Background: Schizophrenia and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased High Mobility Group Protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-Related Protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain-barrier and induce neurotoxic effects and neurocognitive deficits.Aim of the study: The present study aims to examine HMGB1 and DDK1 in non-responders to treatments with antipsychotics (NRTT, n=60), partial RTT (PRTT, n=55) and healthy controls (n=43) in relation to established markers of schizophrenia including IL-6, IL-10 and CLL11 (eotaxin); and to delineate whether these proteins are associated with the schizophrenia symptom subdomains and neurocognitive impairments.Results: HMGB1, DKK1, IL-6 and CCL11 were significantly higher in schizophrenia patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that schizophrenia was best predicted by increased DDK1 and HMGB1 while NRTT (versus PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism and negative (PHEMN) symptoms, and formal thought disorders was explained by HMGB1, IL-6, and CCL11 while most neurocognitive functions were predicted by HMGB1, DDK1 and CCL11. Conclusion: The neurotoxic effects of HMGB1, DKK1, IL-6 and CCL11 including effects on the blood-brain-barrier and the Wnt/β-catenin signaling pathway may cause impairments in executive functions, and working, episodic and semantic memory and explain, in part, PHEMN symptoms and a non-response to treatment with antipsychotic drugs.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of DIPG tumors contain a specific K27M mutation in one of two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p<0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p<0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

The purpose of this case study was to evaluate the benefits that evidence-based nutritional and training recommendations could have on the time course of reconditioning following hip arthroplasty in a competitive master triathlete. Methods: During 38 weeks (from 6 weeks prior to surgery through to the return to competition), the athlete was provided with detailed training and nutritional recommendations based on the latest research evidence. Dietary intake (via the remote food photographic method), body composition (via DXA), peak oxygen uptake (VO2peak), peak power output (PPO) and cycling efficiency (GE) were assessed 6 weeks pre- and 8, 12, 18, 21 and 25-weeks post-surgery. Training load was quantified (TRIMP score) daily during the retraining. Results: Total body mass increased by 8.2 kg (attributable to a 3.5 and 4.6 kg increase in fat mass and lean mass, respectively) between week -6 and week 8 despite a reduction in carbohydrate (CHO) intake post-surgery (<3.0g/kg/day). This was accompanied with a decrease in VO2peak, PPO, and GE due to a drop in training load. From week 7, the athlete resumed training and was advised to gradually increase CHO intake according to the demands of training. Conclusions: Eventually the athlete was able to return to competition in week 32 with a higher PPO, improved VO2peak and GE. Throughout retraining, energy availability was maintained around 30 kcal/kg LBM/day, protein intake was high while CHO intake was periodised. Such dietary conditions allowed the athlete to maintain and even increase lean mass, which represents a major challenge with ageing.

Short chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts is therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1-16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.

In this review, special emphasis will be placed on red grape polyphenols for their anti-oxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of pro-inflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Furthermore, the effects of red grape polyphenols will be analyzed in obesity, as a low grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood-brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great anti-oxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites and interaction with microbiota, deserve deeper studies.

Cervical cancer screening systems aim to detect established HPV infections early. However, if there are no high-grade lesions, the intervention choice is basically limited to observational follow-up with recommendations on life habits like diet, to favor infection control. Therefore, it is important to establish specific feeding guidelines that provide clear evidence about the benefit they may bring against HPV infections. The present study evaluates the benefits of nutritional supplementation with a casein hydrolysate-based formula in patients with HR-HPV infection, compared with a non-supplemented control group. A total of 118 patients completed 6 months of follow-up. Significant differences between supplemented and control groups were observed for total or partial HR-HPV clearance at 6 months (74.6% vs 35.6%). Supplemented patients also suffered a lower occurrence of new intracervical lesions (0% vs 28.6%), a significantly greater resolution (67.4% vs 41.9%) and less progression of pre-existing lesions (4.7% vs 9.7%) at 6 months. An increase in the effectors of cellular immunity that could be responsible for their effect was also observed in supplemented patients. We conclude that nutritional supplementation with this casein hydrolysate-based formula could improve the outcomes of observational management of HPV infection.

Premenstrual syndrome (PMS) frequently occurs in women of childbearing age. There are different case definitions of PMS, one proposed by the American College of Obstetricians and Gynecologists (ACOG) and another based on the Daily Record of Severity of Problems (DRSP) scores. Here we review our recent papers indicating that the discovery of biomarkers of menstrual cycle-related symptoms is strongly dependent on the case definitions used and that the gold standard methods used to asses PMS, including the ACOG case definition, induce a high degree of false-negative findings. We propose a new case definition of the menstrual cycle-associated syndrome (MCAS), which is characterized by increased DRSP scores during the menstrual cycle and additionally by an exaggerated increase in symptoms the week prior to the menses. This case definition performed well and was externally validated by diverse biomarkers including plasma levels of progesterone and estradiol, chemokines (e.g. CCL2, CCL5 and CCL11), epidermal growth factor, hydroperoxides, paraoxonase 1 activity and complement C4. In conclusion, when evaluating menstrual cycle-related symptoms and their associations with biomarkers, we propose to assess daily measurements of the DRSP and based on those scores to a) use the diagnosis of MCAS as an indicant of menstrual cycle-related symptoms; and b) examine the associations of the time series in the DRSP and its subdomains (e.g. depression, physio-somatic, anxiety) and those in biomarkers including distributed lag models.

Most diagnostic tests for tuberculosis (TB) rely on sputum samples, which are difficult to obtain and have low sensitivity in immunocompromised patients, patients with disseminated TB, and children, delaying treatment initiation. The World Health Organization (WHO) calls for the development of a rapid, biomarker-based, non-sputum test capable of detecting all forms of TB at the point-of-care to enable immediate treatment initiation. Lipoarabinomannan (LAM) is the only WHO-endorsed TB biomarker which can be detected in urine, an easily collected sample. This review discusses the characteristics of LAM as a biomarker, describes the performance of first-generation urine LAM tests and reasons for slow uptake, and presents considerations for developing the next-generation of more sensitive and impactful tests. Next-generation urine LAM tests have the potential to reach adult and pediatric patients regardless of HIV status or site of infection and facilitate global TB control. Implementation and scale-up of existing LAM tests and development of next-generation assays should be prioritized.

Purpose: The study is aimed to quantify the effects of social noise (personal music players (PMP), high-intensity noise exposure events) and road traffic noise exposures in the sample of Slovak university students living and studying in Bratislava. Methods: There were 1,003 university students (306 males and 697 females, average age 23.13±2) enrolled in the study; 347 lived in the student housing facility exposed to road traffic noise (LAeq =67.6 dB) and 656 in the control one (LAeq =53.4 dB). Respondents completed a validated ICBEN 5-grade scale “Noise annoyance questionnaire”. The exposure to PMP was objectified by the conversion of the subjective evaluation of the volume setting and duration. With the cooperation of the ENT specialist, we arranged audiometric examinations on the pilot sample of 41 volunteers. Results: From the total sample of 1,003 students, 794 (79.16 %) of them reported the use of PMP in the course of the last week; average time of 285 minutes. There was a significant difference in PMP use between the exposed (85.59 %) and the control group (75.76 %) (p=0.01). Among PMP users 30.7 % exceeded the LAV (lower action value for industry LAeq,8h = 80 dB). On a pilot sample of volunteers (n=41) audiometry testing was performed indicating a hearing threshold shift at higher frequencies in 22% of subjects. Conclusions: The results of the study on a sample of young healthy individuals showed the importance of exposure to environmental noise from different sources (transportation, neighborhood, construction, entertainment facilities, etc.) as well as social noise and the need for prevention and intervention.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an effective and widely used tool in the treatment of Parkinson’s disease (PD). STN-DBS has varied effects on speech. Clinical speech ratings suggest worsening following STN-DBS, but quantitative intelligibility, perceptual, and acoustic studies have produced mixed and inconsistent results. Improvements in phonation and declines in articulation have frequently been reported during different speech tasks under different stimulation conditions. Questions remain about preferred STN-DBS stimulation settings. Seven right-handed, native speakers of English with PD treated with bilateral STN-DBS were studied off medication at three stimulation conditions: stimulators off, 60 Hz (low frequency stimulation - LFS), and the typical clinical setting of 185 Hz (High frequency - HFS). Spontaneous speech was recorded in each condition and excerpts were prepared for transcription (intelligibility) and difficulty judgements. Separate excerpts were prepared for listeners to rate abnormalities in voice, articulation, fluency, and rate. Intelligibility for spontaneous speech was reduced at both HFS and LFS when compared to STN-DBS off. Speech produced at HFS was more intelligible than that produced at LFS, but HFS made the intelligibility task (transcription) subjectively more difficult. Both voice quality and articulation were judged to be more abnormal with STN-DBS on. STN-DBS reduced the intelligibility of spontaneous speech at both LFS and HFS but lowering the frequency did not improve intelligibility. Voice quality ratings with STN-DBS were correlated with the ratings made without stimulation. This was not true for articulation ratings. STN-DBS exacerbated an existing voice disorder and may have introduced new articulatory abnormalities.

The aim of the following paper was to determine the influence of soft tissue therapy on respiratory efficiency and chest mobility of women suffering from breast cancer. This study was a controlled randomized trial. Tests were carried out in a group of patients (n=49), who were hospitalized in the Province Polyclinic Hospital, Konin, Poland. In the study group, irrespective of the standard physical therapy program, an additional therapy program was run. The program consisted in applying specific techniques of soft tissue treatment. All patients in the each term were subject to pulmonary function test, chest mobility and pain assessment. Statistical analysis of the obtained results of spirometry and chest mobility assessment have revealed no differences in the analyzed parameters between the examined groups in the period of joint therapeutic treatment. In the period between the 3rd examination and the end of the 11-month- rehabilitation treatment, statistically significant differences were observed in the analyzed spirometry parameters, however, there was no difference in the parameters describing airflow in small airways (MEF₅₀,PEF) between individual groups, during consecutive examinations in the course of diversified therapeutic treatment. Chest mobility assessment of the patients, performed during diversified therapeutic treatment, revealed statistically significant differences between the groups. However, there was no difference between the examined groups, as far as pain sensation is concerned. Enhancing the regular rehabilitation program by including additional therapeutic methods, which are based on myofascial release and post-isometric relaxation techniques, had a beneficial effects regarding respiratory system efficiency.

Breast cancer is the most common cause of death for women worldwide. Thus, the ability of artificial intelligence systems to predict and classify breast cancer is very important. In this paper, a hybrid ensemble method classification mechanism is proposed based on a majority voting mechanism. First, the performance of different state-of-the-art machine learning classification algorithms for the Wisconsin Breast Cancer Dataset (WBCD) were evaluated. The three best classifiers were then selected based on their F3 score. F3 score is used to emphasize the importance of false negatives (recall) in breast cancer classification. Then, these three classifiers, simple logistic Regression learning, stochastic gradient descent learning and multilayer perceptron network, are used for ensemble classification using a voting mechanism. We also evaluated the performance of hard and soft voting mechanism. For hard voting, majority-based voting mechanism was used and for soft voting we used average of probabilities, product of probabilities, maximum of probabilities and minimum of probabilities-based voting methods. The hard voting (majority-based voting) mechanism shows better performance with 99.42% as compared to the state-of-the-art algorithm for WBCD.

Over the past five years, the popularity of dietary nitrates as an ergogenic device among athletes has increased significantly. Hypoxic and acidic conditions that occur during exercise facilitate the conversion of nitrite to nitric oxide (NO) and increase the physiological efficiency of exogenously produced nitrite. After a few years of our team predicted experiments, as a nitric oxide precursor, amaranth (Amaranthus hypochondriacus) was identified as a source of dietary nitrates (concentrations 9-11%). The aim of this study was to evaluate the effect of single-dose and long- term doses of dietary nitrates from amaranth concentrate on the aerobic capacity of physically active young persons. Thirteen healthy and physically active young participants were randomized to experimental and placebo groups using a increasing cycling exercise (ICE) and placebo- controlled design. Pulmonary gas exchange recording (oxygen uptake (VO 2 ), pulmonary ventilation (VE), respiratory exchange ratio (RER)) and analysis of blood lactate samples were obtained. Our findings indicate that the single dose of dietary amaranth (400 mg) significantly improved only the power of the test performance. Long-term (6 days) intake significantly increased the power of the test performance, the maximum oxygen consumption and the power of the test for the first ventilation threshold value (from 37.7±2.7 mL/kg/min during the first test to 41.2±5.4 mL/kg/min during the third test, p &lt;0.05).

