Psychiatric disorders share the same pattern of longitudinal evolution and have courses that tend to be chronic and recurrent. These aspects of chronicity and longitudinal evolution of psychiatric disorders are currently studied under the neuroprogression framework. Interestingly, considering the plasticity of the brain, it is necessary to emphasize the bidirectional nature of neuroprogression. We review evidence highlighting alterations of the brain associated with the longitudinal evolution of psychiatric disorders from the framework of neuroplastic adaptation to pathology. This new framework highlights that substantial plasticity and remodelling may occur beyond the classic neuroprogressive framework, which is characterized only by loss of grey matter volume, decreased brain connectivity, and chronic inflammation. We also integrate the brain economy concept in the neuroplastic adaptation to pathology framework, emphasizing that to preserve its economy, i.e., function, the brain learns how to cope with the disease by adapting its architecture. This approach can disentangle both the specific pathophysiology of psychiatric symptoms and the adaptation to pathology, thus offering a new framework for both diagnosis and treatment.

Endocannbinoids system (ECS) engrossed a considerable interest as potential therapeutic targets in various carcinomas and cancer related conditions alongside with neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations, so in this short review we tried to shed the light over the potential drug interactions of medicinal cannabis. Hitherto, few data have been provided to the healthcare practitioners about the drug-drug interactions of cannabinoids with other prescription medications. In general, cannabinoids are usually well tolerated, but the bidirectional effects may be expected with concomitant administered agents via affected membrane transporters (glycoprotein p, breast cancer resistance proteins) and metabolizing enzymes (Cytochrome P450 and UDP- glucuronosyltransferases). The caveats should be undertaken to closely monitor the responses of cannabis users with certain drugs to guard their safety, especially for the elderly and people with chronic diseases or kidney and liver conditions.

Background and objectives: Primary brain tumors include any tumors arising in the brain whose prognosis is poor due to their histologic characteristics. The aim of this research was to evaluate the frequency of HER2 tumor marker in primary malignant brain tumors. Materials and Methods: This descriptive study was conducted on the samples admitted to the pathology laboratory with diagnosis of primary brain tumor during 2008–2015. Results: From among 107 patients (61.7% males and the rest females) with mean age of 40.4 years, the highest frequency of tumor location was in supratentorial region of the brain (including lobes and ventricles) (63.85% cases). High-grade astrocytoma had the highest prevalence at diagnosis (43.9%), followed by low-grade astrocytoma (37.4%). As for HER2 score, 42.1% of patients were HER2-positive (scores 2 & 3). On the other hand, 5.6% of patients were HER2-negative (-), 40.2% were positive (+), and 54.2% were positive (++). The patients with high-grade astrocytoma had older age (P < 0.001), higher HER2 positivity (P = 0.024) and percentage (P < 0.001) compared to the patients with low-grade astrocytoma. Conclusions: HER2 expression is dependent on the type of brain tumors. High expression of HER2 in high-grade astrocytoma may be useful for therapeutic purposes. The future research is needed to confirm these results with a large number of patients in different areas.

Purpose: To create a highly balanced comparison of ab interno trabeculectomy (Trabectome, AIT) and trabecular bypass stenting (iStent, TBS).Setting: Eye and Ear Institute, Pittsburgh, Ross Eye Institute, Buffalo, and Glaucoma Associates of Texas, Dallas, USA.Design: Retrospective Exact Matching analysis.Methods: AIT and TBS patients were included from three large glaucoma practices. The primary outcome measure was the unmedicated IOP ≤ 21 mmHg at 2-year follow-up visit. A secondary measure was unmedicated IOP reduction ≥ 20% at 2 years. Patients were matched by baseline IOP, the number of glaucoma medications and glaucoma type using Exact Matching and by age using Nearest Neighbor matching. Patients without a close match were excluded. All surgeries were combined with phacoemulsification. Results: 154 AIT and 110 TBS eyes were analyzed. 48 AIT patients were exactly matched to 48 TBS patients. Both groups had a baseline IOP of 15.3±3.1 mmHg. At 24 months, the mean IOP was 13.9±3.3 for AIT versus 16.8±2.8 mmHg for TBS (p=0.04), while the number of medications was 0.7±1.0 for AIT versus 1.7±1.2 for TBS (p=0.04). The proportion of subjects achieving IOP ≤ 21 mmHg without medications at 24 months was 53% in AIT versus 16.6% in TBS (P < 0.05). At 24-month follow up 17.6% of patients in AIT had ≥ 20% IOP reduction without medication versus no patient in TBS. Conclusions: An Exact Matching comparison of AIT and TBS demonstrated greater IOP reduction with fewer medications in AIT.

Obesity is a condition associated with the accumulation of excess fat in the body, energy imbalance, lipogenesis etc. which increases adipose tissue mass through adipogenesis and probes a health risk. Its prevalence has become a large burden on the world at large. One of the solutions to tackling obesity is with the use of bioactive compounds. We critically examined the effectiveness of hibiscus sabdariffa (HS) on various parameters associated with development of obesity such as; effect of HSE on body weight and energy expenditure, effect of HSE on fat accumulation, effect of HSE on lipase inhibition, effect of HSE on adipocyte differentiation/adipogenesis. This review has gathered reports on the various anti-obesity effects of HS bioactives in cell and animal models, as well as in humans. Reports have shown that hibiscus sabdariffa derived bioactives are potent in the treatment of obesity with evident reduction in body weight, inhibition of lipid accumulation and suppression of adipogenesis through PPARγ pathway and other transcriptional factors.

Bufadienolides-like chemicals, which mostly composed the active ingredient of Chansu, had been widely discovered to possess anti-inflammatory, tumor-suppressing and antipain activity, but the mechanisms of action were not clearly illuminated. In this research, in order to explore the potential mechanism of bufadienolides-like chemicals on breast cancer, a serious of bioinformatics analysis, included (1) differentially expressed genes identification combined with gene set variation analysis, (2) tissue specific co-expression network construction, (3) differentially regulated sub-networks detection with disease phenome, (4) hub gene selection and it’s relation to survival probability, and (5) similar small molecule detection were performed with gene expression profiles of bufadienolides-like chemicals. Results indicated bufadienolides-like chemicals had the most same target with valproic, estradiol and etc, could disturbed the pathways in RNA splicing, apoptotic process, cell migration, extracellular matrix organization, adherens junction organization, synaptic transmission, Wnt signaling, AK-STAT signaling, BMP signaling pathway and unfolded protein response, and had the potential ability to be used as anticancer, hormones and vasoprotectives agents.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

Three-dimensional (3D) cell culture is considered more clinically relevant in mimicking the structural and physiological conditions of tumors in vivo compared to two-dimensional cell cultures. In recent years, high-throughput screening (HTS) in 3D cell arrays has been extensively used for drug discovery because of its usability and applicability. Herein, we developed a microfluidic spheroid culture device (μFSCD) with a concentration gradient generator (CGG) that enabled cells to form spheroids and grow in the presence of cancer drug gradients. The device is composed of concave microwells with several serpentine micro-channels which generate a concentration gradient. Once the colon cancer cells (HCT116) formed a single spheroid (approximately 120 μm in diameter) in each microwell, spheroids were perfused in the presence of the cancer drug gradient irinotecan for 3 days. The number of spheroids, roundness, and cell viability, were inversely proportional to the drug concentration. These results suggest that the μFSCD with a CGG has the potential to become an HTS platform for screening the efficacy of cancer drugs.

Purpose: To investigate the extent of anterior chamber angle circumference needed to maintain a physiological outflow facility (C). Methods: Twenty anterior segments of porcine eyes were assigned to 5 groups, each with a different degree of cyanoacrylate-mediated angle closure: 90° (n = 4), 180° (n = 4), 270° (n = 4), 360° (n = 4) and four unoccluded control eyes. The outflow facility was measured at baseline, 3, 12, 24, and 36 hours after angle closure. Outflow patterns were evaluated with canalograms and the histomorphology was compared. Results: Baseline outflow facilities of the five groups were similar (F = 0.922, P = 0.477). Complete, circumferential occlusion over 360° induced a significant decrease in facility from baseline at all time-points (P ≤ 0.023 at 3, 12, 24 and 36 hours). However, no difference from baseline was found in any of the partially-occluded (0–270°) groups (F ≥ 0.067, P ≥ 0.296 at 3, 12, 24 and 36 hours). The canalograms confirmed the extent of occlusion with flow through the unblocked regions. Histology revealed no adverse effects of blockage on the TM or aqueous plexus in the unoccluded angle portions. The unoccluded TM appeared normal. Conclusion: Cyanoacrylate-mediated angle occlusion created a reproducible angle closure model. 90° of unoccluded anterior chamber angle circumference was sufficient to maintain physiological outflow. This model may help understand how outflow can be regulated in healthy, nonglaucomatous TM.

Abstract Introduction: Antimicrobial resistance (AMR) is a recognised public health threat today globally. Though many active and passive stewardship strategies are employed to counter AMR clinically, educating school going children on AMR could be a futuristic cost-effective measure to minimize AMR development. We hypothesised NICE’s e-bug module to class VII school students on AMR determinants. Methodology: A prospective non-randomized intervention study on 327 students belonging to 9 schools of class VII around Manipal town, Udupi district, Karnataka state, India were included for the study. 10 questions on AMR determinants extracted from NICE’s e-bug program were quizzed in written as pre-test followed by an education intervention on the same questions followed by a post-test to end the session. Descriptive statistics to estimate epidemiological characteristics, Wilcoxon Signed Ranks and Kruskal-Wallis tests were applied to analyse statistical significance of pre/post-test performance scores for the 10 questions and between schools respectively Results: Students had inadequate knowledge on 7 AMR determinants (antimicrobial indication, its course, hand hygiene, fermentation, spread of infection, microbial multiplication and characteristics of microbe) when analysed for post-test performance (p<0.05). Comparison of post-test performance of 9 participating schools revealed statistical significance (p<0.05) for 3 questions (definition on antimicrobial, cover while cough/sneezing and microbial characteristics) Conclusion: Although students exhibited sub-optimal knowledge on few AMR determinants, they showed keenness to learn exhibited by their performance. Our findings and previous similar studies from Europe are suggestive of early pedagogic interventions on AMR through inclusion of such education modules in the curriculum could be potential tool for AMR prevention for future generations.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T-cells for targeted cancer therapy. CAR T-cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T-cell therapies were approved by the U. S Food and Drug Administration; one for the treatment of pediatric Acute Lymphoblastic Leukemia (ALL), the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T-cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B-cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin’s lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T-cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This Commentary summarizes the current state of knowledge on CAR T-cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.

Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders, including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumor-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC.

The NOD2 gene, involved in innate immune responses to bacterial peptidoglycan, has been found to be strongly associated with Crohn’s Disease, with an Odd Ratio ranging from 3 to 36. Families with 3 or more CD affected patients were related to high frequency of NOD2 gene variations as R702W, G908R, 1007fs and were reported in EPIMAD Registry. However, some rare CD multiplex families were described without identification of common NOD2 linked-to-disease variations. In order to identify new genetic variation(s) with a major effect on Crohn’s disease (CD), whole exome sequencing was performed in available subjects comprising 4 patients on 2 generations affected with Crohn’s disease without R702W and G908R variation, and 3 unaffected related subjects. A new rare and not yet reported missense variation of the NOD2 gene, the N1010K, was detected and co-segregated across affected patients. In silico evaluation and modeling highlighted evidences for a deleterious effect of the N1010K variation regarding CD. Moreover cumulative characterization of N1010K and 1007fs as compound heterozygous state in two more severely CD family members strongly suggesting that the N1010K should be a new risk factor involved in Crohn’s disease genetic susceptibility.

