Redox regulation and oxidative stress have become areas of major interest in spermatology. Alteration of redox homeostasis is recognized as a significant cause of male factor infertility and is behind the damage that spermatozoa experience after freezing and thawing or conservation in a liquid state. While for a long time, oxidative stress was just considered an overproduction of ROS, nowadays it is considered as a consequence of redox deregulation. Many essential aspects of spermatozoa functionality are redox regulated, with reversible oxidation of thiols in cysteine residues of key proteins acting as an “on-off” switch controlling spermatic function. However, if deregulation occurs, these residues may experience irreversible oxidation and oxidative stress leading to spermatic malfunction and ultimately death. Stallion spermatozoa are “professional producers” of ROS due to their intense mitochondrial activity, and thus sophisticated systems to control redox homeostasis are also characteristic of this species. As a result, combined with the fact that embryos can easily be collected in this species, horses are a good model for the study of redox biology in the spermatozoa and its impact on the embryo.

Background: Carnitine deficiency is common in patients on dialysis. Serum free carnitine concentration is significantly lower in patients on hemodialysis (HD) than in healthy individuals. However, there are few reports on serum free carnitine concentration in patients on peritoneal dialysis (PD). Methods: We examined serum concentrations of total, free, and acylcarnitine and the acylcarnitine/free carnitine ratio in 34 PD and 34 age-, sex-, and dialysis duration-matched HD patients. We investigated the prevalence of carnitine deficiency and clinical factors associated with carnitine deficiency in the PD group. Results: Prevalence of carnitine deficiency was 8.8% in the PD group and 14.7% in the HD group (P = 0.45). High risk of carnitine deficiency was found in 79.4% of the PD group and 85.3% of the HD group (P = 0.52). Carnitine insufficiency was found in 82.3% of the PD group and 88.2% of HD group (P = 0.49). Multivariate analysis revealed that duration of dialysis and age were independent predictors of serum free carnitine level in the PD group. Conclusions: The prevalence of carnitine deficiency, high risk of carnitine deficiency, and carnitine insufficiency in PD patients was 8.8%, 79.4%, and 82.3%, respectively. These rates were comparable to those in patients on HD.

The cardioprotective effects of volatile anesthetics versus total intravenous anesthesia (TIVA) are controversial, especially in patients undergoing non-cardiac surgery. Using current generation high-sensitivity cardiac troponin (hs-cTn), we aimed to evaluate the effect of anesthetics on the occurrence of myocardial injury after non-cardiac surgery (MINS). From February 2010 to December 2016, 3555 patients without preoperative hs-cTn elevation underwent non-cardiac surgery under general anesthesia. Patients were grouped according to anesthetic agent; 659 patients were classified into a propofol-remifentanil total intravenous anesthesia (TIVA) group, and 2896 patients were classified into into a volatile group. To balance the use of remifentanil between groups, a balanced group (n=1622) was generated with patients who received remifentanil infusion in the volatile group, and two separate comparisons were performed (TIVA vs. volatile and TIVA vs. balanced). The primary outcome was occurrence of MINS, defined as rise of hs-cTn I ≥ 0.04 ng/mL within postoperative 48 hours. The secondary outcomes were 30-day mortality, postoperative acute kidney injury (AKI), and adverse events during hospital stay (mortality, type I myocardial infarction (MI), and new-onset arrhythmia). In propensity-matched analyses, the occurrence of MINS was lower in the TIVA group compared to the volatile group (OR 0.642; 95% CI 0.450-0.914; p = 0.014). However, after balancing the use of remifentanil, there was no difference between groups in the risk of MINS (OR 0.832; 95% CI 0.554-1.251; p-value = 0.377). There were no significant associations between the two groups in type 1 MI, new-onset atrial fibrillation, in-hospital and 30-day mortality before and after balancing the use of remifentanil. However, the incidence of postoperative AKI was lower in the TIVA group (OR 0.362; 95% CI 0.194-0.675; p-value = 0.001). After balancing the use of remifentanil, volatile anesthesia and TIVA showed comparable effects on MINS in patients undergoing non-cardiac surgery without preoperative myocardial injury. Further studies are needed on the benefit of remifentanil infusion.

Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms may differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. Discussion: The novel case definition “MCAS” is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Since 2007, highly pathogenic clade 2.3.2 H5N1 avian influenza A [A(H5N1)] viruses have evolved to clade 2.3.2.1a, b and c, and currently only 2.3.2.1c A(H5N1) viruses circulate in wild birds and poultry. During antigenic evolution, clade 2.3.2.1a and c A(H5N1) viruses acquired both S144N and V223I mutations around the receptor binding site of hemagglutinin (HA), with S144N generating an N-glycosylation sequon. We introduced single or combined reverse mutations, N144S and/or I223V, into the HA gene of clade 2.3.2.1c A(H5N1) virus and generated PR8-derived, 2 + 6 recombinant A(H5N1) viruses. When we compared replication efficiency in embryonated chicken eggs, mammalian cells and mice, the recombinant virus containing both N144S and I223V mutations showed increased replication efficiency in avian and mammalian hosts and pathogenicity in mice. The N144S mutation significantly decreased avian receptor affinity and egg white inhibition, but not all mutations increased mammalian receptor affinity. Interestingly, the combined reverse mutations dramatically increased the thermostability of HA. Therefore, the adaptive mutations possibly acquired to evade avian immunity may decrease viral thermostability as well as mammalian pathogenicity.

The hypothalamus is the site of synthesis and secretion of a number of endocrine peptides that are involved in the regulation of hormonal activity of the pituitary and other endocrine targets. Tumors of the hypothalamus have been recognized to have both structural and functional effects including hormone hypersecretion. The classification of these tumors had advanced over the last few years and biomarkers are now available to classify these tumors and provide accurate structure-function correlations. This review provides an overview of tumors in this region that is critical to metabolic homeostasis with a focus on advances in the diagnosis of gangliocytomas, neurocytomas and pituicytomas that are unique to this region.

A method for classification is introduced in this article, and it is tested on ADNI database to diagnose alzheimer’s disease (AD). It is obvious that tunning the performance of a classification to get better results is a complicated problem, and when we want model’s accuracy or other peformance measurments higher than 90%, the problem will be more complicated. In this study, we tried and succeeded to discover a method to solve this problem. The final feature set can be used clustering too, because outgrowth feature set of the proposed method is invigorated. In the recent years, a lot of activities is done to develop computer aided systems (CAD) for alzheimer’s disease diagnosis. Most of these recently developed systems concenterated on extracting and combining features from MRI, PET, CSF, and …; in this article, we made attempt to do so and utilized one more technique to increase classification performance. Finding and producing the best features to solve three binary classification problems of AD vs. Normal Control (NC), Mild Cognitive Impairment (MCI) vs. NC, and MCI vs. AD are the purposes of this article. Experiments indicate performance and effectiveness rates of the proposed method, which are accuracies of 98.81%, 81.61%, and 81.40% for AD vs. NC, MCI vs. NC, and AD vs. MCI classification problems, respectively. As can be seen, using this method increased the performance of the three binary problems incredibly.

Cancers remain the lead cause of disease-related, pediatric death in North America. The emerging field of complex systems has redefined cancer networks as a computational system with intractable algorithmic complexity. Herein, a tumor and its heterogeneous phenotypes are discussed as dynamical systems having multiple, strange attractors. Machine learning, network science and algorithmic information dynamics are discussed as current tools for cancer network reconstruction. Deep Learning architectures and computational fluid models are proposed for better forecasting gene expression patterns in cancer ecosystems. Cancer cell decision-making is investigated within the framework of complex systems and complexity theory.

Background and objectives: Patients with multiple sclerosis (MS) have many potential factors (spasticity, immobilization, glucocorticoids use) which can deteriorate the anthropometrical status and body composition and may have the potential impact on the functional mobility and basic motor skills improvement after physiotherapy. The aim of the study was to assess the functional mobility and basic motor skills in patients with MS and to correlate them with disability and anthropometrical status and body composition parameters. Materials and Methods: Timed Up-and-Go test (TUG), and six-minute walk test (6MWT) were performed in 36 patients with MS before and after 4 weeks of physiotherapy. Body mass index (BMI), waist to height ratio (W/HtR), and waist-to-hip ratio (WHR) were assessed in this group. Body composition was evaluated by bioelectrical impedance analysis (BIA) and fat mass (FAT), fat free mass (FFM), total body water (TBW) and predicted muscle mass (PMM) were expressed as percentage of body mass. Clinical status was assessed by EDSS and AI scales. Results: After physiotherapy, there was a significant improvement in functional mobility and basic motor skills assessed by total distance in 6MWT (p<0.001) and in TUG trials (p<0.001). Positive significant correlations were found between the results obtained in both tests (either before and after physiotherapy) vs. FFM, TBW and PMM, whilst worse results in functional mobility and basic motor skills correlated significantly with higher WHtR, WHR and FAT (p<0.05). Clinical status (EDSS) were significantly related to the WHtR and body composition parameters with the same manner as the results in the either 6MWT and TUG. However, there were no significant relationships between BMI vs. either clinical status (EDSS, AI) and functional mobility tests results in patients with MS. Conclusions: Functional mobility and basic motor skills may be significantly improved during the physiotherapy, but they are related to the anthropometrical status and body composition of MS patients. Moreover, disability status is also significantly related to this parameters. Body composition deterioration seems to be the important target for the therapeutic intervention in MS patients. For proper nutritional status assessment in patients with MS, body composition analysis or WHtR instead BMI should to be used.

Mast cells (MC) are resident tissue cells found primarily at the interphase between tissues and environment. These evolutionary old cells store large amounts of proteases within cytoplasmic granules, and one of the most abundant of these proteases is the tryptase. To look deeper into the question their in vivo targets, we have analyzed the activity of the human MC tryptase on 69 different human cytokines and chemokines, and the activity of the mouse tryptase (mMCP-6) on 56 mouse cytokines and chemokines. These enzymes were found to be remarkably restrictive in their cleavage of these potential targets. Only five were efficiently cleaved by the human tryptase: TSLP, IL-21, MCP3, MIP-3b and eotaxin. This strict specificity indicates a regulatory function of these proteases and not primarily as unspecific degrading enzymes. We recently showed that the human MC chymase also had a relatively strict specificity, indicating that both of these proteases have regulatory functions. One of the most interesting such regulatory functions may involve controlling excessive TH2 mediated inflammation by cleaving several of the most important TH2-promoting inflammatory cytokines, including IL-18, IL-33, TSLP, IL-15 and IL-21 indicating a potent negative feedback loop on TH2 immunity.

COPD is currently the fourth leading cause of death in the world. Globally, due to continued exposure to COPD risk factors and an aging population, the burden of COPD is expected to increase in the coming decades. The BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index is a practical and multidimensional predictor for prognosis of COPD, and better than FEV1.We used the database of Kaohsiung Chang Gung Memorial Hospital medical center, Taiwan to analyze the correlation between BODE index, healthcare resource utilization, and Charlson comorbidity index (CCI). This retrospective study to collect COPD patients with complete BODE index data who had undergone a 6-minute walk examination in our hospital from January 2015 to December 2016. The medical cost and comorbidities database were analyzed from January 1, 2015, to August 31, 2017. Of 396 patients, 382 (96.5%) were male, with an average age of 71.3 ± 8.4 years. There was a significant association between the BODE index and the CCI of COPD patients (p < 0.001). Healthcare resource utilization was positively correlated with the BODE index during the 32 months of retrospective clinical outcomes: positively correlated with the number of hospitalizations (p<0.001), hospitalization days (p<0.001), hospitalization expenses (p=0.005), and total medical expenses (p=0.024), respectively. Our findings provide the crucial information for clinician to predict medical burden and comorbidities in patients with COPD by using BODE index.

This study aimed to examine the vitamin D status of professional volleyball athletes and to determine its correlation with shoulder muscle strength. We finally included 52 healthy male professional volleyball players (23.2 ± 4.5 years), who were categorized by vitamin D status (<20 ng/mL: deficiency, 20-30 ng/mL: insufficiency, and >30 ng/mL: sufficiency). We examined the strength of the internal rotator (IR) and external rotator (ER) muscles of the shoulder by using isokinetic dynamometer. Fourteen players (26.9%) had vitamin D deficiency, 24 players (46.2%) were vitamin D insufficient, and 14 players (26.9%) were vitamin D sufficient. There was no significant correlation between the vitamin D level and shoulder muscle strength at 60°/s (IR, r = 0.159, p = 0.26; ER, r = 0.245, p = 0.08), and at 180°/s (IR, r = - 0.093, p = 0.51; ER, r = - 0.037, p = 0.79). Moreover, the isokinetic shoulder strengths were not significantly different across the three groups in all settings. In conclusion, vitamin D insufficiency was common in elite volleyball players. Though not being associated with isokinetic muscle weakness, vitamin D should be regularly monitored and supplemented in young elite athletes, considering its importance on musculoskeletal health.