The human innate immune response to the pore-forming toxin of Vibrio cholerae VCC, is currently under study. Here, in vitro studies on a human macrophage cell line (THP-1), helped explore the activated pathways involved on the onset the innate immune response towards the cytotoxin. The secreted monomeric 65 KDa form interacts with mature macrophages in pg/ml concentrations, determined by dose response experiments after treatments under 1 h. Non vacuolating concentrations (pg/ml) were applied to the cells; immunoblots revealed activation of MAPKs: early overexpression of p38 and ERK. Cell lysis by release of lactate dehydrogenase (LDH) was not apparent in the first hour, nonetheless it was positive after 24 h. Finally, to discern whether the VCC stimulates transcriptional activators via MAPKs pathway, NF-κB and AP-1 were studied by real time quantitation. Increased expression of p50 (NF-κB), cJun and cFos (AP-1) was observed. Given that NF-κB is the transcription factor initiating inflammation of innate immune response and in turn, AP-1 is responsible for cell surviving response, results from this study lead us to conclude that VCC in vitro treatments, induce a pro-inflammatory and a surviving response, in less than one hour on activated macrophages.

It is currently recognized that an injudicious strategy in the last decades has been not only focusing of research typically on caries in children, but also the narrow focusing on fluoride, because despite sufficient availability of fluoride in water and oral healthcare products, caries levels escalate steadily as people get older and caries remain a main public health issue to be settled. In the last two decades the scientific community intensified efforts of exploring other products for caries prevention, herbal products being one of these approaches. Because preliminary evidence indicated that clinical trials for caries prevention with herbal products are heterogeneous in design, quality and products evaluated, we performed a scoping review intended to explore the main characteristics of such clinical trials. From an initial collection of 1986 unique papers from different literature databases, 56 articles satisfied the inclusion and exclusion criteria. The species investigated, dosage forms, study designs, duration of intervention, controls, endpoints, quality of reporting and risk of bias are discussed. 85.71% of the trials reviewed here reported positive results but given the methodological flaws and biases affecting them, it is difficult to conclude on the efficacy of those products based on the studies published thus far.

We examined special roles of the Central Nervous System (CNS) in an attempt to resolve the puzzle that chronic diseases cannot be cured by medicine. By exploring a skill-learning model, we found that the CNS is able to remember certain information reflecting biochemical and cellular (B&C) processes in the body. From the skill using ability, we found that the CNS is able to control basic B&C processes that drive and power the skill. From the ability to adjust forces and force direction of a physical act, we found that the CNS is able to adjust B&C processes that drive the physical act. From this adjustment capability, we further inferred that the CNS must also store information on the baseline B&C processes. As a whole, we found that the CNS can maintain information on baseline B&C processes, up-regulate or down-regulate the processes, and make comparisons in performing its regulatory functions. We found that chronic diseases are the results of deviated baseline B&C processes. Per the proved hypothesis, the CNS maintains deviated baseline B&C processes, and thus protects the body states of fully developed diseases. We then used the three CNS roles to explain that cancer progresses with increasing malignancy, cancer quickly returns after a surgery, cancer cells repopulate after chemotherapy and radiotherapy, cancer develops drug resistance inevitably, immune cells rebound after suppression, generally poor benefits of cancer drugs such as beta-blockers, etc. We further showed that long-term exercises generally push most, if not all, baseline B&C processes in diametrical opposing directions against the diseased B&C processes, implying that exercises play unique roles in reversing chronic diseases. Finally, we proposed several strategical approaches to resetting the CNS’ state memory as the essential condition for curing chronic diseases.

After reviewing cancer theories, cancer treatment development histories, randomized clinical trial's performance, cancer treatment strategy, trial follow-up times, and conducting numerous simulations using existing data, the authors found: (1) medical treatments come with three to four lethal factors: treatment side-effects, emotional distress and chronic dress, lack of exercises or physical inactivity, and excessive nutrition in some cases; (2) clinical trial exaggerates the benefits of fast-acting treatments and underestimates the slow-delivering adverse side effects as a result of statistical averaging, interfering effects of personal lifestyle factors, and insufficient follow-up times; (3) the benefits of medical treatments are limited by chain comparison, where surgery sets up a negative standard relative to the best way for resolving cancer; (4) the strategy of destroying the tumor is unworkable; (5) medical treatments can turn natural cancer growth curve into approximately doubly exponential curve; (6) multiple factor non-medical measures are much more powerful than medical treatments in controlling cancer growth and metastasis rates; and (7) cancer early diagnosis and over treatments are bad strategies that have great adverse impacts on cancer patients. Based on huge increases in cancer growth rate constants, substantial of loss of organ functional capacity, and severe systemic aging-like cellular damages, the authors concluded that medical treatments promote cancer growth and metastasis rates and shorten patient lives in most cases, and the claimed benefits are caused by triple biases of clinical trials. The authors believe that the better strategy for ending the global cancer epidemic is abandoning clinical trails as the research model, changing caner treatment strategy from killing cancer cells to slowing down cancer growth rates by using multiple factors optimization approach in personalized medicine.

Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Contributing pathophysiologic factors include endothelial dysfunction caused by excessive production of reactive oxygen species (ROS), increased activity of nuclear factor kB (NFkB), altered macrophage polarization, and reduced synthesis of endothelial progenitor cells (EPC). Consequently, there can be a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque, leading to increased cardiovascular mortality. Management is aimed at prevention, early diagnosis, and treatment of hyperglycemia and vascular complications. Innovative therapeutic approaches for T2DM seek to customize the antidiabetic treatment to each patient in order to optimize glucose-lowering effects, minimize hypoglycemia and adverse effects, and prevent cardiovascular events. The newer drugs (Glucagon Like Peptide-1 Receptor Agonists, GLP-1 RAs; Sodium GLucose coTransporter-2 inhibitors, SGLT2is; DiPeptidyl Peptidase-4 inhibitors, DPP4is) impact body weight, lipid parameters, and blood pressure, as well as endothelial function, inflammatory markers, markers of oxidative stress, and subclinical atherosclerosis. The present review summarizes the results of trials that evaluated the cardiovascular safety of these drugs and found them to be safe from the CV standpoint.

Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis. One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahidrocannabinol and cannabinol have been noticed. The aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression.

Chronic diseases are still known as incurable diseases, and we suspect that the medical research model is unfit for characterizing chronic diseases. In this study, we examined accuracy and reliability required for characterizing chronic diseases, reviewed implied presumptions in clinical trials and assumptions used in statistical analysis, examined sources of variances normally encountered in clinical trials, and conducted numeric simulations by using hypothetical data for several theoretical and hypothetical models. We found that the sources of variances attributable to personal differences in clinical trials can distort hypothesis test outcomes, that clinical trials introduce too many errors and too much inaccuracies that tend to hide weak and slow effects of treatments, and that the means of treatments used in statistical analysis have little or no relevance to specific patients. We further found that a large number of uncontrolled co-causal or interfering factors normally seen in human subjects can greatly enlarge the means and the variances of the experimental errors, and the use of high rejection criteria (e.g., low p values) further raises the chances of failing to find treatment effects. As a whole, we concluded that the research model using clinical trials is wrong on multiple grounds, under any of our realistic theoretical and hypothetical models, and that misuse of statistical analysis is most probably responsible for failure to identify treatment effects for chronic diseases and to detect harmful effects of toxic substances in the environment. We proposed alternative experimental models involving the use of single-person or mini optimization trials for studying low-risk weak treatments.

Our previous studies demonstrated that quercetin (Q) could be ingested and metabolized by macrophages and exerted prophylactic immuno-stimulatory activity and therapeutic anti-inflammatory effects on lipopolysaccharide (LPS)-treated macrophages ex vivo. To further clarify its possible anti-inflammatory mechanism, Q was selected to treat mouse peritoneal macrophages that obtained from female BALB/c mice exposed to LPS i.p. for 12 h. Relative gene expression of pro-/anti-inflammatory (TNF-α/IL-10) cytokines and components of inflammation-related intracellular signaling pathways (TLR2, TLR4, NF-κB, JAK2 and STAT3) was analyzed using two-step reverse transcription (RT) and real-time quantitative polymerase chain reaction (qPCR). STAT3 protein phosphorylation was determined using an in-cell ELISA method. As a result, Q and its metabolite quercetin-3-O-β-D-glucuronide (Q3G) decreased TNF-α gene expression amounts and ratios of pro-/anti-inflammatory (TNF-α/IL-10) cytokine gene expressions, but increased IL-10 gene expression amounts in activated inflammatory macrophages, supporting a substantial anti-inflammatory potential of Q and Q3G treatments. However, Q3G had lower effects than those of Q. Importantly, Q inhibited TLR2 gene expression and phosphorylation of STAT3 protein in the inflamed cells. Our results are the first report to suggest that Q inhibits LPS-induced inflammation ex vivo through suppressing TLR2 gene expression and STAT3 protein phosphorylation in activated inflammatory macrophages. Q has potential to further apply for treating inflammation-associated diseases.

Hizikia fusiformis is a common, edible marine alga found in Asia. Although the anticancer activity of its extracts has previously been investigated, its active compounds have not been identified. In this study, saringosterol acetate (SA) was isolated from H. fusiformis extracts by centrifugal partition chromatography (CPC) system (two phase solvents condition: n-hexane:ethyl acetate/methanol:water = 5:3:7:1, v/v), exhibited anticancer effects in the human lung adenocarcinoma epithelial cell line, A549, by inducing apoptosis and sub-G1 phase cell cycle arrest. In addition, SA increased the expression of the pro-apoptotic proteins, Bax and cleaved caspase 3, and decreased that of the anti-apoptotic protein Bcl-xL. Although, SA did not affect the expression of p53, induces expression of Bid and caspase 8. In conclusion, we suggested that SA induces apoptosis against A549 cells via Bid and caspase 8 dependent pathway.

Relapsed leukemia following initial therapeutic response and remission is difficult to treat and causes high patient mortality. Leukemia relapse is due to residual quiescent leukemia cells that escape conventional therapies and later reemerge. Eliminating not only growing but quiescent leukemia cells is critical to effectively treating leukemia and preventing its recurrence. Such therapeutic agents, however, are lacking in the clinic. Here we report that a 4-arylmethyl derivative of the natural anticancer compound curcumin demonstrates a dual effect in eliminating both growing and quiescent leukemia cells. This curcumin derivative, C212, on the one hand, inhibits growing leukemia cells at a higher efficacy than curcumin by inducing apoptosis and cell cycle arrest; it, on the other hand, kills quiescent leukemia cells that are resistant to conventional chemotherapy drugs. Furthermore, C212 drives leukemia cells into and kills them at deep quiescence, avoiding the potential risk associated with awaking therapy-resistant subpopulation of quiescent leukemia cells. Lastly, we show that C212 induces apoptosis and drives cells into deep dormancy at least partially by binding to and inhibiting Hsp90, leading to client protein degradation and protein aggregation. Further elucidating the molecular mechanisms underlying the dual function of C212 in eliminating both growing and quiescent leukemia cells will aid the development of novel therapies against leukemia relapse.

BRCA-associated hereditary breast and ovarian cancer syndrome (HBOC) implies increased absolute risk also for other malignancies such as cholangiocarcinoma (CCA). However, even if somatic mutations in CCA have been reported, there are no data on its utilization as predisposing genetic factor in a family. For the first time, we utilized CCA somatic BRCA mutation to individualize a family with HBOC. A 47-year-old woman (daughter of a patient died for CCA) accessed to our Genetic Councelling to evaluate her personal cancer risk. We performed a somatic BRCA1/2 NGS analysis on DNA extracted from formalin-fixed, paraffin-embedded CCA-tissue of her mother. After demonstration of pathogenic variant c.6468_6469delTC in BRCA2 gene mutation, the same germline pathogenic variant was found in DNA blood of one of two daugthers. So far, CCA tissue can be utilized, in addition to patient’s selection to specific therapeutic strategies, also to individualize families belonging to HBOC syndrome.