Through the use of a simplified model of consciousness this paper illustrates the symptoms of schizophrenia linked to neocortical structures and functions. It makes the case that the bewildering and varied presentation of symptoms in schizophrenia can be analyzed and explained using such models. The model is used to illustrate the central thesis of the paper, that schizophrenia is a disorder of neurogenesis which leads to progressive neurochemical, functional and neurophysiological changes that create the characteristic behaviors of the disease.

Background: The maximal one-repetition test (1-RM) is widely used in scientific research; however, there are conflict results regarding its reproducibility in elderly population. The present study aimed to analyze the reproducibility the test both before and after a 12 week training period by using the bench press and leg press 45° 1-RM tests in the elderly taking into consideration the training experience and strength level of the women. Methods: Elderly women (n = 376; age, 68.5 ± 14.1 years; height, 162.7 ± 5.5 cm; body mass, 71.2 ± 16.0 kg) who underwent ≥3 months of resistance training performed an initial week of familiarization and a second week of testing and retest, with a 48–72 hour interval. Results: The results showed maximal and relative load strength of 39.3 kg and 0.59 kg/body mass for lower limbs and 20.9 kg and 0.31 kg/body mass for upper limbs. The Kappa indices were 0.93 and 0.95, and the intraclass correlation coefficients were 0.99 and 0.99 for the lower and upper limbs, respectively. Conclusion: Therefore, the present study confirms that the 1-RM test has high reliability and reproducibility in the elderly, for both upper and lower limbs.

Background: Kidney transplantation is considered the first-choice therapy in ESRD patients. Despite recent improvements in terms of outcomes and graft survival in recipients, postoperative complications still concern health-care providers involved in the management of those patients. Particularly challenging are cardiovascular complications. Perioperative goal-directed fluid-therapy (PGDT) and hemodynamic optimization are widely used in high-risk surgical patients, and are associated with a significant reduction in postoperative complication rates and length of stay (LOS). The aim of this work is to compare the effects of perioperative goal-directed therapy (PGDT) with conventional fluid therapy (CFT), and to determine whether there are any differences in major postoperative complications rates and delayed graft function (DGF) outcomes. Methods: Prospective study with historical controls. Two groups, a PGDT- and a CFT- group were used: the stroke volume (SV) optimization protocol was applied in PGDT group throughout the procedure. Conventional fluid therapy with fluids titration at a central venous pressure (CVP) 8-12 mmHg and mean arterial pressure (MAP) >80mmHg was applied to the control-group. Postoperative data collection including vital signs, weight, urinary output, serum creatinine, blood urea nitrogen, serum potassium, and assessement of volemic status and the signs and symptoms of major postoperative complications occurred at 24h, 72h, 7 days and 30 days after transplantation. Results: Among the 66 patients enrolled, 33 were in each group and both groups had similar physical characteristics. Good fuctional recovery was evident in the 94% of patients. The statistical analysis has showed a difference in postoperative complications as follows: significant reduction of cardiovascular complications, DGF episodes (p<0.05) and surgical complications (p<0.01). There were no significant differences in pulmonary or other complication. Conclusions: PGDT and SV optimization effectively influenced the rate of major postoperative complications, reducing the overall morbidity and thus the mortality in patients receiving kidney transplantation.

Background: Parents of preterm infants face major mental health challenges in the Neonatal Intensive Care Unit (NICU). Family-centered music therapy actively integrates and empowers parents in their infant’s care. With the aim to better understand and address parental needs separately from their babies’, a music therapy (MT) self-care group was implemented as part of clinical practice at the hospital Clínica de la Mujer in Bogotá, Colombia. Methods: The group is provided for both parents twice a week in the NICU. Music guided relaxations, breathing techniques, and self-expression are at the center of the MT group sessions. Parents complete a pre/post self-administered Numeric Rating Scale (NRS) including anxiety levels, stress levels, mood and motivation. Results: Parents highly value the MT self-care group at the NICU. On average there is a 37% improvement in anxiety levels, 28% in stress levels, and 12% in mood, restfulness and motivation. Being able to relax, to distract themselves from their worries and having time for themselves are amongst the most frequently mentioned benefits. Conclusions: Addressing parents’ needs separately form their babies’ treatment with culturally sensitive interventions aimed to improve parental mental health, is essential for continuing the development of family-centered music therapy interventions in the NICU.

The circulating transcriptome is a valuable source of cancer biomarkers, which with the exception of miRNAs, remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients of healthy individuals, we used next generation sequencing (NGS) and validation was carried out by qPCR and/or ddPCR. We identified 442 different microRNAs in samples, eleven of which were differentially expressed (P < 0.05). Levels of miR-134-5p and miR-320a-3p were significantly down-regulated (P<0.001) in melanoma samples (n = 96) compared to healthy controls (n = 28). Differentially expressed protein-encoding mRNA, 5´-fragments, were enriched for the angiopoietin, PAK and EIF2 pathways. Levels of ATM1, AMFR, SOS1 and CD109 gene fragments were up-regulated (P < 0.001) in melanoma samples (n=144) compared to healthy controls (n = 41) (AUC = 0.825). Over 40% of mapped reads were YRNAs, a class of non-coding RNAs that to date has been little explored. Expression levels of RNY3P1, RNY4P1 and RNY4P25 were significantly higher in patients with stage 0 disease, than either healthy controls or more advanced stage disease (P < 0.001). In conclusion, we have identified a number of novel RNA biomarkers, which most importantly we validated in multi-centre retrospective and prospective cohorts suggesting potential diagnostic use of these RNA species.

Single-level Principal Components Analysis (PCA) and multi-level PCA (mPCA) methods are applied here to a set of (2D frontal) facial images from a group of 80 Finnish subjects (34 male; 46 female) with two different facial expressions (smiling and neutral) per subject. Inspection of eigenvalues gives insight into the importance of different factors affecting shapes, including: biological sex, facial expression (neutral versus smiling), and all other variations. Biological sex and facial expression are shown to be reflected in those components at appropriate levels of the mPCA model. Dynamic 3D shape data for all phases of a smile made up a second dataset sampled from 60 adult British subjects (31 male; 29 female). Modes of variation reflected the act of smiling at the correct level of the mPCA model. Seven phases of the dynamic smiles are identified: rest pre-smile, onset 1 (acceleration), onset 2 (deceleration), apex, offset 1 (acceleration), offset 2 (deceleration), and rest post-smile. A clear cycle is observed in standardized scores at an appropriate level for mPCA and in single-level PCA. mPCA can be used to study static shapes and images, as well as dynamic changes in shape. It gave us much insight into the question “what’s in a smile?”

We have developed a cast microfluidic chip for concentration gradient generation that contains a thin (~5 μm^2 crosssectional area) microchannel. Durable 2 μm-high microchannel mold features with a smooth bell-shaped sidewall were fabricated by exposing SU-8 photoresist to diffused 185 nm UV light emitted by a low-cost ozone lamp from the backside of the substrate to ensure sufficient crosslinking of small regions of the SU-8 photoresist. An H-shaped microfluidic configuration was used, in which the thin channel was able to maintain constant diffusion fronts beyond purely static diffusion confirmed with experiment. We also demonstrated the long-term effects of a gradient of nerve growth factor on axon elongation by primary neuronal cells cultured in the microfluidic channel.

We present a case of Capnocytophaga canimorsus septic shock after a dog bite in an immunocompetent individual, where real-time nanopore metagenomic sequencing characterized the microbial agent within 19 hours, with subsequent confirmation using droplet digital PCR. Oral swabs from the dog demonstrated a nearly-identical C. canimorsus isolate by sequencing.

The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type–specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR`s actions but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter`s activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted.

The tripeptide-glutathione (GSH, γ-L-glutamyl-L-cysteinyl-glycine) is one of the most important low molecular antioxidant in human body. Enhancing GSH and associated enzymes represents an aim in the search for cytoprotective strategies against cancer, neurologic degeneration, pulmonary and inflammatory conditions, as well as rheumatoid arthritis (RA).The objective of the study was to agree whether crenotherapy (drinking therapy) with sulfide/hydrogen sulfide (SHS) waters from “Zuzanna” spring located in the area of Busko-Zdrój in Poland leads to increasing of reduced glutathione (GSH) content in human blood. SHS water in distinct from mineral water is characterised by specific pharmacokinetic, invariable content and natural microbiological purity. SHS waters contain at least 1 g of total sulfur per kilogram of water and a treatment effect also depends on other bioelements. The method employing capillary electrophoresis with UV detector for the analysis of glutathione in human blood was developed. The group of 106 volunteers consisted of both women and men, in different age range. The therapy with SHS waters lasted 2 weeks. We recently demonstrated that the administration of hydrogen sulfide (H2S) in SHS waters increases GSH concentration in blood, and therefore crenotherapy could be used in therapeutics.

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p<0.001 and HR 0.77, p<0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p<0.012), with the exception of melanoma (in women, HR 0.80, p=0.006). PFS was longer in men than in women (HR 0.67, p<0.001 and HR 0.77, p=0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

BACKGROUND: Endoscopic placement of Self Expandable Metal Stents to relieve malignant colorectal obstruction has become a common therapeutic advancement in clinical practice. MATERIAL: In a 16 year period 167 patients had endoscopic placement of a Self Expandable Metal Stent in a center where gastroenterologists and surgeons cooperate in a daily basis, discussing indications. RESULTS: There was no operative mortality and no major complication in placement of the stent. Technical and clinical success was respectively 95.1% and 92.9%. Consultation among specialists changed the preoperative indication in 60 patients, during the same time period. CONCLUSIONS: Self expandable metal stents placement represents an important tool to treat patients with obstructing colorectal cancer and complications after colorectal resection . A proper training is required, and this training in operative endoscopy is not always available and possible. In this scenario, a close collaboration among specialists in selecting the most appropriate operative procedure is essential and brings to better results.

Background: Malnutrition is a frequent condition in the elderly and is associated with prolonged hospitalization and increased mortality. However, the impact of malnutrition among elderly patients with acute myocardial infarction has not been clarified yet. Methods and Results: We have enrolled 174 patients aged 65 years and over, admitted with the diagnosis of acute myocardial infarction (AMI) who underwent to the evaluation of nutritional status by Mini Nutritional Assessment (MNA) and of mortality risk by Grace score 2.0. All-cause mortality was the outcome considered for this study. Over a mean follow-up of 24.5 ± 18.2 months, 43 deaths have been registered (24.3%). Non-survivors were more likely to be older, with worse GFR, lower SBP, lower albumin and MNA score, higher prevalence of Killip classification III-IV grade, and higher Troponin I levels. Multivariate Cox proportional analysis revealed that Grace score and MNA showed a significant and independent impact on mortality, (HR = 1.76, 95% CI = 1.34–2.32 and HR = 0.56, 95% CI = 0.42–0.73, respectively). Moreover, the clinical decision curve revealed a higher clinical net benefit when the MNA was included compared to the partial models without MNA. Conclusions: Nutritional status is an independent predictor of long-term mortality among elderly patients with AMI. MNA score in elderly patients with AMI may help prognostic stratification and identification of patients with/at risk of malnutrition in order to apply interventions to improve nutritional status and maybe survival in this population.

