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Background: Type 2 diabetes mellitus (T2DM) is a common public health problem in metabolism. Metformin is the oral hypoglycemic agent used as a first line together with life style modification in type 2 diabetes patients worldwide. Continuous metformin therapy increases the risk of vitamin B12 insufficiency, and its medical consequences in T2DM patients. Objective: To detect the prevalence of serum vitamin B12 deficiency in T2DM who has been treated with metformin in Erbil Province. Patients and Methods: The study involved 200 cases (100 patients and 100 controls) that met the study's basic criteria. A completed questionnaire, and a blood test for serum vitamin B12 levels were performed. A deficiency of vitamin B12 is defined as

Copyright of Diyala Journal of Medicine is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Hypertension quality improvement programs reduce uncontrolled blood pressure (BP) but impact may differ by sex and age. Methods: This study examined uncontrolled BP, defined as a BP ≥ 140/90 mmHg, and therapeutic inertia, defined as absence of medication initiation or escalation during visits with uncontrolled BP, by sex and by age group (19–40, 41–65, 66–75, and 76+ years) during a 12 month follow-up period among 21, 861 patients with hypertension and ≥ two visits in primary care clinics enrolled in the American Medical Association (AMA) Measure Accurately, Act Rapidly, and Partner with Patients (MAP) BP hypertension quality improvement program. Results: The mean age was 64.8 years (standard deviation [SD 12.8]) and ranged from 19 to 87 years; 53.6% were female. In age groups 19–40, 41–65, 66–75, 76–87 years, uncontrolled BP at the first clinic visit was present in 51.5%, 42.5%, 37.5% and 36.6% of males, respectively, and in 40.0%, 38.0%, 36.0% and 39.6% of females, respectively. Based on vital signs at the first vs. last clinic visit, the proportion of patients with uncontrolled BP in age groups 19–40, 41–65, 66–75 years declined by 19.4%, 13.5%, 10.1% and 8.7% in males, respectively, and 14.4%, 12.5%, 9.3%, and 8.4%, among females, respectively. Therapeutic inertia ranged from 66.5% and 75.9% of clinic visits among males and females age 19–40 years, to 85.6% and 84.9% of clinic visits among males and females age 76–87 years, respectively. The proportion of clinic visits with therapeutic inertia was lower among males vs. females across all age groups until age 76–87 years. Conclusion: A quality improvement program improves BP control but declines in uncontrolled BP are larger and therapeutic inertia is lower for younger vs. older age groups and for males vs. females. More interventions are needed to reduce sex and age disparities in hypertension management.

Background: Mean platelet volume is an important marker that shows the activation and function of the platelet which is effective in the inflammatory process. Aim of the study: To show the relationship between mean platelet volume and disease activity score in psoriatic arthritis patients (PsA). Methods: a cross-sectional study was done. A total of 90 patients participated in the study. The sample was collected over 6 months. Mean platelet volume was measured and correlated with disease activity score, and the relation between mean platelet volume with other disease activity markers like erythrocyte sedimentation rate (ESR) and C-reactive proteins (CRP)was determined. The serum of (cholesterol, tri-glycerides, low density lipoproteins, and high density lipoproteins) were estimated and correlated with DAPSA scores. Results: The mean (SD) of MPV was 10.4fl .It is evident in Psoriatic arthritis patients that around two thirds (64.9%) of patients were with high MPV and 39.4% of patients were with normal MPV. There is statistically significant positive correlation between the MPV and the DAPSA score, and the positive significant correlation between disease activity score with ESR, and CRP. Also, there was a positive correlation between s. cholesterol, s. triglyceride, LDL and DAPSA score while a negative significant correlation was found between DAPSA score and HDL. Conclusion: Higher disease activity in PsA patients is associated with correspondingly high MPV and high level of inflammatory markers like ESR and CRP, and lipid profiles.

The paper presents studies of annealing effect on the magnetic properties of the bulk Fe62Co10Y8B20 alloy in the form of rods. The thermal treatment was performed at the temperature well below the crystallization temperature. Structure, revealed by X-ray diffraction and Mössbauer spectroscopy and magnetic properties in high magnetic fields in the Fe62Co10Y8B20 alloy after fabricated and after the annealing were studied. We have stated that the investigated alloy was fully amorphous. It is due to the stress relieving of the sample. Using a vibrating sample magnetometer the magnetization in high magnetic fields was studied. For both the sample after solidification and after heat treatment, the magnetization process in the area called "the approach to ferromagnetic saturation" is affected by free volumes. In addition, the heat treatment improved the magnetic properties and increased the packing density of atoms. [ABSTRACT FROM AUTHOR]

Remagnetisation losses are one of the most important performance parameters of materials designed for the production of low-loss transformer cores. Classical Fe–Si alloys are characterised by losses of a few W/kg. However, the crystal structure makes these materials unsuitable for use at high frequencies. The ferromagnetic Fe-based alloys constitute an interesting group of alloys with magnetic soft properties. This group includes alloys from the Fe–Me–B system (where Me is one of the range of transition metals). This study investigates the structure, and losses due to remagnetisation, of bulk amorphous FeYMoNbB-based alloys. It was found that the addition of a small quantity of Nb changes the structure, and the magnitude of the losses. The addition of Nb significantly reduces additional losses; this effect is associated with the changing melt viscosity. [ABSTRACT FROM AUTHOR]