Serious outbreaks of foodborne disease have been caused by Listeria monocytogenes found in retail delicatessens and the severity of disease is significant, with high hospitalization and mortality rates. Little is understood about the formidable public health threat of L. monocytogenesin all four niches, humans, animals, food and environment in Egypt. This study analyzed the presence of L. monocytogenes collected from the four environmental niches and bioinformatic analysis was implemented to analyze and compare the data. PCR was used to detect virulence genes encoded by pathogenicity island (LIPI-1). prfA amino acid substation that causes constitutive expression of virulence was common in 77.7% of isolates. BLAST analysis did not match other isolates in the NCBI database suggesting this may be a characteristic of the region associated with these isolates. A second group included the NH1 isolate originating in China, and BLAST analysis showed this prfA allele was shared with isolates from other global locations such as Europe and North America. Identification of possible links and transmission pathways between the four niches, helps to decrease the risk of disease in humans, to take more specific control measures in the context of disease prevention, to limit economic losses associated with food recalls and highlightens the need to treatment options.

This study assessed bio-equivalence of high-quality, plant-based protein blends versus Whey Protein Isolate (WPI) in healthy, resistance-trained men. The primary endpoint was incremental area under the curve (iAUC) of blood essential Amino Acids (eAAs) 4 hours after consumption of each product. Cmax and Tmax of blood leucine were secondary outcomes. Subjects (n=18) consumed three plant-based protein blends and WPI (control). Analysis of Variance model was used to assess for bio-equivalence of total sum of blood eAA concentrations. The total blood eAA iAUC ratios of the three blends were: [90% CI]: #1: 0.66 [0.58-0.76]; #2: 0.71 [0.62-0.82]; #3: 0.60 [0.52-0.69], not completely within the pre-defined equivalence range [0.80-1.25], indicative of 30-40% lower iAUC versus WPI. Leucine Cmax of the three blends was not equivalent to WPI, #1: 0.70 [0.67-0.73]; #2: 0.72 [0.68-0.75]; #3: 0.65 [0.62 – 0.68], indicative of a 28-35% lower response. Leucine Tmax for two blends were similar to WPI (#1: 0.94 [0.73-1.18]; #2: 1.56 [1.28-1.92]; #3: 1.19 [0.95-1.48]). The plant-based protein blends were not bio-equivalent. However, blood leucine kinetic data across the blends approximately doubled from fasting concentrations whereas blood Tmax data across two blends was similar to WPI. This suggests evidence of rapid hyperleucinemia, which correlates with a protein’s anabolic potential.

Ulmus species have been widely used in Korean folk medicine because of their anti-inflammatory and antimicrobial properties. We intended to investigate the wound healing effect of the powder of Ulmus parvifolia (UP) root bark in a mouse wound healing model. We also determined the mechanisms of effects of Ulmus parvifolia (UP) in skin and skin wound healing effect using keratinocyte model. in vivo experiments showed that the wound lesions in the mice decreased by U. parvifolia with 200 mesh size of root bark powder and significantly reduced by treatment with UP, compared with those treated with U. macrocarpa (UM). Results from in vitro experiments also revealed that UP extract promoted the migration of human skin keratinocytes. UP powder treatment upregulated the expression of the matrix metalloproteinase-2 and -9 protein and significantly increased transforming growth factor (TGF)-β levels. We confirmed that topical administration of the bark powder of exerted a significant effect on skin wound healing by upregulating the expression of MMP and transforming growth factor-β. TGF-β In, Our study suggests that U. parvifolia may be a potential candidate for skin wound healing including epidermal skin rejuvernation.

In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.

Tryptanthrin has not been widely applied in clinical practice due to its poor solubility and low bioavailability in spite of possessing several biological and pharmacological activities. Here, to improve the solubility of tryptanthrin, two types of novel tryptanthrin-loaded micelles were prepared. One was tryptanthrin physically encapsulated by distearoyl phosphatidylethanolamine polyethylene glycol (DSPE-PEG) and the other was pegylated tryptanthrin synthesized by acid-sensitive hydrazone bond and further prepared as micelles. Molecular imprinting technology was used to separate pegylated tryptanthrin and free mPEG-COOH in the preparation of PEGylated tryptanthrin micelles with considerably high separation efficiency. The solubility of tryptanthrin-loaded DSPE-PEG micelles (TDMs) and PEGylated tryptanthrin micelles (PTMs) was increased by 300 and 1493 fold compared with that of tryptanthrin, respectively. The PTMs increased the solubility of tryptanthrin more effectively and 95% of tryptanthrin was released from PTMs at pH 5.5 in 12 h. The cytotoxicity of PTMs decreased under physiological conditions compared with that of tryptanthrin, whereas at pH 5.5, the PTMs showed comparable cytotoxicity with that of tryptanthrin, indicating successful drug release from the carrier in response to tumor cell pH. Overall, we elucidated an efficient method to improve water solubility of tryptanthrin and indicated pegylated tryptanthrin is a promising prodrug.

The purpose of this prospective study was to evaluate the usefulness of interstitial magnetic resonance lymphography (MRL) with superparamagnetic iron oxide (SPIO) in sentinel lymph node (SLN) mapping of clinically N0 early oral cancer, and to conduct a comparative study of this MRL with computed tomography lymphography (CTL). CTL and MRL was performed for SLN mapping before surgery for 24 patients with clinically N0 early oral cancer. SLNs were detected by CTL in 21 (87.5%) patients, and the total and mean number of SLN were 45 and 1.9, respectively. All SLNs could be detected 2 min and 3.5-5 min after contrast medium injection. In all patients, SLNs were detected by MRL at 10 min after SPIO injection, and the total and mean number of SLN was 66 and 2.8, respectively. MRL at 30 min after the injection showed additional 2 secondary lymph nodes. Interstitial MRL with SPIO is safe and useful imaging for detection of SLNs in clinically N0 early oral cancer, and the optimal imaging timing is 10 min after SPIO injection.

BACKGROUND: During the natural history, the incidence HTLV-1 related diseases were 0.5% until 10% after decades of infection. Despite relative low lethality, previous study observed that HTLV-1 infection is associated with significantly increased mortality. For example, the incidence of ATLL and HAM/TSP, co-infections with HIV and HCV, parasitic co-infection with Strongyloides stercoralis may increase morbidity and mortality. OBJECTIVE: Determine the mortality rate and its major variables as possible risk factors, analyzing the HTLV Clinic at Emilio Ribas Institute, a continuous open cohort of HTLV patients since 1997. METHODS: This cohort open cohort possesses new patients added at a rate of approximately 50 patients/year. There were 1100 HTLV-infected subjects identified by September 30th 2018. All clinical data including clinical and laboratory data, which have been updated on a regular basis over the last 22 years, were entered into a specific REDCap database. The Ethical Board of the IIER approved the protocol. RESULTS: Along 22 years of clinical care in the HTLV-out clinic, 727 HTLV-1-infected subjects and 248 HAM/TSP cases. Four-hundred sixty-eight patients of whom remaining under active follow up. The mean follow-up time of the cohort was 12 years. Twenty-seven patients died (median age of 51,5 years old). From this total, 13 was asymptomatic carriers and 14 HAM/TSP subjects, 12 of asymptomatic and seven HAM/TSP possess co-infected with HIV or/and HCV. Other seven presented HAM/TSP without co-infection, and all was female, and sepsis was the majority cases the majority of cases of sepsis were related to infection of the urinary tract (p=0.058) and to ulcers of decubitus (p=0.021), and it was associated with risk factors for mortality. CONCLUSIONS: Overall, the mortality rate for HAM-TSP patients was six percent. The mean life expectancy in Brazil is about 78 years in 2018, twenty-two years higher than HAM/TSP patients without any other coinfection. This study highlights the possibility of higher death risk among HTLV-1-infected patients and HAM/TSP subjects in Brazil, and identified some risk factors for this outcome. Also, these patients may possess higher risk for morbidity, usually urinary tract infections and decubitus scars, which could increase risk for death.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Disease related malnutrition (DRM) is prevalent in hospitals and is associated with increased care needs, prolonged hospital stay, delayed rehabilitation and death. Nutrition care process related activities such as screening, assessment and treatment has been advocated by scientific societies and patient organizations but implementation is variable. We analyzed the cross-sectional nutritionDay database for prevalence of nutrition risk factors, care processes and outcome for medical patients. In 59126 medical patients included between 2006-2015 the prevalence of recent weight loss (45%), history of decreased eating (48%) and low actual eating (53%) was more prevalent than low BMI (8%). Each of these risk factors was associated with a large increase in 30 days hospital mortality. Nutrition care processes increases slightly with presence of risk factors but never done in more than 50% of patients. Only a third of patients not eating in hospital receive oral nutritional supplements or artificial nutrition. We suggest that political action should be taken to raise awareness and formal education on all aspects related to DRM for all stakeholders, to create and support responsibilities within hospitals, and to create adequate reimbursement schemes. Collection of routine and benchmarking data is crucial to tackle DRM.

Malignant mesothelioma is a rare proliferative cancer that develops in the thin layer of tissues surrounding the lungs. Malignant mesothelioma is associated with an extremely poor prognosis and the majority of patients do not show symptoms. The epidemiology of mesothelioma is important for the identification of disease. The primary aim of this study is to explore the risk factors associated with mesothelioma. The dataset consists of healthy and mesothelioma patients but only mesothelioma patients were selected for the identification of symptoms. The raw data set has been pre-processed and then the Apriori method was utilized for association rules with various configurations. The pre-processing task involved the removal of duplicated and irrelevant attributes, balanced the dataset, numerical to the nominal conversion of attributes in the dataset and creating the association rules in the dataset. Strong associations of disease’s factors; asbestos exposure, duration of asbestos exposure, duration of symptoms, erythrocyte sedimentation rate and Pleural to serum LDH ratio determined via Apriori algorithm. The identification of risk factors associated with mesothelioma may prevent patients from going into the high danger of the disease. This will also help to control the comorbidities associated with mesothelioma which are cardiovascular diseases, cancer-related emotional distress, diabetes, anemia, and hypothyroidism.

Incident rates of neurodegenerative diseases have steadily increased globally, but there is no therapeutic access available. We newly prescribed medicinal herbal remedy including five different herbal plants called, Chen-Ma-Dan-Sam-Ga-Mi-Bang (CMST), purposed to prove for pharmacological properties and corresponded actions on hippocampus neuronal cell injury by hypoxia-induced mice model. Mice were adapted to normoxia or hypoxia with or without CMST for 5 days. We gathered pharmacological effects of CMST on cell injury by enhancement of dihydroethidium and 4-hydroxynonenal signals which were correlated with abnormal redox status in the protein or gene expression levels (abnormal elevations of nitric oxide, reactive oxygen species, lipid peroxidation and deteriorations of total glutathione, total antioxidant capacity, and activities of superoxide dismutase and catalase) due to hypoxia. CMST also notably exerted to attenuates molecules for neuronal cell injury markers such as p-tau, cleaved caspase-3 due to DNA oxidations (53bp1and phosphor-histone H2AX), inflammatory cytokines, and hemeoxigenase-1. We further figured out the underlying actions of CMST by in vitro experiment through inactivation of microglial cell which can mediate neuronal cell injury. Collectively, CMST prevented from hippocampal neuronal cells via inactivation of microglial cell with normalization of redox status on hypoxia-induced hippocampus neuronal cell injury.

Background: Elucidation of epigenetic mechanisms correlating with neuropathic pain in humans is crucial for the prevention and treatment of this treatment-resistant pain state. In the present study, associations between neuropathic pain characteristics and DNA methylation of the transient receptor potential ankyrin 1(TRPA1) gene were evaluated in chronic pain patients and preoperative patients. Methods: Pain and psychological states were prospectively assessed in patients who suffered chronic pain or were scheduled for thoracic surgery. Neuropathic characteristics were assessed using the Douleur Neuropathique 4 (DN4) questionnaire. DNA methylation levels of the CpG island in the TRPA1 gene were examined using whole blood. Results: Forty-eight adult patients were enrolled in this study. Increases in DNA methylation rates at CpG -51 showed positive correlations with increases in the DN4 score both in preoperative and chronic pain patients. Combined methylation rates at CpG -51 also significantly increased together with increase in DN4 scores. Conclusions: Neuropathic pain characteristics are likely associated with methylation rates at the promoter region of the TRPA1 gene in human peripheral blood.

Viral diseases are one of the leading causes of morbidity and mortality in the world. Broad-spectrum antiviral agents (BSAAs) are key players in control of human viral diseases. Here, we reviewed the discovery and development process of BSAAs, focusing on compounds with available safety profiles in human. In addition, we summarized the information on approved, investigational and experimental safe-in-man BSAAs in freely accessible database at https://drugvirus.info/. The number of approved BSAAs will be increased as well as their spectrum of indications will be expanded pending the results of further pre-clinical and clinical studies. This will ultimately reinforce the arsenal of available antiviral options and provide better protection of general population from emerging and re-emerging viral diseases.