Here we show how a recently-introduced method from algebraic topology, namely proximal planar vortex 1-cycles, might be helpful in detecting hidden features of the shapes and holes in images, therefore contributing to the solution of both cold and fresh forensic cases. In particular, we test the efficacy of this technique by assessing one of the most puzzling cases of recent history, i.e., Aldo Moro’s death. Terrorists of the Red Brigades claimed that they killed Moro when he was placed inside the trunk of a car,shooting him with a barrage of bullets. We demonstrate, based on the analysis of the photographs taken during the autoptic procedure, that the terrorist’s account does not hold true. Our results, showing different series of shots, point towards a three-step execution, with the first phasestaking place outside the car. In conclusion, the novel forensic analysis method introduced in this paper permits the evaluation of a collection of vortex cycles/nerves equipped with a connectedness proximity, which makes it possible to assess unexpected spatial clusters in photographs.

1) Background: Spirulina (Arthrospira) maxima has shown beneficial effects such anti-dyslipidemic, antiviral, antioxidant and antihypertensive. However, there are few and limited clinical studies. 2) Methods: a prospective, randomized, parallel pilot study of 4.5 g administration of Spirulina maxima or placebo for 12 weeks in 16 patients with systemic arterial hypertension undergoing treatment with ACE inhibitors was performed to assess the effects on endothelial damage and oxidative stress indicators. The blood levels of sICAM-1, sVCAM-1, endothelin-1, and sE-selectin were quantified; the activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and concentrations of reduced glutathione, oxidized glutathione, and thiobarbituric acid reactive susbtances, were also quantified before and after the treatment period. 3) Results: There were statistically significant (p < 0.05) decreases in systolic blood pressure, sVCAM-1, sE-selectin and endothelin-1 levels, and increases in glutathione peroxidase activity and oxidized glutathione levels. 4) Conclusion: The effects found in the present study agree with antihypertensive and antioxidant effects previously reported for Spirulina maxima. However, this is the first report about the effects on indicators of endothelial damage. More research in this field is necessary to gain an insight into the effects of Spirulina on these indicators.

Background and Objectives: Acculturation is associated with excessive weight gain among immigrants to the U.S. Whether dietary factors mediate this association is unclear. This study aimed to examine whether overall diet quality or specific component(s) of diet quality mediate the association between acculturation and Body Mass Index (BMI) among Mexican American (MA) men and women. Material and Methods: This is a secondary data analysis using dietary intake data from 24-hour dietary recalls, measured height and weight, and self-reported acculturation from the National Health and Nutrition Examination Survey (NHANES) cycles 1999-2000 to 2011-2012. A total of 6848 MA adults (≥20 yrs) with reliable dietary recall status and body measures were included in the study. Path analyses was performed in Mplus with complex survey design effects adjusted. Results: HEI components of whole grains and sodium were found to play meditating roles in the acculturation-BMI association, and their effects on BMI were opposing [indirect effect were -0.01 (SE 0.00) and 0.02 (0.01), respectively]. In gender-specific analysis, sodium [0.01 (0.00)] was a significant mediator only in MA men; whereas, whole grains [-0.01 (0.00)] was a significant mediator only in MA women. Conclusions: HEI components of whole grains and sodium appeared to be significant dietary mediators in the acculturation-BMI association. Understanding the variations of dietary components and their relationship with acculturation as well as BMI is useful for developing dietary interventions and obesity reduction.

Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, that have been related to treatment. Several studies have shown that after-treatment, HL patients and survivors present persistent chromosomal instability, including non-clonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting non-clonal chromosomal aberrations and genomic chaos in a fraction of non-cancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.

Background: The febrile patient from tropical areas, in which emerging arboviruses are endemic, represent a diagnostic challenge and potential co-infections with other pathogens (i.e bacteria or parasites) are usually overlooked. Objectives: We present a case of an elderly woman diagnosed with dengue, chikungunya and Leptospira interrogans co-infection. Study Design: Case report. Results: An 87-year old woman from Colombia complained of upper abdominal pain, arthralgia, myalgia, hyporexia, malaise and intermittent fever accompanied with progressive jaundice. She had a medical history of chronic heart failure (Stage C, NYHA III), without documented cardiac murmurs, right bundle branch block, non-valvular atrial fibrillation, hypertension, and chronic venous disease. Her cardiac and pulmonary status quickly deteriorated after 24 hours of her admission without electrocardiographic changes and she required ventilatory and vasopressor support. In the next hours the patient evolved to pulseless electrical activity and then she died. Dengue IgM, NS1 ELISA, MAT for Leptospira interrogans and RT-PCR for chikungunya, were positive. Discussion: This case illustrates a multiple co-infection in a febrile patient from a tropical area of Latin America that evolved to death.

Background: The prognostic value of erythrocyte levels of the n-6 fatty acids (FAs) for total mortality and cardiovascular disease (CVD) outcomes remains an open question. Methods: We examined CV outcomes and death in 2500 individuals in the Framingham Heart Study Offspring cohort without prevalent CVD (mean age 66 years, 57% women) as a function of baseline levels of different length n-6 FAs (18 carbon, 20 carbon and 22 carbon) in the erythrocyte membranes. Clinical outcomes were monitored for up to 9.5 years (median follow up, 7.26 years). Cox proportional hazards models were adjusted for a variety of demographic characteristics, clinical status and RBC n-6 and long chain n-3 FA content. Results: There were 245 CV events, 119 CHD events, 105 ischemic strokes, 58 CVD deaths, and 350 deaths from all causes. Few associations between either mortality or CVD outcomes were observed for the n-6 FAs, with those that were observed becoming non-significant after adjusting for n-3 FA levels. Conclusions: Higher circulating levels of the marine n-3 FA levels are associated with reduced risk for incident CVD and ischemic stroke and for death from CHD and all-causes, however in the same sample, little evidence exists for association with n-6 FAs. Further work is needed to identify a full profile of FAs associated with cardiovascular risk and mortality.

There is a lack of data comparing sugammadex with anticholinesterase for the quality of anaesthesia recovery, especially following a single bolus dose of rocuronium. Thus, we evaluated the influence of reversal with sugammadex or neostigmine on post-operative quality of recovery by using the Post-operative Quality Recovery Scale (PQRS). A total of 86 patients undergoing trans-pars plana vitrectomy (TPPV) under general anaesthesia were intubated following a single bolus dose of rocuronium (0.6 mg/kg). At the end of surgery, patients were received either neostigmine or sugammadex. The quality of recovery was assessed using the PQRS at 15 minutes and 40 minutes after surgery, and on post-operative day 1. The recovery rate in the physiological domain was higher in the sugammadex group at 15 minutes after surgery (P = 0.02). Though there were no significant differences in the overall cognitive recovery domain, patients in the sugammadex group could recall more numbers in reverse order. However, there were no significant differences between the groups in the other domains of the PQRS. The use of sugammadex may increase the quality of the post-operative physiological recovery at early post-operative periods compared with neostigmine use following a single bolus dose of rocuronium in patients undergoing TPPV with general anaesthesia.

Purpose: To evaluate the efficacy and survival rates of trabectome-mediated ab interno trabeculectomy combined with non-fenestrated Baerveldt glaucoma implants (BT) in comparison to Baerveldt glaucoma implant alone (B).Method: A total of 175 eyes undergoing primary glaucoma surgery (60 eyes BT and 115 B) were enrolled in this retrospective comparative case series. Participants were identified using the procedural terminology codes. Groups were then matched using Coarsened Exact Matching (51 eyes in each group). The primary outcome measure was surgical success, defined as 5 mmHg < IOP ≤ 21 mmHg, and IOP reduction ≥ 20% from baseline, and no reoperation for glaucoma. Secondary outcome measures were intraocular pressure, the number of glaucoma medications, and best corrected visual acuity (BCVA).Results: The cumulative probability of success at one year was 61% in BT, and 50% in B. IOP decreased significantly from 23.5±2.4 mmHg at baseline to 14.1±2.7 mmHg at the final follow up in BT (P= 0.001). The corresponding numbers for B were 23.2± 2.0 and 13.9± 1.6, respectively (P= 0.001). There was no significant difference in IOP at the final follow-up (P=0.56). The number of medications at baseline was 2.3±0.3 in both groups. However, BT needed significantly fewer drops at all postoperative time intervals and used 1.1±0.3 (BT) and 2.0±0.4 eye drops (B) at the final follow-up visit (P= 0.004). No dangerous hypotony or hypertension occurred in BT.Conclusion: Similar rates of success and IOP reduction were observed in BT and B. BT needed significantly fewer glaucoma medications. Tube fenestration was not necessary in BT resulting in less postoperative hypotony and hypertension.

In the present work a novel, portable and innovative eNose composed of a surface acoustic wave (SAW) sensor array based ZIF-8, and ZIF-67 nanocrystals (pure and combined with gold nanoparticles) as sensitive layers has been tested as a non-invasive system to detect and differentiate disease markers, such as acetone, ethanol and ammonia, related with early diagnosis of diabetes mellitus through exhaled breath. The sensors have been prepared by spin coating, achieving continuous and homogenous sensitive layers. Low concentrations (5 ppm, 10 ppm and 25ppm) of the marker analytes were measured, obtaining high sensitivities, good reproducibility, short time response and fast signal recovery.

Complementary and alternative treatment approaches are becoming more common among children with chronic conditions. The pravelance of CAM use among US adults was estimated to be around 42% in 2015, and around 44% to 50% among adults with neurologic disorders. Studies report children with chronic illnesses such as cancer, asthma, attention-deficit/hyperactivity disorder (ADHD), genetic disorders, and other neurodevelopmental disorders are treated with complementary and alternative treatments at higher rates. Dietary therapies are gaining increasing popularity in the mainstream population, due to the heavy media involvement. Although, majority of “fad” diets do not have enough supporting evidence, some dietary therapies have been utilized for decades and have numerous published studies. The objective of this review is to describe the dietary interventions used in children with the specific chronic conditions, to evaluate their efficacy based on published data, and to encourage pharmacist involvement in the management and care of such patients.

Hyperkalemia burden in non-dialysis CKD under nephrology care is undefined. We prospectively followed 2443 patients with two visits (referral and control with 12-month interval) in 46 nephrology clinics. Patients were stratified in four categories of hyperkalemia (sK≥5.0 mEq/L) by sK at visit 1 and 2: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). We assessed competing risks of ESKD and death after visit 2. Age was 65±15 y, eGFR 35±17 mL/min/1.73 m2, proteinuria 0.40 (0.14-1.21) g/24h. In the two visits sK was 4.8±0.6 and levels ≥6 mEq/L were observed in  4%. Hyperkalemia was absent in 46%, resolving 17%, new onset 15% and persistent 22%. Renin-angiotensin-system inhibitors (RASI) were prescribed in 79% patients. During 3.6-year follow-up, 567 patients reached ESKD and 349 died. Multivariable competing risk analysis [sub-hazard ratio-sHR, 95%Confidence Interval-CI] evidenced that new onset [sHR 1.34, 95%CI 1.05-1.72] and persistent [sHR 1.27, 95%CI 1.02-1.58] hyperkalemia predicted higher ESKD risk versus absent, independently from main determinants of outcome including eGFR change. Conversely, no effect on mortality was observed. Results were confirmed by testing sK as continuous variable. Therefore, in CKD under nephrology care, mild-to-moderate hyperkalemia status is common (37%) and predicts per se higher ESKD risk but not mortality.

