Monitoring antimicrobial resistance in Campylobacter isolates of chickens and turkeys at the slaughter establishment level across the United States, 2013-2021.

Foodborne infections with antimicrobial-resistant Campylobacter spp. remain an important public health concern. Publicly available data collected by the National Antimicrobial Resistance Monitoring System for Enteric Bacteria related to antimicrobial resistance (AMR) in Campylobacter spp. isolated from broiler chickens and turkeys at the slaughterhouse level across the United States between 2013 and 2021 were analysed. A total of 1,899 chicken-origin (1,031 Campylobacter coli (C. coli) and 868 Campylobacter jejuni (C. jejuni)) and 798 turkey-origin (673 C. coli and 123 C. jejuni) isolates were assessed. Chicken isolates exhibited high resistance to tetracycline (43.65%), moderate resistance to ciprofloxacin (19.5%), and low resistance to clindamycin (4.32%) and azithromycin (3.84%). Turkey isolates exhibited very high resistance to tetracycline (69%) and high resistance to ciprofloxacin (39%). The probability of resistance to all tested antimicrobials, except for tetracycline, significantly decreased during the latter part of the study period. Turkey-origin Campylobacter isolates had higher odds of resistance to all antimicrobials than isolates from chickens. Compared to C. jejuni isolates, C. coli isolates had higher odds of resistance to all antimicrobials, except for ciprofloxacin. The study findings emphasize the need for poultry-type-specific strategies to address differences in AMR among Campylobacter isolates.

A Comprehensive Overview on Chemotherapy-Induced Cardiotoxicity: Insights into the Underlying Inflammatory and Oxidative Mechanisms.

While oncotherapy has made rapid progress in recent years, side effects of anti-cancer drugs and treatments have also come to the fore. These side effects include cardiotoxicity, which can cause irreversible cardiac damages with long-term morbidity and mortality. Despite the continuous in-depth research on anti-cancer drugs, an improved knowledge of the underlying mechanisms of cardiotoxicity are necessary for early detection and management of cardiac risk. Although most reviews focus on the cardiotoxic effect of a specific individual chemotherapeutic agent, the aim of our review is to provide comprehensive insight into various agents that induced cardiotoxicity and their underlying mechanisms. Characterization of these mechanisms are underpinned by research on animal models and clinical studies. In order to gain insight into these complex mechanisms, we emphasize the role of inflammatory processes and oxidative stress on chemotherapy-induced cardiac changes. A better understanding and identification of the interplay between chemotherapy and inflammatory/oxidative processes hold some promise to prevent or at least mitigate cardiotoxicity-associated morbidity and mortality among cancer survivors.

Recurrent rewiring of the adult hippocampal mossy fiber system by a single transcriptional regulator, Id2.

Circuit formation in the central nervous system has been historically studied during development, after which cell-autonomous and nonautonomous wiring factors inactivate. In principle, balanced reactivation of such factors could enable further wiring in adults, but their relative contributions may be circuit dependent and are largely unknown. Here, we investigated hippocampal mossy fiber sprouting to gain insight into wiring mechanisms in mature circuits. We found that sole ectopic expression of Id2 in granule cells is capable of driving mossy fiber sprouting in healthy adult mouse and rat. Mice with the new mossy fiber circuit solved spatial problems equally well as controls but appeared to rely on local rather than global spatial cues. Our results demonstrate reprogrammed connectivity in mature neurons by one defined factor and an assembly of a new synaptic circuit in adult brain.

[Thrombolysis treatment and multi- disciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options]. / Arteria centralis retinae elzáródás thrombolysiskezelése és multidiszciplináris ellátása a hagyományos szemészeti kezelési formákkal összehasonlítva.

Background and purpose:

The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo­gi­cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.

We reviewed CRAO patients’ data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo­gical and cardiovascular findings compared to those in the thrombolysis project. 

Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment. 
2 pa­tients had improved visual acuity, 2 pa­tients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.

CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.

Assessing antimicrobial resistance in Campylobacter jejuni and Campylobacter coli and its association with antimicrobial use in Canadian turkey flocks.