Seirogan, a wood creosote, is a nonprescription drug used to treat diarrhea. However, reports of its clinical use are rare. Here, we report on the efficacy of wood creosote (3 capsules daily) for the alleviation of diarrheal symptoms in 148 patients from 10 clinics in Japan. The wood creosote capsules were classified as remarkably effective (44 patients), effective (71 patients), and partially effective (13 patients) based on the degree of alleviation of diarrheal symptoms that were induced by a variety of causes. The antidiarrheal efficacy of the capsules did not differ between males and females, and young patients (21–30 years) showed greater improvement in diarrheal symptoms than did old patients (> 61 years). Although this report is based on the re-evaluation of old data that had been preserved by our company, the effectiveness and range of symptoms that were treatable with wood creosote has likely remained unchanged. To the best of our knowledge, this is the first public report on the clinical effectiveness of wood creosote capsules for the treatment of a wide range of diarrheal symptoms.

BACKGROUND: During the natural history, the incidence HTLV-1 related diseases were 0.5% until 10% after decades of infection. Despite relative low lethality, previous study observed that HTLV-1 infection is associated with significantly increased mortality. For example, the incidence of ATLL and HAM/TSP, co-infections with HIV and HCV, parasitic co-infection with Strongyloides stercoralis may increase morbidity and mortality. OBJECTIVE: Determine the mortality rate and its major variables as possible risk factors, analyzing the HTLV Clinic at Emilio Ribas Institute, a continuous open cohort of HTLV patients since 1997. METHODS: This cohort open cohort possesses new patients added at a rate of approximately 50 patients/year. There were 1100 HTLV-infected subjects identified by September 30th 2018. All clinical data including clinical and laboratory data, which have been updated on a regular basis over the last 22 years, were entered into a specific REDCap database. The Ethical Board of the IIER approved the protocol. RESULTS: Along 22 years of clinical care in the HTLV-out clinic, 727 HTLV-1-infected subjects and 248 HAM/TSP cases. Four-hundred sixty-eight patients of whom remaining under active follow up. The mean follow-up time of the cohort was 12 years. Twenty-seven patients died (median age of 51,5 years old). From this total, 13 was asymptomatic carriers and 14 HAM/TSP subjects, 12 of asymptomatic and seven HAM/TSP possess co-infected with HIV or/and HCV. Other seven presented HAM/TSP without co-infection, and all was female, and sepsis was the majority cases the majority of cases of sepsis were related to infection of the urinary tract (p=0.058) and to ulcers of decubitus (p=0.021), and it was associated with risk factors for mortality. CONCLUSIONS: Overall, the mortality rate for HAM-TSP patients was six percent. The mean life expectancy in Brazil is about 78 years in 2018, twenty-two years higher than HAM/TSP patients without any other coinfection. This study highlights the possibility of higher death risk among HTLV-1-infected patients and HAM/TSP subjects in Brazil, and identified some risk factors for this outcome. Also, these patients may possess higher risk for morbidity, usually urinary tract infections and decubitus scars, which could increase risk for death.

Background: Sacubitril/valsartan has been shown to be superior to enalapril in reducing the risks of death and hospitalization for heart failure (HF). However the effect on cardiac performance remains unknown. We sought to evaluate the effects of sacubitril/valsartan on clinical, bioumoral and echocardiographic parameters in patients with HFrEF. Methods: Sacubitril/valsartan was administered to 205 HFrEF patients. Results: Among 230 patients (mean age 59 ± 10 years, 46% with ischemic heart disease) 205 (89%) completed the study. After a follow–up of 10.49 (2.93±18.44) months, the percentage of patients in NYHA class III changed from 40% to 17% (p<0.001). Median N–Type natriuretic peptide (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205 pg/mL, (p=0.01). Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p=0.047). Ejection fraction (from 27± 5.9% to 30 ± 7.7% (p<0.001) and E/A ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p=0.002)) improved. Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p=0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/sec to 2.64 ± 0.59 m/sec (p<0.014). CONCLUSIONS: Sacubitril/valsartan induce “hemodynamic reverse remodeling” and in association with Nt-proBNP concentrations lowering improve NYHA class despite a diuretic dose reduction.

Suicide is a major public health concern in South Korea, and self-poisoning by pesticides is one of the common methods of suicide. Pesticide ban policies have been successful for suicide prevention; however, no studies have shown their effect according to occupational groups. The present study analyzed suicide and suicide by pesticide rates among South Korean workers age 15-64 in 2003-2017, their associations with occupational groups, and the impact of three major economic indices on these factors. Workers in the agriculture, forestry, and fishery industries have relative risks of 5.62 (95% CI: 5.54-5.69) for suicide overall and 25.49 (95% CI: 24.46-26.57) for suicide by pesticide. The real gross domestic product (RGDP) has a positive association with suicide overall only in the last five-year period investigated in this study, and the unemployment rate consistently has a positive association. The economic status and policy for suicide prevention affect suicide and suicide by pesticide rates differently among occupational groups and different time periods. Policy addressing suicidal risk for different occupational groups should be of concern in South Korea.

Targeted radioisotope-guided sentinel lymph node dissection (sLND) has shown high diagnostic accuracy in prostate cancer (PCa). To overcome the downsides of the radioactive tracers, magnetometer-guided sLND using superparamagnetic iron oxide nanoparticles (SPIONs) was successfully applied in PCa. This prospective study (SentiMag Pro II, DRKS00007671) determined the diagnostic accuracy of magnetometer-guided sLND in intermediate- and high-risk PCa. Fifty intermediate- or high-risk PCa patients (PSA≥10 ng/ml and/or Gleason score ≥7; median PSA 10.8 ng/ml, IQR 7.4–19.2 ng/ml) were enrolled. After intraprostatic SPIONs injection a day earlier, patients underwent magnetometer-guided sLND and eLND, followed by radical prostatectomy. SLNs were detected in vivo and in ex vivo samples. Diagnostic accuracy of sLND was assessed using eLND as the reference. SLNs were detected in all patients (detection rate 100%), with 447 SLNs (median 9, IQR 6–12) being identified and 966 LNs (median 18, IQR 15-23) being removed. Thirty-six percent (18/50) of patients had LN metastases (median 2, IQR 1–3). Magnetometer-guided sLND had 100% sensitivity, 97.0% specificity, 94.4% positive predictive value, 100% negative predictive value, 0.0% false negative rate, and 3.0% additional diagnostic value (LN metastases only in SLNs outside the eLND template). In vivo, one positive SLN/LN-positive patient was missed, resulting in a sensitivity of 94.4%. In conclusion, this new magnetic sentinel procedure has high accuracy for nodal staging in intermediate- and high-risk PCa. The reliability of intraoperative SLN detection using this magnetometer system requires verification in further multicentric studies.

Background: Pressure ulcers (PU) affect millions of people worldwide and always occur over bony areas of the body where pressure and tissue distortion is greatest. The national pooled prevalence of pressure ulcer remains unknown. Hence, the aim of this meta-analysis was to determine the effect of position change on pressure ulcer among hospitalized clients in Ethiopia. Methods: Studies were retrieved through search engines in PubMed, Scopus, WHO afro library, Google Scholar, Africa journal online, PsycINFO and web-science following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Analysis was done using STATA version 14 software. We checked the between-study heterogeneity using the I² and examined a potential publication bias by visual inspection of the funnel plot and Egger’s regression test statistic. The random-effect model was fitted to estimate the summary effects, odds ratios (ORs), and 95% confidence interval (CIs) across studies. Results: Out of the reviewing 401 studies, 7 studies fulfilled the inclusion criteria and were included in the meta-analysis. The estimated pooled prevalence of pressure ulcer in Ethiopia was 11.7% (95% CI (7.28, 16.13%)). Based on the subgroup analysis, the estimated magnitude of pressure ulcer was 15.89% (95% CI: 35.34, 54.04) among studies their sample size were greater than or equals to 250. Those clients who have position change during hospitalization were 85% less likely to develop pressure ulcer [(OR 0.15, 95%CI (0.06, 0.4)] than their counter part. Conclusion: The overall prevalence of pressure ulcer in Ethiopia was relatively high. Position change of the client during hospitalization had paramount benefit to reduce the burden of pressure ulcer. Therefore, policymakers could give special attention to minimize the magnitude of pressure ulcer in order to improve the overall quality of healthcare service. Further meta-analysis study is need to identify individual and health care service related factors to the occurrence of pressure ulcer.

Lung transplantation offers patients with end stage lung disease an opportunity for a better quality of life, but with limited organ availability it is paramount that selected patients have the best opportunity for successful outcomes. Nutrition plays a central role in post-surgical outcomes and historically, body mass index (BMI) has been used as the de facto method of assessing a lung transplant candidate’s nutritional status. Here we review the historical origins of BMI in lung transplantation, summarize the current BMI literature, and review studies of alternative/complementary body composition assessment tools, including lean psoas area, creatinine-height index, leptin, and dual x-ray absorptometry. These body composition measures quantify lean body mass versus fat mass and may provide a more comprehensive analysis of a patient’s nutritional state than BMI alone.

Background: Effectiveness of Anastrozole and levonorgestrel-releasing intrauterine device (LNG-IUD, Mirena®) in the treatment of endometriosis. Methods: Randomized clinical trial. Elegibility criteria: Endometriomas >3×4 cm, CA-125>35 U/mL and symptoms suggestive of endometriosis. Thirty-one women were randomized to anastrozole+Mirena®+Conservative Surgery(CS) (n=8), anastrozole+Mirena®+transvaginal ultrasound-guided puncture-aspiration(TUGPA) (n=7), Mirena®+CS (n=9), or Mirena®+TUGPA (n=7). Interventions: Anastrozole 1 mg/day and/or only Mirena® for 6 months. CS or TUGPA one month after starting medical treatment. Results: A significant improvement in symptoms during the treatment (difference of 43%, 95% CI 29.9-56.2) occurred, which was maintained at 1 and 2 years. It was more significant in patients treated with anastrozole. For CA-125, the most significant decrease was observed without anastrozole. After CS for endometriosis, a reduction of findings of endometriomas and long-term recurrences occurred, with or without anastrozole, although anastrozole seems to delay recurrences. At 4,2±1,7 years, 88% of the patients who underwent CS were asymptomatic, compared to only 21% if TUGPA was performed, with or without anastrozole (p=0.019). Conclusion: Dosing anastrozole for 6 months, starting one month before CS of endometriosis, reduces more significantly the painful symptoms and delays recurrences, but has no other significant advantages over the single insertion of LNG-IUD (Mirena®) during the same time.

Chronic diseases are the priorities for the health care system and patient-centered care. Because, chronic diseases could cause a disabling which has impacts physically, socially and psychologically. Chronic diseases needs to ongoing care and support to assist patients’ self-management. The aim is to understand the experiences of the treatment of patients with chronic conditions who were able to practice self-management. Within the scope of the phenomenological approach, was carried out in Izmir/Turkey province 10 patients with a chronic disease (e.g., hypertension, diabetes, arthritis) who attended a family health care center. Three main themes were identified, namely social support, disease management, and self-awareness and empowerment. It was determined that the disease management, self-awareness and empowerment sub-themes (chronic disease definition, perceived barriers, emotional and spiritual state, self-monitoring, dietary and medication management) had a significant effect on the self-management. The results have demonstrated that patients’ health outcomes can be affected patients’ experiences and behaviors in the chronic conditions self-management. Planning for self-care programs should be provided by health care professionals, taking into account the variables that affect patients’ self-management of their disease.

