for the synthesis of dehydroxy fengycins derivatives is described. This synthetic approach involved the linkage of a Tyr to a Wang resin via a Mitsunobu reaction and the elongation of the peptide sequence followed by subsequent acylation of the N-terminus of the resulting linear peptidyl resin, esterification of the phenol group of a Tyr with an Ile, and final macrolactamization. The amino acid composition as well as the presence of the N-terminal acyl group significantly influenced the stability of the macrolactone. Cyclic lipodepsipeptides with a l-Tyr3/d-Tyr9 configuration were more stable than those containing the Tyr residues with an opposite configuration. This work constitutes the first approach on the total solid-phase synthesis of dehydroxy fengycin derivatives.

Prospective, Randomized Blind Effect-on-Outcome Study of Conventional vs High-Frequency Spinal Cord Stimulation in Patients with Pain and Disability Due to Failed Back Surgery Syndrome.

OBJECTIVES: Spinal cord stimulation (SCS) for patients with failed back surgery syndrome (FBSS) show variable results and limited to moderate evidence. In the last years the stimulation of high frequency (HF) has been considered as a better alternative in this pathology for its supposed benefits compared to the stimulation with conventional frequency (CF). To compare in one year follow-up, the efficacy of high-frequency SCS (HF) versus conventional frequency SCS (CF) on the patients with FBSS. DESIGN: Prospective, Randomized blind trial. SETTING: Academic University Pain Medicine Center. SUBJECT: Seventy eight patients with FBSS diagnosis based on internationally recognized criteria, and refractory to conservative therapy for at least 6 months, have been initially recruited, and. METHODS: Sixty subjects met the eligibility criteria and were randomized and scheduled for the trial phase.The patients were randomly assigned in either, one of the two groups: CF SCS or HF SCS. Within the study methods, special attention was paid to standardizing patient programming, so that these parameters would not impact the results.The trial period was considered successful if there was ?50% reduction in the NRS from baseline. RESULTS: A total of 55 subjects successfully completed all assessments during one year follow-up. Change patterns in scores do not differ based on high versus conventional frequency, with significant global average reduction at 1 year similarly for both groups. Among all the items included in the Short Form-12 questionnaire (SF-12), only the variations in the social function score between the instants t1 and t2 are somewhat higher in the high frequency group. CONCLUSION: The evolutionary pattern of the different parameters studied in our patients with FBSS does not differ according to their treatment by spinal stimulation, with conventional or high frequency, in one year follow-up.

Vulvodynia--An Evidence-Based Literature Review and Proposed Treatment Algorithm.

OBJECTIVE: We searched the medical literature from the last 15 years (1998 to 2013) relating to the etiology, diagnosis, and treatment of vulvodynia. The evidence was reviewed supporting the therapeutic proposals currently in use and propose the incorporation of novel, minimally invasive, interventional therapies, within the context of a multidisciplinary approach. METHODS: This was a systematic review of all relevant studies with no language restrictions. Studies were identified through Medline/PubMed (1998 to March 2013), the Cochrane Library (2001 to 2013), and conference records and book chapters. The keywords used included "chronic pelvic pain," "vulvodynia," "vestibulodynia," and search terms "etiology," "diagnosis," and "treatment" were added. The levels of evidence were assessed using grading system for "Therapy/Prevention/Etiology/Harm" developed by the Centre for Evidence-Based Medicine (CEBM). The grading system assists in clinical decision-making, and we decided to use "The Grading of Recommendations Assessment, Development, and Evaluation (GRADE)." RESULTS: A total of 391 papers were assessed. Of these, 215 were analyzed and 175 were excluded, as they pertained to areas not directly related to the disease under review. CONCLUSION: The optimal therapy for vulvar pain syndrome remains elusive, with low percentages of therapeutic success, using either local or systemic pharmacological approaches. Surgery involving invasive and often irreversible therapeutic procedures has resulted in success for certain subtypes of vulvodynia. We present a multidisciplinary approach whereby pain treatment units may provide an intermediate level of care between standard medical and surgical treatments.

High-Protein Processed Foods: Impact on Diet, Nutritional Status, and Possible Effects on Health.