Employees with mental health problems often struggle to remain in employment. During the COVID-19 pandemic, these employees face multiple additional stressors, which are likely to worsen their mental health and work productivity. Currently, it is unclear how to best support employees with mental health problems (and their managers) to improve wellbeing and productivity. We aim to develop a new intervention (MENTOR) that will jointly involve employees, managers, and a new professional (mental health employment liaison worker, MHELW), to help employees who are still at work with a mental health condition and currently receiving professional support for their mental health. A feasibility pilot study will then be undertaken to examine the feasibility and acceptability of the intervention from the perspective of employees and line managers. The study involves a feasibility randomised controlled study comparing outcomes of participants randomised to receive the intervention (MENTOR) with wait-list controls. Participants allocated to the waitlist control group will receive the intervention after three months. We aim to randomise 56 employee-manager pairs recruited from multiple organisations in the Midlands region of England. An intervention including 10 sessions for employees and managers (3 individual sessions and 4 joint sessions) will be delivered over 12 weeks by trained MHELWs. Primary outcomes include measures of feasibility and acceptability of the intervention and work productivity. Secondary outcomes include mental health outcomes. Qualitative interviews will be undertaken with a purposively selected sub-sample of employees and line managers at three-month post-intervention assessment. To our knowledge, this will be the first trial with a joint employee-manager intervention delivered by MHELWs. Anticipated challenges are dual-level consent (employees and managers), participants' attrition, and recruitment strategies. If the intervention and trial processes are shown to be feasible and acceptable, the outcomes from this study will inform future randomised controlled trials. Trial registration: This trial is pre-registered with the ISRCTN registry, registration number: ISRCTN79256498. Protocol version: 3.0_March_2023. https://www.isrctn.com/ISRCTN79256498.

Abstract Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient’s own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.

Objective: Determine sex differences in hypertension control by age group in a diverse cohort of adults age 45–84 years at baseline followed for an average of 12 years. Methods: The Multi-Ethnic Study of Atherosclerosis enrolled 3213 men and 3601 women from six communities in the U.S. during years 2000–2002 with follow-up exams completed approximately every two years. At each exam, resting blood pressure (BP) was measured in triplicate, and the last two values were averaged. Hypertension was defined as a BP ≥ 140/90 mmHg and/or use of antihypertensive medications. Hypertension control was defined as a BP < 140/90 mmHg and in separate analyses as < 130/90 mmHg. Generalized linear mixed effects models with a binomial function were used to calculate the odds of hypertension control by age group (45–64,75–74, 75+) at a given exam and by sex, while accounting for the intra-individual correlation, and adjustment for demographics, co-morbidities, smoking, alcohol use, education and site among participants with hypertension at any of the first five exams. Results: At baseline, mean age was 64.1 (9.1 [SD]) years, 48.0% were men, and race/ethnicity was Non-Hispanic white in 34.1%, 10.1% Chinese, 35.1% Non-Hispanic Black and 20.7% Hispanic. Average SBP was lower while average DBP was higher among men vs. women at each exam. Adjusted odds ratios of hypertension control defined as BP < 140/90 mmHg among men vs. women was 0.89 (95% CI 0.67, 1.19) for age 45–64 years, 1.37 (95% CI 1.04, 1.81) for age 65–74 years and 2.08 (95% CI 1.43, 3.02) for age 75+ years. When defined as < 130/80 mmHg, adjusted odds of hypertension control among men vs. women was 0.60 (OR 0.60; 95% CI 0.46, 0.79) at age 45–64 years, 1.01 (OR 1.01; 95% CI 0.77, 1.31) at age 65–74 years and 1.71 (95% CI 1.19, 2.45) at age 75+ years. Conclusion: Sex disparities in hypertension control increase with advancing age and are greatest among adults age 75+ years.

Abstract Background The prevalence of pediatric allergic diseases has increased rapidly in the United States over the past few decades. Recent studies suggest an association between the increase in allergic disease and early disturbances to the gut microbiome. The gut microbiome is a set of intestinal microorganisms that begins to form during birth and is highly susceptible to disturbance during the first year of life. Early antibiotic exposure may negatively impact the gut microbiota by altering the bacterial composition and causing dysbiosis, thus increasing the risk for developing childhood allergic disease. Methods We performed a retrospective chart review of data in Loyola University Medical Center’s (LUMC) Epic system from 2007 to 2016. We defined antibiotic exposure as orders in both the outpatient and inpatient settings. Inclusion criteria were being born at LUMC with at least two follow up visits. Asthma and allergic rhinitis diagnoses were obtained using ICD 9 and ICD 10 codes. We controlled for multiple confounding factors. Using Stata, bivariate logistic regression was performed between antibiotics from 0 to 12 months of life and development of disease. This analysis was repeated for total lifetime antibiotics. We defined statistically significant as p

Nearly one in five young people in the United States has obesity, putting one-fifth of America’s children at higher risk of having chronic health conditions and of having obesity into adulthood. Family-based lifestyle interventions (FBLI) have been proposed as effective mechanisms to improve the health through health education and the adoption of healthier behaviors. The aim of this review is to identify and summarize effective intervention activities and lessons learned that organizations can adopt when planning health promotion interventions for families, and to assess the effect of family-based lifestyle interventions on BMI z-score. A systematic review on lifestyle health-promotion interventions for families was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) statements. Inclusion criteria were: duration ≥12 weeks and inclusion of family members. Summary data about the assessment tools, intervention strategies, and outcomes in parents and children were extracted and compared for all studies. A meta-analysis of BMI z-score change was conducted. Thirty-four articles were included in this review. Frequent strategies used were delivering education and training on healthy habits and well-being (94%), engaging community in the planning and implementation phases (80.6%) and providing reminders and feedback (47.2%). BMI z-score mean differences were reported in 40 cohorts and included in a meta-analysis, with no statistically significant differences between groups. The findings of this systematic review and meta-analysis indicate that components of a successful family lifestyle intervention program include duration between six to twelve months and delivery in a community setting. Other key factors include constructing a multidisciplinary team, using a mentor/role model approach, and reinforcing messaging with technology.