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

This paper questions the potential shift of reproduction towards assisted reproductive technologies due to benefits provided by genetic manipulation of embryos. In order to examine the viability of such a shift and its implications from a regulatory perspective, we relied on two panels of experts from Israel and Spain, using the Delphi method and a series of in-depth interviews. We anticipate, at a first stage, a continuous-steady growth in the use of IVF, supplemented by preimplantation genetic diagnosis and the introduction of CRISPR/Cas. At a second stage, attracting a growing share of fertile people would require developments in genomics. While it is unclear whether these developments will fully materialize, they could be replaced by technoscientific imaginaries generating perceived benefits. We conclude that the regulation of reproductive genetics is becoming more critical and complex. The aim should be to ensure good practices and equity, while providing more information to the public. A broad and inclusive societal debate may overcome the difficulty of drawing a clear line between medical uses and non-medical uses of genetic selection and engineering and may contribute to finding the right balance between allowing autonomous decisions of patients and protecting the public interest.

A large body of evidence has linked unhealthy eating patterns with an alarming increase in obesity and chronic disease worldwide. However, existing methods of assessing dietary intake in nutritional epidemiology rely on food frequency questionnaires or dietary records that are prone to bias and selective reporting. Herein, metabolic phenotyping was performed on 42 healthy participants from the Diet and Gene Intervention (DIGEST) pilot study, a parallel two-arm randomized clinical trial that provided complete diets to all participants. Matching urine and plasma specimens were collected at baseline and following 2 weeks of provision of either a Prudent or Western diet with a weight-maintaining menu plan designed by a dietician. Targeted and nontargeted metabolite profiling was conducted using three complementary analytical platforms, where 80 plasma metabolites and 84 creatinine-normalized urinary metabolites were reliably measured (CV < 30%) in the majority of participants (> 75%) after implementing a rigorous data workflow for metabolite authentication with stringent quality control. We classified a panel of metabolites with distinctive trajectories following 2 weeks of food provisions when using complementary univariate and multivariate statistical models. Unknown metabolites associated with contrasting dietary patterns were identified with high resolution MS/MS and/or co-elution after spiking with authentic standards. Overall, 3-methylhistidine and proline betaine concentrations increased consistently after participants were assigned a Prudent diet (q< 0.05) in both plasma and urine samples with a corresponding decrease in the Western diet group. Similarly, creatinine-normalized urinary imidazole propionate, hydroxypipecolic acid, dihydroxybenzoic acid, and enterolactone glucuronide, as well as plasma ketoleucine and ketovaline increased with a Prudent diet (p< 0.05) after adjustments for age, sex and BMI. In contrast, plasma myristic acid, linoelaidic acid, linoleic acid, a-linoleic acid, pentadecanoic acid, alanine, proline, carnitine and deoxycarnitine, as well as urinary acesulfame K increased among participants following a Western diet. Most metabolites were also correlated (r > ±0.30, p< 0.05) to changes in average intake of specific nutrients from self-reported diet records reflecting good adherence to assigned food provisions. Our study revealed robust biomarkers sensitive to short-term changes in habitual diet for accurate monitoring of healthy eating patterns in free-living populations, which is required for validating evidence-based public health policies for chronic disease prevention.

Preeclampsia (PE) is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction and the impairment of placenta vascular endothelial integrity. This study aimed to investigate the effect of serum copper (Cu) level on some angiogenesis-related factors including vascular endothelial growth factor-A (VEGF-A), soluble Fms-like tyrosine kinase-1 (sVEGF-R1), soluble endoglin (sEng) and cerruloplasmin (Cp) in Iraqi women with preeclampsia (PE) and control pregnant women. Therefore, 60 women with PE in addition to 30 healthy pregnant women were enrolled in the study. Serum concentration of sEng, VEGF-A, sVEGF-R1, and Cu in PE group significantly increased (p<0.05) in the PE group compared with that in the control group. Increased production of antiangiogenic factors, soluble VEGF-A and sEng contribute to the pathophysiology of PE, indicating the involvement of these parameters in the angiogenic balance in patients with PE. Tests for between-subject effects showed that the circulating angiogenesis factors and Cu were significantly associated with the presence of PE. Serum Cu level was significantly correlated with VEGF- A and VEGF-R1 levels but not with sEng. Multiple regression analysis revealed that only Cp and BP can significantly predict the complications in women with PE. In conclusion, serum Cu has a role in the angiogenesis in women with PE and may be a new drug target in the prevention or treatment of PE.

Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten and affects approximately 1% of the global population. Currently, the only treatment available is lifelong strict adherence to a gluten-free diet (GFD). Chronic diseases such as CD affect patients and their family members’ quality of life (QoL); particularly parents and caregivers who play an essential role in the child’s care and treatment. A higher level of psychological distress has been found in the parents of children with chronic ailments due to limited control over the child’s daily activities and the child’s illness. In this context, the validation of a specific questionnaire of QoL is a valuable tool to evaluate the difficulties faced by parents or caregivers of children with this chronic illness. A specific questionnaire for this population can elucidate the reasons for stress in their daily lives as well as the physical, mental, emotional, and social impact caused by CD. Therefore, this study aimed to develop and validate a specific questionnaire to evaluate the QoL of parents and caregivers of children and adolescents with CD. The study was developed in six steps: (i) development of the CD parent/caregiver QoL questionnaire (CDPC-QoL); (ii) subjective evaluation; (iii) validation of the questionnaire by the Delphi method; (iv) evaluation of the internal consistency and reproducibility of the CDPC-QoL; (v) application of the questionnaire to Brazilian CD parents or caregivers; and (vi) statistical analysis. Overall results showed that a higher family income resulted in a higher score of the worries domain. In addition, having another illness besides CD decreased the QoL (except in the worries domain). The other variables studied did not present a statistically significant impact on the QoL, which was shown to be low in all aspects. Knowledge of the QoL is important to help implement effective strategies to improve celiac patients’ quality of life and reduce their physical, emotional, and social burden.

Hearing impairment (HI) is a common sensory disorder that is defined as the partial or complete inability to detect sound in one or both ears. This diverse pathology is associated with a myriad of phenotypic expressions and/or syndromes. HI can be caused by various intrinsic, environmental and/or unknown factors. Some ontologies capture some relevant HI forms, phenotypes and syndromes, but there is no comprehensive knowledge portal which includes aspects specific to the HI disease state. This hampers inter-study comparability, integration and interoperability within and across disciplines. This work describes the HI Ontology (HIO) that was developed based on the Sickle Cell Disease Ontology (SCDO) model. This is a collaboratively developed resource built around the 'Hearing Impairment' concept by a group of experts in different aspects of HI and ontologies. HIO is the first comprehensive, standardized, hierarchical and logical representation of existing HI knowledge. HIO allows researchers and clinicians alike to readily access standardized HI-related knowledge in a single location and promote collaborations and HI information sharing, including epidemiological, socio-environmental, biomedical, genetic and phenotypic information. Furthermore, this ontology illustrates the adaptability of the SCDO framework for use in developing a disease-specific ontology.

Detection of PLA2R and THSD7A among primary membranous glomerulonephritis (MGN) patients transformed the diagnosis, treatment monitoring and prognosis. Anti-PLA2R can be detected in 70-90% of primary MGN patients while anti-THSD7A in 2-3% of anti-PLA2R negative primary MGN patients depending on the technique used. Serum and urine samples are less invasive and non-invasive respectively and can detect the presence of anti-PLA2R and anti-THSD7A with higher sensitivity and specificity, significant in patients’ monitoring and prognosis better than exposing patients to frequent biopsy which is an invasive procedure. Different techniques of detection of PLA2R and THSD7A in patients’ urine and sera were reviewed with the aim of providing newer and alternative techniques. We proposed the use of biomarkers (PLA2R and THSD7A) in making the diagnosis, treatment decision and follow up of patients with primary MGN. We also reviewed other prognostic renal biomarkers like retinol binding protein (RBP) and beta-2 microglobulin in order to detect progression of renal damage for early intervention.

Endoscopic retrograde cholangiopancreatography (ERCP) is a routinely used therapeutic procedure for the biliary and pancreatic diseases. Population aging may increase the typical indications of ERCP and come with more complexity and difficulties, especially in cannulation. This study aimed to evaluate the incidence, causes, and management of difficult biliary cannulation during ERCP in super-aged patients and the role of difficult cannulation as a risk factor for adverse events. A total of 614 patients, underwent ERCP, were prospectively studied as a cohort and divided into two groups based on their age. There were 146 patients aged 80 years or older in group A and 468 patients aged less than 80 years in group B. The primary outcome measures were the difficulty grade of papilla cannulation, clinical outcomes, and ERCP-related complications in the two groups. The adverse events were analyzed using logistic regression for patient age, co-morbidities, indications, and cannulation difficulty grade variables. There was no difference in the incidence of difficult cannulation between the two groups (32.9% vs. 34.4%, p=0.765) though, as expected, super-aged Group A had a higher prevalence of periampullary diverticulum (29.5% vs. 16.7%, p=0.001). The technical cannulation success rate was (96.6% vs. 96.8%, p= 0.54). All used cannulation techniques in the elderly group were efficient and safe. Logistic regression showed that age ≥80 was not associated with increased adverse events; however, difficult cannulation (adjusted odds ratio [AOR]=3.478; 95% confidence interval [CI]=1.877, 6.442; p<0.001) and CCI ≥2 (AOR=1.824; 95% CI=0.993, 3.349; p=0.045) were more likely to have adverse events. Age ≤65 (AOR=3.460; 95% CI=1.511, 7.922; p=0.003), female gender (AOR=2.362; 95% CI=1.089, 5.124; p=0.030), difficult cannulation (AOR=4.527; 95% CI=2.078, 9.860; p<0.001), and patients with cholangitis (AOR=3.261; 95% CI=1.204, 8.832; p=0.020) were strongly associated with increasing Post-ERCP Pancreatitis (PEP). Advanced age has not proved to be a risk factor of difficult cannulation, and secondary cannulation techniques can be safely and efficaciously utilized for this group. CCI ≥2 and difficult cannulation are associated with increased overall adverse events rate while age ≥80 factor is not.

Sickle cell disease (SCD) is an inherited disorder of major health challenge in Nigeria. Micronutrients deficiencies often associated with the disorder may cause inflammation and abnormal metabolisms in the body. The copper-to-zinc ratio is a more important assessment than the concentrations of either of the metals in clinical practice. This study seeks to evaluate serum levels of c-reactive protein (CRP), copper, zinc and copper-to-zinc ratio and to correlate copper-to-zinc ratio with CRP in adult subjects with SCD. Serum copper, zinc, CRP and plasma fibrinogen were assayed in 100 confirmed SCD patients in steady clinical state and 100 age and sex matched subjects with normal haemoglobin. Serum copper and zinc were assayed by colorimetric method using reagents supplied by Centronic, Germany while CRP and fibrinogen were assayed using reagents supplied by Sigma (St. Louis, MO, USA) and Anogen (Ontario, Canada), respectively. The copper to zinc ratio was calculated from serum levels of copper and zinc. The measured parameters were compared between the groups using Students t-test and Pearson correlation coefficient was used to relate CRP with the other parameters. Serum copper, CRP, fibrinogen and copper-to-zinc ratio were significantly higher (p < 0.001) while zinc level was lower in SCD patients than controls. Serum CRP concentration correlated with copper (r = 0.10; p < 0.02), zinc (r = −0.199; p < 0.05) and Copper-to-zinc ratio (r = 0.312; p < 0.002) but the correlation between CRP and fibrinogen was not significant. Inflammatory condition may modulate copper and zinc homeostasis and copper-to-zinc ratio may be used as marker of nutritional deficiency and inflammation in SCD patients.

Among the different applicable irrigants for root canal disinfection, sodium hypochlorite 5.25% is one of the most attractive ones. The quality of root canal disinfection is dependent on some factors such as the employed approach, type of flow rate of irrigant and the size of needle. The majority of studies in the field of root canal disinfection are experimentally carried out. In the current article, Computation Fluid Dynamic (CFD) is used for modeling the antimicrobial liquid flow in the root canal and evaluate the effects of needle size and flow rate. Two needles, G28 and G30, are used for irrigation in three volumetric rates of flow including 0.10 mL⁄s , 0.20 mL⁄s and 0.30 mL⁄s. The results of numerical simulations revealed the improved quality of root canal disinfection by augmentation in the rate of flow and decrease in the inner diameter of the needle. According to the outcomes of the modeling, the highest average wall shear stress obtained in the case of using G28 needle and 30 mL⁄s flow rate, which was approximately 10.21 Pa.

Background: Essential hypertension is a major public health associated with increase pressure on the vascular walls and red blood cells (RBCs). In the present work, osmotic fragility (OF) of RBCs was reexamined in the means of its correlation with two risk factor; iron status and lipid profile. Experimental: OF, iron status parameters, and lipid profile components were measured in 60 patients and compared with the results of 30 controls. Results: The results showed a significant increase in all iron indices of hypertensive patients in comparing with healthy control group except TIBC, UIBC, and transferrin concentrations, which decrease in these patients in comparing with control group. Serum TGs, total cholesterol, VLDLc, and LDLc were increased while there is no significant in serum HDLc in patients to comparing with control group. There is no significant change in OF between patients and controls where p=0.173. The iron status parameters and lipid profile components were dependent on sex and smoking state. Hemoglobin and PCV were correlated significantly with total cholesterol and LDLc. Transferrin saturation showed a positive correlation with cholesterol, LDLc, and TGs, but negatively correlated with HDL_c. No significant correlation between all the measured parameters and OF in HT patients. There is a significant correlation between serum ferritin and systolic BP and between Hb and systolic BP. Conclusion: No significant effect on the OF in HT patients. HT patients have elevated level of iron parameters in comparing with controls. OD has no correlation with iron status parameters or with lipid profile components.

