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Fabry disease (FD) is a rare genetic disorder that affects various organs and systems in the body. The disease is caused by a deficiency in the lysosomal enzyme α-galactosidase A (AGAL), which leads to the accumulation of globotriaosylceramide (Gb3) within lysosomes. This accumulation can cause damage to cells and organ systems, leading to a wide range of symptoms and complications. FD is a heterogeneous disorder, with a wide range of clinical phenotypes, ranging from the classic form, which is severe and associated with early onset, to milder non-classical forms, which are often limited to one organ and manifest later in life. We describe the case of a 23-year-old FD patient who was admitted as an emergency transfer due to newly discovered severe aortic regurgitation and suspected aortic valve endocarditis with vegetations of high embolic potential. Three years ago, the patient underwent a living donor kidney transplantation-the kidney graft lost its function 1 year after transplantation, and a chronic hemodialysis program was reinstituted., Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-024-01717-6., Competing Interests: Conflict of interestNo competing interests exist., (© Indian Association of Cardiovascular-Thoracic Surgeons 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Changes in K + channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K + channels. Their involvement in hydrogen sulfide (H 2 S)-mediated vasorelaxation is still unclear, and data about human vessels are limited., Objective: To determine the role of K + channel subtypes in the vasorelaxant mechanism of H 2 S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA)., Results: NaHS (1 × 10 -6 -3 × 10 -3  mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K + . Among K + channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01)., Conclusion: Our results demonstrated that H 2 S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H 2 S included direct or indirect opening of different K + channel subtypes, K ATP , BK Ca , SK Ca /IK Ca , and K V (subtype K V 1.3), in addition to NO pathway activation and interference with extracellular Ca 2+ influx., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

The formation of amyloid-β (Aβ) plaques is a neuropathological hallmark of Alzheimer's disease (AD), however, these pathological aggregates can also be found in the brains of cognitively unimpaired elderly population. In that context, individual variations in the Aβ-specific immune response could be key factors that determine the level of Aβ-induced neuroinflammation and thus the propensity to develop AD. CD4 + T cells are the cornerstone of the immune response that coordinate the effector functions of both adaptive and innate immunity. However, despite intensive research efforts, the precise role of these cells during AD pathogenesis is still not fully elucidated. Both pathogenic and beneficial effects have been observed in various animal models of AD, as well as in humans with AD. Although this functional duality of CD4 + T cells in AD can be simply attributed to the vast phenotype heterogeneity of this cell lineage, disease stage-specific effect have also been proposed. Therefore, in this review, we summarized the current understanding of the role of CD4 + T cells in the pathophysiology of AD, from the aspect of their antigen specificity, activation, and phenotype characteristics. Such knowledge is of practical importance as it paves the way for immunomodulation as a therapeutic option for AD treatment, given that currently available therapies have not yielded satisfactory results., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Neurons are highly energy-dependent and highly specialized cells, showing great sensitivity to oxidative stress (OS). Nitric oxide (NO) and its oxidation products play a central role in neurodegeneration. This study aimed to contribute to the further elucidation of the role of OS in the pathogenesis of amyotrophic lateral sclerosis (ALS)., Methods: We assessed NO and superoxide dismutase (SOD) levels in cerebrospinal fluid (CSF) of 24 sporadic ALS (sALS) patients (13 of them presented with spinal form while 11 patients had bulbar form) and 20 controls (CG)., Results: The obtained SOD levels in sALS patients were lower than those in CG (p < 0.001), while NO showed higher levels compared to CG (p < 0.001). Observed separately, there were no significant differences in the levels of NO and SOD in CSF between patients about their clinical presentations (p > 0.05). There were significant negative correlations between SOD and NO levels in all sALS patients (r = 0.31, P = 0.025). Significant correlation between SOD and functional rating scale as well as disease progression index was recorded in patients with sALS (r = 0.618. r = 0.425, P < 0.01), while NO levels were significantly associated with disease progression only (r = 0.348, P < 0.01)., Conclusion: The data presented clearly support the role of impaired oxidant/antioxidant balance in the pathogenesis of ALS, where NO overproduction and decreased SOD defense activity seem to be particularly involved. The CSF SOD and NO level might serve as useful biomarkers for functional disorder and progression of the disease., Competing Interests: None