Rationale & Objective: Persons with end-stage kidney disease receiving in-center maintenance hemodialysis may be at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and severe outcomes with coronavirus disease 2019 (COVID-19). The objective of this study was to examine the correlation of SARS-CoV-2 positivity rate per capita and COVID-19–associated deaths with number of dialysis stations and demographics of residents within zip codes in Cook County, IL. Study Design: Ecological analysis. Setting & Participants: Data for SARS-CoV-2 test results and COVID-19–associated deaths during January 21 to June 15, 2020, among the 5,232,412 residents living within the 163 zip codes in Cook County, IL, were merged with demographic and income data from the US Census Bureau. The total number of positive test results in this population was 84,353 and total number of deaths was 4,007. Assessments: Number of dialysis stations and stations per capita within a zip code were calculated. SARS-CoV-2–positive test results per capita were calculated as number of positive test results divided by the zip code population. COVID-19–associated deaths per capita were calculated as COVID-19 deaths among residents for a given zip code divided by the zip code population. Analytic Approach: Spearman rank correlation coefficients were calculated to examine the correlation of SARS-CoV-2–positive tests per capita and COVID-19–associated deaths per capita with dialysis stations, demographics, and household poverty. To account for multiple testing, statistical significance was considered as P

While Scholastic Assessment Test (SAT) scores are becoming less widespread than in previous years, they continue to be used as an input by many higher education institutions in the United States to select which students to accept among applicants. This paper explores the association between average SAT scores of incoming undergraduate cohorts and major completions of graduating student cohorts. College Scorecard data from 2019 is collected from all U.S. undergraduate degree-granting, higher education institutions reporting average SAT scores of incoming cohorts (n=1,389). A multivariate beta regression approach, which allows for overdispersion and unit-interval responses, is proposed to explore associations between graduation rates by major (explanatory variables) and SAT percentiles of new student cohorts (response). Forty-nine percent of the variability in average SAT percentiles of incoming cohorts can be explained by the graduation proportions by major within institutions. Results show strong concurrent positive associations between average SAT percentiles of incoming cohorts and proportions of students graduating in: STEM fields; ethnic, cultural, and gender studies; social science; or languages, among others (p

Introduction: The emergency department (ED) has long served as a safety net for the uninsured and those with limited access to routine healthcare. This study aimed to compare the characteristics and severity of ED visits in an Illinois academic medical center (AMC) and community hospital (CH) of a single health system before and after the implementation of the Affordable Care Act (ACA). Methods: This was a retrospective record review of 357,764 ED visits from January 1, 2011–December 31, 2016, of which 74% were at the AMC and 26% at the CH. We assessed the severity of ED visits by applying the previously validated Ballard algorithm, which classifies ED visits as non-emergent, intermediate, or emergent. Descriptive analyses were conducted to compare the characteristics of ED visits before and after the implementation of the ACA. We conducted multilevel logistic regression analysis to examine the odds of non-emergent compared to intermediate/emergent ED visits by the ACA implementation status controlling for patient demographic characteristics, insurance status, and multiple visits per patient. Results: ED visits for patients with Medicaid or other governmental coverages increased in the post-ACA compared to pre-ACA period (Pre: 33.2 % vs Post: 38.3% at the AMC, and Pre: 29.7% vs Post: 35.1% at the CH). A statistically significant decrease in ED visits for uninsured patients was observed at the AMC and CH in the post-ACA period compared to the pre-ACA period (Pre: 12.1% vs Post: 6.4%, and Pre: 13.9% vs Post: 9.8%, respectively). Results from the regression analysis showed a significant decreased odds of non-emergent vs intermediate/emergent ED visits during the post-ACA period compared to the pre-ACA period at the AMC (odds ratio [OR] 0.68; confidence interval [CI], 0.66–0.70). However, an increased odds of non-emergent vs. intermediate/emergent ED visits was observed at the CH (OR 1.09; CI, 1.04–1.14). Conclusion: Similar to other Medicaid expansion states, ED utilization for uninsured patients decreased at both the AMC and the CH in the post-ACA period. While Medicaid visits for children < 18 years declined in the post-ACA period, it increased for ages 21 to 65 years of age. Contrary to our hypothesis, the severity of emergent ED visits increased in the post-ACA period but not at the CH.

Atopic skin is dry and itchy and lacks integrity. Impaired skin barrier results from altered lipid composition of the skin. A crucial skin lipid, cholesterol, provides flexibility and homeostasis of the cell membranes' lipid bilayer. Cholesterol-based creams and natural oils, especially blackcurrant seed oil, are beneficial for skin care as they hydrate the skin and improve its integrity. The major atopic symptom, skin dryness, can be overcome by the application of porous patches enhanced with cholesterol and natural oil. The base of the patches is constructed of polyimide (PI) nanofibers with cholesterol coatings and externally added blackcurrant seed oil. The presence of cholesterol in PI mats hinders the passage of oil through the patches to the skin, resulting in sustained and prolonged skin hydration. The theoretical and numerical investigations of oil dynamics in porous mats confirmed the experimental results, showing a prolonged skin hydration effect up to 6 h. Additionally, as demonstrated by in vivo tests on atopic mice, cholesterol patches lower serum immunoglobulin E levels and expression of proinflammatory cytokines in the skin, thereby accelerating skin healing. Our results hold great promise for the long-term application of the patches in atopic dermatitis treatment.