New research points to a possible link between Autism Spectrum Disorder and the gut microbiota as many autistic children have co-occurring gastrointestinal problems. This review focuses on specific alterations of gut microbiota mostly observed in autistic patients. Particularly, the mechanisms through which such alterations may trigger the production of the bacterial metabolites or leaky gut in autistic people are described. Various altered metabolite levels were observed in autistic children, many of those were of bacterial origin such as short chain fatty acids (SCFAs), indoles and lipopolysaccharides. A less integrative gut-blood-barrier is abundant in autistic individuals. This explains the leakage of bacterial metabolites into the patients triggering new body responses or altered metabolism. Some other co-occurring symptoms such as mitochondrial dysfunction, oxidative stress in the cells, altered tight junctions in the blood brain barrier and structural changes in cortex, hippocampus, amygdala and cerebellum were detected. Moreover, this paper suggests that autism is associated with an unbalanced gut microbiota (dysbiosis). Although the cause-effect relationship between autism and gut microbiota is not yet well established, consumption of specific probiotics may represent a powerful tool to re-establish gut homeostasis and promote gut health. Diagnostic and therapeutic value of new biomarkers leading to the perturbation in the phenylalanine metabolism will be discussed.

We describe a model of neurological disease based on dysfunctional brain oscillators. This is not a new model, but it is not one that is generally appreciated by clinicians. The value of this model lies in the predictions it makes and the utility it provides in translational applications, in particular for neuromodulation devices. We provide a perspective on the difference between neuromodulation devices that enforce an externally administered stimulus with devices that provide input to sensory receptors and thus stimulate endogenous sensory networks. Current forms of clinically applied neuromodulation are of the former type, including devices such as (implanted) deep brain stimulators (DBS) and various, noninvasive methods such as transcranial magnetic stimulation (TMS) and transcranial current methods (tACS, tDCS). The challenge with these methods is that they are not sensitive to underlying neuronal dynamics and work by applying an empirically derived electrical current waveform to affect dynamical patterns. Neuromodulation of a sensory organ accesses the same pathways that natural environmental stimuli do and, importantly, the modulatory signal will be transformed as it travels through the brain, allowing the modulation input to be consistent with regional dynamics. We present specific examples of devices that rely on sensory neuromodulation and evaluate the translational potential of these approaches. We argue that sensory neuromodulation is well suited to probe and, ideally, repair dysfunctional brain oscillators, thus providing a novel therapeutic approach for neurological diseases.

The study investigated, in a rat model of low-level and moderate environmental exposure to cadmium (Cd; 1 or 5 mg Cd/kg diet, respectively, for 3-24 months), whether the co-administration of 0.1% extract from Aronia melanocarpa L. berries (AE) may protect against oxidative stress in the liver. The intoxication with Cd, dose- and duration-dependently, weakened the enzymatic antioxidative barrier (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase), decreased the concentrations of non-enzymatic antioxidants (reduced glutathione and total thiol groups), and increased the concentrations of oxidized glutathione, hydrogen peroxide, xanthine oxidase, and myeloperoxidase in this organ. These resulted in a decrease in the total antioxidative status (TAS), an increase in the total oxidative status (TOS), and development of oxidative stress in the liver (evaluated based on the index of oxidative stress calculated as the ratio of TOS and TAS). The administration of AE at both levels of Cd treatment significantly improved the enzymatic and non-enzymatic antioxidative barrier, decreased the concentration of pro-oxidants, and protected from the development of oxidative stress in the liver. In conclusion, consumption of aronia products may prevent Cd-induced destroying the oxidative/antioxidative balance and development of oxidative stress in the liver protecting against this organ damage.

Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist’s daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs.

Athletes are exposed to high-intensity loads to promote athletic performance, however without appropriate evaluation for its effects. This study investigates the effects of four types of exhaustion exercises on Heart Rate Variability (HRV) and Poincaré features as markers of central fatigue; Creatine Kinase (CK) and blood lactate concentrations ([LA-]b) as biomarkers of peripheral fatigue. To achieve this purpose, ten healthy volunteers were exposed to exhaustive exercise using isotonic-, isometric-, aerobic-, and anaerobic-fatigue protocols. HRV Poincaré features, standard deviation of instantaneous beat-to-beat R-R interval variability (SD1) and standard deviation of continuous long-term R-R interval variability (SD2) variables were collected. Central fatigue was tested through the sympathetic stress index (SS) and the sympathetic and parasympathetic index (SS/SD1). Blood samples were collected at the beginning and at the end of the exercises to determine CK and [LA-]b. The SD1 decreased in each exercise protocol, while the SS and SS/SD1 increased. [LA-]b and CK increased at the end of each protocol and correlated with SD1 and SS/SD1. HRV, CK, and [LA^-]_b are acute markers to detect, both central and peripheral fatigue; sensitive to the type, duration, and intensity of exercise, being HRV a novel noninvasive marker, simple and useful for sports coaches and athletes.

One control challenge in prosthetic legs is seamless transition from one gait mode to another. User intent recognition (UIR) is a high-level controller that tells a low-level controller to switch to the identified activity mode, depending on the user’s intent and environment. We propose a new framework to design an optimal UIR system with simultaneous maximum performance and parsimony for gait mode recognition. We use multi-objective optimization (MOO) to find an optimal feature subset that creates a trade-off between these two conflicting objectives. The main contribution of this paper is two-fold: (1) a new gradient-based multi-objective feature selection (GMOFS) method for optimal UIR design; and (2) the application of advanced evolutionary MOO methods for UIR. GMOFS is an embedded method that simultaneously performs feature selection and classification by incorporating an elastic net in multilayer perceptron neural network training. Experimental data are collected from six subjects, including three able-bodied subjects and three transfemoral amputees. We implement GMOFS and four variants of multi-objective biogeography-based optimization (MOBBO) for optimal feature subset selection, and we compare their performances using normalized hypervolume and relative coverage. GMOFS demonstrates competitive performance compared to the four MOBBO methods. We achieve a mean classification accuracy of 97.14% ± 1.51% and 98.45% ± 1.22% with the optimal selected subset for able-bodied and amputee subjects, respectively, while using only 23% of the available features. Results thus indicate the potential of advanced optimization methods to simultaneously achieve accurate, reliable, and compact UIR for locomotion mode detection of lower-limb amputees with prostheses.

The purpose of work is to quantify the changes of the organism functional reserves during the successive phases of the human health Space-Time Continuum (STC) on the basis of postulates of reliability complex systems theory. The study is devoted to the problem of age-related human involution, which is evaluated not from the causal, but from the kinetic point of view. The analysis of 10 most important basic life support systems of human body — cardiovascular (CVS), respiratory (RS), nervous (NS), digestive (DS), endocrine (ES), immune (IS), excretory (EXS), brain (BS), musculo-skeletal (MSS), hematopoietic (HS) was carried out. Based on this analysis two levels of ensuring the reliability of organism’s work were revealed: sequential and parallel. The system of logical equations for reduced sequential system is: Ys1 = CVS ∧ RS ∧ BS, where ∧ is the notation for the conjunctions of set elements. The system of logical equations for the reduced parallel system is: Ys2 = NS ∨ DS ∨ ES ∨ IS ∨ HS ∨ EXS ∨ MSS ,where ∨ is the disjunction of the scheme elements. Visualization of human STC changes the concept of the kinetics of age-related changes in the organism and the role of determinants of health as a stable factor accompanying a uniform, smooth transition from the most pronounced functions of the body to their gradual extinction. For human STC is formulated the following regularity kinetics of involutionary processes: after 30 years of age in the human body morphological changes regress in arithmetic progression, and the functions of organs in a geometric one. Assumption of health as a state redundancy of functions is suggested.

Myocardial deformation imaging (strain imaging) is a technique to directly quantify the extent of myocardial contractility and overcomes several of the limitations of ejection fraction. The application of the most commonly used strain imaging method; speckle-tracking echocardiography to patients with sepsis cardiomyopathy heralds an exciting development to the field. However; the body of evidence and knowledge on the utility, feasibility and prognostic value of left ventricular global longitudinal strain in sepsis cardiomyopathy is still evolving. We conducted a review of literature on utility of left ventricular global longitudinal strain in sepsis cardiomyopathy. We discuss the role of left ventricular global longitudinal strain in mortality prediction, utility and limitations of the technique in the context of sepsis cardiomyopathy.

Dietary factors are one of the risk factors that can impact the brain chemistry, which leads to mental distress. Based on our data mining approach, we found that mental distress in men is associated with eating unhealthy food. Our aim in this paper is to apply results from our big data analytics approach to inform system dynamics (SD) modeling to investigate the causal relationships between brain structures, nutrients from food and dietary supplements, and mental health. We perform descriptive analysis based on a large data set to estimate the SD modeling parameters. Finally, we calibrate the model towards a time series data collected for individuals on their dietary and distress patterns. The results reveal that bridging these different methodologies leads to further insights from the SD model and decreases the error of calibrated parameter values. Future research is needed to validate our initial results for investigating the relationship between mental distress and dietary intake.

The acute phase protein serum amyloid A (SAA) is associated with endothelial dysfunction and early-stage atherogenesis. Stimulation of vascular cells with SAA increases gene expression of pro-inflammation cytokines and tissue factor (TF). Activation of the transcription factor, nuclear factor kappa-B (NFkB), may be central to SAA-mediated endothelial cell inflammation, dysfunction and pro-thrombotic responses, while targeting NFkB with a pharmacologic inhibitor, BAY11-7082, may mitigate SAA activity. Human carotid artery endothelial cells (HCtAEC) were pre-incubated (1.5 h) with 10 µM BAY11-7082 or vehicle (control) followed by SAA (10 μg/mL; 4.5 h). Under these conditions gene expression for TF and TNF increased in SAA-treated HCtAEC and pre-treatment with BAY11-7082 significantly (TNF) and marginally (TF) reduced mRNA expression. Intracellular TNF and IL-6 protein also increased in HCtAEC supplemented with SAA and this expression was inhibited by BAY11-7082. Supplemented BAY11-7082 also significantly decreased SAA-mediated leukocyte adhesion to apolipoprotein E-deficient mouse aorta in ex vivo vascular flow studies. In vascular function studies, isolated aortic rings pre-treated with BAY11-7082 prior to incubation with SAA showed improved endothelium-dependent vasorelaxation and increased vascular cGMP content. Together these data suggest that inhibition of NFkB activation may protect endothelial function by inhibiting the pro-inflammatory and pro-thrombotic activities of SAA.

Subjective Cognitive Decline (SCD) is a possible earliest detectable sign of dementia, but we do not know what mental processes lead to elevated concern. We summarize the previous literature on the biomarkers and functional neuroanatomy of SCD. To extend the current most-popular theory of SCD, compensatory hyperactivition, we introduce a new model: breakdown of homeostasis in the prediction error minimization system. A cognitive prediction error is a discrepancy between an implicit cognitive predictions and the corresponding outcome. Experiencing frequent prediction errors may be a primary source of elevated subjective concern. Our homeostasis breakdown model explains the progression both from normal cognition to SCD and from SCD to advanced dementia stages.

Hippocrate, the father of medicine, already said:"Wine is a thing wonderfully appropriate to man if, in health as in disease, it is administered with appropriate and just measure according to the individual constitution." wine has always accompanied humanity, for religion or for health. Christians and Jews need wine for the liturgy. For Platon the wine was an indispensable element in society and took all its importance in the symposium. In this second part of the banquet, mixed with water, the wine gave the word. If the french paradox made a lot of ink flow; it was the wine that was originally responsible for it. Many researchers have tried to share the alcohol and polyphenols in order to solve the mystery. Beyond its cardiovascular effects, there are also effects on longevity, metabolism, cancer prevention and neuroprotection, and the list goes on. The purpose of this work is to make an analysis of current knowledge on the subject. Indeed, if the paradigm of the antioxidants is seductive, it is perhaps by their prooxidant effect that the polyphenols could act, by an epigenetic process mediated by nrf2. Wine is a preserve of antioxidants for the winter and it is by this property that the wine acts, in alcoholic solution. A wine without alcohol is pure heresy. By the way, we were not talking about elixir to design all this millennial pharmacopee that made the man was able to heal and prosper on the planet. From Alvise Cornaro to Serge Renaud, nutrition was the key to health and longevity, whether Cretan or Okinawa diet, it is the small dose of alcohol (wine or sake) that allows the bioavailability of polyphenols. Moderate drinking give a protection for diseases and a longevity potential. In conclusion, let’s drink fewer, but drink better to live older.