In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. The use of small molecules, called pharmacological chaperones (PCs), that can restore the folding, trafficking and biological activity of mutated enzymes has been extensively explored in LSDs as a therapeutic alternative. PCs have the advantage of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules, mainly based in molecules mimicking the enzyme substrates, have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of the identified PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

The vegan diet excludes animal-derived product consumption and health advantages had been reported when followed. However, heterogeneous eating habits, food availability, and sociocultural characteristics among regions could lead to different physiological results. The objective of this case-control cross-sectional pilot study was to analyze body composition, daily nutrients consumption, and basic serum biomarkers as a general overview of the health status of Mexican adults with a vegan diet for ≥3 years, randomly paired with omnivores. Body composition was assessed through bioelectric impedance analysis. Eating patterns were evaluated and daily nutrients intake was calculated. A complete blood count, glycated hemoglobin, cobalamin, and creatinine serum concentrations were analyzed. We hypothesized certain nutrient deficits and specific biomarker impairments originated from cultural particularities driving food selection in Mexicans following a plant-based diet. Body composition did not differ among groups. Lower protein, niacin, pantothenic acid, pyridoxine, cobalamin, calciferol, fluoride, iodine, and selenium intake yet greater fiber, folic acid, vitamin E, copper, and molybdenum were observed in the plant-based group when compared with controls. Vegans presented lower cobalamin and creatinine serum concentrations. Hematologic abnormalities were prevalent in vegans. Insufficient consumption of several nutriments was identified in both dietary groups, suggesting that the local diet may be unbalanced, affecting both vegans and non-vegan individuals. However, vegans might present additional deficiencies, especially vitamin B₁₂, with potential repercussions. Clinical and nutritional guidance is required in this particular population to avoid possible health adverse events.

This study measures the noise levels in a baseball stadium and analyzes baseball fans’ attitude of effect of recreational noise exposure on their hearing. In the baseball stadium, noise levels were measured in four seating sections using a sound level meter during the games. The LAeq average of the 16 measures produced 91.7 dBA, showing a significantly high noise level in the red and navy sections. As a function of frequency by LZeq analysis, the noise levels were significantly higher in low frequencies than other frequencies. For the survey sample, 688 randomly selected participants completed a 16-question survey on their noise exposure during the game and on the potential risk of hearing loss. Despite the very high noise levels, 70% of the respondents preferred sitting in either the red or the navy section to be closer to the cheerleaders and to obtain a good view. Most respondents reported that they did not consider wearing earplugs, and one-third experienced hearing muffled speech after the game. We conclude that the noise levels in baseball stadiums are high enough to cause hearing damage and/or tinnitus later, but expect these results to improve public education regarding safe noise exposure during popular sports activities.

Killer immunoglobulin-like receptor (KIR) 2DL4 (CD158d) was previously thought to be a human NK-cell-specific protein but its expression has also been demonstrated in human mast cells. Mast cells are involved in allergic reactions via their KIT-mediated and IgE receptor-mediated responses. We recently detected the expression of KIR2DL4 in human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), a human mast cell line (LAD2), and non-neoplastic mast cells, including pathological specimens. An agonistic antibody against KIR2DL4 negatively regulates the KIT- and IgE-receptor-mediated responses of PB-mast and LAD2 cells. In addition, agonistic antibodies and human leukocyte antigen (HLA)-G, a natural ligand for KIR2DL4, induce the secretion from these cells of leukemia inhibitory factor and serine proteases, which have been implicated in pregnancy establishment and cancer metastasis. Therefore, KIR2DL4 stimulation with agonistic antibodies and recombinant HLA-G protein may enhance both processes, in addition to suppressing mast-cell-mediated allergic reactions.

In the Republic of Moldova, nearly 90% of all deaths are due to noncommunicable diseases (NCDs), tha majority of which (58%) are caused by cardiovascular disease (CVD). Excess salt (sodium) and inadequate potassium intakes are associated with high CVD. Moreover, salt iodisation is the preferred policy to prevent iodine deficiency and associated disorders. However, there is no survey that has directly measured sodium, potassium and iodine consumption in adults in the Republic of Moldova. The aim is to estimate population sodium, potassium and iodine intakes and explore knowledge, attitudes and behaviour (KAB) towards the use of salt, amongst the adult population in the Republic of Moldova. Proportional random samples of adults were obtained from 28 of the 37 Districts and Municipalities and one Administrative Territorial Unit of Moldova. Participants attended a screening including demographic, anthropometric and physical measurements. Dietary sodium, potassium and iodine intakes were assessed by 24h urinary sodium (UNa), potassium (UK) and iodine (UI) excretions. Creatinine was measured. KAB was collected by questionnaire. Eight hundred and fifty-eight participants (326 men and 532 women, 18–69 years) were included in the analysis (response rate 66%). Mean age was 48.5 yrs (SD 13.8). Mean UNa was 172.7 (79.3) mmoL/day, equivalent to 10.8 g of salt/day and potassium excretion 72.7 (31.5) mmoL/day, equivalent to 3.26 g/day. Men ate more sodium and potassium than women. Only 11.3% of the sample had a salt intake below the World Health Organization (WHO) recommended target of 5 g/day and approximately 39% met WHO targets for potassium excretion (>90 mmoL/day). Whilst 81.7% declared limiting their consumption of processed food and over 70% declared not adding salt at the table, only 8.8% looked at sodium content of food, 31% still added salt when cooking and less than 1% took other measures to control salt consumption. Measures of awareness were significantly more common in urban compared to rural areas. Mean urinary iodine was 225 (SD: 152; median 196) mcg/24h, with no difference between sexes. According to WHO criteria, 41.0% had adequate iodine intake, 28.6% had intake below requirements and 17.8% and 12.6% had above requirement or excessive levels, respectively. Iodine content of salt table was 21.0 (SD: 18.6) mg/kg, with no difference between men and women. However, the content was lower in rural than urban areas (16.7 [SD: 18.6] vs 28.1 [SD: 16.5] mg/kg, p<0.001). There were weak or no correlations between urinary sodium and iodine excretions, and between urinary iodine excretion and iodine concentration in the table salt used in the participants’ households, indicating that in most cases participants were not using iodised salt as their main source of salt, more so in rural areas. In the Republic of Moldova, salt consumption is unequivocally high, potassium consumption is lower than recommended, both in men and in women, whilst iodine intake is still inadequate in 1 in 3 people, although severe iodine deficiency is rare. Salt consumed is often not iodised, with less iodised salt being used in rural areas.

Objective: Rheumatoid Arthritis (RA) is a chronic inflammatory disease affecting the synovium and articular cartilage that initiates joint damage. RA associates with a change in many inflammatory biomarkers. The present study aims to measure the levels of inflammatory adipocytokines (chemerin and visfatin) and their ratio in addition to some related biomarkers in RA patients group in comparison to healthy control group and find out their efficacy in diagnosis of RA.Methods: The study included 60 RA patients and 30 healthy control group. Serum visfatin and chemerin were measured by using ELISA technique, while other biomarkers were determined spectrophotometrically. Multivariate general linear model analysis and Receiver operating curve was used to study the opportunity of using chemerin and visfatin as diagnostic tools for RA.Results: The results indicated that there was a significant increase (p<0.05) in all lipid profile components, except HDLc that decreased, in RA patients in comparison with healthy control group; while significant decrease (p<0.001) in high density lipoprotein-cholesterol of RA patients in comparison with control group. Serum chemerin, visfatin, C-reactive protein, and uric acid levels were significantly higher (p<0.05) in RA patients than those of control group. The results showed a relatively good sensitivity and specificity of chemerin (sensitivity=88.1, specificity=75.9) at a concentration=187.88ng in diagnosis of RA.Conclusions: chemerin is able to diagnose RA efficiently but this diagnoses, due to relatively small specificity, may interfere with other inflammatory disorders. However, with adjuvant with other diagnostic parameters, chemerin may represent a useful addition in diagnosis of RA.

Gold nanoparticles (GNPs) have demonstrated significant dose enhancement with kilovoltage (kV) X-rays however recent studies have shown inconsistent findings with megavoltage (MV) X-rays. We proposed to evaluate the radiosensitization effect in U87 glioblastoma (GBM) cells in the presence of 42 nm GNPs and irradiated with a clinical 6 MV photon beam. Cytotoxicity and radiosensitization was observed using MTS and clonogenic cellular radiation sensitivity assays respectively. Sensitization enhancement ratio was calculated for 2 Gy (SER2Gy) with GNP (100 μg/mL). Dark field and MTS assay revealed high co-localization and good biocompatibility of the GNPs with GBM cells. Significant sensitization enhancement of 1.45 (P = 0.001) was observed with GNP 100 μg/mL. Similarly, at 6 Gy there was significant difference in the survival fraction between GBM alone group (Mean (M) = 0.26, Standard Deviation (SD) = 0.008) and GBM plus GNP group (M = 0.07, SD = 0.05, P = 0.03). GNPs enable radiosensitization in U87 GBM cells at 2 Gy when irradiated using a clinical platform. In addition to the potential clinical utility of GNPs, these studies demonstrate the effectiveness of a robust and easy to standardise in-vitro model that can be employed for future studies involving metal nanoparticle plus irradiation.

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible than others to develop due to ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

Glioblastoma (GBM) is the most lethal form of brain tumor, characterized by rapid growth and surrounding tissue invasion. The current standard treatment is surgery followed by radiotherapy, and concurrent chemotherapy, typically with temozolomide. Although extensive research has been performed over the past years to develop an effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in the overall survival of patients with GBM. Thus, new therapeutic approaches are urgently needed. A major challenge in the development of therapies for central nervous system (CNS) disorders is overcoming the blood–brain barrier (BBB). In this context, the intranasal (IN) route of drug administration has been proposed as a non-invasive alternative route to directly targeting the CNS. In fact, this route of drug administration may bypass the blood-brain barrier and reduce systemic side effects. Recently, formulations have been developed to further enhance nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review will be on the strategies developed to deliver a number of anticancer compounds for the treatment of GBM using the nasal administration. In particular, the specific properties of nanomedicines proposed for the nose-to-brain delivery will be critically evaluated. The number of preclinical and clinical data reviewed support the idea that nasal delivery of anticancer drugs might represent a breakthrough advancement in the fight against GBM.

The study explored the community perception of maternal deaths influenced by natural disaster, practice of maternal complications during natural disaster among the rural population in Bangladesh. It also explored the challenges faced by the community for providing health care and referring the complicated pregnant mothers during disaster. Three focus group discussions (FGDs) and eight in-depth interviews (IDIs) were conducted in the marginalized rural communities in the flood-prone Khaliajhuri sub-district, Netrakona district, Bangladesh. Flood is one of the major risk factors for influencing maternal death. Pregnant mothers seriously suffer from maternal complication, lack of antenatal checkup and even any doctor during flood. During the time of delivery, it is difficult to find even a skilled attendant and referring the patient with delivery complications to the healthcare facility. Boat is the only mode of transport. Majority maternal deaths occur on the boats during transfer from the community to the hospital. The rural people feel that the maternal deaths influenced by natural disaster are the natural phenomena. It needs some pre-preparation to support pregnant women during the disaster. There is unawareness of maternal health, related care and complications during disaster among the local health service providers and volunteers.

High fat-diet (HFD) feeding is known to induce metabolic dysregulation, however less is known on its impact in promoting the hypercoagulable state. The current study aimed to evaluate platelet-monocyte aggregate (PMA) formation following short-term HFD feeding. This is particularly important for understanding the link between inflammation and the hypercoagulable state during the early onset of metabolic dysregulation. To explore such a hypothesis, mice were fed a HFD for 8 weeks, with body weights as well as insulin and blood glucose levels monitored on weekly basis during this period. Basal hematological measurements were determined and the levels of spontaneous peripheral blood PMAs were assessed using whole blood flow cytometry. The results showed that although there were no significant differences in body weights, mice on HFD displayed impaired glucose tolerance and markedly raised insulin levels. These metabolic abnormalities were accompanied by elevated baseline PMA levels as an indication of hypercoagulation. Importantly, it was evident that baseline levels of monocytes, measured using the CD14 monocyte marker were significantly decreased in HFD-fed mice when compared to controls. In summary, the current evidence shows that in addition to causing glucose intolerance, such as that identified in a prediabetic state, HFD-feeding can promote undesirable hypercoagulation, the major consequence implicated in the development of cardiovascular complications.

C-reactive protein (CRP) and leukocytes are blood biomarkers involved in "Inflamm-Aging", which is a risk factor for the onset and progression of age-related diseases. Studies show that higher serum concentrations of these biomarkers are associated with functional disability, increased risk of low muscle strength, decreased muscle mass and mortality in the elderly. The objective was to estimate the predictive power and discriminating criteria of C-reactive protein and leukocyte concentrations for the risk of adverse health factors in the elderly within 30 days after hospital discharge (HD). Prospective cohort study using exploratory methods and blood biomarkers with 135 older adults admitted to medical and surgical clinics at a government hospital. The elderly were monitored at home after 30 days of HD for adverse health factors (rehospitalization, falls, amount of medication consumed, disability in basic and instrumental activities of daily living and mortality). CRP> 2.4; ≥ 0.7 and> 24.7 mg / dL and leukocytes ≥ 6.410; ≥ 8.690 and> 8.310 mm³ were discriminant for rehospitalization, falls and mortality within 30 days after HD, respectively. The cut-off points described may be used as a reference in the screening of hospitalized elderly vulnerable to adverse health events after hospital discharge.