Background: Colorectal cancer (CRC) is one of the leading causes of death globally. Multiple factors may contribute to the pathogenesis of CRC, including the abnormalities in the functioning of the endogenous opioid system (EOS) or adiponectin-related signaling. The aim of our study was to evaluate if differences in the expression of opioid receptors (ORs) influence the development of CRC and if modulation of adiponectin receptors using AdipoRon, a selective AdipoR1 receptor agonist, affects colorectal carcinogenesis., Methods: Naltrexone, an opioid receptor antagonist, was injected intraperitoneally every second day for 2 weeks, at the dose of 1 mg/kg in healthy Balb/C mice to induce changes in ORs expression. CRC was induced by a single intraperitoneal injection of azoxymethane (AOM) and the addition of dextran sodium sulfate (DSS) into drinking water in three-week cycles. The development of CRC was assessed using macro- and microscopic scoring and molecular analysis (RT qPCR, ELISA) after 14 weeks., Results: Naltrexone significantly increased the mRNA expression of Oprm1, Oprd1, and Oprk1 in the mouse colon and in the brain (non-significantly). The pretreatment of mice with naltrexone aggravated the course of CRC (as indicated by tumor area, colon thickness, and spleen weight). The level of circulatory adiponectin was lowered in mice with CRC and increased in the colon as compared with healthy mice. The β-endorphin level was increased in the plasma of mice with CRC and decreased in the colon as compared to healthy mice. AdipoRon, AdipoR1 agonist, worsened the CRC development, and pretreatment with naltrexone enhanced this negative effect in mice. CRC did not affect the expression of the Adipor1 gene, but the Adipor1 level was increased in mice pretreated with naltrexone (AOM/DSS and healthy mice). AdipoRon did not influence the expression of opioid receptors at the mRNA level in the colon of mice with CRC. The mRNA expression of Ptgs2, Il6, Nos2, Il1b, Il18, Gsdmd, and Rela was increased in mice with CRC as compared to the healthy colon. AdipoRon significantly decreased mRNA expression of Ptgs2, Il6, Il1b, and Il18 as compared to CRC mice., Conclusion: EOS and adiponectin-related signaling may play a role in the pathogenesis of CRC and these systems may present some additivity during carcinogenesis., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Background: Chronic inflammation in the course of inflammatory bowel disease may result in colon cancer, or colitis-associated colorectal cancer (CACRC). It is well established that CACRC is associated with oxidative stress and secretion of multiple pro-inflammatory cytokines, e.g. tumor necrosis factor-α. Recently, we proved that the administration of gold(III) complexes resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the antitumor effect of a novel series of gold(III) complexes: TGS 121, 404, 512, 701, 702, and 703., Materials: Analyzed gold(III) complexes were screened in the in vitro studies using colorectal cancer and normal colon epithelium cell lines, SW480, HT-29, and CCD 841 CoN, and in vivo, in the CACRC mouse model., Results: Of all tested complexes, TGS 121, 404, and 702 exhibited the strongest anti-tumor effect in in vitro viability assay of colon cancer cell lines and in in vivo CACRC model, in which these complexes decreased the total number of colonic tumors and macroscopic score. We also evidenced that the mechanism of action was linked to the enzymatic antioxidant system and inflammatory cytokines., Conclusions: TGS 121, 404, and 702 present anti-tumor potential and are an attractive therapeutic option for colorectal cancer., (© 2023. The Author(s).)

Background: G protein-coupled receptor 35 (GPR35) is involved in the carcinogenesis; however, limited data exist on its relevance for overall survival (OS) and disease-specific survival (DSS) in patients with cancer., Methods: We have examined The Cancer Genome Atlas dataset to check the relations between GPR35 expression pattern and OS or DSS of patients with colorectal cancer (CRC)., Results: The performed analysis showed a negative association between positive GPR35 expression Z score and OS in males, which remains statistically significant in advanced stages of colon (COAD) and rectal (READ) adenocarcinoma combined., Conclusions: These findings suggest the prognostic value of early testing of GPR35 in male patients with an increased risk of CRC development and warrant further clinical confirmation., (© 2022. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Nearly 20% of elderly patients suffer from constipation, but the age-related changes in the gastrointestinal (GI) tract remain insufficiently elucidated. In this study, the alterations within the endogenous opioid system (EOS) as a potential cause of constipation in the elderly were evaluated. The GI functions were assessed in vitro and in vivo and compared between 6-, 12- and 18-month old mice. Moreover, the effect of opioid receptor (MOP, DOP, KOP) agonists on the mouse GI tract functions and the EOS components expression in mouse tissues and colonic biopsies from patients with functional constipation were determined. In the oldest mice, the GI peristalsis was significantly impaired as compared to the younger groups. The tissue response to MOP and DOP, but not KOP, agonists weakened with age in vitro; for DOP, it was confirmed in vivo. In the mouse upper GI tract, Oprm1, Oprd1, Oprk1 expression decreased with age; in the colon, Oprm1 expression increased. There were no differences in the expression of these genes in the colonic biopsies from patients >50 years old as compared to the younger group. In conclusion, the age-related impairment of the GI peristalsis may result from reduced MOP and DOP response to the activation with opioid agonists or the alterations in the EOS expression.

Background: The role of circadian rhythm abnormalities in patients with inflammatory bowel disease (IBD) remains relatively unknown. The aim of this study was to identify the inflammatory cytokine profile in the IBD patients and its relationship with the quality of sleep., Methods: Prospective, single-center observational cohort study was performed. In all enrolled adult IBD patients, the disease activity was assessed using Crohn's Disease Activity Index (CDAI) for Crohn's disease (CD) and Partial Mayo Score for ulcerative colitis (UC), respectively. To assess the quality of sleep, all patients were asked to respond to a questionnaire to define Pittsburgh Quality Sleep Index (PSQI). From all enrolled patients, 15 ml venous blood was taken to determine serum inflammatory cytokine levels and perform standard laboratory tests., Results: Fifty-two IBD patients were enrolled in the study: 32 with CD and 20 with UC. The poor sleep was noted in 69.4% of patients with clinically active and in 6.3% of patients with inactive disease. In the group of IBD patients with poor sleep, the significantly higher level of serum IL-6, IL-17, and IL-23 were observed. In IBD patients with exacerbation, the significantly higher level of serum IL-6, IL-17, and IL-23 were recorded., Conclusions: The relationship between quality of sleep and proinflammatory cytokine profile may show us a predisposition for the development of inflammatory intestinal lesions in IBD patients with sleep disturbances. This knowledge may allow the pharmacological and behavioral therapies of circadian rhythm abnormalities to become new significant targets in IBD patients., (© 2021. The Author(s).)

Background: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis., Methods: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days., Results: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group., Conclusions: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Background: The pathogenesis of acute pancreatitis (AP) initiation and progression is still unknown, and effective treatment is limited to supportive care. Many phytochemicals have the potential to alleviate AP symptoms and may be a useful and effective supplement to standard AP treatment. The objective of the study was to examine the potential role of chlorogenic acid (CGA), a polyphenol known for anti-inflammatory effect, in the treatment of experimental AP in mice., Methods: Two intraperitoneal (ip) injections of L-arginine (dosage 400 mg/100 g BW) were given 1 h apart to generate the AP murine model. Mice were separated into two experimental groups after 12 h from the first L-arginine injection: AP mice treated with CGA (oral gavage (po) every 12 h; 20 mg/kg BW) and non-treated AP mice (po vehicle, 5% dimethyl sulfoxide every 12 h). Every 12 h, control mice were given an equivalent volume of vehicle. At 72 h, mice were slaughtered. Histology, as well as myeloperoxidase (MPO) and amylase activity assays, were performed on pancreatic tissues., Results: In murine mouse model of AP po administration of CGA decreased MPO vs. AP (40.40 ± 2.10 U vs. 7.39 ± 0.34; p < 0.001) as well as amylase activity vs. AP (1444 ± 56 mU/mL vs. 3340 ± 144 mU/mL, Fig. 2B; p < 0.001). When comparing CGA mice to AP mice, histological research demonstrated that the severity of AP was reduced following CGA treatment., Conclusions: The current study found that CGA might have anti-inflammatory effect on L-arginine-induced pancreatitis. Dietary intervention with CGA may be advised as a supportive treatment for AP, according to our findings., (© 2021. The Author(s).)