Prostanoids modulate the pathogenesis of vascular diseases such as atherosclerosis, in which inflammation has an important role. It is well known that inducible Ciclooxygenase-2 (COX-2) is responsible for prostanoid production associated with inflammation. Angiotensin II may be implicated through the expression of COX-2 in the vascular wall. The purpose of this study was to examine in angiotensin II-stimulated adventitial fibroblasts the anti-inflammatory activity of different food peptides by inhibiting COX-2 expression, and the production of pro-inflammatory prostanoids. Fibroblasts from aorta of Sprague-Dawley rats were incubated with different food derived peptides followed by incubation with Angiotensin II. COX-2 expression was determined by western blot, transcriptional activity by luciferase assays and prostaglandin E2 by enzyme immunoassay. COX-2 expression was inhibited in the presence of Val-Pro-Pro (bovine β-casein 84–86), Arg-Asp-Ile-Leu-Asn-Gln (ovalbumin 84–89) and Tyr-Arg-Gly-Gly-Leu-Glu-Pro-Ile-Asn-Phe (ovalbumin 125–134). Angiotensin II-induced prostaglandin E2 production was also reduced by all the above-mentioned sequences. The incubation with ovalbumin-derived peptides displayed a significant reduction of COX-2 promoter activity compared to the stimuli with Angiotensin II in transiently transfected cells. These three sequences could potentially be used as functional food ingredients to reduce inflammation related to cardiovascular diseases.

Background: Periodontitis is a disease that leads to serious functional and aesthetic dysfunctions resulting in impairment of life quality; it exists in different forms and its etiology is related with multiple component causes. Angiogenesis, together with inflammatory infiltrate, are two key processes in the evolution of inflammatory processes involving gingival tissues. The aim of this study was to evaluate their alterations in relation to some important periodontal diseases-associated factors (i.e. smoke, sex, age, plaque, pus, probing pocket depth) in patients with diagnosis of Generalized Aggressive Periodontitis (GAP). Methods: Eighteen subjects with GAP were enrolled for this study. Percentage of inflammatory cells and vascular area were measured and evaluated in relation with each periodontal diseases-associated factor. Results: The results showed a significant decrease of the percentage of vascular area in association with almost all the periodontal diseases-related factors (smoke, age, PPD, plaque) and not significant differences in the percentage of inflammatory cells. Conclusions: Data suggest that, even if these factors are often commonly related to worsening of periodontal status, they did not affect inflammatory and vascular pattern, as we can assume. For the future, additional studies, aimed to evaluated each singular factor in a wider sample size, should be planned.

Marine algae have been considered as abundant source of bioactive compounds with cosmeceutical potential. Recently, a great deal of interest has focused on the health-promoting effects of marine bioactive compounds. Carbohydrate is a major and abundant constitute of marine algae that have been utilized in cosmetic formulations, such as moisturizing and thickening agents. In addition, marine carbohydrates have been suggested as promising bioactive biomaterials for various skin beneficial properties, such as anti-oxidant, anti-melanogenic and anti-skin aging. Therefore, marine algae carbohydrates have potential of skin health benefits for value-added cosmeceutical application. The present review focused on the various biological capacities and potential skin health benefits of bioactive marine carbohydrates.

Pharmacists and pharmacies are highly visible and accessible to the public and have long been regarded as a source for immunization services in the United States. As international travel continues to increase and grow in popularity in this country, there is a pressing need for expanded access to preventative health services including routine and travel vaccinations and medications for prophylaxis or self-treatment of conditions that may be acquired overseas. In the United States, the scope of pharmacy practice continues to expand and incorporate these preventable health services to varying degrees on a state-by-state level. As a result, pharmacists can help to increase access to and awareness of the need for these services to insure that patients remain healthy while traveling abroad and that they do not acquire a travel-related disease while on their trip. For those pharmacists interested in starting a travel health service, considerations should be undertaken that ensures that they have the necessary training, education, and skill set in order to provide this specialty level of care and that their practice setting is optimally designed to facilitate this service. Outcomes from studies that have evaluated pharmacy-based travel health services are positive, which further supports the role of the pharmacist in this setting. Therefore, the purpose of this paper is to highlight United States pharmacy laws and regulations, pharmacist training, travel clinic considerations, and patient care outcomes from pharmacy-based travel health services.

Objective: To evaluate the status of receiving education on rational drug use, the criteria in medical drug selection, and level of knowledge of dentists working in a dentistry faculty in Turkey. Material and Methods: This was a descriptive study based on a questionnaire. One hundred seventeen (74%) dentists volunteered to participate in the study. The questionnaire consisted of 20 questions investigating sociodemographic features and rational drug use. Results: The mean age of the dentists was 30.8 ± 7.2 years, and 62.4% were men. The mean period of professional experience was 8.9±7.1 years. The most frequently used resources of references while prescribing medicine were Vademecum (medical drug guide) (61.5%), the internet (59.0%), and colleagues (49.6%). The most frequently reported condition described as ‘good’ was drug indications (43.6%). The dentists had a moderate level of information about posology, and administration route (48.7%), pharmacologic features (48.7%), and contraindications (46.2%). The number of dentists who stated that they considered cost while prescribing was low [always (6%), and frequently (15.4%)]. Rational drug use education had been received by 23.9% of the dentists. Conclusions: The dentists were found to have a lack of adequate and effective education on rational use of drugs. Regular and continuous education before and after graduation is a necessity for dentists and for their patients.

Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCCD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function granting a fine tuning of immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro – or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer.

Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads from lower motor neuron involvement to progressive muscle atrophy, weakness, fasciculations for the upper motor neuron involvement to spasticity. Muscle atrophy in ALS is caused by a dysregulation in the molecular network controlling fast and slow muscle fibres. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a wide range of biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a, miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. We correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, myomiRNAs were down-regulated, suggesting an active proliferation of satellite cells in muscle and increased neuromuscular junctions. Our data suggest that circulating miRNAs modulate during skeletal muscle recovery in response to physical rehabilitation in ALS.

Food security (FS) during infancy is associated with lifelong outcomes. New Zealand is a developed economy that reports poor childhood nutrition-related health statistics, particularly among minority children, yet has no measure of FS applicable to infancy. The objective was to develop a FS index for New Zealand infants and examine its association with demographic covariates and health outcomes. Within a large (n=6853) nationally representative cohort, variables describing infant food consumption, breastfeeding, and maternal food-related coping methods were collected from mothers during late infancy. A FS index was derived using confirmatory factor analysis. Associations were assessed by logistic regressions and described using odds ratios (OR) and ≥95% confidence intervals (CI). 15% of the cohort was highly FS, 43% tenuously food insecure (FIS), and 16% highly food insecure (FIS). Infants from minority ethnic groups had lower odds of being food secure, as did those born to the youngest mothers, mothers who smoked, or lived in low-income households. FIS infants had higher odds of morbidity. Interventions to improve infant FS should focus on improving dietary quality, and give particular consideration to minority infants. We identified that FIS shows wide ethnic and socioeconomic inequity, and is associated with poorer health. The most important driving factors of FIS included poor quality weaning diets, and poverty and its proxies. Any interventions to improve infant FS should focus on increasing fruit and vegetable consumption to recommended intake levels, and give particular consideration to minority infants.

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its selective conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently marketed drugs - the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat - that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial.

Text fields in electronic medical records (EMR) contain information on important factors that influence health outcomes, however, they are underutilized in clinical decision making due to their unstructured nature. We analyzed 6,497 inpatient surgical cases with 719,308 free text notes from Le Bonheur Children’s Hospital EMR. We used a text mining approach on preoperative notes to obtain the text-based risk score algorithm as predictive of death within 30 days of surgery. We studied the additional performance obtained by including text-based risk score as a predictor of death along with other structured data based clinical risk factors. The C-statistic of a logistic regression model with 5-fold cross-validation significantly improved from 0.76 to 0.92 when text-based risk scores were included in addition to structured data. We conclude that preoperative free text notes in EMR include significant information that can predict adverse surgery outcomes.

The paper aims in assessing risks of mandible fractures consequent to impacts or sport accidents. The role of the structural stiffness of mandible, related to disocclusion state, is evaluated through numerical simulations using the finite element method (FEM). It has been assumed that the quasi-static stress field, due to distributed forces developed during accidents, could explain the common types of mandibular fractures. Geometric model of adolescent mandible was built, upon the basis of medical imaging, in CAD software with distinction between cortical layer and inner spongy bone. The finite element model of disoccluded mandible was next created. Mandibular condyles were supposed jammed in the maxillary fossae. The total force of 700 N, simulating an impact on mandible, has been sequentially applied in three distinct areas: centrally, at canine zone and at the mandibular angle. Clinically most frequent fractures of mandible were recognized through the analysis of maximal principal stress and maximal principal strain fields. Mandibular fracture during accidents can be analyzed at satisfactory level using linear quasi-static FE models for designing protections in sport and transport. The proposed approach can be improved by introducing more realistic interactions between condylar processes and fossae.

Visfatin, a member of the adipokine family, plays an important role in many metabolic and stress responses. The mechanisms underlying the direct therapeutic effects of visfatin on wound healing have not been reported yet. In this study, we examined the effects of visfatin on wound healing in vitro and in vivo. Visfatin enhanced the proliferation and migration of human dermal fibroblasts (HDFs) and keratinocytes, and significantly increased the expression of wound healing-related vascular endothelial growth factor (VEGF) in vitro and in vivo. Treatment of HDFs with visfatin induced activation of both extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) in a time-dependent manner. Inhibition of ERK1/2 and JNK1/2 led to a significant decrease in visfatin-induced proliferation and migration of HDFs. Importantly, blocking VEGF with its neutralizing antibodies suppressed the visfatin-induced proliferation and migration of HDFs and human keratinocytes, indicating that visfatin induces the proliferation and migration of HDFs and human keratinocytes via increased VEGF expression. Moreover, visfatin effectively improved wound repair in vivo, which was comparable to the wound healing activity of epidermal growth factor (EGF). Taken together, we demonstrate that visfatin promotes the proliferation and migration of HDFs and human keratinocytes by inducing VEGF expression and can be used as a potential novel therapeutic agent for wound healing.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis, published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial-mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

Sleep disorders (SD) have a complex aetiology, and socioeconomic status (SES) as determined by social class, household income, ethnicity and education plays an important role in their development. As SD are associated with cognitive impairment and mood disorders, they in turn impact SES. Socioeconomic status also influences allostatic load caused by chronic accumulation of stress throughout life. Environmental and psychological stressors have a direct effect on SD, and they are modulated by SES, in combination with comorbidities like obesity and cardiovascular disease. This review explores the recent theories about the influence of SES on the development of SD in the general population, whether or not occurring with comorbidities, and also focusses on the interplay between socioeconomic status, circadian rhythms, aging and clinical outcomes like metabolic diseases and cancer.