Nonalcoholic steatohepatitis (NASH), which is characterized by liver steatosis, inflammation and fibrosis, is the most severe variation of nonalcoholic fatty liver disease (NAFLD). This disease is a consequence of several metabolic alterations such as type 2 diabetes and dyslipidemia that trigger different pathways of cell dysfunction and systemic inflammation which ultimately affect the liver. Furthermore, those mechanisms activate a complex cascade of immune response after repeated cell aggression. In the liver cytokines and interleukins interact with network of innate immune cells, including Kupffer cells (KCs), dendritic cells (DCs), lymphocytes and hepatic stellate cells (HSC). These cells translate those signals into immune responses and pathologic hepatic changes during the development of NASH. In this scenario the development of fibrosis is the most important change since it is an adaptive mechanism that in the short time has the objective of repair the damaged tissue but after prolonged injury it progresses to parenchymal scarring, cellular dysfunction and finally to organ failure. Finally, since NASH is an important cause of liver cirrhosis; this review addresses the cellular pathways of fibrosis in the setting of NASH explained by the interaction between immune and hepatic cells.

Failure of various weight-loss programs and long-term maintenance of favorable body composition in all kinds of people is high, since the majority go back to old dietary patterns. Many studies have documented the efficacy of a plant-based diet (PBD) for body mass management, but there are opinions that maintaining a PBD is difficult. We aimed to evaluate the long-term success of a whole-food plant-based (WFPB) lifestyle program. We investigated the differences in the obesity indices and lifestyle of 151 adults (39.6 ± SD 12.5 years), who were on our program for short (0.5–<2 years), medium (2–<5 years), or long term (5–10 years). Body-composition changes were favourable for all three groups, both genders and all participants. There were no differences in relative body-composition changes (BMI, body fat percentage and muscle mass index (MMI)) between the three groups. All participants improved their BMI (baseline mean pre-obesity BMI range (kg/m²): 26.4 ± 5.6 to normal 23.9 ± 3.8, p < 0.001), decreased body mass (–7.1 ± 8.3 kg, p < 0.001) and body fat percentage (–6.4 ± 5.6 % points, p < 0.001). Those with the highest BMI at baseline lost the most of: a) BMI units, b) total body mass and c) body fat (a) (kg/m²) (–5.6 ± SD 2.9, –2.4 ± 1.8 and –0.9 ± 1.5), b) (kg) (–16.1 ± SD 8.8, –7.1 ± 5.4 and –2.5 ± 4.5) and c) (% points) (–9.5 ± SD 5.7, –6.6 ± 4.6 and –4.7 ± 5.3) for participants who had baseline BMI in obese, overweight and normal range, respectively; p_{baseline vs. current} < 0.001 for all). 85.6% (101 out of 118) of parents of underage children (< 18 years), introduced WFPB lifestyle to their children. WFPB lifestyle program provides long-term lifestyle changes for reversal of obesity and is effective transferred to the next generation.

Background: Feasibility trials are preliminary trials that assess the viability and acceptability of intervention studies and the effects of the intervention on intermediate endpoints. Due to their short duration, they are unable to establish the effects of the intervention on long-term clinical outcomes. We propose a novel method that could transform the interpretation of feasibility trials using modified two-stage randomisation analyses. Methods In this two-stage process, we explored the effects of a 6-month feasibility factorial randomised controlled trial (RCT) of lycopene and green tea dietary interventions (ProDiet) on 159 serum metabolic traits in 133 men with raised PSA levels but prostate cancer (PCA) free. In the first stage, we conducted an intention-to-treat analysis, using linear regression to examine the effects of the interventions on metabolic traits, compared to the placebo group and instrumental variable analysis to assess the causal effect of the intervention on the outcomes. In the second stage, we used a two-sample Mendelian Randomization (MR) approach to assess the causal effect of metabolic traits altered by the interventions, on PCA risk, using summary statistics data from an international PCA consortium of 44,825 cancer cases and 27,904 controls. ResultsThe systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2= 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate (standard deviation difference versus placebo (β)): 0.69; 95% CI= 0.24, 1.15; p=0.003), valine (β: -0.62; -1.03, -0.02; p=0.004), pyruvate (β: -0.56; -0.95, -0.16; p=0.006), and docosahexaenoic acid (β: -0.50; -085, -0.14; p=0.006). The instrumental variable analysis showed there was no evidence that green tea altered the metabolome, but lycopene was associated with an increase in acetate (β=2.13; p=0.006) and decreases in pyruvate (β=-1.90; p=0.009), valine (β=-1.79; p=0.023), diacylglycerol (β=-1.81; p=0.026), alanine (β=-1.55; p=0.015) and DHA (p=0.097), where the regression coefficient represents the standard deviation (SD) difference in metabolite measures per unit change in lycopene (µmol/L) or EGCG (nM).Using MR, a genetically instrumented SD increase in pyruvate increased the odds of PCA by 1.29 (1.03, 1.62; p=0.027). Conclusion Using a two-stage randomization analysis in a feasibility RCT, we found that lycopene lowered levels of pyruvate, which our Mendelian randomization analysis suggests may be causally related to reduced PCA risk.

Preeclampsia (PE) is a common pregnancy complication. It is associated with high maternal morbidity and mortality rates and intrauterine foetal growth restriction. This condition is characterised by high blood pressure and urinary protein levels. Apelin and galectin-3 (Gal- 3) are peptides involved in the regulation of body fluid homeostasis, inflammation and cardiovascular functions. This study aimed to determine the correlations amongst serum apelin and Gal-3 levels and insulin resistance (IR) in women with PE. Sixty patients with PE and 30 healthy controls participated in this study. The PE group had significantly lower apelin levels (p < 0.01) and higher Gal-3 levels (p < 0.05) than the control group. The PE group had higher serum glucose levels and β-cell functions than the control group. Moreover, patients with PE exhibited dyslipidaemia. Correlation analysis indicated that apelin and Gal-3 levels were not significantly correlated. Moreover, no correlation existed between the apelin levels and any measured parameters of the PE group. In conclusion, the elevations in serum Gal-3 levels with increments in IR-related parameters and lipid profiles reflect the possible contribution of Gal-3 to the harmful effects of IR and dyslipidemia levels on women with PE.

The purpose of this study was to select target nutrients to be included in the nutritional standards of school lunches in Korea. The dietary intake data of children and adolescents aged 6-17 years old from the Korea National Health and Nutrition Examination Survey Ⅵ were analyzed for eight groups based on gender and age (6-8, 9-11, 12-14, and 15-17 years old). First, the usual intake of the 3,091 subjects was estimated and assessed to identify nutrients with insufficient or excessive intake prevalence. Along with the nutrients identified by the assessment, the energy and nutrients prioritized in the meal planning procedure of the 2015 Dietary Reference Intakes for Koreans were the initial candidates: energy, the percentages of energy from carbohydrates, protein, and fat, vitamin A, riboflavin, niacin, vitamin C, calcium, phosphorus, sodium, and iron. Phosphorus was excluded due to little evidence of clinical symptoms caused by insufficient intake. Sodium was excluded because reliable data on added salt were not available among the school lunch recipes in Korea. Therefore, energy, the percentages of energy from carbohydrates, protein, and fat, vitamin A, riboflavin, niacin, vitamin C, calcium, and iron were selected to be included in the nutritional standards of school lunches in Korea.

In Schizophrenia, pathway-genotypes may be constructed by combining interrelated immune biomarkers with changes in specific neurocognitive functions that represent aberrations in brain neuronal circuits. These constructs provide insight on the phenome of schizophrenia and show how pathway-phenotypes mediate the effects of genome X environmentome interactions on the symptomatology/phenomenology of schizophrenia. Nevertheless, there is a lack of knowledge how to construct pathway-phenotypes using Partial Least Squares (PLS) path modeling and Soft Independent Modeling of Class Analogy (SIMCA). This paper aims to provide a step-by-step utilization guide for the construction of pathway-phenotypes that reflect aberrations in the neuroimmune - brain circuit axis (NIBCA) in deficit schizophrenia. This NIBCA index is constructed using immune biomarkers (CCL-2, CCL-11, IL-1β, sIL-1RA, TNF-α, sTNFR1, sTNFR2) and neurocognitive tests (Brief Assessment of Cognition in Schizophrenia) predicting overall severity of schizophrenia (OSOS) in 120 deficit SCZ and 54 healthy participants. Using SmartPLS path analysis, a latent vector is extracted from those biomarkers and cognitive tests, which shows a good construct reliability (Cronbach alpha and composite reliability) and replicability and which is reflectively measured through its NIBCA manifestations. This NIBCA pathway-phenotype explains 75.0% of the variance in PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. Using SIMCA, we constructed a NIBCA pathway-class that defines deficit schizophrenia as a qualitatively distinct nosological entity and which allows patients with deficit schizophrenia to be authenticated as belonging to the deficit schizophrenia class. In conclusion, our nomothetic approach to develop a nomological network combining neuro-immune and neurocognitive phenome markers to predict OSOS and cross-validate a diagnostic class generated replicable models reflecting the key phenome of the illness, which may mediate the effects of genome X environmentome interactions on the final outcome phenome features, namely symptomatology and phenomenology.

PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present studies, we evaluated the effects of PDEF on total and phospho (Ser-127)YAP1 protein(a downstream effector of the Hippo pathway) levels in PC3 cells, a line of castrate resistant prostate cancer. We observed that the expression of PDEF in PC3 cells resulted in increased increased phospho(Ser127) -YAP1 protein levels. Our immunofluorescence analysis for YAP1 revealed an increased cytoplasmic/nuclear ratio of YAP1 in PDEF-PC3 cells as compared to VC-PC3 cells, suggesting PDEF may play a critical role in modulating YAP1 phosphorylation, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 protein levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels which we reported earlier. In addition we observed further decreased in PDEF and YAP1 expression in Neuro-Endocrine Prostate Cancer (NEPC), and a direct correlation between PDEF and YAP1 expression. To the best of our knowledge, these results provide the first demonstration of modulation of YAP1 by PDEF in any system and suggest a cross-talk between PDEF and the Hippo pathway.

Purpose: Carotid intraplaque hemorrhage (IPH) increases risk of territorial cerebral ischemic events, but different sequences or criteria have been used to diagnose or quantify carotid IPH. The purpose of this study was to compare manual segmentation and semi-automatic segmentation for quantification of carotid IPH on magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) sequences. Methods: Forty patients with 16–79% carotid stenosis and IPH on MPRAGE sequences were reviewed by two trained radiologists with more than five years of specialized experience in carotid plaque characterization with carotid plaque MRI. Initially, the radiologists manually viewed the IPH based on the MPRAGE sequence. IPH volume was then measured by three different semi-automatic methods, with high signal intensity 150%, 175%, and 200%, respectively, above that of adjacent muscle on the MPRAGE sequence. Agreement on measurements between manual segmentation and semi-automatic segmentation was assessed using the intraclass correlation coefficient (ICC). Results: There was near-perfect agreement between manual segmentation and the 150% and 175% criteria for semi-automatic segmentation in quantification of IPH volume. The ICC of each semi-automatic segmentation were as follows: 150% criteria: 0.861, 175% criteria: 0.809, 200% criteria: 0.491. The ICC value of manual vs. 150% criteria and manual vs. 175% criteria were significantly better than the manual vs. 200% criteria (p < 0.001). Conclusions: The ICC of 150% and 175% criteria for semi-automatic segmentation are more reliable for quantification of IPH volume. Semi-automatic classification tools may be beneficial in large-scale multicenter studies by reducing image analysis time and avoiding bias between human reviewers.