Acute pancreatitis (AP) is an inflammatory disease that causes severe tissue damage. Ghee butter from bovine colostrum (GBBC) is a clarified butter produced by heating milk fat to 40 °C and separating the precipitating protein. As colostrum mainly contains fatty acids (FAs), immunoglobulins, maternal immune cells, and cytokines, we hypothesized that it may exert anti-inflammatory effects. We investigated the effects of GBBC on experimental AP in mice. Two intraperitoneal ( ip ) injections of L-arginine (8%) were given 1 h apart to generate the AP murine model. After 12 h from the first L-arginine injection, mice were divided into the following experimental groups: AP mice treated with GBBC (oral gavage ( po ) every 12 h) and non-treated AP mice ( po vehicle every 12 h). Control animals received vehicle only. At 72 h, mice were euthanized. Histopathological examination along with myeloperoxidase (MPO) and amylase/lipase activity assays were performed. In a separate set of experiments, FFAR1 and FFAR4 antagonists were used to verify the involvement of respective receptors. Administration of GBBC decreased MPO activity in the pancreas and lungs along with the microscopical severity of AP in mice. Moreover, treatment with GBBC normalized pancreatic enzyme activity. FFAR1 and FFAR4 antagonists tended to reverse the anti-inflammatory effect of GBBC in mouse AP. Our results suggest that GBBC displays anti-inflammatory effects in the mouse model of AP, with the putative involvement of FFARs. This is the first study to show the anti-inflammatory potential of a nutritional supplement derived from GBBC.

Diet is considered an important trigger in inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of bacterial antigens, consequently influencing the immune system. Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of colitis. Therapeutic activity of GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic colitis: induced by trinitrobenzenesulfonic acid (TNBS), mimicking Crohn's disease, as well as induced by dextran sulfate sodium (DSS), which recapitulates ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by forskolin and veratridine. Administration of FFAR4 agonist GSK137647 attenuated both TNBS-induced and DSS-induced colitis in mice, as indicated by macroscopic parameters and myeloperoxidase activity. The action of FFAR4 agonist GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain fatty acids, attenuates intestinal inflammation.

Introduction: Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract., Methods: TOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The OR/CB interactions were evaluated using mixed agonist (PR-38) and AM-251 (CB1 antagonist)., Results: The inhibitory effect of morphine on ileal contractions was weaker in tissue incubated with this opioid than in tissue incubated without opioid. The opposite was noted for PR-38. In tissues exposed to morphine, but not to PR-38, naloxone induced a WR. The blockage of CB1 receptors with AM-251 before the addition of PR-38 resulted in a naloxone-induced WR., Conclusion: The co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs., (© 2021. The Author(s).)

Blood platelets' adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y 12 could serve as components of dual anti-platelet therapy. We have found that a selective A 2A agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y 12 inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood-brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood-brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood-brain barrier. We conclude that chronic administration of the A 2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146.

Background: The negative impact of a high-fat diet on the course of gastroesophageal reflux disease (GERD) has been previously reported. Free fatty acid receptors (FFARs) may be mediators of this phenomenon. The aim of this study was to characterize the role of FFARs in the course of nonerosive (NERD) and erosive (ERD) reflux disease., Methods: Collectively, 73 patients (62 with GERD and 11 healthy controls (HCs)) were recruited to the study. Esophageal biopsies were drawn from the lower third of the esophagus and kept for further experiments. Quantitative, real-time polymerase chain reaction was used to assess the expression of FFAR1, FFAR2, FFAR3, and FFAR4 in biopsies. Histological evaluation of dilated intracellular spaces (DISs) was also performed., Results: FFAR3 exhibited the highest expression, and FFAR4 exhibited the lowest expression in all esophageal samples. Higher relative expression of FFAR1 and FFAR2 and significantly higher expression of FFAR3 ( p = 0.04) was noted in patients with GERD compared to respective HCs. Patients with nonerosive GERD (NERD) presented higher expression of all FFARs compared to patients with erosive GERD (ERD) and respective HCs. Interestingly, in patients with ERD, the expression of FFAR3 was lower than in HCs. Significant, weak, positive correlation was found for FFAR3 and FFAR4 expression and DIS scores (r = 0.36, p < 0.05 for FFAR 3, and r = 0.39, p < 0.05 for FFAR4)., Conclusions: In this study, we show that FFARs may play a role in GERD pathogenesis, particularly in the NERD type. It may be assumed that FFARs, in particular FFAR3 and FFAR4, may have diagnostic and therapeutic potential in GERD.

Platelet biology owes to intravital studies not only a better understanding of platelets' role in primary hemostasis but also findings that platelets are important factors in inflammation and atherosclerosis. Researchers who enter the field of intravital platelet studies may be confused by the heterogeneity of experimental protocols utilized. On the one hand, there are a variety of stimuli used to activate platelet response, and on the other hand there are several approaches to measure the outcome of the activation. A number of possible combinations of activation factors with measurement approaches result in the aforementioned heterogeneity. The aim of this review is to present the most often used protocols in a systematic way depending on the stimulus used to activate platelets. By providing examples of studies performed with each of the protocols, we attempt to explain why a particular combination of stimuli and measurement method was applied to study a given aspect of platelet biology.