Turkeys are important sources of antimicrobial-resistant Campylobacter. A total of 1063 isolates were obtained from 293 turkey flocks across Canada between 2016 and 2021 to evaluate their antimicrobial resistance (AMR) prevalence, patterns, distribution, and association with antimicrobial use (AMU). A high proportion of C. jejuni and C. coli isolates were resistant to tetracyclines and fluoroquinolones, despite the very low use of these drugs. C. jejuni isolates had a higher probability of being resistant to tetracyclines than C. coli isolates. The chance of C. jejuni isolates being resistant to fluoroquinolones, macrolides, and lincosamides was lower compared to C. coli. Isolates from the western region had a higher probability of being resistant to fluoroquinolones than isolates from Ontario. Isolates from Ontario had higher odds of being resistant to tetracyclines than isolates from Quebec. No associations were noted between the resistance and use of the same antimicrobial, but the use of certain antimicrobial classes may have played a role in the maintenance of resistance in Campylobacter (fluoroquinolone resistance - bacitracin and streptogramin use, tetracycline resistance - flavophospholipids and streptogramins use, macrolide resistance - flavophospholipid use). Low-level multidrug-resistant Campylobacter was observed indicating a stable AMR in turkeys. This study provided insights aiding future AMU and AMR surveillance.

Experimental Determination of a Chiral Ternary Solubility Diagram and Its Interpretation in Gas Antisolvent Fractionation.

Although crystallization has been widely applied for the enantiomeric enrichment of non-racemates both in research and in industrial applications, the physical-chemical background of chiral crystallizations is not as frequently discussed. A guide for the experimental determination of such phase equilibrium information is lacking. In the current paper, the experimental investigation of chiral melting phase equilibria, chiral solubility phase diagrams and their application in atmospheric and supercritical carbon dioxide-assisted enantiomeric enrichment is described and compared. Benzylammonium mandelate is a racemic compound; it shows eutectic behavior when molten. A similar eutonic composition was observed in its methanol phase diagram at 1 °C. The influence of the ternary solubility plot could be unequivocally discovered in atmospheric recrystallization experiments, which proved that the crystalline solid phase and the liquid phase were in an equilibrium. The interpretation of the results obtained at 20 MPa and 40 °C, using the methanol-carbon dioxide mixture as a pseudo-component, was more challenging. Although the eutonic composition was found to be the limiting enantiomeric excess value in this purification process as well, the high-pressure gas antisolvent fractionation results were only clearly thermodynamically controlled in certain concentration ranges.

Incidence, Demographic, and Seasonal Risk Factors of Infections Caused by Five Major Enteric Pathogens, Ontario, Canada, 2010-2017.

In Canada, enteric infections cause significant health and economic burden. We evaluated the individual characteristics of laboratory-confirmed cases of Campylobacter spp. (n = 28,728), non-typhoidal Salmonella spp. (n = 22,640), Yersinia spp. (n = 1674), Verotoxin-producing Escherichia coli (VTEC; n = 1340), and Listeria monocytogenes (n = 471), reported between 2010 and 2017 inclusive, in Ontario, Canada (population ∼13,500,000). We calculated overall and pathogen-specific annual and mean incidence rates (IRs) for Ontario. We used multivariable Poisson and negative binomial regression models to estimate incidence rate ratios (IRRs) for years, seasons, age groups, and sexes, and we included two-way age and sex interaction terms in the models. Campylobacter and Salmonella infections had the highest IRs whereas Listeria infections had the lowest IRs. None of the infections showed long-term trends over the 8-year study period; however, rates of all five infections were elevated in the summer. More Salmonella, VTEC, and Listeria infections were linked to disease outbreaks than were Campylobacter and Yersinia infections. Overall, mean IRs of Campylobacter, Salmonella, Yersinia, and VTEC infections were highest in children 0-4 years old, whereas Listeria IRs peaked in adults 60 years and older. Higher mean IRs of Campylobacter were observed in males. No other differences by sex were statistically significant. The same mean rate was observed in both sexes for Listeria. Adjusting for all other factors, significant age- and sex-specific differences in IRs were observed in Campylobacter, Salmonella, and VTEC infection rates. No significant interactions of age and sex were found for Yersinia and Listeria infections. Future research should focus on the pathogen-specific socioeconomic, environmental, or agricultural risk factors that might be responsible for these infections.

Main reasons and predictive factors of cancer-related emergency department visits in a Hungarian tertiary care center.