Cancer stem cells (CSCs) have been identified in many cancer types. This study identified and characterized CSCs in head and neck metastatic malignant melanoma (HNmMM) to regional lymph nodes using induced pluripotent stem cell (iPSC) markers. Immunohistochemical (IHC) staining performed on 20 HNmMM tissue samples demonstrated expression of iPSC markers OCT4, SOX2, KLF4 and c-MYC in all samples while NANOG was expressed at low levels in two samples. Immunofluorescence (IF) staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ CSC subpopulation within the tumor nests (TNs) and another within the peritumoral stroma (PTS) of HNmMM tissues. IF also showed expression of NANOG by some OCT4+/SOX2+/KLF4+/c-MYC+ cells within the TNs in an HNmMM tissue sample that expressed NANOG on IHC staining. In situ hybridization (n=6) and reverse-transcription quantitative polymerase chain reaction (n=5) on the HNmMM samples confirmed expression of all five iPSC markers. Western blotting of four primary cell lines derived from four of the 20 HNmMM tissue samples showed expression of SOX2, KLF4, and c-MYC but not OCT4 and NANOG, and three of these cell lines formed tumorspheres in vitro. We demonstrate the presence of two putative CSC subpopulations within HNmMM, which may be a novel therapeutic target in the treatment of this aggressive cancer.

(1) Background: Previous systematic review suggested a beneficial effect of progressive muscle relaxation (PMR) for cancer patients receiving chemotherapy. However, poor quality of eligible studies impaired the reliability and validity of findings. Moreover, additional potential studies with good quality published in Chinese language have been published recently. The aim of the present systematic review was to investigate the value of PMR training in preventing and alleviating nausea and vomiting caused by chemotherapy among cancer patients. (2) Methods: We assigned two independent investigators to search all potential studies in PubMed, Cochrane Controlled Register of Trial (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), China Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang data. We used data extraction sheet extracted all essential information, and used the Cochrane risk of bias assessment tool to appraise the quality of eligible studies. Finally, we qualitatively summarized the results of all included studies. (3) Results: Six studies enrolling 288 patients were considered to meet our selection criteria finally. Of these 6 studies, three were labeled as moderate quality, and the remaining studies were low quality. All included studies consistently suggested that PMR has a positive impact on nausea and vomiting caused by chemotherapy among cancer patients especially alleviating the incidence, frequency and degree of delayed nausea and vomiting. (4) Conclusions: Independent studies indicated that PMR was a beneficial approach to prevent and alleviate nausea and vomiting caused by chemotherapy among cancer patients. However, further studies considering other types of primary tumors should be designed in order to increase the generality of PMR because studies included in the present systematic review mainly enrolled lung cancer and breast cancer.

Snakebite envenomation, cognized as a neglected tropical disease, is a dread public health concern with the most susceptible groups being herdsmen, the elderly, active farmers, hunters, fishers, firewood collectors, 10 to 14-year old working children and individuals with limited access to education and health care. Snakebites are fragmentarily documented in Uganda primarily because most occur in rural settings where traditional therapists end up being the first line defence for treatment. Ethnobotanical surveys in Uganda have unveiled that some plants are used to antagonize the activity of various snake venoms. This review was sought to compile the sporadic information on the vegetal species reported as antivenins in Uganda. Electronic data indicate that no study entirely reported on antivenin plants in Uganda. A total of 77 plant species belonging to 65 genera, distributed among 42 botanical families claimed as antiophidic in Uganda are used for treatment of snakebites. Majority of these species belong to family Fabaceae (30.9%), Euphorbiaceae (14.3%), Asteraceae (11.9%), Amaryllidaceae (9.5%) and Solanaceae (9.5%). The antiophidic species listed are shrubs (40.5%), trees (32.9%) and herbs (17.7%), usually found in the wild and uncultivated. Antivenin extracts are primarily prepared from roots and leaves, through decoctions, infusions, powders and juices and administered orally or topically. The most frequently encountered therapeutically important species are Allium cepa L., Carica papaya L., Securidaca longipedunculata Fres., Harrisonia abyssinica Oliv. and Nicotiana tabacum L. Baseline epidemiological data on snake envenomation and antivenin plants in Uganda remain incomplete due to inadequate research and diverse ethnic groups in the country. There is a dire need to isolate and characterize the bioactive compounds in the claimed plants to enable their adroit utilization in handling the plague of snake envenomation. More baseline data should be collected on snake ecology and human behaviour as well as antivenin plants in Uganda. Indigenous knowledge on the use of plant preparations in traditional medicine in Uganda is humongous, but if this is not quickly researched and appropriately documented, indications as to the usefulness of this vegetal treasure house will be lost in the not so distant future.

Inflammatory bowel disease (IBD) is a chronic disease mediated by the immune system and characterized by the inflammation of the gastrointestinal tract. This study is to understand how the use of parenteral nutrition (PN) can affect the adult population diagnosed with IBD. We conducted a systematic review, meta-analysis and a meta-regression. On the different databases, (MEDLINE, Scopus, Cochrane, LILACS, CINAHL, WOS) we found 119 registers, the accuracy was 16% (19 registers); After a Full-text review, only 15 research studies were selected for qualitative synthesis and 10 for Meta-analysis and Meta-regression. The variables used were Crohn’s Disease Activity Index (CDAI), albumin, body weight (BW) and post-operative complications (COM). PN has shown to have efficacy for the treatment of IBD and is compatible with other medicines. The CDAI and albumin improve although the effect of PN are greater after a while. However, the effect on the albumin could be less than the observed value in the meta-analysis, due to a possible publication bias. The BW does not change after intervention. COM utilizing PN has been observed, although the proportion is low.

The national rate of obesity in US Hispanic/Latinos exceeds all other major ethnic subgroups and represents an important health disparity. Plant-based diet interventions that emphasize whole plant foods with minimal processing and less refined grains and sugar have shown have shown great promise in control of obesity, but there is a paucity of data translating this treatment effect to disparity populations. The objective of our study was to evaluate the efficacy and scalability of the Healthy Eating Lifestyle Program (HELP) – a hospital-based, family centered, culturally tailored, plant-based diet intervention for Hispanic/Latino pediatric obesity patients and their families. Our evaluation methods included: 1) a quasi-experimental, one group, longitudinal study to measures changes in BMI at 0, 6, and 18 weeks of follow-up, and 2) A stakeholder analysis consisting of six key informant interviews of HELP program staff. We found a significant decrease in body mass index across all adults (-0.2 kg/m² p=0.0047), that was much stronger in men. For children ages 5-12 years, there was also a significant decrease in BMI Z score from pre- to post- intervention (p=0.04). Program strengths were the cultural tailoring of the plant-based diet choices, and allowing a tiered approached that did not require adherence to strict vegetarianism. Our pilot study findings from HELP raise the possibility that incorporating plant-based diet choices into the treatment of pediatric obesity patients and their families can be an effective addition to a culturally responsive care model.

Aberration in microRNA (miRNA) expression or DNA methylation is a causal factor for polycystic ovarian syndrome (PCOS), a common endocrine disorder and leading cause of infertility. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. In this study, we conducted an integrated analysis of RNA-seq, miRNA-seq and MBD-seq on ovarian granulosa cells of PCOS and control groups to reveal the epigenetic interactions involved in the pathogenesis of PCOS. Firstly, we identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs were found to negatively regulate targeted mRNA expression. Next, in total, 130 miRNAs were found to be significantly differently methylated in promoter regions, while 13 were found to be associated with miRNA expression. Furthermore, the promoter hypermethylation of miR-429, miR-141-3p, and miR-126-3p was proven to suppress miRNA expression and therefore upregulate their corresponding genes, including XIAP, BRD3, MAPK14 and SLC7A5. Our results demonstrate that DNA methylation regulates miRNA expression and therefore controls its corresponding gene expression. The reactivation of the transcription of epigenetically silenced genes may be one of the key elements in PCOS pathogenesis. Meanwhile, the epigenetic mechanisms underlying the regulation of miRNA expression can provide a potential therapeutic target for PCOS in the future.

Risk of cardiovascular disease (CVD), common in childhood cancer survivors (CCSs), may be affected by diet. We assessed sodium (Na) and potassium (K) intake, estimated from food frequency questionnaires (FFQs) and morning urine spots, and its associations with cardiovascular risk in CCSs. We stratified CCS into three risk profiles based on A) personal history (CVD, CVD risk factors, or CVD risk free), B) body mass index (obese, overweight, or normal/underweight), and C) cardiotoxic treatment (anthracyclines and/or chest irradiation, or neither). We obtained a FFQ from 802, and sent a spot urine sample collection kit to 212, of which 111 (52%) returned. We estimated Na intake 2.9 g/day based on spot urine and 2.8 g/day based on FFQ; estimated K intake was 1.6 g/day (spot urine) and 2.7 g/day (FFQ). CCSs with CVD risk factors had a slightly higher Na intake (3.3 g/day), than CCSs risk free (2.9 g/day) or with CVD (2.7 g/day, p = 0.017), and obese participants had higher Na intake (4.2 g/day) than normal/underweight CCSs (2.7 g/day, p<0.001). Daily Na intake was above, and daily K intake below national recommended levels. Adult survivors of childhood cancer need dietary assistance to reduce Na and increase K intake.

Background: Glioblastomas (GBM) is generally burdened, to date, by a dismal prognosis, although Long Term Survivors have a relatively significant incidence. Our specific aim was to determine the exact impact of many surgery-, patient- and tumor-related variable on Survival parameters. Methods: The surgical, radiological and clinical outcomes of patients have been retrospectively reviewed for the present study. All the patients have been operated on in our Institution and classified according their Overall Survival in LTS (Long Term Survivors) and STS (Short Term Survivors). A thorough Review of our surgical series was conducted to compare the oncologic results of the patients in regards to 1. Surgical , 2. Molecular, and 3.Treatment related features. Results: A total of 177 patients were included in the final cohort. Extensive statistical analysis by means of univariate, multivariate and survival analyses disclosed a survival advantage for patients presenting a younger age, a smaller lesion and a better functional status at presentation. From the Histochemical point of view, Ki67(%) was the strongest predictor of better oncologic outcomes. A stepwise analysis of variance outlines the existence of 8 prognostic subgroups according to the molecular patterns of Ki67 overexpression and EGFR, p53 and IDH mutations. Conclusions: On the ground of our statistical analyses we can affirm that the following factors were significant predictors of survival advantage: KPS, Age, Volume of the lesion, Motor disorder at presentation, a Ki67 overexpression. A fine molecular profiling is feasible to precisely stratify the prognosis of GBM patients.

Background Human parvovirus B19, a human pathogen of the erythroparvovirus genus, is responsible for a variety of diseases. Despite less symptoms caused by B19 infection in healthy individuals, this pathogen can not be neglected in specific groups who exhibit severe anemia. Main body of abstract Transient aplastic crisis and pure red cell aplasia are two kinds of anemic hemogram respectively in acute phase and chronic B19 infection, especially occur in individuals with a shortened red cell survival or immunocompromised patients. In addition, B19 infected pregnant women may suffer risks of hydrops fetalis secondary to severe anemia and fetal loss. B19 possesses high affinity to bone marrow and fetal liver due to its extremely restricted cytotoxicity to erythroid progenitor cells mediated by viral proteins. The nonstructural protein NS1 is considered to be the major pathogenic factor, which takes parts in differentiational inhibition and apoptosis of erythroid progenitor cells through inducing viral DNA damage responses and cell cycle arrest. The time phase property of NS1 activity during DNA replication and conformity to transient change of hemogram are suggestive of its role in regulating differentiation of hematopoietic cells, which is not completely understood. Conclusion In this review, we set up a hypothetic bridge between B19 NS1 and Notch signaling pathway or transcriptional factors GATA which are essential in hematopoiesis, to provide a new insight of the potential mechanism of B19-induced differentiational inhibition of erythroid progenitor cells.

Bartonella henselae is a fastidious Gram-negative intracellular bacterium which can cause cat scratch disease, endocarditis in humans and animals as well as other complications, leading to acute or chronic infections. The current treatment for Bartonella infections is not very effective due to antibiotic resistance and also persistence. To develop better therapies for persistent and chronic Bartonella infections, in this study, with the help of SYBR Green I/PI viability assay, we performed a high-throughput screening of an essential oil library against stationary phase B. henselae. We successfully identified 32 essential oils that had high activity, including four essential oils extracted from Citrus plants, three from Origanum, three from Cinnamomum, two from Pelargonium and two from Melaleuca, as well as frankincense, ylang ylang, fir needle, mountain savory (winter), citronella, spearmint, elemi, vetiver, clove bud, allspice and cedarwood essential oils. The minimal inhibitory concentration (MIC) determination of these 32 top hits indicated they were not only active against stationary phase non-growing B. henselae but also had good activity against log phase growing B. henselae. The time-kill curve by drug exposure assay showed 13 active hits, including essential oils of oregano, cinnamon bark, mountain savory (winter), cinnamon leaf, geranium, clove bud, allspice, geranium bourbon, ylang ylang, citronella, elemi and vetiver, could eradicate all stationary phase B. henselae cells within 7 days at the concentration of 0.032% (v/v). Two active ingredients, carvacrol and cinnamaldehyde, of oregano and cinnamon bark essential oils, respectively, were shown to be very active against stationary phase B. henselae such that they were able to eradicate all the bacterial cells even at the concentration ≤ 0.01% (v/v). Our finding of active essential oils may help to develop more effective treatments for persistent Bartonella infections.