Background: The aim of this paper is to analyze the results of virtual reality (VR) antromastoidectomy simulation training and the transferability of the obtained skills to real temporal bone surgery., Methods: The study was conducted prospectively on a group of 10 physicians, and was composed of five VR simulation training sessions followed by live temporal bone surgery. The quality of performance was evaluated with a Task-Based Checklist (TBC) prepared by John Hopkins Hospital. Additionally, during every VR session, the number and type of mistakes (complications) were noted., Results: The quality of performance measured by the TBC increased significantly during consecutive VR sessions. The mean scores for the first and fifth sessions were 1.84 and 4.27, respectively ( p < 0.001). Furthermore, the number of mistakes in consecutive VR sessions was gradually reduced from 11 to 0. During supervised surgery, all the participants were able to perform at least part of an antromastoidectomy, and the mean TBC score was 3.57. There was a significant strong positive correlation between the individual results of the fifth VR session and the individual results of supervised surgery in the operating room (r p = 0.89, p = 0.001)., Conclusions: Virtual reality for temporal bone training makes it possible to acquire surgical skills in a safe environment before performing supervised surgery. Furthermore, the individual final score of virtual antromastoidectomy training allows a prediction of the quality of performance in real surgery.

The data in this article focus on the F11 Receptor (F11R/JAM-A; Junctional Adhesion Molecule-A; JAM-A, F11R), a cell adhesion protein constitutively expressed on the membrane surface of circulating platelets and localized within the tight junctions of healthy endothelial cells (ECs). Previous reports have shown that F11R/JAM-A plays a critical role in the adhesion of platelets to an inflamed endothelium due to its' pathological expression on the luminal surface of the cytokine-inflamed endothelium. Since platelet adhesion to an inflamed endothelium is an early step in the development of atherosclerotic plaque formation, and with time, resulting in heart attacks and stroke, we conducted a long-term, study utilizing the atherosclerosis-prone ApoE -/- mice to attempt a blockade of the formation of atherosclerotic plaques by preventing the adhesion of platelets to the inflamed vasculature in vivo . Utilizing a nonhydrolyzable peptide derived from an amino acid sequence of F11R/JAM-A, peptide 4D, we have shown in culture that the adhesion of platelets to the inflamed endothelial cells could be blocked by peptide 4D. The present data demonstrate the positive health benefits of chronic peptide 4D administration to the atherosclerosis-prone ApoE -/- mice, and provides new information for potential use of this F11R derived peptide in the prevention of atherosclerosis. The data presented in this article provide further experimental support for the study presented in Babinska et al., Atherosclerosis 284 (2019) 92-101., (© 2020 The Author(s). Published by Elsevier Inc.)

In 2018, during a circumnavigation of Antarctica below 62° S by the sailing boat Katharsis II, the presence of plastics was investigated with surface sampling nets at ten evenly spaced locations (every 36° of longitude). Although fibres that appeared to be plastic (particles up to 2 cm) were found in numbers ranging from 1 particle (0.002 particles per m 3 ) to 171 particles (1.366 particles per m 3 ) per station, a Fourier-transform infrared spectroscopy (FT-IR) analysis indicated that these particles were not composed of plastic. The fibres which superficially reminded plastic were composed of silica and are of biological origin most likely generated by phytoplankton (diatoms). Therefore, the offshore Antarctic locations were proven to be free of floating microplastics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Aims: The F11 Receptor (F11R), AKA Junctional Adhesion Molecule-A (JAM-A) (F11R/JAM-A), is an adhesion protein constitutively expressed on the membrane surface of circulating platelets and the luminal surface of inflamed endothelial cells (EC). Platelet adhesion to an inflamed endothelium is one of the early steps of atherosclerotic plaque formation. Our previous studies, conducted with cultured EC in vitro, have demonstrated the expression of F11R/JAM-A on the luminal surface of inflamed EC, platelet adhesion to inflamed EC through F11R/JAM-A interactions, and inhibition of this interaction by the presence of F11R/JAM-A antagonistic peptide (F11Rpeptide 4D). In the present study, we examined in vivo the overall health-benefits and cardiovascular effects of long-term treatment of animals prone to atherosclerosis, ApoE -/- mice, with F11R-peptide 4D., Methods: Twenty ApoE -/- mice were assigned to daily treatment with peptide 4D and compared to their counterparts control untreated mice. Mice were observed for wellness and survival. Plaque size in the aorta and heart was measured using histological analysis. Effects of peptide 4D (or scramble control) on platelet adhesion to inflamed endothelium were measured using intravital microscopy., Results: Significant reductions in atherosclerotic plaques number and size, an overall robust health with longer survival were found in the peptide 4D treated group of ApoE -/- mice. Intravital microscopic studies conducted in exposed vessels of ApoE -/- mice demonstrated significant inhibition by peptide 4D of platelet adhesion to the cytokine-inflamed endothelium., Conclusions: Our results demonstrate that peptide 4D significantly reduces atherosclerotic plaque formation in ApoE -/- mice and inhibits platelet adhesion to the inflamed arterial endothelium., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Diabetes is associated with an increased risk of cardiovascular disease. This is partially attributed to an altered activation status of blood platelets in this disease. Previously, alterations have been shown in COX-1 and protease activated receptor (PAR)-3 receptor expression in platelets in two animal models of diabetes, there have not been studies which address expression of these proteins in mice with long-term streptozotocin (STZ)-induced diabetes. We have also addressed the effect of diabetes on platelet adhesion under flow conditions. With the use of flow cytometry, we have shown that certain markers of platelet basal activation, such as active form of α II b β 3 and of CD40L were increased in STZ-induced diabetic mice. Platelets from STZ-induced diabetic mice were also more reactive when stimulated with PAR-4 activating peptide as revealed by higher expression of active form of α II b β 3 , membrane-bound on vWillebrand Factor and binding of exogenous fluorescein isothyanate-labelled fibrinogen. Expression of COX-1 and production of thromboxane A 2 in platelets of STZ-induced diabetic mice were higher than in control animals. We observed no effect of diabetes on ability of platelets to form stable adhesions with fibrinogen in flow conditions. We conclude that although certain similarities exist between patterns of activation of platelets in animal models of diabetes, the differences should also be taken into account., (© 2019 The Authors. International Journal of Experimental Pathology © 2019 International Journal of Experimental Pathology.)