BACKGROUND: Identifying the reasons for the Emergency Department (ED) visit of patients with cancer would be essential for possibly decreasing the burden of ED use. The aim of our study was to analyze the distribution of the demographic and clinical parameters of patients with cancer based on the reasons for the ED visits and to identify possible predictive factors for their visits. METHODS: This retrospective study, carried out at a large, public tertiary hospital in Hungary, involved all patients 18 years or over, who had received a cancer diagnosis latest within five years of their visit to the ED in 2018. Demographic and clinical characteristics were collected partly via automated data collection and partly through the manual chart review by a team of experts, including six emergency physicians and an oncologist. Five main reasons for the ED visit were hypothesized, pilot-tested, then identified, including those with cancer-related ED visits (whose visit was unambiguously related to their cancer illness) and those with non-cancer-related ED visits (whose visit to the ED was in no way associated with their cancer illness.) A descriptive approach was used for data analysis and binary logistic regression was used to determine predictive factors for patients with cancer visiting the ED. RESULTS: 23.2% of the altogether 2383 ED visits were directly cancer-related, and these patients had a significantly worse overall survival than patients with non-cancer related ED visits. Age 65 or below (Odds Ratio: 1.51), presence of two more comorbidities (OR: 7.14), dyspnea as chief complaint (OR: 1.52), respiratory cancer (OR: 3.37), any prior chemotherapy (OR: 1.8), any prior immune/biological treatment (OR: 2.21), any prior Best Supportive Care/palliative care (OR: 19.06), or any prior hospice care (OR: 9.43), and hospitalization (OR:2.88) were independent risk factors for the ED visit to be cancer-related. CONCLUSIONS: Our study is the first to identify independent predictive factors of ED use by patients with cancer based on the chief cause of their visit in the Central and Eastern European region. These results may provide important information for the development of algorithms intended to identify the needs of care of patients with cancer at the ED.

Exercise-mitigated sex-based differences in aging: from genetic alterations to heart performance.

The prevalence of cardiovascular diseases dramatically increases with age; therefore, striving to maintain a physiological heart function is particularly important. Our aim was to study the voluntary exercise-evoked cardioprotective effects in aged male and female rats, from genetic alterations to changes in heart performance. We divided 20-month-old female and male Wistar rats to control and running groups. After the 12-wk-long experimental period, echocardiographic measurements were performed. Afterwards, hearts were either removed for biochemical measurements or mounted into a Langendorff-perfusion system to detect infarct size. The following genes and their proteins were analyzed from heart: catechol-O-methyltransferase (Comt), endothelin-1 (Esm1), Purkinje cell protein-4 (Pcp4), and osteoglycin (Ogn). Recreational exercise caused functional improvements; however, changes were more prominent in males. Cardiac expression of Comt and Ogn was reduced as a result of exercise in aged males, whereas Pcp4 and Esm1 showed a marked overexpression, along with a markedly improved diastolic function. The key result of this study is that exercise enhanced the expression of the Pcp4 gene and protein, a recently described regulator of calcium balance in cardiomyocytes, and suppressed Comt and Ogn gene expression, which has been associated with impaired cardiac function. In addition, as a result of exercise, a significant improvement was observed in the size of infarct elicited by left anterior descending coronary artery occlusion. Our results clearly show that age and sex-dependent changes were both apparent in key proteins linked to cardiovascular physiology. Exercise-moderated fundamental genetic alterations may have contributed to the functional adaptation of the heart.NEW & NOTEWORTHY Voluntary exercise has proved to be an effective therapeutic tool to improve cardiac function in aged rats with clearly visible sex differences. Long-term exercise is associated with decreased Ogn and Comt expression and enhanced presence of Pcp4 and Esm1 genes. Sex-dependent changes were also observed in the expression of the cardiovascular key proteins. Fundamental alterations in gene and protein expression may contribute to the improvement of cardiac performance.

Identifying risks for severity of neurological symptoms in Hungarian West Nile virus patients.