Abdominal aortic aneurysm (AAA) represents an important public health problem with a prevalence between 1.3% and 12.5%. Several population-based randomized trials have evaluated ultrasound screening for AAA providing evidence of a reduction in aneurysm-related mortality in the screened population. The aim of our study was to perform a systematic review and meta-analysis of the risk factors for AAA. We conducted a systematic review of observational studies and we performed a meta-analysis that evaluated the following risk factors: gender, smoking habits, hypertension, diabetes mellitus, Coronary Artery Disease and family history of AAA. Abdominal aortic aneurysm prevalence is higher in smokers and in males. It is important to underline that all countries, where AAA screening was set up, had high income level and the majority belong to Western Europe (United Kingdom, Sweden, Italy, Poland, Spain and Belgium). Abdominal aortic aneurysm screening is fundamental for public health. It would avoid deaths, ruptures, and emergency surgical interventions if abdominal aortic aneurysm was diagnosed early in the population target for screening.

L-glutamate is one the most important excitatory neurotransmitter at central nervous system level and it is implicated in several pathologies. So, it is very important to monitor its variations, in real time in animal models’ brain. Amperometric biosensors have been used because of their very high temporal and spatial resolution, and because suitable for a short to mid-term implantation. The present study aimed to develop and characterize a new glutamate biosensor design that exploits the selectivity of Glutamate Oxidase (GluOx) for l-glutamate, and the capability of a small molecule as propylene glycol (PG) to influence and extend the stability and the activity of enzyme. Different designs were evaluated by modifying the main components in their concentrations to find the most suitable design. Moreover, enzyme concentrations from 100 U/ml up to 200 U/ml were verified and different PG concentrations (1%, 0.1% and 0.05%) were tested. The most suitable selected design was Pt_c/PPD/PEI(1%)₂/GlutOx₅/PG(0.1%) and it was compared to the same already described design loading PEDGE, instead of PG, in terms of over-time performances. PG has proved to be capable of determining an over-time stability of the glutamate biosensor in particular in terms of linear region slope (LRS) up to 21 days.

The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 FDA approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.

Butyric acid as a histone deacetylase (HDAC) inhibitor was produced by a number of periodontal and root canal microorganisms (such as Porphyromonas, Fusobacterium etc.). Butyric acid may affect the biological activities of periodontal/periapical cells such as osteoblasts, periodontal ligament cells etc., and thus affect periodontal/periapical tissue destruction and healing. The purposes of this study were to study the toxic effects of butyrate on matrix and mineralization markers’ expression of MG-63 osteoblasts. Cell viability and proliferation were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cellular apoptosis and necrosis were analyzed by propidium iodide/Annexin V flow cytometry. Protein and mRNA expression of OPG, and RANKL were analyzed by western blotting and RT-PCR. OPG, soluble RANKL (sRANKL), 8-isoprostane, pro-collagen I, MMP-2, osteonectin (SPARC), osteocalcin and osteopontin secretion into culture medium were measured by enzyme-linked immunosorbant assay. Histone H3 acetylation levels were evaluated by immunofluorescent staining (IF) and western blot. We found that butyrate induced morphologic changes of growing MG-63 cells, with bigger and flattened in appearance. Butyrate activated histone H3 acetylation of MG-63 cells. Exposure of MG-63 cells to butyrate partly decreased cell number with no marked increase in apoptosis and necrosis. Butyrate stimulated RANKL protein expression, whereas it inhibited OPG protein expression. Butyrate also inhibited the secretion of OPG in MG-63 cells, whereas sRANKL level was below detection limit. Butyrate stimulated 8-isoprostane, MMP-2 and osteopontin secretion, but not procollagen I, osteonectin, osteocalcin in MG-63 cells. In conclusion, butyric acid generated by periodontal and root canal microorganisms may potentially induce bony destruction and impair bone repair by alteration of OPG/RANKL expression/secretion, 8-isoprostane, MMP-2, and osteopontin secretion, and affect cell proliferation. These effects are possibly related to increased histone acetylation. These events are important in the pathogenesis of periodontal and periapical destruction.

Beginning with the discovery of the BRCA ovarian cancer susceptibility genes and subsequent detailed examination of risk reduction salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous cancer - serous tubal intraepithelial carcinoma or STIC - has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in fallopian tubes of women with advanced malignancy. This paradox, a high-frequency of tubal involvement early and a low-frequency late in the disease process has spurred interest in other potential sources, such as the ovarian surface or secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of "precursor escape". This creates a 2nd component of the paradigm by which cells from early lesions can escape the fallopian tube and undergo future malignant transformation later, emerging suddenly as widespread malignancy. This dualistic model thus explains the paradox and opens new questions pertaining to the challenge of both early detection and prevention of this lethal malignancy.

EZH2 overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibiting EZH2 may be an effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We previously analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (P < 0.001) and the methylation index of tumor suppressor genes (P < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (P = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, P < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390–3.127; P < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients.

Evaluation of the effects of a high-frequency acceleration (HFA) device on patient pain response to orthodontic forces. A multi-centered trial investigating pain sensitivity to orthodontic forces on 75 subjects at 4 study centers. Subjects underwent clear aligner treatment, with or without adjunctive HFA and documented their pain intensity using the validated NRS10 numeric rating scale. In-Office and At-Home ratings were measured separately for each subject for immediate and extended effect evaluations. Use of HFA devices in conjunction with clear aligner orthodontic treatment demonstrated significant reduction in subjects’ recorded pain ratings vs controls within 5 minutes of aligner exchange, (p = 0.006) and significant reduction in recorded pain ratings vs controls over a 7-day period following aligner exchange (p = 0.018). A 99.6% daily compliance rate with at home use of the HFA device was recorded for all subjects in the study. HFA significantly reduces pain attributed to orthodontic force. HFA delivers clinically significant immediate pain relief, and clinically significant extended pain relief over the 7 days following adjustment.

The central nervous system (CNS) and the human gastrointestinal (GI) tract communicate through the gut-brain axis (GBA). Such communication is bi-directional and involves neuronal, endocrine and immunological mechanisms. The scientific data are mounting that gut microbiota is a source of a number of neuroactive and immunocompetent substances, which shape the structure and function of brain regions involved in control of emotions, physical activity and cognition. Most of GI maladies are associated with altered transmission within the GBA and influenced both by genetic and environmental factors. Current treatment protocols widely advocated for the treatment of GI disorders may positively or adversely affect the composition of intestinal microbiota with diverse impact on therapeutic outcome. The alterations of gut microbiota have been associated with mood and depressive disorders. and mental health is frequently altered in the course of many GI and non-GI ailments. Deregulation of the GBA may constitute a grip point for the development of diagnostic tools and personalized microbiota-based therapy. For example next generation sequencing (NGS) offers detailed analysis of microbiome footprints in patients with mental and GI disorders. Psychobiotics are new class of beneficial bacteria, with documented efficacy in the treatment of gut-brain axis disorders.

We asked whether the level of peripheral fatigue would differ when three consecutive exercise trials were completed to task failure, and whether there would be delayed recovery in maximal voluntary contraction (MVC) force, neuromuscular activation and peripheral fatigue following task failure. Ten trained sport students performed three consecutive knee extension isometric trials (T1, T2, T3) to task failure without breaks between trials. T1 and T2 consisted of repeated 5-s contractions followed by 5-s rest. In T1, contractions were performed at a target force at 60% pre-exercise MVC. In T2, all contractions were MVCs, and task failure occurred at 50% MVC. T3 was a sustained MVC performed until force fell below 15% MVC. Evoked force responses to supramaximal electrical femoral nerve stimulation were recorded to assess peripheral fatigue. Electromyography signals were normalized to M-wave amplitude to assess neuromuscular activation. Lower levels of evoked peak forces were observed at T3 compared to T2 and T1. Within 5 s of task failure in T3, MVC force and neuromuscular activation recovered substantially without any recovery in evoked peak force. Neuromuscular activation 5-10 s after T3 was unchanged from pre-exercise values, but evoked peak forces were substantially reduced. These results challenge the existence of a critical peripheral fatigue threshold that reduces neuromuscular activation. Since neuromuscular activation changed independently of any change in evoked peak force, immediate recovery in force production after exercise is due to increased central recruitment and not to peripheral mechanisms.

Abstract: Background and objective: Propofol is an anesthetic agent that is frequently used in anesthesia induction, maintenance and sedation. Propofol has severe side effects such as hypotension, bradycardia and respiratory depression. Although propofol is commonly used, there is no known antidote for its toxic effects. An approach to prevent toxic effects of propofol would be beneficial. The aim of this study was to assess the effects of intravenous lipid emulsion (ILE) therapy in the prevention of depressive effects of propofol on cardiovascular and respiratory systems. Materials and methods: Twenty-eight Sprague-Dawley adult rats were randomly divided into 4 groups. The saline-administered group was determined as the Control group. The second group was administered propofol (PP group); the third group was administered ILE (ILE group), and the fourth was administered propofol with ILE therapy (ILE+PP group). Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Mean arterial blood pressure (MAP), Respiratory rate (RR), Heart rate (HR) and mortality were recorded at 10 points during 60 minutes. A repeated measures linear mixed-effect model with unstructured covariance was used to compare the groups. Results: In the PP group, SBP, DBP, MAP, RR and HR levels were declining steadily; all rats in this group died after 60 minutes. In the ILE+PP group, after a while, the decreased SBP, DBP, MAP, RR and HR levels increased SBP, DBP, MAP, RR and HR levels of the Propofol group were found to be significantly lower than those of the other groups (p<0.01). The mortality rate was 100% (surviving period, 60 min) for the PP group, whereas 0% for the ILE, ILE+PP and Control groups. Conclusion: Our results suggest that undesirable side effects that can be seen after propofol application such as hypotension, bradycardia and respiratory depression might be prevented by using ILE therapy.

Background: In hepatocytes and alcohol-metabolizing cultured cells, Golgi undergoes ethanol (EtOH)-induced disorganization. Periniclear and organized Golgi is important in liver homeostasis, but how the Golgi remains intact is unknown. Work from our laboratories showed that EtOH-altered cellular function could be reversed after alcohol removal; we wanted to determine whether this recovery would apply to Golgi. Methods: We used alcohol-metabolizing HepG2 (VA-13) cells (cultured with or without EtOH for 72 h) and rat hepatocytes (control and EtOH-fed (Lieber-DeCarli diet). For recovery, EtOH was removed and replenished with control medium (48 hours for VA-13 cells) or control diet (10 days for rats). Results: EtOH-induced Golgi disassembly was associated with de-dimerization of the largest Golgi matrix protein giantin, along with impaired transport of selected hepatic proteins. After recovery from EtOH, Golgi regained their compact structure, and alterations in giantin and protein transport were restored. In VA-13 cells, when we knocked down giantin, Rab6a GTPase or non-muscle Myosin IIB, minimal changes were observed in control conditions, but post-EtOH recovery was impaired. Conclusions: These data provide a link between Golgi organization and plasma membrane protein expression and identify several proteins whose expression is important to maintain Golgi structure during the recovery phase after EtOH administration.

Diatom microalgae are the most outstanding natural source of porous silica. Diatom cell is enclosed in 3-D ordered nanopatterned silica cell wall, called frustule. The unique properties of diatoms frustule, including high specific surface area, thermal stability, biocompatibility, tailorable surface chemistry, make them really promising for biomedical applications. Moreover, diatoms are easy to cultivate in artificial environment and there is a huge availability of diatom frustules as fossil material (diatomite) in several areas of the world. For all these reasons, diatoms are an intriguing alternative to synthetic materials for the development of low-cost drug delivery systems. This review article focuses on the possible use of diatoms derived silica as drug carrier systems. The functionalization strategies of diatom micro-/nanoparticles for improving their biophysical properties, such as cellular internalization and drug loading/release kinetics, are described. In addition, the realization of hybrid diatom-based devices with advanced properties for theranostics and targeted or augmented drug delivery applications, are also discussed.