Introduction: Thrombus formation in vitro in flow conditions and its visualization and quantification with the use of microscopy are widely utilized to evaluate activity of compounds with a potential antithrombotic activity. Visualization and quantification of thrombi can be performed with the use of wide-field or confocal microscopy. Acquiring reliable numerical data from wide-field microscopy images of objects which have a complex three-dimensional structure is strongly influenced by the methods used for image analysis. This can be a possible source of inaccuracy in assessment of antithrombotic activity of a tested substance. We aimed to verify how different approaches to the quantification of wide-field images can affect the evaluation of an antiplatelet effect of a tested substance., Methods: We compared three algorithms of image analysis to evaluate an effect of 2-hexynyl-5'-ethylcarboxamidoadenosine (HE-NECA), a compound of a moderate antiplatelet activity on thrombus formation, and of abciximab - a potent antiplatelet compound. Also, we studied how the results obtained in a wide-field imaging correspond to those obtained by means of confocal imaging., Results: Three algorithms for analysis of wide-field images showed antiplatelet effect of HE-NECA or abciximab. Absolute values of thrombus area and outcomes of the evaluation of inhibition efficacy of HE-NECA were significantly different between the algorithms. Analysis of volumes and heights of thrombi obtained by confocal imaging confirmed inhibitory effect of HE-NECA, but the evaluated levels of inhibition were significantly different from that obtained by wide-field imaging., Discussion: We conclude that wide-field imaging provides reliable qualitative data on an inhibitory effect on thrombus formation, despite differences which can emerge from various approaches to image analysis. However, quantitative evaluation and comparison of the efficacy of inhibitors on the basis of total area occupied by thrombi obtained by wide-field microscopy should be made with caution. To obtain a reliable quantitative assessment of the effect of a tested compound on thrombus structure the use of confocal microscopy is inevitable., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Numerous in vitro experiments have confirmed that a dysfunctional endothelium is characterized by, inter alia, a higher affinity for binding of platelets and leukocytes. However, there is still no direct evidence for greater interaction between platelets and intact endothelium in in vivo animal models of diabetes. Therefore, the present study examines the pro-adhesive properties of endothelium change in vivo as an effect of streptozotocin (STZ)-induced diabetes and the role of two key platelet receptors: GPIb-IX-V and GPIIb/IIIa. Mice of C57BL strain with streptozotocin-induced diabetes were used in the study. Flow cytometry was used to assess basal activation and reactivity of platelets. Adhesion of platelets to the vascular wall was visualized with the use of intravital microscopy in mesentery. The contribution of GPIIb/IIIa and GPIb-IX-V was evaluated by the injection of Fab fragments of respective antibodies. The integrity of the endothelium and vWf expression were evaluated histochemically. Basal activation and reactivity of platelets in streptozotocin-diabetic mice were elevated. Blood platelets adhered more often to the vascular wall of diabetic mice than nondiabetic animals: 11.9 (6.4; 32.8) plt/min/mm 2 (median [IQR]) vs 2.7 (1.3; 6.4) plt/min/mm 2 . The injection of anti-GPIbα antibodies decreased the number of adhering platelets from 89.5 (34.0; 113.1) plt/min/mm 2 (median [IQR]) in mice treated with isotype antibodies to 3.1 (1.7; 5.6) plt/min/mm 2 in mice treated with blocking antibodies. The effect of GPIIb/IIIa blockage was not significant. Immunohistochemistry revealed a higher expression of vWF in the endothelium of STZ mice, but no substantial changes in endothelial morphology were detected. To conclude, the study shows that the platelets interact more frequently with the mesenteric vascular bed in mice with 1-month STZ-induced diabetes than in healthy mice. These interactions are mediated via platelet GPIb-IX-V and are driven by increased expression of vWF in endothelial cells.

Introduction: Recent studies have shown that it may be the concentration of thrombin, which is discriminative in determining of the mechanism of platelet activation via protease activated receptors (PARs). Whether the observed phenomenon of differentiated responses of mouse platelets to various thrombin concentrations in non-diabetic db/+ and diabetic db/db mice depends upon the concerted action of various PARs, remains to be established., Results: We found elevated reactivity of platelets, as well as the enhanced PAR-3 expression in response to both the used concentrations of AYPGKF in db/db mice, as compared to db/+ heterozygotes. At low concentration of thrombin platelets from diabetic mice demonstrated hyperreactivity, reflected by higher expression of PAR-3. For higher thrombin concentration, blood platelets from db/db mice appeared hyporeactive, compared to db/+ animals, while no significant differences in PAR-3 expression were observed between diabetic and non-diabetic mice., Conclusions: The novel and previously unreported finding resulting from our study is that the increased expression of PAR-3 in response to either TRAP for PAR-4 or low thrombin (when PAR-4 is not the efficient thrombin receptor) may be one of the key events contributing to higher reactivity of platelets in db/db mice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The heterogeneity of melanoma needs to be addressed and combination therapies seem to be necessary to overcome intrinsic and acquired resistance to newly developed immunotherapies and targeted therapies. Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized. Using patient-derived melanoma cell populations, we investigated the influence of pentoxifylline on melanoma cells with either high or low expression of β-catenin., Findings: Our results indicate that pentoxifylline inhibits the activity of the canonical WNT pathway in melanoma cell populations with high basal activity of this signalling. This is supported by lowered overall activity of transcription factors TCF/LEF and reduced nuclear localisation of active β-catenin. Moreover, treatment of β-cateninhigh melanoma cell populations with pentoxifylline induces downregulation of genes that are targets of the WNT/β-catenin pathway including connective tissue growth factor (CTGF) and microphthalmia-associated transcription factor (MITF-M), a melanocyte- and melanoma cell-specific regulator., Conclusions: These results suggest that pentoxifylline, a drug approved by the FDA in the treatment of peripheral arterial disease, might be tested in a subset of melanoma patients with elevated activity of β-catenin. This pharmaceutical might be tested as an adjuvant drug in combination therapies when the response to immunotherapy is prevented by high activity of the WNT/β-catenin pathway.