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n=12) and CKD-aP (mild, moderate, or severe pruritus; n=11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8，and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in expression of ion channels at the skin tissue including specific for cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib has been the standard of care for almost a decade until 2018 when FDA approved an alternative first-line agent namely lenvatinib. Whereas FOLFOX4 results an alternative first-line treatment for the chinese clinical oncology guidelines. In addition to cabozantinib, regorafenib, and ramucirumab, two therapeutics against the PD-L1/PD1 axis have been recently approved for subsequent-line therapy, as nivolumab and pembrolizumab. However, similar to other solid tumors, the response rate of single-agent targeting PD-L1/PD1 axis is low. Therefore a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors, the addition of immune checkpoint inhibitors after resection or during locoregional therapy, immune checkpoint inhibitors in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with an attent evaluation of new ICIs based combinatory approaches.

Background: Active case finding for TB was implemented in selected sixty high TB burden wards of Kolkata, India. Community volunteers called TOUCH agents (TAs) identified and referred presumptive TB patients (PTBPs) to health facilities for TB diagnosis and treatment. We aimed to describe the ‘care cascade’ of PTBPs identified during July to December, 2018 and to explore the reasons for attrition as perceived by TAs and PTBPs. Methods: An explanatory mixed methods study with quantitative phase of cohort study using routinely collected data followed by descriptive qualitative study with in-depth interviews was conducted. Results: Of the 3, 86,242 individuals enumerated, 1132 (0.3%) PTBPs were identified. Only 713 (63.0%) PTBPs visited referred facility for TB diagnosis. TB was diagnosed in 177 (24.8%) and the number needed to screen for one TB was 2,183 individuals. The potential reasons for low yield were stigma and apprehension about TB, distrust about TA, wage loss for attending health facilities and substance abuse among PTBPs. Conclusion: The yield of ACF was suboptimal with low PTBP identification rate and high attrition rate. Interviewing each individual for symptoms of TB and supporting PTBPs for diagnosis through sputum collection and transport can be adopted to improve the yield.

We are witnessing a dramatic transformation in the way we do science. In recent years, significant flaws with existing scientific methods have come to light, including lack of transparency, insufficient involvement of stakeholders, disconnection from the public, and limited reproducibility of research findings. These concerns have sparked a global movement to revolutionize scientific practice and the emergence of Open Science. This new approach to science extends principles of openness to the entire research cycle, from hypothesis generation to data collection, analysis, replication, and translation from research to practice. Open Science seeks to remove all barriers to conducting high quality, rigorous, and impactful scientific research by ensuring that the data, methods, and opportunities for collaboration are open to all. Emerging digital technologies and "big data" (see "Ten simple rules for responsible big data research") have further accelerated the Open Science movement by affording new approaches to data sharing, connecting researcher networks, and facilitating the dissemination of research findings. Open scientific practices are also having a profound impact on the health sciences and medical research, and specifically how we conduct clinical research with human participants. Human health research necessitates careful considerations for practicing science in an ethical manner. There is also a particular urgency to human health research since the goal is to help people, so doing good science takes on a different meaning than simply doing science well. It also implores the scientist to reassess the conventional view of human health research as a pursuit conducted by scientists on human subjects, and lays a greater emphasis on inclusive and ethical practices to ensure that the research takes into account the interests of those who would be most impacted by the research. Openness in the context of human health research also raises greater concerns about privacy and security and presents more opportunities for people, including participants of research studies, to contribute in every capacity. At the core of open health research, scientific discoveries are not only the product of collaboration across disciplines, but must also be owned by the community that is inclusive of researchers, health workers, and patients and their families. To guide successful open health research practices, it is essential to carefully consider and delineate its guiding principles. This editorial is aimed at individuals participating in health science in any capacity, including but not limited to people living with medical conditions, health professionals, study participants, and researchers spanning all types of disciplines. We present ten simple rules that, while not comprehensive, offer guidance for conducting health research with human participants in an open, ethical, and rigorous manner. These rules can be difficult, resource-intensive, and can conflict with one another. They are aspirational and are intended to accelerate and improve the quality of human health research. Work that fails to follow these rules is not necessarily an indication of poor quality research, especially if the reasons for breaking the rules are considered and articulated (see rule 6: document everything). While most of the responsibility of following these rules falls on researchers, anyone involved in human health research in any capacity can apply them.

Statins prevent cardiovascular diseases, yet their use is limited by the muscle disturbances they cause. Rarely, statin-induced myopathy is autoimmune, but more commonly it is due to direct muscle toxicity. Available evidence suggests that statin-induced creatine deficiency may be a major cause of this toxicity, and that creatine supplementation prevents it. Statins inhibit guanidinoacetate methyl transferase (GAMT), the last enzyme in the synthesis of creatine, thus they decrease its intracellular content. Such decreased content could cause mitochondrial impairment, since creatine is the final acceptor of the phosphate group of adenosine triphosphate (ATP) at the end of mitochondrial oxidative phosphorylation. Decreased cellular synthesis of adenosine triphosphate (ATP) would follow. Accordingly, ATP synthesis is decreased in statin-treated cells. In vitro, creatine supplementation prevents the opening of mitochondrial permeability transition pore caused by statins. Clinically, creatine administration prevents statin myopathy in statin-intolerant patients. Additional research is warranted to hopefully confirm these findings. However, creatine is widely used by athletes with no adverse events, and has demonstrated to be safe even in double-blind, placebo-controlled trials of elder individuals. Thus, it should be trialed, under medical supervision, in patients who cannot assume statin due to the occurrence of muscular symptoms.

Background: Antibiotic lock therapy is an interventional modality used for treatment and prevention of central-line associated bloodstream infections. Stability and compatibility data for combinations are lacking, limiting clinical use. Objective: Compatibility and stability of daptomycin lock solutions in combination with azithromycin, gentamicin, and heparin or sodium citrate were evaluated up to 96 hours. Methods: Eight candidate lock solutions were prepared for compatibility and stability testing. All solutions were prepared in glass vials, and included daptomycin 1mg/mL in varying combinations with heparin 100 – 1,000 units/mL, trisodium citrate, azithromycin and/or gentamicin. Lactated Ringer’s solution was added as a diluent in a sufficient quantity to bring the total volume up to 5mL. Drug stability in the admixture was determined by the degradation of the components. The quantification of drugs was performed using Waters Alliance HPLC using Phenomenex Luna C8 (2), 150*2.6mm, 5µ column. A gradient run was executed for 20 minutes with 0.45% ammonium dihydrogen phosphate, pH 3.25 as eluent A and acetonitrile as eluent B at a flow rate of 1.0mL/min. Each solution was visually inspected for particulates and color change. Lock solutions were tested in triplicate. Results: Daptomycin degradation was <10% for all solutions at 48 hours, and for 7 of the 8 solutions at 72 hours. Gentamicin degradation was <5% for solutions in combination with daptomycin and trisodium citrate. No physical incompatibilities were detected. Conclusion: Study data support the stability and compatibility of daptomycin with additives in solution, allowing for fewer exchanges and longer dwell times for a lock solution. The addition of azithromycin or gentamicin may offer synergy and/or extended spectrum of activity. Daptomycin bioactivity with trisodium citrate needs confirmation.

Background: This research presents the use of photoplethsmography combined with Traditional Tibetan Pulse reading for the estimation of the three energies of a person: Activity, Transformation and Stability. The growing interest to revive traditional finger pulse reading attests of the need to find alternative ways to approach complex multi-source diseases as well as individualised diagnostic wearable or portable cost effective systems. Method: Our work is presented in two studies. The first study presents the development of the technique of photoplethsmography to classify the three energies. The second study presents a validation of this methodology on mental stress and relaxation. Results: Energies classification achieved a sensitivity above 85% and specificity above 72%. Mental stress and relaxation could be significantly discriminated from baseline condition. Harmonic analysis gave further insights into the dynamic of the pulse wave under stress/relaxation. Conclusion: The photoplethsmogram contains information pertaining to the mental and physiological state of a person as interpreted with the Eastern energies concepts. The implication of this work points towards a holistic understanding and impact of human activities, health and its environment.

The endoplasmic reticulum (ER) comprises a network of tubules and vesicles that constitutes the largest organelle of the eukaryotic cell. Being the location where most proteins are synthesized and folded, it is crucial for the upkeep of cellular homeostasis. In addition, it is the largest ionic calcium reservoir in cells, tightly regulating the levels of this second messenger according to cellular necessities. Disturbed ER homeostasis triggers the activation of an intricate and conserved molecular machinery, termed the unfolded protein response (UPR). Given the impact of this signaling network upon an extensive list of cellular processes, ER stress is involved in the onset and progression of multiple diseases, including cancer and neurodegenerative disorders. There is, for this reason, an increasing number of publications focused on characterizing and/or modulating ER stress, which have resulted in a wide array of techniques employed to study ER-related molecular events. This review aims to sum up the tools available design a study of this nature.

Background: Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods: In this case-control study, Thai women and men, aged 18-65 years, were divided in DS (n=40) and NDS (n=40) and were compared to controls (n=40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and IgA levels responses directed to Gram-negative bacteria were measured. Results: DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions: The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing towards greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

It is unclear which noise exposure time window and noise characteristics during nighttime are most detrimental for sleep quality in real life settings. We have conducted a field study with 105 volunteers wearing a wrist actimeter to record their sleep during seven days, together with concurrent outdoor noise measurements at their bedroom window. Actimetry recorded sleep latency increased by 5.6 minutes (95% confidence interval: 1.6 to 9.6 minutes) per 10 dB(A) increase in noise exposure during the first hour after bedtime. Actimetry assessed sleep efficiency was significantly reduced by 2-3 percent per 10 dB(A) increase in measured outdoor noise (Leq, 1h) for the last three hours of sleep. For subjectively reported sleepiness, noise exposure during the last hour prior to wake up was most crucial with an increase in the sleepiness score of 0.31 units (95% CI: 0.08 to 0.54) per 10 dB(A) Leq,1h. Associations for estimated indoor noise were not more pronounced than for outdoor noise. Considering noise events in addition to equivalent sound pressure levels (Leq) only marginally improved the statistical models. Our study provides evidence that matching the nighttime noise exposure time window to the individual’s diurnal sleep-wake pattern results in a better estimate of detrimental nighttime noise effects on sleep. We found that noise exposure at the beginning and the end of the sleep is most crucial for sleep quality.

Psoriasis is a chronic immune-mediated skin disease that involves interaction of both immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation and angiogenesis. Because available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can rescind molecular defects associated with psoriasis and could be developed for its management. Fisetin (3,7,3′,4′- tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables has demonstrated pro-apoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological and tissue-engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC) and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α-stimulated NHEKs significantly inhibited the activation of p38 and JNK, but had no effect on ERK1/2. In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFNγ and IL-17A by 12-O- tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in-vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in-vivo human psoriatic skin-lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify pro-differentiative, anti-proliferative and anti-inflammatory effects of fisetin, via modulation of PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin model of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

Background: It is well known the adverse effect of mercury exposure on pregnant women and newborns. Interactions between environmental factors and individual genetic susceptibility have been identified, particularly polymorphisms of codifying genes for the Glutathione S-transferase family (GSTs). Herein, we report a case series of patients with high Hg levels in biosamples. Case Series: Fourteen cases with high Hg levels were identified. Non-occupational or home exposure risk factors were identified. All mothers reported fish consumption during pregnancy. Almost 60% of the individuals were null for either one GSTs gene. To date, in the subsequent mother-child pairs toxicology controls no signs or symptoms of poisoning were identified and most of the mercury levels decreased and are below the accepted limit. Discussion: In this case series we found some similarities with the literature; among them, the relation of Hg ratio in maternal blood and umbilical cord, a possible exposure factor is the consumption of fish during pregnancy and, the high levels of Hg may be related with susceptibility biomarkers such as GSTs gene polymorphisms. This case series highlights the need to develop studies that evaluate the interactions between environmental factors and individual genetic susceptibility. Additionally, the importance of evaluating which Colombian fish species present the highest levels of Hg.

Buerger's disease or Thromboangiitis Obliterans (TAO) is a nonatherosclerotic segmental vascular disease which affects small and medium arteries and veins in the upper and lower extremities. Based on pathological findings, TAO can be considered as a distinct form of vasculitis that is most prevalent in young male smokers. There is no definitive cure for this disease as therapeutic modalities are limited in number and efficacy. Surgical bypass has limited utility and 24% of patients will ultimately require amputation. Recently, studies have shown that therapeutic angiogenesis and immunomodulatory approaches through the delivery of cells to target tissues are potential options for ischemic lesion treatment. In this review, we summarize the current knowledge of TAO treatment and provide an overview of stem cell-based treatment modalities.

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, currently predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.

We compared the efficacy of a tailored and a targeted intervention designed to increase clinical breast exam (CBE), mammography, and genetic services/testing among young breast cancer survivors (YBCS) (diagnosed <45 years old) and their blood relatives. A two-arm cluster randomized trial recruited a random sample of YBCS from the Michigan cancer registry and up to two of their blood relatives. Participants were stratified according to race and randomly assigned as family units to the tailored (n=637) or the targeted (n=595) intervention. Approximately 40% of participants were Black; 12% YBCS and 27% relatives were living in more than 20 different U.S. States. Higher screening rates were reported by YBCS (CBE p=0.05; mammography p=0.04) and relatives (CBE p<0.01; mammography p=0.04) in the tailored arm, and by White/Other YBCS (CBE p=0.02) and relatives (CBE p<0.01; mammography p=0.03). YBCS genetic testing rates increased from 22% to 26% (p=0.11). Black YBCS and relatives reported higher self-efficacy and intention for genetic testing, and higher satisfaction and intervention acceptance. The tailored intervention improved CBE and mammography uptake - despite having minimal contact with participants. Professional referrals will improve genetic testing uptake. Intervention materials increased self-efficacy and satisfaction for Black women but could not overcome multiple access barriers.