BACKGROUND: West Nile virus (WNV) infections have become increasingly prevalent in certain European countries, including Hungary. Although most human infections do not cause severe symptoms, in approximately 1% of cases WNV infections can lead to severe WNV neuroinvasive disease (WNND) and death. The goal of our study was to assess the neurological status changes of WNV -infected patients admitted to inpatient care and to identify potential risk factors as underlying reasons for severe neurological outcome. METHODS: We conducted a retrospective chart review of 66 WNV-infected patients from four Hungarian medical centers. Patients' neurological status at hospital admission and at two follow-up intervals (1st follow-up, within 60-90 days and 2nd follow-up, within 150-180 days, after hospital discharge) were assessed. All of the 66 patients in the initial sample had some type of neurological symptoms and 56 patients were diagnosed with WNND. The modified Rankin Scale (mRS) and the West Nile Virus Neurological Index (WNV-N Index), a scoring system designed for the purpose of this study, were used for neurological status assessment. Patients were dichotomized into two categories, "moderately severe" and "severe" based on their neurological status. Descriptive analysis for sample description, stratified analysis for calculation of odds ratio (OR) and logistic regression for continuous input variables, were performed. RESULTS: The average number of days between the onset of neurological symptoms and hospital admission (the neurological symptom interval) was 6.01 days. Complications during the hospital stay arose in almost a fifth of the patients (18.2%) and 5 patients died. Each day's increase in the neurological symptom interval significantly increased the risk for developing a severe neurological status following hospital admission (0.799-fold and 0.688-fold, based on the WNV-N Index and mRS, respectively). Patients' age, comorbidity, presence of complications and symptoms of malaise, and gait uncertainty were shown to be independent risk factors for severe neurological status. CONCLUSIONS: Timely hospital admission of patients with neurological symptoms as well as risk assessment by clinicians - possibly with an optimal assessment tool for estimating neurological status- could improve the neurological outcome of WNV-infected patients.

Lymphoma in Psittacine Birds: A Histological and Immunohistochemical Assessment.

In psittacine birds, round cell neoplasms that originate from lymphocytes, plasma cells, histiocytes, or mast cells are sporadic and poorly described. The lack of morphological and immunohistochemical diagnostic criteria or grading schemes make specific diagnoses and prognoses challenging. We assessed cases of psittacine birds diagnosed with round cell neoplasia from 3 North American veterinary diagnostic laboratories to describe the diagnostic features of these tumors. For all cases, demographic data, anatomic distribution, histological features, and immunoreactivity for T (CD3) and B (Pax5 and MUM-1) cell markers were assessed using tissue microarrays and whole slide mounts. Thirty-eight psittacine birds representing 14 species were included. Tumors were mainly infiltrative and multicentric, were composed of homogenous sheets of round to polygonal cells, and commonly presented with a high mitotic count (average 21 mitoses per high-power field). Based on Pax5 immunoreactivity, B-cell lymphoma was most common (19/38 [50%]), and was significantly associated with involvement of the gastrointestinal and urogenital systems. Of the 38 cases, 6 (16%) were consistent with T-cell lymphoma, 3 (8%) with plasma cell tumor, and 3 (8%) were double-reactive for both B- and T-lymphocyte markers. This is the first study to describe morphologic and immunohistochemical features of round cell neoplasia in a large number of psittacine birds, and provides benchmark data for future studies aimed at elucidating the diagnosis and prognosis of these neoplasms. These data also provide useful information about reactivity of commercially available antibodies as lymphocyte markers in tissues of multiple psittacine species.

Area-Level Clustering of Shiga Toxin-Producing Escherichia coli Infections and Their Socioeconomic and Demographic Factors in Ontario, Canada: An Ecological Study.

Shiga toxin-producing Escherichia coli (STEC) infections are an important health burden for human populations in Ontario and worldwide. We assessed 452 STEC cases that were reported to Ontario's reportable disease surveillance system between 2015 and 2017. A retrospective scan statistic using a Poisson model was used to detect high-rate STEC clusters at the forward sortation area (FSA; the first three digits of a postal code) level. A significant spatial cluster in the southwest region of Ontario was identified. A case-case logistic regression analysis was applied to compare FSA-level socioeconomic and demographic characteristics among STEC cases included inside the spatial cluster with cases outside of the cluster. Cases included in the spatial cluster had higher odds of living in FSAs with a low median family income, low proportion of lone-parent families, and low proportion of the visible minority population. In addition, STEC cases inside the cluster had higher odds of coming from rural FSAs. Our study demonstrated that STEC cases were spatially clustered in Ontario and their clustering was associated with FSA-level socioeconomic and demographic determinants of cases.

Investigation of H2S Donor Treatment on Neutrophil Extracellular Traps in Experimental Colitis.

Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders, which affect the gastrointestinal tract with intermittent ulceration. It is increasingly clear that neutrophil extracellular traps (NETs) seem to have a role in IBD; however, the associated pathogenesis is still not known. Furthermore, several conventional therapies are available against IBD, although these might have side effects. Our current study aimed to investigate the effects of hydrogen sulfide (H2S) treatment on NETs formation and on the expression of inflammatory mediators in experimental rat colitis. To model IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was administered intracolonically (i.c.) to Wistar-Harlan male rats. Animals were treated (2 times/day) with H2S donor Lawesson's reagent per os. Our results showed that H2S treatment significantly decreased the extent of colonic lesions. Furthermore, the expression of members of NETs formation: peptidyl arginine deiminase 4 (PAD4), citrullinated histone H3 (citH3), myeloperoxidase (MPO) and inflammatory regulators, such as nuclear transcription factor-kappa B (NF-κB) and high-mobility group box 1 (HMGB1) were reduced in H2S treated group compared to TNBS. Additionally, H2S donor administration elevated the expression of ubiquitin C-terminal hydroxylase L1 (UCHL-1), a potential anti-inflammatory mediator. Taken together, our results showed that H2S may exert anti-inflammatory effect through the inhibition of NETs formation, which suggests a new therapeutic approach against IBD.

Live-Cell Imaging of Single Neurotrophin Receptor Molecules on Human Neurons in Alzheimer's Disease.

Neurotrophin receptors such as the tropomyosin receptor kinase A receptor (TrkA) and the low-affinity binding p75 neurotrophin receptor p75NTR play a critical role in neuronal survival and their functions are altered in Alzheimer's disease (AD). Changes in the dynamics of receptors on the plasma membrane are essential to receptor function. However, whether receptor dynamics are affected in different pathophysiological conditions is unexplored. Using live-cell single-molecule imaging, we examined the surface trafficking of TrkA and p75NTR molecules on live neurons that were derived from human-induced pluripotent stem cells (hiPSCs) of presenilin 1 (PSEN1) mutant familial AD (fAD) patients and non-demented control subjects. Our results show that the surface movement of TrkA and p75NTR and the activation of TrkA- and p75NTR-related phosphoinositide-3-kinase (PI3K)/serine/threonine-protein kinase (AKT) signaling pathways are altered in neurons that are derived from patients suffering from fAD compared to controls. These results provide evidence for altered surface movement of receptors in AD and highlight the importance of investigating receptor dynamics in disease conditions. Uncovering these mechanisms might enable novel therapies for AD.

Finding possible pharmacological effects of identified organic compounds in medicinal waters (BTEX and phenolic compounds).

Medicinal thermal waters consist of a mixture of different organic and inorganic compounds. Traditionally, these waters are only characterized and classified by their inorganic composition; however, the bioavailability of the majority of these inorganic compounds is limited. Many authors investigate the organic fractions of thermal waters. These authors propose that these compounds have a potential effect on health. To elucidate the underlying mechanisms, it is crucial to know the composition of the organic fractions. The absorption of these compounds on intact skin or mucosa is notable. Some of them have local anaesthetic effect or affect receptors in the central nervous system. In the knowledge of the chemical composition, we are able to estimate the possible pharmacological effect or might be able to assess possible toxicity risks. In the present article, we aim to review possible health effects of two of the identified organic fractions: benzene and alkylbenzenes and phenolic compounds that might correlate with the therapeutic effect on rheumatological or other diseases.

A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and "Medical Cannabinoids".

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E2) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E2 treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.

Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway.

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar-Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [3H](+)-pentazocine binding sites, and FLV treatment increased the reduced σ1R maximum binding capacity in TNBS-induced colitis. Furthermore, FLV significantly attenuated the colonic damage, the effect of which was abolished by the administration of BD1063. Additionally, FLV potentially increased the expression of ubiquitin C-terminal hydrolase ligase-1 (UCHL-1) and the levels of endothelial nitric oxide synthase (eNOS), and decreased the levels of interleukin-6 (IL-6) and inducible NOS (iNOS) expression. In summary, our study offers evidence for the anti-inflammatory potential of FLV and σ1R in experimental colitis, and our results present a promising approach to the development of new σ1R-targeted treatment options against IBD.

Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells.

Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xlbright and pAktbright cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38bright cells followed apoptosis (IC50: 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo.

Postconditioning-like effect of exercis: new paradigm in experimental menopause.