The results of this study offer a potential to gain a better understanding of the mechanisms underlying the falls in the elderly. The results were recorded for a group of 27 women in a control group (CON) and 16 women in an experimental group (EXP), aged 60-70. Participants took part in the six-weeks Elderly Recreation Movement Program (ERMP) with the difference, that the EXP group practiced twice as often as the CON group. The measurement of variations in the index called limits of stability (LOS) was performed by application of Kistler force plate and the coactivation index (CI) was registered by means of sEMG. The results demonstrate the existence of statistically significant differences in terms of the principal outcome of the exercise time in the measurements of LOS (F (1.42) = 10.0, p = 0.003), and CI (F (1.42) = 10.5, p = 0.002). The effect of the program was associated with an increase the level of the maximum LOS, and a decrease of the CI level, especially in the experimental group. Hence, the implementation of an innovative ERMP exercise program results in the improvement of the physical capabilities of senior subjects and a reduction of the risk of falls.

Background and Aim: Zinc plays a pivotal role in various zinc enzymes, resulting in the maintenance of liver function. Patients with chronic liver diseases (CLDs) usually have lower concentrations of zinc, which decrease further as liver fibrosis progresses. It remains unknown whether long-term zinc supplementation improves liver function and reduces the risk of hepatocellular carcinoma (HCC) development. Patients and Methods: Two hundred sixty-seven patients with CLDs who received a zinc preparation (Zn-group; 196 patients), or who did not receive zinc (no Zn-treatment group; 71 patients) were retrospectively analyzed in this study. The Zn-group was divided into 4 groups according to their serum Zn concentrations at 6 months after the start of Zn treatment. Results: Liver function significantly deteriorated in the no Zn-treatment group, while no notable change was observed in the Zn-group. The cumulative incidence rates of events and HCC at 3 years were lower in the Zn-group (9.5%, 7.6%) than in the no Zn-treatment group (24.9%, 19.2%) (p<0.001). According to the serum Zn concentrations, the cumulative incidence rates of events and HCC were significantly decreased in patients with Zn concentrations ≥ 70 µg/dl (p<0.001). Conclusion: Zinc supplementation appears to be effective at maintaining liver function and suppressing events and HCC development, especially among patients whose Zn concentration is greater than 70 µg/dl.

Although the existing paradigm states that CMV reactivation is under control of cellular immune response, the role of humoral counterpart is underestimated. Anti-CMV positive woman after conditioning with Bu-Flu-ATG underwent stem cell transplantation from fully matched, seronegative sibling donor. In immunodeficient recipient fast and significant decrease of specific immune response was observed but reconstitution of marrow-derived B and NK cells was prior thymic origin T cells. The lowest CMV-IgG(89 U/ml) was observed just before CMV viremia. Noteworthy, the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was observed later, but in the first phase immune reconstitution of the PHA-induced IFNγ release was significantly lower than that CMV-induced. It corresponds with NK cells increase at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells by pentamer technique. Most of NK cells are CD16+, thus are stimulated by residual IgG. In immunocompetent donor the cellular and humoral immune response increases in parallel manner but symptoms of CMV mononucleosis were observed till the increase of specific IgG. Our observations shed light on a unique host-CMV interaction: indicate that significant decrease of CMV-IgG is a good predictor for CMV reactivation during secondary immunodeficiency.

Perilla frutescens (L.) Britt. (PF) is an annual herbal medicinal, aromatic, functional food and ornamental plant that belongs to the mint family, Lamiaceae. The origin of perilla traces back to East Asian countries (China, Japan, Korea, Taiwan, Vietnam and India), where it has been used as a valuable source of culinary and traditional medicinal uses. Leaves, seeds and stems of P. frutescens are used for various therapeutic applications in folk medicine. In the absence of comprehensive review regarding all aspects of perilla, thus this review aims to present an overview pertaining to the botanical drug, ethnobotany, phytochemistry and biological activity. It was found that the taxonomic classification of perilla species is quite confused, and the number of species is vague. Perilla has traditionally been prescribed to treat depression-related disease, anxiety, asthma, chest stuffiness, vomiting, cough, cold, flus, phlegm, tumour, allergy, intoxication, fever, headache, stuffy nose, constipation, abdominal pain, indigestion, analgesic, anti-abortive agent, and sedative. Until now, 271 natural molecules have been identified in perilla organs including; polyphenols, flavonoids, essential oils, triterpenes, carotenoids, phytosterols, fatty acids, tocopherols and policosanols. In addition to solvent extracts, these individual compounds (rosmarinic acid, perillaldehyde, luteolin, apigenin, tormentic acid, isoegomaketone) have attracted researchers' interest for pharmacological properties. Its bioactivity showed antioxidant, antimicrobial, anti-allergic, antidepressant, anti-inflammatory, anticancer, neuroprotection activity. Although the results are promising in preclinical studies (in vitro and in vivo) as well, clinical studies are insufficient, therefore further study needs to be done to validate its therapeutic effects and to ensure its safety and efficacy.

Chronic kidney disease (CKD) is a major non-communicable disease associated with high rates of premature morbidity and mortality. The prevalence of hypovitaminosis D (deficiency of 25(OH)D or 25D) is greater in racial/ethnic minorities and in patients with CKD than the general population. Low 25D is associated with bone and mineral disorders as well as immune, cardiometabolic and cardiovascular (CV) diseases. Thus, it has been suggested low 25D contributes to the poor outcomes in patients with CKD. The prevalence of hypovitaminosis D rises progressively with advancing severity of kidney disease with over 30% of patients with CKD stage 3 and 70% patients with CKD stage 5 estimated to have low levels of 25D. This report describes several of the abnormal physiologic and counter-regulatory actions related to low 25D in CKD such as those in oxidative stress and inflammatory systems, and some of the preclinical and clinical evidence or lack of thereof of normalizing serum 25D levels to improve outcomes in patients with CKD, and especially for the high risk subset of racial/ethnic minorities who suffer from higher rates of advanced CKD and hypovitaminosis D.

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

Reducing sedentary behaviours can help prevent non-communicable diseases, particularly among young adolescents with long term illnesses or disabilities (LTID). Much of young people’s voluntary sedentary time is related to screen-time behaviours (STBs) such as TV viewing, playing computer games, and using the computer for other activities. Although public health data on adolescents’ STB is growing, information about adolescents with LTID is currently lacking in a European context. The purpose of this study is to compare time on STBs between adolescents with and without LTID in European Countries through the HBSC 2013/14 study. Young adolescents (n = 61,329; boys 47.8%) from 15 European countries reported the time spent on TV viewing, playing computer games, and using the computer for other purposes on weekdays and the weekend. STBs were dichotomised based on international recommendations of less than 2 h per day, and Chi-square tests of independence were performed to investigate differences. STB time was combined to produce a sum score as dependent variable in multiple analysis of covariance with age and family affluence as covariates. There were statistically significant differences in computer gaming among boys and other computer use among girls for both weekdays and weekends, whereby adolescents with LTID reported higher use. In addition, both boys and girls with LTID spent more time on STBs than their same sex peers without LTID (Boys, F = 28.17, p < 0.001; Girls, F = 9.60, p = 0.002). The results of this study indicate a need for preventive strategies to address high levels of STB among young adolescents with LTID and reduce the risk of poor health outcomes associated with higher levels of sedentary behaviour.

Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.

Production of energy is a main task of cancer cells metabolism, since costs of duplicating are enormous. Although energy is derived in cells by dismantling carbon to carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as dependent on glycolysis. Since the end of the last century, awareness of dependence of cancer metabolism on amino acids not only for protein syntheses but also for matching energy needs has grown. The roles of specific amino acids, like glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, there are epidemiological evidences that some amino acids used as supplement for therapeutic reasons (the branched chain ones) may reduce incidence of liver cancer, and some molecular mechanism has been proposed as functional to their protective action. On the contrary, metabolic signature of some pathology connected with increased risk of cancer, like prolonged hyperinsulinemia in insulin resistant patients, is signed by plasma elevated levels of the same branched chain amino acids, posing puzzling questions to clinicians. Most recently, peculiar formulations of amino acids, deeply different if compared to amino acids compositions normally present in foods, have shown the power to master epigenetics slowing growth or driving cancer cells to apoptotic death, while being even beneficial for normal cells and for animals health and life span. In this review, we will analyze and try to disentangle some of the many knots dealing with complexities of amino acids biology and linked to cancer metabolism.

The purpose of this study was to (a) compare macro- and micronutrient intakes between male and female CD patients (b) compare micronutrient intakes of CD patients to a representative population of healthy individuals, and; (c) describe Mediterranean diet scores (P-MDS) of male and female CD patients in remission recruited from an IBD clinic in Calgary, AB. Consecutive patients with ileal and/or colonic CD in endoscopic remission were recruited for participation in this cross-sectional study. Sixty-seven patients were enrolled, with a mean age of 45, and a BMI ≥ 25. Compared with the healthy population, patients with CD had similar energy, protein, carbohydrate and total fat intake. However, PUFA, omega-6 and 3 and MUFA were lower in CD patients and dietary fibre intake was higher. Vitamins C, D, thiamin, niacin, magnesium, phosphorus, zinc and potassium were all significantly lower in all CD patients compared to a healthy population. Few patients with CD met P-MDS criteria for olive oil, vegetable, legumes, and fish intake or consuming Sofrito sauce (mean 4.5, SD=1.1 in males and 4.7, SD=1.8 in females). Patients with CD in remission have suboptimal dietary intakes and patterns and targeted dietary interventions may be beneficial in this population to improve intake.

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative specific epitopes (OSEs), which are a first line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls.Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all 5 Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the ROC curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the PANSS negative score was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the 5 enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini Mental State Examination, Boston naming test, Verbal Fluency and Word List Memory test scores.These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.

Background: Hypoalbuminemia is known to be associated with adverse outcome in critical illness. In this study, we attempted to identify if hypoalbuminemia on emergency department (ED) arrival a reliable predictor for in-hospital mortality in necrotizing fasciitis (NF). patients. Method: A retrospective cohort study of hospitalized patients with NF was conducted in a tertiary teaching hospital in Taiwan between March 2010 and March 2018. Blood samples were collected in the ED upon arrival, and serum albumin levels were determined. we evaluated the predictive value of serum albumin level at ED presentation for in-hospital mortality. All collected data were statistically analyzed. Result: Of the 707 NF patients, 40 (5.66%) died in the hospital. The mean serum albumin level was 3.1 ± 0.9 g/dL and serum albumin levels were significantly lower in the non-survivor group than in the survivor group (2.8± 0.7 g/dL vs. 3.5 ± 0.8 g/dL). In the multivariable logistic regression model, albumin was associated with in-hospital mortality significantly (odds ratio[OR] 0.92, 95% confidential interval (CI) 0.88–0.96, P <0.001). The area under-the-receiver-operating-characteristic curve (AUC) for in-hospital survival was 0.77 (95% CI 0.72–0.82) and corresponding sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratio were 66%, 74%, 33%, 88%, 2.25 and 0.48, respectively. High sensitivity (96%) was shown at albumin level of 4.0 g/dL and high specificity (91%) was shown at level of 2.5 g/dL. Conclusion: Initial serum albumin levels were independently associated with in-hospital mortality among adult patients with necrotizing fasciitis and demonstrated fair discriminative performance in the prediction of in-hospital mortality. NF patients with hypoalbuminemia on ED arrival should be closely monitored for signs of deterioration and consider early and aggressive intervention to prevent mortality.