Background Telomere shortening is related to aging and unfavourable health outcomes. Obesity and metabolic diseases are important factors for accelerating aging. This study aimed to find out the association between obesity, metabolic disease, and telomere length in metabolically healthy adults. Methods 237 adults were enrolled with written consents at a health promotion centre of a tertiary hospital from February 2014 to March 2015. After excluding 99 subjects who met the exclusion criterion, a total of 130 metabolically healthy subjects were selected for final analysis. The subjects were divided into quartile groups according to the telomere lengths of their oral mucosal cells. Results The subjects consisted of 66 (50.8%) males with a mean age of 58.59 years. The body mass index (BMI, kg/m2) increased significantly along with the quartile groups (Q1, 23.00; Q2, 23.96; Q3, 23.70; Q4, 25.20; P-for trend=0.008). Waist circumference (WC, P-for trend=0.022), waist-to-hip ratio (WHR, P-for trend=0.005), and waist-to-height ratio (WHtR, P=0.001) also increased along with the quartile groups. Obesity prevalence (BMI ≥25 kg/m2), abdominal obesity (WC ≥90 cm for men, ≥85 cm for women), WHR 〉1.0 for men or 〉0.85 for women, and WHtR ≥0.5 increased significantly as the telomere length increased (P-for trend <0.05). After adjusting for covariates, the ORs for each obesity markers increased as the telomere length increased (P-for trend <0.05); and the ORs of WHtR were especially meaningful (Q1, 1.00; Q2, 2.53; Q3, 2.97; Q4, 7.81; P-for trend = 0.001). There were no significant trends for metabolic syndrome and its components along with the prevalence of fatty liver disease. Conclusion Obesity markers and telomere length had significant positive correlation despite the established theory. The obesity paradox may exist in metabolically healthy adults with regard to telomere length, However, further studies with larger sample sizes for the association between obesity and telomere length are needed.

Activation of the EGFR pathway plays an important role in the progression of cancer and is associated with a poor prognosis in patients. The monoclonal antibody cetuximab, which displays EGFR extracellular domain-specific binding, has proven effective in the treatment of locally advanced disease and relapsed/metastatic disease. However, the effects of cetuximab are weaker than those of EGFR tyrosine kinase inhibitors (TKIs). This study investigates differences in the effects on cell growth of cetuximab and EGFR TKI AG1478 at the molecular level using oral squamous cell carcinoma (OSCC) cell lines. First, we found that there were EGFR-inhibitor sensitive (EIS) and EGFR-inhibitor resistant cell lines. The EIS cell lines expressed not only EGFR but also ErbB3, and both were clearly phosphorylated. The levels of phosphorylated ErbB3 were unaffected by cetuximab but were reduced by AG1478. EGFR ligand treatment increased the levels of phosphorylated EGFR but not phosphorylated ErbB3. Moreover, when EIS cell lines that were only capable of anchorage-dependent growth were grown in suspension, cell growth was suppressed and the levels of phosphorylated FAK, Src, and ErbB3 were significantly reduced. The levels of phosphorylated ErbB3 were unaffected by the FAK inhibitor PF573228, but were reduced by Src inhibition. Finally, combining cetuximab and a Src inhibitor produced an additive effect on the inhibition of EIS cell line growth.

Background: This retrospective study evaluate the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. We also demonstrated that EGFR-knockout Caco2 cells are more sensitive to the inhibition effect of fluoropyrimidine than the control those. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression and treatment strategies, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

Beta-thalassemia major (β-TM) patients are treated with repeated blood transfusions, which may cause iron overload (IO), which in turn may induce immune aberrations. Patients with β-TM have an increased risk of major depressive disorder (MDD). The aims of the present study are to examine whether repeated blood transfusions, IO and immune-inflammatory responses are associated with MDD in children (6-12 years) with β-TM. The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%) and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in β-TM with (n=54) and without (n=57) MDD and in healthy children (n=55). The results show that MDD in β-TM is associated with a greater number of blood transfusions, increased IO and IL-1β levels. Partial Least Squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, IO, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of IO on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by IO and the path from IO to immune activation. IO is also associated with increased IL-10 and lower CCL11 levels but these alterations are not significantly associated with MDD. In conclusion, blood transfusions may be causally related to MDD in β-TM children and their effects are in part mediated by increased IO and the consequent immune-inflammatory response. The results suggest that not only IO and its consequences including inflammation and ferroptosis, but also other factors related to the number of transfusions may cause MDD including psychosocial stressors. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate IO and immune-inflammatory responses and to prevent MDD is children with β-TM undergoing blood transfusions.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

Inflammatory bowel disease (IBD) is a chronic disease mediated by the immune system and characterized by the inflammation of the gastrointestinal tract. One of the possible treatments for this pathology is a change in the type of diet, the enteral nutrition (EN) is one of them. This study is to understand how the use of EN 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, Cinhal, WOS) we found 363 registers, the accuracy was 12% (44 registers); After a Full-text review, only 30 research studies were selected for qualitative synthesis and 11 for Meta-analysis and Meta-regression. The variables used were Crohn’s Disease Activity Index (CDAI), C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR). EN has shown to have efficacy for the treatment of Crohn’s Disease and is compatible with other medicines. As for the CDAI or the rates of remission, there were no differences between enteral and parenteral nutrition. Polymeric formulas, have shown better results with respect to the CRP. The long-term treatment could dilute the good CDAI results that are obtained at the start of the EN treatment.

Data can be illustrated in shapes, and the shapes could provide insight for data modeling and information extraction. Topological data analysis provides an alternative insight in biomedical data analysis and knowledge discovery with the algebra topology tools. In present work, we study the application of topological data analysis for personalized electrocardiographic signal classification toward arrhythmia analysis. Using phase space reconstruction technique, the signal samples are converted into point clouds for topological analysis facility. With topological techniques the persistence landscapes from the point clouds are extracted as features to perform the arrhythmia classification task. We find that the proposed method is robust to the training set size, with only a training set size of 20% percents, the normal heartbeat class are 100% recognized, ventricular beats for 97.13%, supra-ventricular beats for 94.27% and fusion beats for 94.27% within the corresponding experiments. The property of keeping high performance when using smaller training sample proves that the proposed method is especially applicable to personalized analysis. With the present study, we show that the topological data analysis technique could be a useful tool in biomedical signal analysis, and provide powerful ability in personalized analysis.

Background and Objective: In the present study, the purpose was to compare the demographic, clinical and laboratory results of pediatric brucella cases who had liver involvement and who had no specific organ involvement. Material and Methods: The data of 248 patients between 2 and 18 years of age diagnosed with Brucellosis between July 2017 and August 2018 were analyzed retrospectively. The patients who had liver involvement and who did not have other specific organ involvement were compared in terms of presentation, physical examination findings, age, gender, hemogram, AST, ALT, GGT, ALP, bilirubines, sedimentation, CRP, clinical and laboratory findings, and culture and relapse rates. Results: No significant differences were detected between the patients who had liver involvement (n=92) and who did not have specific organ involvement (n=156) in terms of diagnosis age and gender. Loss of appetite, nausea and sensitive stomach were higher in the patients who had hepatic involvement, and weariness was determined to be more in the control group patients. In the patients who had hepatic involvement, the hemoglobin and platelet values were lower, and the sedimentation, CRP and blood culture growth were higher. The relapse rates were lower in patients who had liver involvement. Conclusion: In patients who have liver involvement, in addition to elevated hepatomegaly and transaminase levels, the growth rate of the acute-phase reactants and brucella is higher in blood culture; and the relapse rate is lower after treatment. Brucellosis must be considered in the differential diagnosis of hepatomegaly and transaminase elevation where brucellosis is seen endemically. We believe that early diagnosis of brucellosis is important in treatment response.

Polo is an equestrian team sport, consisting of Open and Women’s only handicapping systems. As cumulative player handicap increases in Open Polo, distance covered, average speeds and high intensity work performed per chukka also increase. These activities may differ in terms of distribution of, and their affect upon, match outcome in Women’s Polo, and thus have implications for equine preparation and management. This study aimed to quantify spatiotemporal differences between Open and Women’s Polo when matched for handicap and assess their affect upon chukka and match outcome using a prospective cohort design. Distance, speed and high intensity activity data were collected via player worn global positioning system (GPS) units during 16-goal Open and Women’s Polo tournaments. Notational analysis quantified chukka duration and chukka and game outcomes. Between group differences were assessed by independent samples t-tests, and two factor mixed effects ANOVA for within group analyses. Between group differences were analysed using an independent samples t-test with alpha defined a priori as p<0.05. Open and Women’s Polo differed by a small to large extent (ES: 0.54 – 1.81) for all spatiotemporal metrics. In Open Polo, players covered moderately more distance (429.0m; 238.9m to 619.0m), with small to large increases in high intensity activities performed in games won. Whereas in Women’s Polo, moderately higher maximum speeds were attained in games won (17.13 km/h; 11.86 km/h to 22.40 km/h) and a small increase in accelerations performed (5.1; 0.2 to 10.0). Open and Women’s Polo, when matched for handicap, present with small to large spatiotemporal differences that are likely of practical significance, and influence game outcome differently between codes. These differences do not necessarily mean that Polo ponies need to be trained differently for each code.

Background and objective: Addressing the global morbidity associated with pulmonary disease is an important need for the respiratory community. However, there is also a growing momentum to show the efficacy of new tools of diagnosis. Despite this, there are few physiotherapeutic tools that help identify and categorize these conditions. The aim was to analyze the variables of physiotherapy index of the ventilatory workload (PIVW) in people with chronic obstructive pulmonary disease (COPD) during stability and exacerbation in an outpatient setting. Material and Methods: Analyzed retrospectively of 198 clinical records were reviewed. The PIVW was extracted in stability and exacerbation of these patients with COPD. After applying the exclusion and inclusion criteria; 54 patients were classified. Through the statistical analysis of chi-square, a significant association was reported for each of the variables and the total PIVW score. Results: when analyzing the baseline with the peak of PIVW, there was a significant increase in patients COPD exacerbation. Similarly, the variables that constitute the loads, translations and supports underwent a significant increase from baseline to exacerbation (p<0.0001), except for the additional oxygen contribution, where the frequency of patients was the same in basal and exacerbation as well. Conclusions: the PIVW, serves to determine ventilatory problemas in outpatients, characterizing the specific changes of loads, translators or assistance.

The ability to predict the skin sensitization potential of small organic molecules is of high importance to the development and safe application of cosmetics, drugs and pesticides. One of the most widely accepted methods for predicting this hazard is the rodent local lymph node assay (LLNA). The goal of this work was to develop in silico models for the prediction of the skin sensitization potential of small molecules that go beyond the state of the art, with larger LLNA data sets and, most importantly, a robust and intuitive definition of the applicability domain, paired with additional indicators of the reliability of predictions. We explored a large variety of molecular descriptors and fingerprints in combination with random forest and support vector machine classifiers. The most suitable models were tested on holdout data, on which they yielded competitive performance (Matthews correlation coefficients up to 0.52; accuracies up to 0.76; areas under the receiver operating characteristic curves up to 0.83). The most favorable models are available via a public web service at https://nerdd.zbh.uni-hamburg.de/skinDoctor/ that, in addition to predictions, provides assessments of the applicability domain and indicators of the reliability of the individual predictions.

Background: The purpose was to develop a novel hypothetical method to increase the size of coronary arteries. Methods: In the long-term observation the coronary sizes were dilated in three unexpected scenarios. The coronary artery sizes were observed in patients with mitral stenosis (n=59) by angiogram prior to percutaneous balloon mitral valvuloplasty or valve replacement surgery for severe mitral stenosis. The coronaries of patients with patent ductus arteriosus who underwent surgical closure in the past (n=12) were examined by echocardiogram. Patients with renal failure on long-term dialysis through peripheral arterio-venous fistula without left ventricular hypertrophy (n=17) were studied by echocardiography. Normal age, weight and sex matched coronary sizes served as controls in the study. All these observations were made over a period of 11.5 years. Results: The sizes of coronaries in patients with mitral stenosis, patients who underwent closure for patent ductus arteriosus, and in patients on hemodialysis through arteriovenous fistulas were higher than normal controls (p<0.05, for all). A hypothetical model to increase the coronary sizes could be developed based on the analysis of the differential equations of Poiseuille’s. The proposed method is creating a peripheral arterio-venous fistula, which could be closed later electively by a percutaneous method/surgery. The closure time needs to be determined by experimental studies. The other methods could be a continuous exercise program or usage of beta-blockers. Conclusion: A novel hypothetical method of peripheral arteriovenous fistula formation could potentially increase the size of the coronaries, and this could be closed later.