Previously we demonstrated, in rats, that the treatment with growth hormone (GH) and rehabilitation, carried out immediately after a motor cortical ablation, significantly improved the motor affectation produced by the lesion and induced the re-expression of nestin in the contralateral motor cortex. Here we analyze cortical proliferation after ablation of the frontal motor cortex and investigate the re-expression of nestin in the contralateral motor cortex and the role of the striatum and thalamus in motor recovery. The rats were subjected to ablation of the frontal motor cortex in the dominant hemisphere or sham-operated and immediately treated with GH or vehicle (V), for five days. At 1 dpi (days after injury), 5 rats received daily injections (4 days) of bromodeoxyuridine and were sacrificed. The other 15 rats (n = 5 / group) underwent treatment and rehabilitation and were sacrificed at 25 dpi. GH induced the greatest number of proliferating cells in the perilesional cortex. GH and rehabilitation produced the functional recovery of the motor lesion and increased the expression of nestin in the striatum. In the thalamic ventral nucleus ipsilateral to the lesion, cells positive for nestin and actin were detected, but this was independent of GH. Our data suggest that GH-induced striatal nestin is involved in motor recovery.

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors. The A2BAR, coupled to both Gαi and Gαq G proteins, is one of the several G-protein-coupled receptors that are expressed in a significantly higher level in some cancer tissues in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are potentially novel attractive anticancer agents. Several antagonists targeting at the A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various types cancers, and the rationale of using A2BAR antagonists in cancer therapy

Viral diseases are the leading cause of morbidity and mortality in developing countries. Broad-spectrum antiviral agents (BSAA) are key players in control of viral diseases. Here, we reviewed the discovery and development process of BSAAs, focusing on compounds with available safety profiles in human. We summarized the information on approved, investigational and experimental safe-in-man BSAAs in freely accessible database at https://drugvirus.info/. The number of these BSAAs will be increased as well as their spectrum of indications will be expanded pending the results of further pre-clinical and clinical studies. This will ultimately reinforce the arsenal of available antiviral options and provide better protection of general population from emerging and re-emerging viral diseases.

Ulcerative colitis (UC) is a relatively frequent, chronic disease that impacts significantly the patient’s quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental UC. UC was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Some mice received i.v. dose of CT-1 (200 µg/kg) 2 hours before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS. The severity of UC was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before UC induction improves the clinical course, tissue damage and inflammation degree in DSS-induced UC in mice.

Background: Many randomized controlled trials (RCTs) and systematic reviews (SRs) on acupuncture treatment for post-acute stroke dysphagia have been published. Due to conflicting results an overview of SRs to summarize and assess the quality of this evidence to determine whether acupuncture is effective for this disease was conducted. Methods: Seven databases were searched for SRs and/or Meta-analysis of RCTs and quasi-RCTs on acupuncture for post-acute stroke dysphagia. Two authors independently identified SRs and meta-analyses, collected data to assess the quality of included SRs and meta analyses according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the revised Assessment of Multiple Systematic Reviews (AMSTAR 2). Results: 31 SRs were identified. Quality of 22 SRs was critically low, 5 SRs were low, and 4 Cochrane SRs were moderate when evaluated by AMSTAR2. 17 SRs reported 85.2-96.3% items of PRISMA. Five SRs included explanatory RCTs, 16 SRs included pragmatic RCTs, and 10 SRs included both. Conclusion: Currently evidence on the effectiveness of acupuncture on post-acute stroke dysphagia is low quality. Type of study appeared to have no direct influence on the result, but the primary outcome measures showed a relationship with the quality of SRs. High quality trials with large sample sizes should be the focus of future research. PROSPERO REGISTRATION NUMBER: CRD42019134163

The aim of this study was to establish the blood glucose response to different cooking methods of pasta. Participants consumed three identical meals in a random order that were freshly cooked (hot), cooled and reheated. Blood glucose concentrations were assessed before, and every 15 minutes after ingestion of each meal for 120 minutes. There was a significant interaction between temperature and time (F_{(8.46-372.34)} = 2.75, p = 0.005), with the reheated (90 minutes) condition returning to baseline faster than both cold (120 minutes) and hot conditions. Blood glucose AUC was significantly lower in the reheated (703 ± 56 mmol L^-1 min^-1) compared with the hot condition (735 ± 77 mmol L^-1 min^-1, t(92) = -3.36, pbonferroni = 0.003), with no significant difference with the cold condition (722 ± 62 mmol L^-1 min^-1). To our knowledge, the current study is the first to show that reheating pasta causes changes in post-prandial glucose response, with a quicker return to fasting levels in both the reheated and cooled conditions compared with the hot condition. The mechanisms behind the changes in post-prandial blood glucose seen in this study are most likely related to changes in starch structure and how these changes influence glycaemic response.

The aim of this study was to investigate the size of the change in fatigability of gluteus maximus muscles during difficult endurance training in dynamic conditions. The research covered involved eight female athletes of the Polish National Team in short track, which had been prepared to the Olympic Games in PyeongChang. The sEMG system was used to measure fatigue of right and left gluteus maximus muscles, in the modified Biering-Sorensen test. The test was conducted five times during the training: before training, after warmup, and after each of 3 series of the endurance training. Comparing the mean frequency of the surface electromyography power spectrum of the first and the last seconds of the test, statistically significant reduction (p<0.05) of the average frequency value of the right muscle from 55.61±7.08 Hz to 48.64±4.48 Hz and left muscle from 58.78±4.98 Hz to 53.18±4.62 Hz was reported. In the conducted Biering-Sorensen test, the value of the muscle signal frequency measured by surface electromyography decreases, which may prove the muscle fatigue. Reductions in the frequency measured in the first and the last second of the test, was higher of the right lower limb. The size of the d Cohen effect in fatigue drops along with subsequent five tests during the training.

Background and Objectives: Ischemic and idiopathic heart failure are two different etiologies, however reactive cardiac fibrosis together with impaired vasculogenesis has been described in both of them. Implication of main proangiogenic factors as: angiogenin, agiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) has been described mainly in experimental models of heart failure. However, differences in molecular pathways between these cardiomyopathies are still under investigation. In this short communication we aimed to evaluate and compare the expression of pro-angiogenic molecules in the heart tissue of patients with advanced chronic heart failure (CHF) of ischemic and idiopathic etiology. Methods and Results: Heart tissue from left ventricular walls was obtained at transplantation from ischemic heart disease (IHD), idiopathic cardiomyopathy (ICM) patients. Tissue samples were examined using immunohistochemistry for angiogenic molecules. Immunopositivity (I-pos) for angiopoietin-1 was mainly observed in the cardiomyocytes, while I-pos for Ang-2 and Tie-2 receptor mainly in endothelial cells. Procollagen-I (PICP), angiogenin, Ang-1, Tie-2 receptor, were similarly expressed in IHD and ICM patients. In contrast, endothelial immunopositivity for Ang-2 was higher in IHD samples compared to ICM (p=0.03). Conclusions: Ang-2 expression is different in heart tissue of ICM and ICM patients and distribution of Ang-1 and angiogenin is higher in cardiomyocytes, whereas Ang-2 higher in endothelial cells, suggesting a different pattern of angiogenic stimulation, or at least of altered endothelial integrity. This data may serve for further studies investigating angiogenesis signaling pathways and in HF of different etiology.

The Clinical Trials Transformation Initiative (CTTI) Investigator Qualification Project addresses the need for a more efficient and effective means of identifying qualified clinical investigators and delegates. Selection of investigators and delegates who are qualified by training and experience to conduct clinical trials is essential to safeguarding protections for study participants and ensuring data quality and integrity. Sponsors generally document investigator qualification through training on the principles of good clinical practice (GCP), as defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), adopted by regulatory authorities in the US, Japan and the European Union. Although these GCP principles provide an important foundation for promoting the conduct of quality clinical trials, the industry standard “one-size-fits-all” GCP training may not fully prepare investigators and delegates for conducting quality clinical trials. Routine GCP training alone may not be sufficient to prepare an inexperienced member of a site team, while repeating such training is unlikely to enhance the qualifications of an experienced researcher. The CTTI project team used findings from qualitative research activities, as well as input from an expert meeting with multiple stakeholders, to identify gaps and redundancies in the current training of investigators and their delegates and recommend practical, action-based solutions. CTTI provides recommendations on how to implement a more efficient and effective means of qualification for investigators and delegates, determine whether a site team is a good fit for a particular protocol, and improve the quality of clinical trial conduct.

Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Attenuation of virulence by QS inhibition could be an alternative and effective approach to control infections. Therefore, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. E-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs due to their higher binding affinity to LasR receptor (-7.53 to -10.32 kcal/mol compared to -7.43 kcal/mol of native ligands). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed good binding stability and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections.

Importance: Because of the high prevalence of myopia in Taiwan, understanding the risk factors for its development and progression is important to public health. Background: This study investigated the risk factors for myopia and their influence on the progression of myopia in schoolchildren in Taiwan. Design: Patients’ clinical records were obtained retrospectively from ophthalmologists. Questionnaires were given to collect demographic information, family background, hours spent on daily activities, myopia progression, and treatment methods. Participants: A total of 522 schoolchildren with myopia from a regional medical hospital in northern Taiwan participated the study. Written informed consent was obtained from the participants of legal age or the parents or legal guardians. Methods: Multivariable regression analyses were performed. Myopia measured in dioptres was analysed, controlling for patients’ family and demographic information as well as their daily behaviours. Main Outcome Results: Children with high myopic parents were more myopic. Earlier onset age of myopia was associated with a higher level of myopia and greater annual myopic progression. Children reporting more near work activities had higher levels of myopia and greater progression of myopia. Lower levels of myopia were associated with more exercise, longer periods of sleep, and better vision care knowledge in children and parents. Intake of food supplements had no effect on myopia. Conclusions and Relevance: In addition to genetics, education, environment, and near work activity can influence the development of myopia. Health policies for schoolchildren should promote protective activities and vision care knowledge in order to protect the eyesight of schoolchildren.

Seirogan, a wood creosote, is a nonprescription drug used to treat diarrhea. However, reports of its clinical use are rare. Here, we report on the efficacy of wood creosote (3 capsules daily) for the alleviation of diarrheal symptoms in 148 patients from 10 clinics in Japan. The wood creosote capsules were classified as remarkably effective (44 patients), effective (71 patients), and partially effective (13 patients) based on the degree of alleviation of diarrheal symptoms that were induced by a variety of causes. The antidiarrheal efficacy of the capsules did not differ between males and females, and young patients (21–30 years) showed greater improvement in diarrheal symptoms than did old patients (> 61 years). Although this report is based on the re-evaluation of old data that had been preserved by our company, the effectiveness and range of symptoms that were treatable with wood creosote has likely remained unchanged. To the best of our knowledge, this is the first public report on the clinical effectiveness of wood creosote capsules for the treatment of a wide range of diarrheal symptoms.

The use of circulating cell-free (cf) DNA to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing of cfDNA can accurately profile the mutation landscape of metastatic melanoma. We used whole-exome sequencing (WES) to identify variants in matched tumor-derived genomic (g) DNA and plasma-derived cfDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and cfDNA. There was significant concordance between gDNA and cfDNA based on the total number of variants identified and the degree of overlap in variants which was independent of the site of tumor biopsy. The mutant allele frequency of common single nucleotide variants was lower in cfDNA reflecting lower read depth and dilution of circulating tumor DNA in the circulation by other cfDNA species. In addition to known melanoma driver mutations, several other melanoma-associated mutations were found to be concordant between matched gDNA and cfDNA. This study highlights that WES of cfDNA can capture clinically-relevant mutations present in melanoma metastases, but does not appear to provide any additional unique information on tumor heterogeneity. Targeted deep sequencing may be required to detect low frequency genomic aberrations known for predicting therapy resistance.