Due to its ability to inhibit the blood platelet PGHS-1, acetylsalicylic acid (ASA, Aspirin(®)) is widely used as a preventive agent in atherothrombotic diseases. However, its beneficial effects seem to be lower in diabetic patients, suggesting that protein glycation may impair effective ASA-mediated acetylation process. On the other hand, it is proposed that ASA can prevent some of the late complications of diabetes by lowering the extent of glycation at protein free amino groups. The aim of this work was to evaluate the extents of non-enzymatic N-glycosylation (glycation) and acetylation of blood platelet PGHS-1 (COX-1) and the competition between glycation and acetylation was investigated in order to demonstrate how these two reactions may compete against platelet PGHS-1. When PGHS-1 was incubated with glycating/acetylating agents (glucose, Glu; 1,6-bisphosphofructose, 1,6-BPF; methylglyoxal, MGO, acetylsalicylic acid, ASA), the enzyme was modified in 13.4 ± 1.6, 5.3 ± 0.5, 10.7 ± 1.2 and 6.4 ± 1.1 mol/mol protein, respectively, and its activity was significantly reduced. The prior glycation/carbonylation of PGHS-1 with Glu, 1,6-BPF or MGO decreased the extent of acetylation from 6.4 ± 1.1 down to 2.5 ± 0.2, 3.6 ± 0.3 and 5.2 ± 0.2 mol/mol protein, respectively, but the enzyme still remained susceptible to the subsequent inhibition of its activity with ASA. When PGHS-1 was first acetylated with ASA and then incubated with glycating/carbonylating agents, we observed the following reductions in the enzyme modifications: from 13.4 ± 1.6 to 8.7 ± 0.6 mol/mol protein for Glu, from 5.3 ± 0.5 to 3.9 ± 0.3 mol/mol protein for 1,6-BPF and from 10.7 ± 1.2 to 7.5 ± 0.5 mol/mol protein for MGO, however subsequent glycation/carbonylation did not significantly affect PGHS-1 function. Overall, our outcomes allow to better understand the structural aspects of the chemical competition between glycation and acetylation of PGHS-1., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Direct use of poly(amido)amine (PAMAM) dendrimers as drugs may be limited, due to uncertain (cyto)toxicity. Peripheral blood components, which constitute the first line of a contact with administered pharmaceuticals, may become vastly affected by PAMAM dendrimers. The aim of this study was to explore how PAMAMs' polycationicity might affect blood platelet activation and reactivity, and thus trigger various haemostatic events. We monitored blood platelet reactivity in rats with experimental diabetes upon a long-term administration of the unmodified PAMAM dendrimers. In parallel, the effects on blood flow in a systemic circulation was recorded intravitally in mice administered with PAMAM G2, G3 or G4. Compounding was the in vitro approach to monitor the impact of PAMAM dendrimers on blood platelet activation and reactivity and on selected haemostatic and protein conformation parameters. We demonstrated the activating effects of polycations on blood platelets. Some diversity of the revealed outcomes considerably depended on the used approach and the particular technique employed to monitor blood platelet function. We discovered undesirable impact of plain PAMAM dendrimers on primary haemostasis and their prothrombotic influence. We emphasize the need of a more profound verifying of all the promising findings collected for PAMAMs with the use of well-designed in vivo preclinical studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aims: The high glucose concentration observed in diabetic patients is a recognized factor of mitochondrial damage in various cell types. Its impact on mitochondrial bioenergetics in blood platelets remains largely vague. The aim of the study was to determine how the metabolism of carbohydrates, which has been impaired by streptozotocin-induced diabetes may affect the functioning of platelet mitochondria., Materials and Methods: Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Platelet mitochondrial respiratory capacity was monitored as oxygen consumption (high-resolution respirometry). Mitochondrial membrane potential was assessed using a fluorescent probe, JC-1. Activation of circulating platelets was monitored by flow cytometry measuring of the expressions of CD61 and CD62P on a blood platelet surface. To determine mitochondrial protein density in platelets, Western Blot technique was used., Key Findings: The results indicate significantly elevated mitochondria mass, increased mitochondrial membrane potential (ΔΨm) and enhanced respiration in STZ-diabetic animals, although the respiration control ratios appear to remain unchanged. Higher ΔΨm and elevated mitochondrial respiration were closely related to the excessive activation of circulating platelets in diabetic animals., Significance: Long-term diabetes can result in increased mitochondrial mass and may lead to hyperpolarization of blood platelet mitochondrial membrane. These alterations may be a potential underlying cause of abnormal platelet functioning in diabetes mellitus and hence, a potential target for antiplatelet therapies in diabetes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: The paper describes an alternative method for quantification of in vivo ADP-induced thromboembolism. The aim of the studies was to develop a method of quantification which would not require either extravasation or labelling of platelets. Our proposed approach is based on the monitoring of changes of blood flow with the use of laser Doppler flowmetry., Materials and Methods: Mice of C57Bl strain were used in the study. ADP was injected to the vena cava and blood flow was monitored with the use of a laser Doppler flowmeter in the mesentery. Measurements in platelet-depleted mice, mice pretreated with cangrelor, an ADP receptor antagonist, and eptifibatide, a blocker of fibrinogen binding to GPIIbIIIa, were conducted as the proof-of-concept in the performed experiments. Intravital microscopy and ex vivo imaging of organs was performed to identify the sites of aggregate formation resulting from ADP injection., Results: The injection of ADP resulted in a dose-dependent reduction of the blood flow in the mesentery. These responses were fully attributable to blood platelet aggregation, as shown by the lack of the effect in platelet-depleted mice, and significantly reduced responses in mice pretreated with cangrelor and eptifibatide. No platelet aggregate formation in mesenteric vessels was revealed by intravital microscopy, while ex vivo imaging showed accumulation of fluorescent labelled platelets in the lung., Conclusions: Injection of ADP to the venous system results in the formation of platelet aggregates predominantly in the lung. This results in reversible blood flow cessation in peripheral blood vessels. The measurement of this blood flow cessation in the mesentery allows indirect measurement of ADP-induced pulmonary thromboembolism. We suggest that this approach can be useful for in vivo screening for antiplatelet drug candidates.