Obesity is one of the factors leading to the development of atherosclerosis. This metabolic disorder is associated with an increased production of reactive oxygen species, which affect the oxidative stress level. The aim of this study was to evaluate oxidative/antioxidative status and to investigate the correlation between redox markers and anthropometric parameters and body composition in adult patients after myocardial infarction and in individuals without a cardiovascular event in the past. Descriptive data on socio-demographic, clinical, and anthropometric features and blood samples were collected and categorized into two equal groups: after myocardial infarction (study group (SG), n = 80) and without a cardiovascular event (control group (CG), n = 80). The oxidative/antioxidative status was assessed in plasma on the basis of total oxidative/capacitive status (PerOx), total antioxidative status/capacity (ImAnOx), and oxidized low-density lipoprotein (oxLDL). OxLDL was significantly higher in the CG group compared to the SG group (p = 0.02). No significant differences were found with regard to PerOx and ImAnOx values between the studied groups. Significant positive correlation between PerOx and percentage of adipose tissue (FM [%]) and body adiposity index (BAI) was found in the two studied groups. ImAnOx significantly positively correlated with VAI in SG and FM% in CG. OxLDL negatively correlated with body mass index and waist to hip circumference ratio in CG. The total oxidative/antioxidative status is related to the amount of adipose tissue and the BAI of the subjects. It was observed that it correlates more frequently with the visceral distribution of body fat.

MicroRNAs (miRNAs) dysregulation contribute the cancer pathogenesis. However, the miRNA profile of canine oral melanoma (COM), one of the frequent malignant melanoma in dog is still unrevealed. The aim of this study is to reveal the miRNA profile in canine oral melanoma. MicroRNAs profile of oral tissues from normal healthy dogs and COM patients were compared by next-generation sequencing. Along with tumour suppressor microRNAs (miRNAs), we report 30 oncogenic miRNAs in COM. Expression of miRNAs were further confirmed by quantitative real-time PCR (qPCR). Pathway analysis showed that deregulated miRNAs impact on cancer and signalling pathways. Three oncogenic miRNAs targets (miR-450b, 301a, and 223) from human study also were down-regulated in COM and had significant negative co-relation with their respective miRNA. Furthermore, we found that miR-450b expression is higher in metastatic cells and regulated MMP9 expression through a PAX9-BMP4-MMP9 axis. In silico analysis indicated that miR-126, miR-20b, and miR-106a regulated the highest numbers of differentially expressed transcription factors in respect to human melanoma. Chromosomal enrichment analysis revealed the X chromosome was enriched with oncogenic miRNAs. We comprehensively analyzed the miRNA’s profile in COM which will be a useful resource for developing therapeutic interventions in both species.

Pre-diabetes is a serious health condition where blood sugar levels are higher than normal, but not high enough yet to be diagnosed as type 2 diabetes. Pre-diabetes puts one at an increased risk of developing type 2 diabetes and heart disease Methodology: A cross-sectional study was carried out on 384 patients aged 20-70 years old, attending the dental clinics to assess the risk for diabetes, using the FINDRISC questionnaire, HbA1c blood test and a periodontal examination. Results: The mean age of participants was 38.90±10.74. 32.3% were categorized as no risk, 46.6% low risk, while 19% and 2.1% moderate and high risk of developing diabetes respectively. Tests for serum HbA1c Level showed 46.1 % had normal HbA1c followed by 18.0% and 3.6 % were pre-diabetic and diabetic respectively. 19.3% of participants had periodontal pockets measuring more than 4mm and 15.9% measuring more than 6mm. Conclusion: The study has proven to be useful in identifying patients at high-risk of developing diabetes. Controlling and managing periodontal disease could be a new aspect to include in the standards for diabetes care. Dental settings could be a successful platform to carry out the screening and risk stratification of pre-diabetic patients.

Metastatic pancreatic ductal adenocarcinoma pancreatic (PDAC) is characterized by poor prognosis and short survival. Today, the use of new polytherapeutic regimens increases clinical outcome of these patients opening new clinical scenario. A crucial issue related to the actual improvement achieved with these new regimens is represented by the occasional possibility to observe a radiological complete response of metastatic lesions in patients with synchronous primary tumor. What could be the best therapeutic management of these patients? Could surgery represent an indication? Herein we reported a case of a patient with a PDAC of the head with multiple liver metastasis, who underwent first line chemotherapy with mFOLFIRINOX. After 10 cycles, he achieved a complete radiological response of liver metastases and a partial response of pancreatic lesion. A, duodenocephalopancreasectomy was performed. Due to liver a lung metastases after 8 months from surgery, a second line therapy was started with a disease free survival and overall survival of 8 months and 45 months, respectively. Improvement in the molecular characterization of PDAC could help in the selection of patients suitable for multimodal treatments.

Nutrition is crucial for the management of patients affected by chronic kidney disease (CKD) to slow down disease progression and to correct symptoms. The mainstay of the nutritional approach to renal patients is protein restriction coupled with adequate energy supply to prevent malnutrition. However, other aspects of renal diets, including fiber content, can be beneficial. This paper summarizes the latest literature on the role of different types of dietary fiber in CKD, with special attention to intestinal microbiota and the potential protective role of renal diets. Fibers have been identified based on aqueous solubility, but other features, such as viscosity, fermentability, and bulking effect in the colon should be considered. A proper amount of fiber should be recommended not only in the general population but also in CKD patients, to achieve an adequate composition and metabolism of intestinal microbiota and to reduce the risks connected with obesity, diabetes, and dyslipidemia.

With the continuous progress in modern medicine, the early detection rate of gastric cancer has increased, and the mortality rate has decreased. However, gastric cancer remains the third leading cause of cancer-related death worldwide, with a high recurrence rate. Metastasis is the leading cause of death and recurrence of gastric cancer, which greatly hinders treatment success. Cancer development is a complex process involving multiple sequential steps. In the metastatic cascade, local invasion may be considered an initial, crucial step in the development of a malignant tumor, which leads to distant metastasis. Epithelial-mesenchymal transformation (EMT) is one of the most important developmental processes that occur during tumor invasion. EMT confers certain basic abilities to cancer cells, such as migration, invasion and anti-apoptotic ability, thus initiating and increasing metastasis. However, little is known about the molecular mechanisms that promote EMT and gastric cancer cell metastasis. A number of recent studies have found that circular RNAs（circRNAs）are associated with gastric cancer EMT, regulating the EMT process and promoting the occurrence and development of tumors. Because of their unique continuous circular structure, circRNAs have relatively high stability in plasma and cells, making them more suitable as diagnostic biomarkers in malignant tumors. Therefore, understanding the mechanism of circRNAs in EMT in gastric cancer is an important research direction to actively prevent tumor metastasis and improve the therapeutic effect on advanced malignant tumors.

Evidence has shown that the state of the patient care environment has a direct impact in heightening the risks of hospital acquired infections among patients admitted in hospitals. And in view of the sub-optimal standard of cleanings by housekeeping staff, the quest for a better approach to reliably disinfect environmental surfaces in healthcare facilities. The ultraviolet light has been known for its antimicrobial property, and have been used in water treatment, food processing and in-duct cleaning of ventilations. A recent introduction of its use for surface decontamination has raised interest among hospitals.However, studies have shown that, in spite of its relative success in other applications, there is doubt in its efficacy in decontaminating shadowed areas of the room, and therefore, would not be seen as justifying its capital intensiveness.

Background: Qazvin province has suffered a lot of natural disasters (earthquakes) for a long time. so, the establishment of the first industrial city in Iran, has always been a source of concern. One of these problems is the possibility of chlorine gas leaking from the chlorination system of drinking water and treatment plant the existing ones are on the health of the inhabitants of this region.Material and method: This analytical study was carried out in Novorossiysk district of Alborz in December 2012. Initially, chlorine gas leakage scenarios from these facilities were simulated by ALOHA and WISER software, and then using the Emergency Level System, according to the CCPS Consultative Center's Chemical Process Safety Advice, the Emergency Response Program was presented. Results: ALOHA software, in comparison with WISER software, has more precision to identify and address the consequences of chlorine gas leakage hazards and according to the simulation of this software in the event of a leak from the well and water resources unit at 8240 m from the area and at night 7520 meters will be affected. Due to the speed of delivering results through the WISER software, this software can be used at times when the operating speed is considered (incident time).Conclusion: According to the CCPS model, the emergency conditions were classified at levels 3 and 4, therefore, the relevant crisis management agencies (Qazvin Crisis Management Committee, Alborz City Health Center, Red Crescent and Firefighting Authority) should provide training maneuvers At Alborz city level, and informing people of cities and industrial companies, many efforts have been made to reduce human and environmental damage in case of possible leakage.

Aurora kinase A (AURKA) is a normal cell proliferation-inducing enzyme encoded by AURKA gene, with over-expression observed in different types of malignancies. Hence, the goal is to find potential inhibitors against AURKA. In this study, molecular docking, Standard Precision and Extra Precision methods were employed. After the docking study, the ligands showed an extremely low binding score which suggested very high binding affinity of the ligands. Furthermore, Quantum polarized ligand docking (QPLD) was performed to predict the binding status of the molecules. Based on the binding affinity, the top four compounds were chosen for further analysis. The docked complexes were further analyzed in explicit water conditions using 100 ns molecular dynamics simulations and binding free energy calculation. Then, density functional theory (DFT) calculation was used to calculate the molecular properties of the molecules. Finally, systems biology experiments validated the molecular docking and molecular dynamics simulation studies and indicated that quercetin, kaempferol, luteolin and rutin could inhibit the AURKA. The results show that, these four molecules have high binding affinity to the AURKA and significant interactions (LEU139, GLU211and ALA213) were also identified with the hinge region of Aurora kinase A. Thus, LEU139, GLU211, and ALA213 were identified as the crucial protein mechanisms.

This article focuses on the current state-of-the-art in the area of cellular and molecular biotechnology for over-production of clinically relevant therapeutic growth factors and how the technology can be used for the treatment of osteoarthritis (OA). Transfected and irradiated protein packaging cell lines may be used as “cellular factories” for large-scale production of therapeutic proteins and pro-anabolic growth factors, particularly in the context of cartilage matrix regeneration. We discuss the potential for new innovations in regenerative medicine for degenerative diseases of synovial joints using mammalian protein production platforms, specifically protein packaging cell lines, for over-producing growth factors for cartilage tissue regeneration and give recent examples. Mammalian protein production platforms that incorporate protein packaging cell lines are superior to bacterial expression systems and are likely to have a significant impact on the development of new biological therapies for treating focal cartilage defects and more generally for the treatment of degenerative joint diseases such as OA.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are environmental pollutants with a great persistence, capacity of bioaccumulation, and well known important toxic effects in humans and animals. Incinerators of hazardous, municipal and medical waste, chlorine bleaching of paper pulp, cement plants, and the traffic of motor vehicles are the most frequent emission sources of these compounds. The diet, followed at a great distance by inhalation, is generally the main way of human exposure to PCDD/Fs. Human biomonitoring is of a great importance to prevent potential adverse effects derived from exposure to chemicals such as PCDD/Fs. In relation to this, blood is among the most used biological monitors. In the current review, we have summarized the recent information (2000-2009) published in the scientific literature (databases: Scopus and PubMed) on the concentrations of PCDD/Fs in blood samples of non-occupationally exposed populations, as well as in some groups of occupationally exposed individuals. We have revised a number of studies conducted in various African American, Asian and European countries, and Australia. Unfortunately, the information is quite limited. No data are available for most countries over the world. Based on the results here reviewed –where available- the current health risks for the general populations do not seem to be of concern. Moreover, taking into account the important reductions observed in the levels of PCDD/Fs in foodstuffs, new decreases in the concentrations of PCDD/Fs in blood -and other biological tissues- are very probable in the immediate years.

Background: Peroxiredoxins (Prxs) comprise antioxidant factors that are widely found in prokaryotes and eukaryotes. Abnormal expression of Prxs is closely related to tumorigenesis. Methods: This study examined the prognostic value and expression of Prxs in lung cancer by Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan-Meier Plotter, cBioPortal and Functional Enrichment Analysis Tool (FunRich) databases. Results: We found that Prx1/2/3/4/5 were overexpressed in both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) relative to normal lung cells. However, the expression level of Prx6 was lower in LUAD and higher in LUSC than normal lung cells. The level of Prx3 and Prx6 were associated with pathological stage. Prognostic analysis showed that elevated Prx1 and Prx2 expression were correlated with low Overall Survival (OS), whereas high Prx5 and Prx6 expression level predicted high OS. Conclusions: Our results effectively revealed the level of Prxs in lung cancer and its influence on the prognosis of lung carcinoma, contributing to the study of the role of Prxs in tumorigenesis.

The association between the choice of general anesthetic agents and the risk of acute kidney injury (AKI) and long-term renal function after nephrectomy has not yet been evaluated. We reviewed 1087 cases of partial or radical nephrectomy. The incidence of postoperative AKI, new-onset chronic kidney disease (CKD) stage 3a and CKD upstaging were compared between different general anesthetic agent groups: propofol, sevoflurane, and desflurane. Four different propensity score analyses were performed to minimize confounding for each pair of comparison (propofol vs sevoflurane; propofol vs desflurane; sevoflurane vs desflurane; propofol vs volatile agents). Study outcomes were compared before and after matching. Kaplan-Meier survival curve analysis was performed to compare renal survival determined by the development of CKD stage 3a between groups up to 36 months after nephrectomy before and after matching. Propofol was associated with a lower incidence of AKI, CKD upstaging and a higher three-year renal survival after nephrectomy compared to sevoflurane or desflurane group after matching (AKI: propofol 23.2% vs. sevoflurane 39.5%, P=0.004, vs. desflurane 34.3%, P=0.031; CKD upstaging: propofol 27.2% vs. sevoflurane 58.4%, P<0.001, vs. desflurane 48.6%, P=0.017; Log-rank test propofol vs. sevoflurane P<0.001, vs. desflurane P=0.015). Propofol was also associated with a lower incidence of new-onset CKD after nephrectomy compared to sevoflurane after matching (P<0.001). However, there were no significant differences between sevoflurane and desflurane. In conclusion, propofol, compared to volatile agents, may be the reasonable choice of general anesthetic agent for nephrectomy to attenuate postoperative renal dysfunction. Randomized prospective trials are warranted to test this hypothesis.