Proteins are macronutrients with multiple health benefits, but excessive consumption can negatively affect health. This study aimed to evaluate the characteristics of a sample of high-protein processed foods (HPPFs), describe how their consumption affects dietary balance, and acquire knowledge of the consumption patterns of these products in a Spanish population. A sample of HPPFs available in supermarkets and on websites was collected. The contribution to recommended protein intakes was calculated using national and international references and considering the single consumption of the HPPFs and the product plus 150 g of meat. Furthermore, an online survey was conducted among a convenience sample. A total of 36 enriched protein products were evaluated. The percentage of proteins in these products ranges from 10 to 88%. The contribution of the protein recommended intake was within a range of 87.4-306.6% and 66.4-232.8% (women and men, respectively), only considering the additional proteins from 150 g of meat. One hundred thirty-nine participants completed the survey; 67.6% affirmed that they had consumed HPPFs, and half consumed them without following any consumption control. Since these products are accessible to everyone in supermarkets and protein intake is generally higher than the recommended limits, regulating the mass sale of HPPFs is essential to ensure they do not lead to protein overconsumption.

A callosal biomarker of behavioral intervention outcomes for autism spectrum disorder? A case-control feasibility study with diffusion tensor imaging.

Tentative results from feasibility analyses are critical for planning future randomized control trials (RCTs) in the emerging field of neural biomarkers of behavioral interventions. The current feasibility study used MRI-derived diffusion imaging data to investigate whether it would be possible to identify neural biomarkers of a behavioral intervention among people diagnosed with autism spectrum disorder (ASD). The corpus callosum has been linked to cognitive processing and callosal abnormalities have been previously found in people diagnosed with ASD. We used a case-control design to evaluate the association between the type of intervention people diagnosed with ASD had previously received and their current white matter integrity in the corpus callosum. Twenty-six children and adolescents with ASD, with and without a history of parent-managed behavioral intervention, underwent an MRI scan with a diffusion data acquisition sequence. We conducted tract-based spatial statistics and a region of interest analysis. The fractional anisotropy values (believed to indicate white matter integrity) in the posterior corpus callosum was significantly different across cases (exposed to parent-managed behavioral intervention) and controls (not exposed to parent-managed behavioral intervention). The effect was modulated by the intensity of the behavioral intervention according to a dose-response relationship. The current feasibility case-control study provides the basis for estimating the statistical power required for future RCTs in this field. In addition, the study demonstrated the effectiveness of purposely-developed motion control protocols and helped to identify regions of interest candidates. Potential clinical applications of diffusion tensor imaging in the evaluation of treatment outcomes in ASD are discussed.

How Can We Increase Neighbors' Intention to Report Intimate Partner Violence Against Women During the Pandemic?

During the pandemic, neighbors can be potential allies to prevent intimate partner violence against women (IPVAW). Based on the reasoned action approach, we identified the predictors and the most relevant beliefs behind neighbors' intention to report to authorities that a woman is being victimized by IPVAW. A total of 352 Spanish participants completed a questionnaire. The regression analysis showed that perceived control and subjective norm were the best predictors of the intention (33% explained variance). Social media campaigns should target perceived inhibitors such as citizens' guilt for reporting ambiguous cases and close referents (friends and family) as prescribers of the helping behavior.

The commensal bacterium Lactiplantibacillus plantarum imprints innate memory-like responses in mononuclear phagocytes.

Gut microbiota is a constant source of antigens and stimuli to which the resident immune system has developed tolerance. However, the mechanisms by which mononuclear phagocytes, specifically monocytes/macrophages, cope with these usually pro-inflammatory signals are poorly understood. Here, we show that innate immune memory promotes anti-inflammatory homeostasis, using as model strains of the commensal bacterium Lactiplantibacillus plantarum. Priming of monocytes/macrophages with bacteria, especially in its live form, enhances bacterial intracellular survival and decreases the release of pro-inflammatory signals to the environment, with lower production of TNF and higher levels of IL-10. Analysis of the transcriptomic landscape of these cells shows downregulation of pathways associated with the production of reactive oxygen species (ROS) and the release of cytokines, chemokines and antimicrobial peptides. Indeed, the induction of ROS prevents memory-induced bacterial survival. In addition, there is a dysregulation in gene expression of several metabolic pathways leading to decreased glycolytic and respiratory rates in memory cells. These data support commensal microbe-specific metabolic changes in innate immune memory cells that might contribute to homeostasis in the gut.

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques.

The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits ("endophenotypes"), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.

Medical Device Related Pressure Injury in the Treatment of Chronic Pain: An Early Sign of Explantation in Suspected Infection.