The progression of coronary artery diseases in premenopausal women is lower than in age-matched men; however, its probability increases rapidly after menopause. The aim of our study was to investigate the postconditioning-like effects of voluntary physical exercise on postmenopausal cardiovascular outcomes after myocardial infarction. We used fertile Wistar females [control (CTRL)] and pharmacologically induced estrogen-deficient (POVX; 750 µg/kg triptorelin im, every 4th week) rats. CTRL and POVX animals were randomly assigned to receive an injection of 0.1 mg isoproterenol (ISO)/kg. At the 20th hour after ISO injection, serum markers of myocardial injury, such as lactate dehydrogenase (LDH) and myoglobin, were measured. After a 3-wk resting period, ISO-treated and untreated animals were further divided into subgroups on the basis of 6 wk of physical exercise. At the end of the experiment, cardiac activity and content of the antioxidative heme oxygenase (HO) enzyme, levels of GSH and GSH + GSSG, activity of myeloperoxidase, as well as the concentration of TNF-α were determined. At the end of the experimental period, we observed a significant decrease in the activity and content of HO enzymes in POVX and POVX/ISO rats, whereas physical exercise significantly improved HO and GSH values in both CTRL and POVX rats. Furthermore, our training protocol significantly reduced the pathological levels of myeloperoxidase and TNF-α. Our findings clearly demonstrate that modulation of the HO system by voluntary physical exercise is a key process to decrease inflammatory parameters and ameliorate the antioxidative status in estrogen-deficient conditions postmyocardial injury. NEW & NOTEWORTHY We used a noninvasive rat model of estrogen deficiency and myocardial infarction. The long-term effects of isoproterenol treatment revealed reduced heme oxygenase enzyme activity and expression and decreased glutathione levels. Isoproterenol treatment enhanced the myeloperoxidase enzyme activity. Voluntary physical exercise ameliorated the antioxidative status by increasing of the heme oxygenase enzyme system. Voluntary physical exercise is a potential therapeutic tool to improve cardiac antioxidant status in menopausal women postmyocardial injury.

Antimicrobial resistance in fecal Escherichia coli and Salmonella enterica isolates: a two-year prospective study of small poultry flocks in Ontario, Canada.

BACKGROUND: Although keeping small poultry flocks is increasingly popular in Ontario, information on the antimicrobial susceptibility of enteric bacteria of such flocks is lacking. The current study was conducted on small poultry flocks in Ontario between October 2015 and September 2017, and samples were submitted on a voluntary basis to Ontario's Animal Health Laboratory. From each submission, a pooled cecal sample was obtained from all the birds of the same species from the same flock and tested for the presence of two common enteric pathogens, E. coli and Salmonella. Three different isolates from each E. coli-positive sample and one isolate from each Salmonella-positive sample were selected and tested for susceptibility to 14 antimicrobials using a broth microdilution technique. RESULTS: A total of 433 fecal E. coli isolates (358 chicken, 27 turkey, 24 duck, and 24 game bird) and 5 Salmonella isolates (3 chicken, 1 turkey, and 1 duck) were recovered. One hundred and sixty-seven chicken, 5 turkey, 14 duck, and 15 game bird E. coli isolates were pan-susceptible. For E. coli, a moderate to high proportion of isolates were resistant to tetracycline (43% chicken, 81% turkey, 42% duck, and 38% game bird isolates), streptomycin (29% chicken, 37% turkey, and 33% game bird isolates), sulfonamides (17% chicken, 37% turkey, and 21% duck isolates), and ampicillin (16% chicken and 41% turkey isolates). Multidrug resistance was found in 37% of turkey, 20% of chicken, 13% of duck, and 8% of game bird E. coli isolates. Salmonella isolates were most frequently resistant to streptomycin, tetracycline, and sulfonamides. Resistance to cephalosporins, carbapenems, macrolides, and quinolones was infrequent in both E. coli and Salmonella isolates. Cluster and correlation analyses identified streptomycin-tetracycline-sulfisoxazole-trimethoprim-sulfamethoxazole as the most common resistance pattern in chicken E. coli isolates. Turkey E. coli isolates compared to all the other poultry species had higher odds of resistance to tetracycline and ampicillin, and a higher multidrug resistance rate. CONCLUSIONS: Escherichia coli isolates were frequently resistant to antimicrobials commonly used to treat poultry bacterial infections, which highlights the necessity of judicious antimicrobial use to limit the emergence of multidrug resistant bacteria.