The focus of the presented work was to isolate and characterize circulating endometrial cells (CECs) enriched from peripheral blood (PB) of patients with diagnosed endometriosis to support endometriosis diagnosis and treatment. Material and Methods Blood samples (n=423) were tested for CECs presence. Subsequently, gene expression analysis (GEA) was carried out for CECs. In parallel, the presence and character of CECs was tested during phases of menstrual cycle (MC) (n= 11). CECs were isolated by size-based separation from 2x 8ml PB. Results CECs were detected in 78.4% of blood samples. In line with the revised American Fertility Society (rAFS) classification CECs presence was confirmed in all the acknowledged endometriosis stages: minimal, mild, moderate and severe. Surprisingly, the highest CEC negativity rate was reported for severe disease (21.1%). The highest CEC numbers were detected in the mid-secretory periods of MC, which corresponds with uterine lining decidualization. The cytomorphology of CECs captured during MC is changing between the epithelial, stromal and stem cell-like. CECs captured in mid-secretory period expressed KRT18, NANOG and VIM in higher amounts when compared to the genes in the proliferative phase of MC when KRT19 and ESR1 were mostly observed. GEA of the super-positive CECs samples (1000 CECs/8mL PB) revealed high expression of KRT18, VIM, NANOG and FLT1. The expression of these genes was elevated in the endometriosis tissue samples and endometrioma, too. Conclusion The panel of the identified CECs - genes could be tested in a prospective manner to confirm the predictive value of CECs in endometriosis diagnostics.

Emergency Health Services refers to the urgent care. Ambulance abuse threaten the provision of proper health services and at the same time it affects the country's economy negatively. It was aimed to determine ambulance abuse level. This was a retrospective cohort research. In order to carry out our study, we analyzed 12,207 cases who called to the 112 Emergency Ambulance Services between 01.01.2016 and 31.12.2016. The data of the study has been obtained from the Emergency Health Automation System of the Provincial Health Directorate. According to preliminary diagnoses, traumatic cases were found to be 19.4% and cardiovascular cases were 12%. According to the World Health Organization 32 Critical Code List 59.6% of the cases who called to the 112 Emergency Ambulance Services in 2016 were inappropriate. Ambulance abuse rate was 59.6%. The high rate of misuse of 112 emergency ambulances affects the service flow and motivation of the staff negatively and causes extra financial burden. Thereof, awareness trainings should be given to the public and task and duties of the paramedics and emergency medical technicians who work at emergency ambulances should be expanded so that the transfer of unnecessary cases should be prevented.

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm constituting approximately 15% of newly diagnosed leukemia in adult patients. Development of tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with chronic CML in chronic phase. However, adverse drug events (ADEs) associated with TKI therapy have influenced drug adherence, resulting in adverse clinical outcomes and a decline in the quality of life (QoL). In this study, we carried out a unique questionnaire survey to evaluate ADEs, which comprised 14 adverse events. We compared drug adherence rates between patients using imatinib and those who switched from imatinib to nilotinib, a second-generation TKI. Following the switch, the total number of ADEs decreased considerably in most cases. Simultaneously, better QoL was observed in the nilotinib group than in the imatinib group. Drug adherence was measured using Morisky’s 9-item Medication Adherence Scale (MMAS). MMAS increased significantly after switching to nilotinib in all cases. Drug adherence is a critical factor for achieving molecular response in patients with CML. In fact, our results showed a strong inverse correlation between clinical outcome [international scale (IS)] and adherence (MMAS), with a stronger tendency in the nilotinib group than in the imatinib group. In conclusion, low occurrence of ADEs induced a high level of QoL and a good clinical response with second-generation TKI nilotinib treatment.

Gait is a basic cognitive propositive action that has been shown to be altered in late stages of neurodegenerative dementias. Nevertheless, alterations are less clear in mild forms of dementia, and the potential use of gait analysis as a biomarker of initial cognitive decline has hitherto mostly been neglected. We here report the results of a study of gait kinematic time series for two groups of patients (Mild Cognitive Impairment and mild Alzheimer's disease) and a group of matched control subjects. Two metrics based on permutation patterns are considered, respectively measuring the complexity and irreversibility of the time series. Results indicate that kinematic disorganisation is present at early phases of cognitive impairment; in addition, they depict a rich scenario, in which some joint movements display an increased complexity and irreversibility, while others a marked decrease. Beyond their potential use as biomarkers, complexity and irreversibility metrics can open a new door towards the understanding of the role of the nervous system in gait, as well as its adaptation and compensatory mechanisms.

Pulse oximetry is the current standard for detecting drops in arterial blood oxygen saturation (SpO₂) associated with obstructive sleep apnea and hypopnea events in polysomnographic (PSG) testing. In cases of hypoxic challenge, such as occurs during apneic events, regulatory mechanisms restrict blood flow to the skin to preferentially maintain SpO₂ for more vital organs. As a result, a measure related to skin tissue oxygenation is likely to be more sensitive to inadequate breathing during sleep than pulse oximetry. Energy Conversion Monitoring (ECM) provides a method for measuring skin tissue oxygen-dependent energy conversion and, as such, is promising for more sensitively detecting sleep disordered breathing (SDB) events compared to pulse oximetry. We hypothesized that ECM would detect hypoxia occurring with SDB events associated with drops in SpO₂ but also would detect hypoxic challenge occurring with SDB events not associated with drops in SpO₂ (hypopneas defined by a drop in nasal pressure occurring in conjunction with an arousal, respiratory-related arousals, and primary snoring). Primary snoring is of particular interest with respect to the potential of ECM because it is statistically associated with co-morbidities of SDB, such as hypertension, but is not considered pathological because of the lack of a proximal measure of pathology occurring with PSG. In this article we review ECM technology and methodology, present preliminary data indicating that it detects hypoxia occurring in the skin during SDB events that is not detected as blood desaturation by pulse oximetry, and make the case that it is a promising tool for identifying pathology occurring at the mild end of the SDB spectrum.

As mental health problems tend to increase during adolescence and is a serious public health issue in the Republic of Kazakhstan. Early detection is necessary and monitoring at the population level can be used to evaluate the progress of national programmes promoting positive well-being. Physical activity (PA) can be protective whereas increased screen time behaviours (STB) can be a risk for low levels of well-being. A national representative sample (n=4,731) of young adolescents aged 11y, 13y, and 15y from the Republic of Kazakhstan took part in the WHO collaborative Health Behaviour in School-aged Children (HBSC) study. Respondents completed the WHO-5 Well-being scale, and items in on PA and STB. Internationally recognised, recommended cut-offs were used for analyses. Two models of binary logistic regressions were performed to examine the associations with PA (Model 1) and PA with STB (Model 2) after stratification by gender and controlling for age, locality and family affluence. Three quarters of young adolescents in the Republic of Kazakhstan have good overall well-being, despite the proportion reduces as adolescents age from 11y to 15y (boys, OR=0.66 CI=0.49-0.80; girls, OR=0.55, CI=0.43-0.71). The odds ratio for positive well-being were more than twice for boys and more than 3.5 for girls who reported daily PA than not being active daily. Spending less time on STB for girls was associated with positive well-being than spending more STB time (OR=1.28, CI=1.04-1.59). Well-being among young adolescents drops dramatically between the ages of 11y and 15y and is higher among rural schools attendees than in urban schools. The recommended amounts of PA can be protective of low well-being for both boys and girls. However, meeting reporting STB recommendations was only protective for girls and not boys. Designing and implementing positive well-being programmes require consideration of locality and amounts of PA and STB

Many lifestyle and occupational habits negatively impact on physical and mental health, increasing the risk of cardiovascular and other diseases. While larger institutions fulfill occupational health requirements to ensure their employees’ wellbeing at work, smaller business workers and entrepreneurs may neglect initial signs of stress or physical decline, putting themselves at increased risk. Early detection of compromised cardiopulmonary health or fitness has the potential to flag up indications for early interventions and reduce the risk of disease onset and progression. This case study highlights the usefulness of respiratory muscle training (RMT) in improving pulmonary and cardiovascular parameters as an early countermeasure to cardiopulmonary decline. We suggest RMT as an easily accessible, cost- and time effective opportunity to support a healthy lifestyle.

Background: Green synthesis of silver (Ag) nanoparticle was performed with the fruit extract of Scindapsus officinalis and test against HepG-2, MCF-7 cancer cell lines. These biosynthesized metal nanoparticles have a potential of therapeutic use as an alternative medicine for the treatment of hepatic & breast cancer cases. Results : AgNPs were identified by change of color & their absobtion at 340 nm measured by UV-visible spectroscopy, FTIR spectral analysis confirmed phenolic compounds presence, morphology & size visualized in SEM, TEM used for determination of size, shape & light scattering analysis. Synthesized silver nanoparticles were spherical in shape and size less than 50 nm. XRD analysis was affirmed the crystalline nature of metal particles. In-vitro cytotoxic result showed an excellent IC50 value of 155.81μg/ml and 114.74 μg/ml against HepG-2 & MCF-7 cell lines. Conclusion: The current study reveals green synthesized AgNPs possess high cytotoxic action against HepG-2 & MCF-7 cell lines which suggested the use of silver nanoparticles as a medicine to treat hepatic & breast cancer.

The aim of the study is to assess enjoyment and intensity of physical exercise while practicing physical activity (PA) in immersive virtual reality (IVR) using innovative training devices (omni-directional Omni treadmill and Icaros Pro flight simulator). The study also contains the results of subjective research on the usefulness of such a form of PA in the opinion of users. In total, 61 adults (10 women and 50 men) took part in the study. To assess the enjoyment level (EL) Interest/Enjoyment subscale of Intrinsic Motivation Inventory (IMI) was used. Exercise intensity was assessed during 10-minute sessions of active video games (AVGs) in IVR based on heart rate (HR). The average enjoyment level during physical exercise in IVR on the tested training devices was relatively high (Omni 5.74 points, Icaros 5.60 points). In the opinion of the majority of participants, AVGs on IVR training devices constitute a sufficiently useful form of movement to meet the needs of PA practiced in free time, and they can even replace some of the classic forms of movement. Intensity of PA during games on training devices was at the level recommended for health benefits for 92% (Omni) and 84% (Icaros Pro) of its duration. Based on the conducted research, it can be assumed that AVGs in IVR using a multi-directional treadmill and a flight simulator can be an effective tool for increasing participation in health-oriented PA.

Titanium micro-scale topography results in excellent osteoconductivity and bone-implant integration. However, the biological effects of sub-micron topography are unknown. We compared osteoblastic phenotypes and in vivo bone and implant integration abilities between titanium surfaces with micro- (1–5 µm) and sub-micro-scale (0.1–0.5 µm) topographies and machined titanium. Average roughness was 12.5 ± 0.65 nm, 123 ± 6.15 nm, and 24 ± 1.2 nm for machined, micro-rough, and sub-micro-rough surfaces, respectively. The micro-rough surface showed the fewest cells attaching during the initial stage and the lowest proliferation. Calcium deposition and expression of osteoblastic genes were highest on the sub-micro-rough surface and lowest on the machined surface. Bone-to-implant integration was strongest for the micro-rough surface, consistent with it having the greatest ability to retain cells in vitro. Thus, the biological effects of titanium surfaces are not necessarily proportional to the degree of roughness in osteoblastic cultures or in vivo. Sub-micro-rough titanium ameliorates the disadvantage of micro-rough titanium by restoring cell attachment and proliferation and enhances the rate of osteoblastic differentiation over that of micro-rough titanium; however, bone integration and the ability to retain cells are compromised due to its lower interfacial mechanical locking compared to that of micro-rough titanium.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

Aim: aim of this study is to evaluate the clinical and radiographic healing after repairing mechanical furcal perforations that occurred in primary molars by using MTA (Mineral Trioxide Aggregate) and search in some factors that may affect the prognosis of the treatment. Materials & Methods: we had 34 primary molars in 32 children aged 5–10 years, were treated by using MTA material after the occurrence of furcal perforation during pulpotomy procedure. Cases had been followed clinically and radiographically within 12 months. Statistical analyses were performed at p-value = 0.05. Results: All teeth were asymptomatic at the first week. Overall success rate was 79.3%. There was no significant statistically differences between overall-success rates according to the perforation size and continues bleeding in the furcation area (p-value > 0.05). Conclusions: Iatrogenic furcal perforations that may occur during pulpotomy in primary molars can be treated successfully by using MTA, and small sized-perforations may have more favorable prognosis than the large ones. Iatrogenic furcal perforations that may occur during pulpotomy in primary molars can be treated successfully by using MTA, and small sized- perforations may have more favorable prognosis than the large ones.