Exhaled breath condensate (EBC) sample analysis is an entirely non-invasive novel sample collection method that is fast, easy to perform, and effort-appeared independent. EBC samples can be very useful in identifying the biomarkers of many diseases. This review provides an updated overview of EBC pH disturbances in different disorders as well as physiological levels among healthy individuals since 2012. Our meta-analysis addresses some of the key questions related to sample processing before pH measurement and discusses various methods of condensate standardization that can be employed prior to conducting a pH assay. Given the recent widespread interest in research into the use of EBC to identify biomarkers, it is necessary to establish a pathway leading from analytical methods for biomarker evaluation using EBC pH to clinical applications of this technology. This review fills a gap in the literature and attempts to connect theory to practical analytical approaches to analyzing EBC samples and making critical treatment-related decisions next to the patient's bed.

Wingless-type MMTV integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation, axonal extension, synapse formation, neurogenesis and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as Lymphoid Enhancer Factor (LEF) and T Cell Factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. Here I focus on a “Wnt/β-catenin-glial connection” in Parkinson’s disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. I will summarize the work of the last decade documenting that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every levels in the regulation of nigrostriatal DAergic neuronal health, protection and regeneration in the MPTP mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.

The aim of this study was to examine pathologic complete response (pCR) and overall survival (OS) of patients diagnosed with non-metastatic inflammatory breast cancer (IBC). A total of N=8,550 cases undergoing surgery were identified between 2004-2013, using the National Cancer Database (NCDB). Patients were grouped into 4 biologic subtypes (HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-). The median age at diagnosis was 56 years. On average, women were followed for 3.7 years [interquartile range=3.0]. The majority were white (80%), had private health insurance (50%), and presented with poorly differentiated tumors (57%). Approximately 46% of the cancers were >5cm. Most patients underwent mastectomy (94%) and received radiotherapy (71%). Differences by biologic subtypes were observed for grade, lymph node invasion, race, and tumor size (p<.0001). Compared with non-pCR (54%), patients experiencing pCR had superior 5-year survival (77%) (p<.0001). Survival was poor for triple-negative (TN) tumors (37%) vs. other biologic subtypes (60%) (p<.0001). On multivariable analysis, TN-IBC, positive margins, and not receiving either chemotherapy, hormonal therapy or radiotherapy were independently associated with poor 5-year survival (p<.0001). In this large multicentric analysis of IBC, categorized by biologic subtypes, we observed significant differential tumor, patient and treatment characteristics, and OS.

Age-related macular degeneration (AMD) is a complex multifactorial disease and the primary cause of legal and irreversible blindness among individuals aged >=65 years in developed countries. Globally, it affects 30-50 million individuals, with an estimated increase of approximately 200 million by 2020 and approximately 300 million by 2040. Currently, the neovascular form may be able to be treated with the use of anti-VEGF drugs, while no effective treatments are available for the dry form. Many observational studies, such as AREDS-1 and AREDS 2, have shown a potential role of micronutrient supplementation in lowering the risk of progression of the early stages of AMD. Recently, low-grade inflammation, sustained by dysbiosis and a leaky gut, has been shown to contribute to the development of AMD. Given the ascertained influence of the gut microbiota in systemic low-grade inflammation and its potential modulation by macro- and micro-nutrients, a potential role of diet in AMD has been proposed. This review discusses the role of the gut microbiota in the development of AMD. Using PubMed, Web of Science and Scopus, we searched for recent scientific evidence discussing the impact of dietary habits (high fat and high glucose or fructose diets), micronutrients (vitamins C, E, and D, zinc, beta-carotene, lutein and zeaxanthin) and omega-3 fatty acids on the modulation of the gut microbiota and their relationship with AMD risk and progression.

BACKGROUND G6PD deficiency is an inherited an X-linked recessive condition leading to insufficient levels of glucose-6-phosphate dehydrogenase, thus causing hemolytic anaemia under certain conditions. METHODS Our study is explorative for cases admitted to Jordan University Hospital. The studied parameters include demographics, clinical manifestations, biochemical markers including Hb level, WBC count, liver enzymes, and blood grouping. RESULTS Most of the patients were admitted to the emergency unit (53.13%). Individuals who were Rh-positive represented 57.81%, while patients of AB blood group accounted for 75%. The mean values were 4.81 years (age), 29.06 hours (time-to-hospital admission), 38.10 degree Celsius (temperature), 6.11 gm/dl (Hb), 13242.19 (WBC count), 343.20 U/L (S. ALP), and 50.98 IU/L (S. ALT). There was no significant difference between males and females or between favism-induced versus drug-induced hemolytic episodes. AB and Rh positive blood groups are of protective effect in relation to liver enzymes. Patients who were admitted to the hospital within 24 hours from having clinical manifestations had a better prognosis. CONCLUSION This study is the first inferential research on G6PD deficiency from the Middle East to explore cases from one of the largest healthcare centres in Jordan. The role of blood grouping should be investigated prospectively.

The mechanization of agricultural activities has led to indiscriminate deposition of toxic xenobiotics, including organophosphates in the biomes, and this has led to intoxication characterized with deleterious oxidative and neuronal changes. This study investigated the consequences of oxidative and neurogenic disruptions that follow exposure to two organophosphates, chlorpyrifos (CPF) and dichlorvos (DDVP) on neuro-cognitive performance and anxiety-like behaviors in rats Thirty-two adult male Wistar rats (150 – 170g) were randomly divided into 4 groups, orally exposed to normal saline (NS), DDVP (8.8mg/kg), CPF (14.9mg/kg) and DDVP+CPF for 14 consecutive days. On day 10 of exposures, anxiety-like behaviors and amygdala dependent fear learning were assessed using Open Field and Elevated Plus Maze paradigms respectively, while spatial working memory was assessed on day 14 in the Morris water maze paradigm, following 3 training trials each on days 11, 12 and 13. On day 15, the rats were euthanized, and their brains excised, hippocampus and amygdala removed, 5 of which were homogenized and centrifuged to analyze nitric oxide (NO) metabolites, total reactive oxygen species (ROS), and acetylcholinesterase (AChE) activity, and the other three processed for histology (cresyl violet stain) and proliferative marker (Ki67 immunohistochemistry). Marked (p≤0.05) loss in body weight, AChE depletion, and overproduction of both NO and ROS were observed after repeated exposure to individual and combined doses of CPF and DDVP. Insults from DDVP exposure appeared more severe owing to the observed greater losses in the body weights of exposed rats. There was also a significant (p≤0.05) effect on the cognitive behaviors recorded from the exposed rats, and these deficits were related to the oxidative damage and neurogenic cell loss in the hippocampus and the amygdala of the exposed rats. Taken together, these results provided an insight that oxidative and neurogenic damages are central to the severity of neuro-cognitive dysfunction and increased anxiety-like behaviors that follow organophosphate poisoning.

In recent years, biomedical research has faced increased scrutiny over issues related to reproducibility and quality in scientific findings(1-3). In response to this scrutiny, funding institutions and journals have implemented top-down policies for grant and manuscript review. While a positive step forward, the long-term merit of these policies is questionable given their emphasis on completing a check-list of items instead of a fundamental re-assessment of how scientific investigation is conducted. Moreover, the top-down style of management used to institute these policies can be argued as being ineffective in engaging the scientific workforce to act upon these issues. To meet current and future biomedical needs, new investigative methods that emphasize collective-thinking, teamwork, shared knowledge and cultivate change from the bottom-up are warranted. Here, a perspective on a new approach to biomedical investigation within the individual laboratory that emphasizes collaboration and quality is discussed.

Celiac disease (CD) is a genetically conditioned autoimmune process that appears in susceptible people. It can affect people of any age, and slightly predominates in females. It has a fairly homogenous global distribution, with an average prevalence of 1-2%, the frequency having increased in recent decades. The only effective treatment is a strict and permanent gluten-free diet (GFD), although the level of compliance with it is poor, at about 50% of cases. To monitor the effectiveness of the GFD, several procedures involving various approaches are employed: a) periodic interviews by nutritionists; b) clinical follow-up; c) serological controls of specific antibodies; d) endoscopies with collection of duodenal biopsies; e) structured questionnaires; f) determination of gluten peptides derived from gluten in feces and/or urine. All of these procedures are useful when applied, alone or in combination, depending on the cases. Some patients will only need to consult to their doctors, while others will require a multidisciplinary approach to assess their compliance with the GFD. In children, normalization of duodenal mucosa was achieved in 95% of cases within 2 years, while it is more delayed in adults, whose mucosa take longer to heal completely.

S100A10, which is also known as p11 is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of 2 subunits of annexin A2 and S100A10, activates the plasminogen activation pathway which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin which promote degradation of the extracellular matrix, increased angiogenesis and invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4 fold increased risk of progression and 7.9 fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer, however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding on S100A10 function in cancer with a particular focus on ovarian cancer.

The primary and proven therapy, in cases of celiac disease (CD), is a rigorous gluten-free diet. However, there are reports of its negative effects in the form of nutritional deficiencies, obesity and adverse changes in body composition. The aim of the study was to assess the impact of a gluten free diet (GFD) on the body composition of children with CD. In a case-controlled study (n = 41; mean age 10.81 y; SD = 3.96) children with CD, in various stages of treatment, underwent medical assessment. The control group consisted of healthy children and adolescents, strictly matched for gender and age in a 1:1 case-control manner. More than half of the examined children (n = 26) followed a GFD. CD children had significantly higher mean values of the fat free mass (FFM% = 80.68 vs. 76.66, p = 0.015), and total body water (TBW% = 65.22 vs. 60.47, p = 0.012), and lower mean values of the fat mass (FM% = 19.32 vs. 23.34, p = 0.015). Children who were on a GFD presented slightly higher, but not statistically significant, mean values of FM and FFM, than children who did not follow dietary recommendations (FM [kg] = 7.48 vs. 5.24, p = 0.064; FM% = 20.81 vs. 16.73, p = 0.087; FFM [kg] = 28.19 vs. 22.62, p = 0.110). After minimum one year of a GFD, CD children showed significantly higher values of FFM [kg] (p = 0.001), MM [kg] (p < 0.001), TBW [L] (p < 0.001) and BCM [kg] (p < 0.001). Furthermore, CD children who were on a GFD presented significantly higher weight (p = 0.034) and body mass index (BMI) (p = 0.021) increase. The children adhering to a GFD demonstrate a tendency towards higher indices of selected body composition components.

Previous research suggests that the economic crisis can affect mental health. The purpose of this study was to analyse the association of risk of poor mental health with various socioeconomic, demographic, health, quality of life and social support variables; and to evaluate the contribution of socioeconomic variables most affected by the beginning of the economic crisis (employment situation and income) on the changes in the prevalence of the risk of poor mental health between 2005 and 2010. A study of prevalence evolution in adult population residents of the Valencian Community in the Spanish Mediterranean was conducted. We studied 5781 subjects in 2005 and 3479 in 2010. Logistic regression models have been adjusted to analyse the association between variables. A standardization procedure was carried out to evaluate which part of the changes in overall prevalence could be attributed to variations in the population structure by age, sex, employment status and income between the years under study. The prevalence of GHQ + increased from 2005 to 2010, in both men and women. Several variables were closely associated with the risk of poor mental health (sex, age, country of birth, number of non-mental chronic diseases, social support, disability, cohabitation in couple, employment status, and income). The changes produced as a result of the onset of the economic crisis in income and unemployment (increase in low income and in unemployment rates) contributed to the increase of poor mental health risk. This could confirm the sensitivity of mental health to the economic deterioration caused by the crisis.