BACKGROUND: Chronic back pain is a prevalent disease and has a high impact in daily life. Implantable devices (IDs) for chronic pain management include spinal cord stimulation (SCS) systems and intrathecal drug delivery (ITDD) pumps. The number of ITDD implants have increased exponentially in the last decade. The number of complications, such as infections, are also more prevalent. Infection management guidelines are needed to standarize our clinical practice and define protocols of explantation. OBJECTIVES: The primary outcome is to define the likelihood of device explantation regarding some covariates related to the patient, antibiotic therapy or surgerical procedures. The secondary outcome is to evaluate performance compared to the results published in the literature. STUDY DESIGN: Retrospective study. SETTING: Hospital General of Valencia. Valencia. Spain. METHODS: A retrospective study of 288 implantable device surgeries was conducted at the Hospital General Universitary of Valencia (Spain) from 1994 to 2015. Demographical and infection data were collected. We have followed the "guidelines for the diagnosis, prevention and management of implantable electronic cardiac device infection" due to the lack of a specific guideline in our field. RESULTS: Forty-three out of 288 procedures were identified as suspected device-infected interventions. Half of the patients had microbiologically confirmed infection after wound, blood or lumbar fluid culture. The odds ratio (OR) for explantation of the device was 19 for the presence of decubitus, a sign of medical device related pressure injury (P < 0.0005) and 5 for positive wound culture (P < 0.0452). Medical indication leading to device implantation and the antibiotics on discharge also played a role in the decision of device explantation. LIMITATIONS: Lack of external validity and others. CONCLUSION: In this study, presence of decubitus is the defining variable for device explantation when a infection is suspected rather than waiting to culture results. Due to a high variability in infection rates, multidisciplinary guidelines are needed to provide an approach that focuses on accurate data monitoring, rigurous implantation technique and standardized protocols. KEY WORDS: Chronic pain, spinal cord stimulation infection, neurostimulator, intrathecal drug delivery pump, complication, infection, explantation.

Management of acute pain in patients on treatment with opioids.

The use of opioids for both benign and cancer-related chronic pain has increased exponentially over the last few years. For this reason, increasing numbers of such patients are presenting for surgery. It is known that continuous use of opioids is associated with an increase in postoperative analgesic requirements. This is believed to be mediated by the development of tolerance and opioid-induced hyperalgesia. Patients treated with opioids have special needs in the perioperative setting and it is the anesthesiologist's responsibility to manage these needs optimally. The aim of the present paper is to briefly orient the reader in the management of postoperative pain in patients chronically treated with licit opioids.

Patient-specific simulation of implant placement and function for cochlear implantation surgery planning.

We present a framework for patient specific electrical stimulation of the cochlea, that allows to perform in-silico analysis of implant placement and function before surgery. A Statistical Shape Model (SSM) is created from high-resolution human µCT data to capture important anatomical details. A Finite Element Model (FEM) is built and adapted to the patient using the results of the SSM. Electrical simulations based on Maxwell's equations for the electromagnetic field are performed on this personalized model. The model includes implanted electrodes and nerve fibers. We present the results for the bipolar stimulation protocol and predict the voltage spread and the locations of nerve excitation.

Peripheral subcutaneous vulvar stimulation in the management of severe and refractory vulvodynia.

BACKGROUND: Vulvodynia is a complex and multifactorial clinical condition with severe pain that occurs in the absence of visible infectious, inflammatory, neoplastic, or neurological findings. CASE: A 35-year-old woman with 3 years of dysesthetic vulvodynia tried conventional and interventional medical treatment with inadequate relief. She was offered peripheral subcutaneous vulvar field stimulation and underwent implantation of two vulvar subcutaneous electrodes. At 15 days after treatment and during 1-year follow-up, the patient scored 1 out of 15 on Friedrich scale, 1 out of 10 on the visual analog scale, and 1 out of 10 on the tampon test. The patient no longer requires oral medication. CONCLUSION: Stimulation with subcutaneous electrodes provided relief from vulvodynia to a patient in whom all previous therapeutic approaches had failed.

SO(2) protects the amino nitrogen metabolism of Saccharomyces cerevisiae under thermal stress.

Thermal stress conditions during alcoholic fermentation modify yeasts' plasma membrane since they become more hyperfluid, which results in a loss of bilayer integrity. In this study, the influence of elevated temperatures on nitrogen metabolism of a Saccharomyces cerevisiae strain was studied, as well as the effect of different concentrations of SO(2) on nitrogen metabolism under thermal stress conditions. The results obtained revealed that amino nitrogen consumption was lower in the fermentation sample subjected to thermal stress than in the control, and differences in amino acid consumption preferences were also detected, especially at the beginning of the fermentation. Under thermal stress conditions, among the three doses of SO(2) studied (0, 35, 70 mg l(-1) SO(2) ), the highest dose was observed to favour amino acid utilization during the fermentative process, whereas sugar consumption presented higher rates at medium doses.