Elevated levels of immunoglobulin E (IgE) are associated with allergies and other immunological disorders. Experimentally, sensitization with alum adjuvant favors IgE production while CpG-ODN adjuvant, a synthetic toll-like receptor 9 (TLR9) agonist, inhibits it. The cellular mechanisms underlying TLR-regulation of immunoglobulin production are still controversial. Specifically, TLR-mediated IgE regulation in vivo is not yet known. We show that augmented levels of IgE induced by sensitizations to OVA with or without alum adjuvant or with OVA-pulsed dendritic cells (DCs) were inhibited when sensitization to OVA was performed in the presence of CpG. Notably, CpG-mediated suppression of IgE production required MyD88-expression on DCs but not on B-cells. This contrasts with previous reports of in vitro regulation IgE where CpG acted directly on B cells via MyD88 pathway. In addition, CpG also inhibited IgE production in a MyD88-dependent manner when sensitization was performed with OVA-pulsed DCs. Finally, CpG signaling through MyD88 pathway was also necessary and sufficient to prevent anaphylactic antibody production involved in active cutaneous anaphylaxis.

Ion channels contribute fundamental properties to all cell membranes. The ion channels are highly diverse in conductivity, structure, location and function. However, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Considering primarily pain-related ion channels, this review covers more novel and less known features of ion channel function, also with the aim to transfer knowledge between fields, which get inevitably more separate due to their size.

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs has a strong prognostic role in triple negative breast cancer (TNBC). Little is known about his interaction with Androgen receptor (AR) and Forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), Breast Cancer Type 1 susceptibility protein (BRCA1), Poly [ADP-Ribose] Polymerase 1 (PARP1) and Na+/H+ Exchanger Regulatory Factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS) (p=0.045). A Kaplan-Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p=0.037), and the phenotypes TILs-/AR+ and TILs-/FOXA1- had a worse DFS (p=0.032, p=0.001 respectively). AR was associated with FOXA1 expression (p=0.007), and the tumors FOXA1+ presented low levels of TILs (p=0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p=0.0117). Low TILs score was associated with poor patients’ survival, and TILs level in combination with AR or FOXA1 expression affected patient’s clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.

Obesity in children is associated with vitamin D (VD) deficiency and cardiometabolic abnormalities. To analyze the effects of VD supplementation in adolescents with obesity enrolled in a weight-loss program. Adolescents with obesity (n=26) and with normal weight (n=23; controls) were matched for age, sex, and puberty stage. The obesity group followed a 3-month weight-loss program that combined a reduced caloric intake with interval training physical activity and during which they received or not VD supplementation (4000 IU/d) (n=13/group; random assignation). The anthropometric parameters (BMI z-score, fat mass); serum levels of 25(OH)D, calcium and parathyroid hormone (PTH), cardiometabolic factors (triglycerides, HDL, and LDL cholesterol), fasting glucose and insulin, and homeostasis model assessment of insulin resistance index; diastolic, systolic and mean blood pressure, and inflammatory status (C-reactive protein, CRP) were measured at baseline and at the end of the 3-month program. At baseline, 25(OH)D concentration was lower and VD insufficiency (25(OH)D levels <50 nmol/L) rate was higher (73% vs 22%) in the obesity than in the normal-weight group. All cardiometabolic factors were altered in the obesity compared with the normal-weight group. After the 3-month weight-loss program, 25(OH)D levels was >50 nmol in all adolescents with obesity, but only in 46% of normal-weight adolescents. Moreover, the weight-loss program improved the cardiometabolic factors, inflammatory status (CRP) and physical performance, but VD supplementation did not have any additional effect. Analysis only of the adolescents with obesity and VD deficiency (25(OH)D <50 nmol/L) at baseline showed a significant correlation between the change in PTH and CRP (p=0.02) in the supplemented obesity group, while the increase in 25(OH)D only tended to be correlated with CRP decrease. Vitamin D supplementation could reduce VD insufficiency in adolescent with obesity, but does not have any additional effect on cardiometabolic factors when combined with a weight-loss program.

Turmeric is a popular ingredient in the cuisine of many Asian countries. Turmeric is known for its use in Chinese and Ayurvedic medicine and comes from the roots of the Curcuma longa. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcumin has potent anti-inflammatory and anti-carcinogenic activities. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the bioactivity of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. Curcuminoids were extracted from turmeric with organic solvents. We conducted a cell-based assay for CYP17A1 and CYP21A2 activities using human adrenal cell line NCI-H295R. 3H-pregnenolone was used for CYP17A1 assays, and 3H-17alpha-hydroxyprogesterone was used as a substrate for CYP21A2. Curcuminoids were added at different concentrations and incubated for 24h. Steroids were separated by thin layer chromatography and analyzed by phosphorimager analysis. For CYP19A1 activity, an in vitro assay using endoplasmic reticulum from JEG3 were used with 3H-androstenedione as the substrate. Curcuminoids were incubated for 1h, and the formation of 3H-water from the androstenedione breakdown was measured by scintillation counting. When using 10 µg/ml of curcuminoids, both the 17-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, CYP21A2 activity was only reduced to ~50% control. Furthermore, CYP19A1 activity was reduced to ~20% of control when using 1-100 µg/ml of curcuminoids in a dose-dependent manner. No effect on the activity of 5alpha reductase for the conversion of androstenedione to androstanedione was observed. Molecular docking studies confirmed that curcumin could dock into the active sites of CYP17A1, CYP19A1 as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies show that curcuminoids may potentially cause inhibition of steroid metabolism, especially at higher dosages. The activities of CYP17A1 and CYP19A1 were inhibited by curcuminoids, which indicate potential anti-carcinogenic effects in case of prostate cancer as well as breast cancer, which can be targeted by inhibition of steroidogenesis. Also, the recent popularity of turmeric powder/curcumin as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. Curcuminoids present in curcumin may affect activities of multiple steroid metabolizing cytochrome P450 enzymes. Computational docking suggests curcumin binds into the active sites of steroid metabolizing P450s and may serve as a model for lead discovery. Molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.

Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1 or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene results in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, Bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, ATP production, oxygen consumption and s improved mitochondrial morphology in patient’s fibroblasts, albeit concomitantly causing a mild increase ROS production. Further studies would be needed to show the consistency of the response to Bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that Bezafibrate could be a possible treatment option for patients with certain DNM1L mutations.

Background: Ongoing molecular profiling studies enabled by advances in biomedical technologies are producing vast amounts of ‘omic’ data for early detection, monitoring, and prognosis of diverse diseases. A major common limitation is the scarcity of biological samples, necessitating integrative modeling frameworks that can make optimal use of available data for disease classification tasks. Related data sets are often available from different studies, but may have been generated using different technology platforms. Thus, there is a critical need for flexible modeling methods that can handle data from diverse sources to facilitate the discovery of robust biomarkers that underlie disease regulatory processes. Results: In this paper, we introduce a novel framework called Knowledge Augmented Rule Learning (KARL), which incorporates two sources of knowledge, domain, and data, for pattern discovery from small and high-dimensional datasets, such as transcriptomic data. We propose KARL as a transfer rule learning framework in which knowledge of the domain is transferred to the learning process on data in order to 1) improve the reliability of the discovered patterns, and 2) study the knowledge of the domain when used along with data for modeling. In this work, we generated KARL models on gene expression datasets for five types of cancer, including brain, breast, colon, lung, and prostate. As our knowledge of the domain, we used the Ingenuity Knowledge Base (IKB) to extract genes related to hallmarks of cancer and annotated these prior relationships before learning classifiers from these datasets. Conclusions: Our results show that KARL produces, on average, rule models that are more robust classifiers than the baseline without such background knowledge, for our tasks of cancer prediction using 25 publicly available gene expression datasets. Moreover, KARL helped us learn insights about previously known relationships in these gene expression datasets, along with new relationships not input as known, to enable informed biomarker discovery for cancer prediction tasks. KARL can be applied to modeling similar data from any other domain and classification task. Future work would involve extensions to KARL to handle hierarchical knowledge to derive more general hypotheses to drive biomedicine.

Pyrrole-imidazole (PI) polyamides are novel gene silencers that strongly bind the promoter region of target genes in a sequence-specific manner to inhibit gene transcription. We developed a PI polyamide targeting human TGF-b1 (hTGF-b1). To develop PI polyamide targeting hTGF-b1 (Polyamide) as a practical medicine for progressive renal diseases, we examined the effects of Polyamide in two common marmoset models of nephropathy.We performed lead optimization of PI polyamides targeting hTGF-b1 by the dose-dependent inhibition of the PMA-stimulated expression of TGF-b1 mRNA in marmoset fibroblasts. Marmosets were housed with a 0.05% NaCl and magnesium diet and treated with cyclosporine A (CsA; 37.5 mg/kg/day, 8 weeks) to establish chronic nephropathy. Marmosets with nephropathy were treated with Polyamide (1 mg/kg/week, 4 weeks). We also established a unilateral urethral obstruction(UUO) model and examined the effects of Polyamide (1 mg/kg/week, 4 times) in marmosets.Histologically, the renal medulla from CsA-treated marmosets showed cast formation and interstitial fibrosis in the renal medulla. Immunohistochemistry showed strong staining of Polyamide in the renal medulla from CsA-treated marmosets.Polyamidetreatment (1 mg/kg/week, 4 times) reduced hTGF-b1 staining and urinary protein excretion in CsA-treated marmosets. Polyamide reduced the glomerular injury score (GIS) and tubulointerstitial injury score (TIS) in UUO kidneys from marmosets. Polyamide significantly suppressed the hTGF-b1 and Snail mRNA expressionin UUO kidneys from marmosets.PI polyamide effectively improved CsA- and UUO-associated nephropathy, indicating its potential application in the prevention of renal fibrosis in progressive renal diseases.

Skeletal metastases of unknown primary (SMUP) represent a clinical challenge dealing with patients diagnosed with bone metastases. The management have improved significantly in the past years, however fraught with lack of evidences, approach to these patients held out hope for more systematic and tailored treatment—and some patients can achieve impressive gains. Nevertheless, in real-life practice the outlook at the beginning of the take in charge of SMUP is decidedly more somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidences and highlighted three key points that emerge. The characterization of the SMUP biologic profile is essential to drive clinical decisions, integrating genetic and molecular profile into a multi-step diagnostic work-up. Nonetheless, pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials within. This review argues that greater efforts are required to face the unmet need dealing with SMUP patients in oncology. Finally, we provide an original functional network analysis, identifying novel therapeutic targets.

Stroke is one of the most prevalent cardiovascular diseases worldwide, both in high-income countries and in medium and low-medium income countries. The WHO report on non-communicable diseases (NCDs) indicates that the highest behavioral risk in NCDs is attributable to incorrect nutrition. The objective of our work is to present an overview of meta-analyses that have investigated the impact of different foods and / or drinks in relationship with the risk of stroke events (ischemic/ hemorrhagic). The papers to be included in the overview were sought in the MEDLINE, EMBASE, Scopus, Clinicaltrials.gov, Web of Science, and Cochrane Library and were selected according to PRIMA flow chart. Quality assessment were made according to AMSTAR scale. This overview shows that all primary studies came from countries with high income level. This evidence shows that many countries are not represented. Therefore, different lifestyles, ethnic groups, potentially harmful or virtuous eating habits are not reported. It is important to underline how the choose of foods may help reduce the risk of cardiovascular diseases and stroke in particular.

Background: To evaluate the effect of systemic erythropoietin, as well as oral steroids, in the management of recent onset non-arteritic anterior ischemic optic neuropathy (NAION). Method: Ninety-nine eyes of 99 patients diagnosed with NAION within 5 days of onset were included in this single masked randomized clinical trial. Thirty-four patients were randomized into group 1 (systemic erythropoietin), group 2 (oral steroids), and group 3 (control). Group A received 10,000 units of erythropoietin twice a day for three days. Group B received oral prednisone 75 mg daily for two weeks followed by a tapering dose (70 mg for 5 days, 60 mg for 5 days, and 5 mg reductions thereafter every 5 days). Functional and structural outcomes were analyzed at 3 and 6 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measure, and mean deviation (MD) of visual field (VF) test and peripapillary retinal nerve fiber layer thickness (PRNFLT) were secondary outcome measures. Results:The mean BCVA (±SD) at the time of presentation was 1 ± 0.56, 1.01 ± 0.6, and 0.94 ± 0.47 logMAR in groups A, B, and C, respectively (P = 0.140); corresponding values were 0.72 ± 0.45, 0.83 ± 0.46, and 0.78 ± 0.4 logMAR (P = 0.417), and at 6-month follow-up, they were 0.70 ± 0.44, 0.73 ± 0.35, and 0.75 ± 0.39 logMAR, respectively (P = 0.597). Fifty-five percent of patients in group A vesus 34.3% in group B, and 31.2% in group C had an improvement of at least 3 lines in the BCVA values at the 6th-month follow-up visit. (P= 0.04) The mean deviation (MD) at the time of presentation was 19.67 ± 6.2, 20.83 ± 4.83, and 18.94 ± 6.92 decibels (db), respectively (P= 0.483).The corresponding values at month 3 were 18.22 ± 7.5, 19.82 ± 7.15, and 17.65 ± 7.22 db, (P = 0.848); and at month 6 they were 16.56 ± 7.08, 18.15 ± 6.57, and 15.9 ± 5.97 db, respectively. (P = 0.699) PRNFLT at presentation was 189 ± 58, 193 ± 64, and 199 ± 62 micrometers, respectively (P = 0.779), which decreased to 110 ± 45, 127 ± 37, and 119 ± 37 at month 3 (P = 0.423). The corresponding values for month 6 were 88 ± 12, 74 ± 25, and 71 ± 18, respectively (P = 0.041). Conclusion: The findings of our study indicate the beneficial effects of systemic erythropoietin in preserving the function and structure of the optic nerve in recent onset NAION.

Data on the KIT mutation rate in skin melanoma in the central European region is missing. Accordingly, in a cohort of 79 double wild type (BRAF/NRAS) skin melanoma KIT mutation was assessed by Sanger sequencing of exons 9,11,13,17 and 18. In this skin melanoma cohort KIT mutation frequency was found to be 34/79 (43%) with a significantly higher rate in acrolentiginous melanoma (ALM) as compared to UV-induced common variants (20/34, 58.8% versus 14/45, 31.1%, p=0.014). Exon 11 was the most frequent mutation site (44.7%) followed by exon 9 (21.1%) equally characterizing UV-induced common histotypes and ALM tumors. KIT mutation hotspots were identified in exon 9 (c491/492), in exon 11 (c559,c572, c570), in exon 13 (c642), in exon 17 (c822) and in exon 18 (c853). The relatively high KIT mutation rate in skin melanoma in this central-European cohort justifies regular testing of this molecular target.

Background: Malignant pleural mesothelioma (MPM) is an atypical, belligerent tumor that matures into cancer in the pleura, a stratum of tissue bordering the lungs. Pleural mesothelioma is a common type of mesothelioma that accounts for about 75 percent of all mesothelioma diagnosed yearly in the United States. Diagnosis of mesothelioma takes several months and is expensive. Given the difficulty of diagnosing MPM, early identification is crucial for patient survival. Our study implements artificial intelligence and recommends the best fit model for early diagnosis and prognosis of MPM. Method: We retrospectively retrieved patient’s medical reports generated by Dicle University, Turkey and implemented multi-layered perceptron (MLP), voted perceptron (VP), Clojure classifier (CC), kernel logistic regression (KLR), stochastic gradient decent SGD), adaptive boosting (AdaBoost), Hoeffding tree (VFDT), and primal estimated sub-gradient solver for support vector machine (s-Pegasos). We evaluated the models, compared and tested using paired T-test (corrected) at 0.05 significance based on their respective classification accuracy, f-measure, precision, recall, root mean squared error, receivers characteristic curve (ROC), and precision-recall curve (PRC). Results: In phase-1 SGD, AdaBoost.M1, KLR, MLP, VFDT generates optimal results with the highest possible performance measures. In phase-2, AdaBoost with a classification accuracy of 71.29% outperformed all other algorithms. C-reactive protein, platelet count, duration of symptoms, gender, and pleural protein were found to be the most relevant predictors that can prognosticate mesothelioma. Conclusion: This study confirms that data obtained from biopsy and imagining tests are strong predictors of mesothelioma but are associated with high cost, however, can identify mesothelioma with optimal accuracy. Predictive analytics without using biopsy results can diagnose mesothelioma with acceptable accuracy. Implementation of phase-2 followed by phase-1 can address diagnosis expenses and maximize disease prognosis. Additionally, results indicate improved MPM diagnosis using AI methods dependent upon the specific application.

Background: Acute appendicitis (AA) is the most common cause of emergency surgery. Perforation is more common than adults. Early diagnosis and new markers are needed. The aim of this study was to investigate the effects of plasma Fetuin-A (FA) levels in patients with the acute abdomen (AB). Material and Method: This prospective study included 107 patients younger than 16 years of age who were admitted to the emergency department for abdominal pain between January 2018 and December 2018. The patients who presented to abdominal pain were divided into two groups as AA and other causes (OC) of AB. T Patients with acute appendicitis; intraperitoneal, retrocolic / retrocecal and appendicitis were divided into three groups. Also, the AA group was divided into two groups as perforated appendicitis and non-perforated appendicitis. Serum FA levels of the patients were evaluated in the emergency department. Results: In the AA group, C-reactive protein (CRP) and white blood cell (WBC) levels were higher, and FA levels were significantly lower than in the AB group. Intraperitoneal localization was 95.2% and perforation was frequent. When significant values in the univariate regression analysis for acute abdomen and perforation were compared in the multivariate regression analysis, CRP, WBC, and FA levels were found to be prognostic. Also, decreased FA levels were associated with AA while too much decreased FA levels were associated with the risk of perforation. Conclusion: While trying to diagnose AA in children, the FA level, CRP and WBC may be predictive values to identify risk factors.

Hantavirus cardiopulmonary syndrome (HCPS) is characterized by capillary leak, pulmonary edema (PE) and shock that leads to death in up to 40% of patients. Treatment is supportive, including mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO). Hemodynamic monitoring is critical to titrate therapy and to decide ECMO support. Transpulmonary thermodilution (TPTD) provides hemodynamic and PE data that has not been systematically used to understand HCPS pathophysiology. We identified 11 HCPS patients monitored with TPTD; 5 on MV, 3 on ECMO. We analyzed 133 measurements to describe the hemodynamic pattern and its association to PE. The main findings were reduced stroke volume, global ejection fraction (GEF) and preload parameters associated to increased extravascular lung water and pulmonary vascular permeability compatible with hypovolemia, myocardial dysfunction and increased permeability PE. Lung water correlated positively with heart rate (HR, r=0.20) and negatively with mean arterial pressure (r=-0.27) and GEF (r=-0.36), suggesting that PE is linked to hemodynamic impairment. Pulmonary vascular permeability correlated positively with HR (r=0.31) and negatively with cardiac index (r=-0.49), end-diastolic volume (r=-0.48) and GEF (r=-0.40), suggesting that capillary leak contributes to hypovolemia and systolic dysfunction. In conclusion, TPTD data suggests that in HCPS patients, increased permeability leads to PE, hypovolemia and circulatory impairment.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

Pomegranate peel is a natural source of phenolics, claimed to possess healing properties, among which antioxidant and antidiabetic. In line with this evidence, the ethyl acetate PGE extract, obtained by Soxhlet from the peel of Dente di cavallo DC2 variety and characterized by a 4% amount of ellagic acid, has been studied for its hypoglycemic, antiglycation and antioxidative cytoprotective properties, in order to support a possible further nutraceutical interest. The α-amylase and α-glucosidase enzyme inhibition, interference with advanced glycation end-products (AGE) formation and metal chelating abilities were evaluated as hypoglycemic mechanisms. Also, considering that oxidative stress is associated with hyperglycemia complications, PGE antioxidant cytoprotective properties under hyperglycemic conditions were assayed. Phenolic profile was characterized by integrated chromatographic and spectrophotometric methods. Under our experimental conditions, PGE strongly inhibited the tested enzymes, especially α-glucosidase, and exerted chelating and antiglycation properties. Also, it reduced both ROS and GSH levels under hyperglycemic conditions, thus suggesting its ability to support cell functions by counteracting intracellular oxidative stress. Along with ellagic acid, rutin was the major identified flavonoid (about 4 %) of PGE. Present results suggest PGE to be a possible remedy for hyperglycemia management and encourage further studies to exploit its promising properties.

Evidence has been accumulated demonstrating that heavy metals may accumulate in various organs leading to tissue damage and toxic effects in mammals. In particular, the Central Nervous System (CNS) seems to be particularly vulnerable to cumulative concentrations of heavy metals, though the pathophysiological mechanisms is still to be clarified. In particular the potential role of oligodendrocyte dysfunction and myelin production after exposure to subtoxic concentration of heavy metals is to be better assessed. Here we investigated on the effect of sub-toxic concentration of several essential (Cu^{2 +}, Cr³⁺, Ni²⁺, Co²⁺) and non-essential (Pb²⁺, Cd²⁺, Al³⁺) heavy metals on MO3.13 and SHSY5Y human oligodendrocyte and neuronal cell lines (grown individually or in co-culture). In particular, exposure of both cell lines to heavy metals produced a reduced cell viability of co-cultured cell lines compared to cells grown separately. This effect was more pronounced in neurons which were more sensitive to metals than oligodendrocytes when the cells were grown in co-culture. On the other hand, a significant reduction of lipid component in cells occurred after their exposure to heavy metals, an effect accompanied by substantial reduction of the main protein that makes up myelin (MBP) in co-cultured cells. Finally, the effect of heavy metals in oligodendrocytes were associated to imbalanced intracellular calcium ion concentration as measured through the fluorescent Rhod-2 probe, thus confirming that heavy metals, even used at subtoxic concentrations, lead to dysfunctional oligodendrocytes. In conclusion, our data show, for the first time, that sub-toxic concentrations of several heavy metals lead to dysfunctional oligodendrocytes, an effect highlighted when these cells are co-cultured with neurons. The pathophysiological mechanism(s) underlying this effect is to be better clarified. However, imbalanced intracellular calcium ion regulation, altered lipid formation and, finally, imbalanced myelin formation seem to play a major role in early stages of heavy metal-related oligodendrocyte dysfunction.

Lead pollutants mainly from urban agricultural practices, Leaded paints, Leaded fuels spillages, Lead-contaminated air, soils, and water sources pause a health threat to urban children in Uganda. Prolonged Lead exposure affects iron metabolism, by competitively blocking iron absorption leading to anemia. Blood Lead (BL) inhibits key enzymes ferrochelatase and aminolevulinic acid dehydrogenase (ALAD) involved in hemoglobin (Hb) biosynthesis even at very low levels. Lead poisoning and malaria infection geographically overlap, and both produce similar hematological outcome especially in children. Malaria parasites cause anemia by destroying parasitized red blood cells, therefore, co-existence of BL and malaria parasites infection worsens the anemia status of the host. This study aimed at expounding the extent of heme synthesis inhibition by BL levels among a study group of malaria positive children by measuring levels of free erythrocyte protoporphyrin (FEP) in blood samples. Briefly venous blood samples from 198 children were analyzed for malaria parasite densities by the thick smear method, hemoglobin (Hb) concentrations determined by the standard cyan methemoglobin method, BLL were analyzed on an atomic absorption spectrophotometer and FEP levels were fluorometrically measured. The results showed means of BLL (9.3 µg/dL), Hb (7.5 g/dL), FEP/Hb (8.3 µg/g) and parasite density (PD) (3.21×10³ parasites / µL) among the study group. A majority of 151/198 (76.3%) of the children were moderately anemic while 8/198 (4%) were severely anemic. There was weak correlation between PD and Hb (R²= -0.15, P-value < 0.001), as compared to one between FEP/Hb and Hb (R²= -0.6, P-value=0.001). The study concludes that BL is a significant contributor to malaria anemia and should be considered in the management of anemia in malaria-endemic areas.

In tumour cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls. Interestingly, high expression of CXCR4 was associated with poor clinical outcome. Furthermore, in corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Furthermore, the niacin derivate of the CXCR4 antagonist AMD070, which was synthesized by us, demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of certain pro-apoptotic genes in CXCR4 positive lymphoma cell lines. Finally, WK1 treatment resulted in reduced expression of JNK-, ERK1/2- and NFκB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

To evaluate whether autologous mesenchymal cells, adipose derived stem cells and platelet-rich plasma, grafted into the supracoroideal space by surgical treatment according to Limoli retinal restoration technique (LRRT), can produce growth factors in order to exert a beneficial effect in retinitis pigmentosa (RP) patients. Twenty-one eyes underwent surgery and divided based on retinal foveal thickness ≤ 190 or >190 µm into group A and group B, respectively. The specific LRRT triad was grafted in a deep scleral pocket above the choroid of each eye. At 6-month follow-up, group B showed an improvement in residual close-up visus and sensitivity at microperimetry compared to group A. After an in-depth review of molecular biology studies concerning degenerative phenomena underlying the etiopathogenesis of RP, it can be confirmed that further research is needed on tapeto-retinal degenerations both from a clinical and molecular point of view to obtain better functional results. In particular, it is necessary to increase the number of patients, extend observation times, and treat subjects in the presence of still trophic retinal tissue to allow adequate biochemical and functional catering.

Alzheimer's is a disease for which there is no cure. Diagnosing Alzheimer's Disease (AD) early facilitates family planning and cost control. The purpose of this study is to predict the presence of AD using socio-demographic, clinical, and Magnetic Resonance Imaging (MRI) data. Early detection of AD enables family planning and may reduce costs by delaying long-term care. Accurate, non-imagery methods also reduce patient costs. The Open Access Series of Imaging Studies (OASIS-1) cross-sectional MRI data were analyzed. A gradient boosted machine (GBM) predicted the presence of AD as a function of gender, age, education, socioeconomic status (SES), and Mini-Mental State Exam (MMSE). A Residual Network with 50 layers (ResNet-50) predicted CDR presence and severity from MRI's (multi-class classification). The GBM achieved a mean 91.3% prediction accuracy (10-fold stratified cross validation) for dichotomous CDR using socio-demographic and MMSE variables. MMSE was the most important feature. ResNet-50 using image generation techniques based on an 80% training set resulted in 98.99% three class prediction accuracy on 4,139 images (20% validation set) at Epoch 133 and nearly perfect multi-class predication accuracy on the training set (99.34%). Machine Learning methods classify AD with high accuracy. GBM models may help provide initial detection based on non-imagery analysis, while ResNet-50 network models might help identify AD patients automatically prior to provider review.