Background and Objectives : There is a lack of data about the survival of patients after the implantation of sutureless relative to stented bioprostheses in middle-income settings. The objective of this study was to compare the survival of people with isolated severe aortic stenosis after the implantation of sutureless and stented bioprostheses in a tertiary referral center in Serbia. Materials and Methods : This retrospective cohort study included all people treated for isolated severe aortic stenosis with sutureless and stented bioprostheses from 1 January 2018 to 1 July 2021 at the Institute for Cardiovascular Diseases "Dedinje". Demographic, clinical, perioperative and postoperative data were extracted from the medical records. The follow-up lasted for a median of 2 years. Results : The study sample comprised a total of 238 people with a stented (conventional) bioprosthesis and 101 people with a sutureless bioprosthesis (Perceval). Over the follow-up, 13.9% of people who received the conventional and 10.9% of people who received the Perceval valve died ( p = 0.400). No difference in the overall survival was observed ( p = 0.797). The multivariate Cox proportional hazard model suggested that being older, having a higher preoperative EuroScore II, having a stroke over the follow-up period and having valve-related complications were independently associated with all-cause mortality over a median of 2 years after the bioprosthesis implantation. Conclusions : This research conducted in a middle-income country supports previous findings in high-income countries regarding the survival of people with sutureless and stented valves. Survival after bioprosthesis implantation should be monitored long-term to ensure optimum postoperative outcomes., Competing Interests: The authors declare no conflict of interest.

Background: Anterior mitral leaflet prolapse repair is a highly effective procedure, but despite excellent operative results still has an inferior long-term durability when compared to posterior leaflet repair., Methods: We analysed mitral repair durability in 74 consecutive patients operated for anterior leaflet prolapse between 2010 and 2021. Their pre- and postoperative clinical, echocardiographic data and repair durability as well, were compared with 74 randomly assigned posterior leaflet prolapse patients who underwent valve repair during the same period., Results: While groups were of similar age, patients with anterior leaflet prolapse had an inferior preoperative status in terms of functional reserve, atrial fibrillation, operative risk, ejection fraction and had more dilated left heart chambers as well. 1, 5, and 10-year freedom from repair failure was 87.1 ± 4.6%, 79.8 ± 6.5% and 50.7 ± 12.5% in the anterior, and 98.5 ± 1.5% respectively in the posterior leaflet group. Atrial fibrilation (hazard ratio [HR] 5.365; 95%; confidence interval [CI] 1.093-26.324 p = .038) and left ventricle end-systolic diameter (HR 1.160 95%; CI 1.037-1.299 p = .010) independently predicted anterior leaflet repair failure. Receiver Operating Curve analysis established left ventricle end-systolic diameter ≤42 mm as a cut-off value associated with improved anterior leaflet repair durability. Accordingly, 10-year repair durability in a subset of patients, with preserved left ventricle end-systolic diameter (≤42 mm) was 86.4 ± 7.8%., Conclusion: Better long-term repair durability in patients with anterior mitral leaflet prolapse and preserved sinus rhytm and left-ventricle diameters justifies early reconstructive approach., (© 2022 Wiley Periodicals LLC.)

Intracerebroventricularly (icv) injected streptozotocin (STZ) model of Alzheimer's disease (AD) is used to explore the effect of intermittent theta burst stimulation (iTBS) on astrocyte and microglia reactivity in selectively vulnerable brain regions and answer the question whether these changes are in the context of cognitive capacity. The iTBS is a non-invasive approach for stimulating neuronal and glial activity with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for different neurological diseases, including AD. Male Wistar rats were assigned to five groups: 1. Control subjected to icv saline solution, 2. STZ subjected to icv-STZ (bilaterally, 3 mg/kg), 3. STZ+iTBS subjected to iTBS therapy after icv-STZ, 4. STZ+iTBS placebo subjected to noise artifact after icv-STZ and 5. Control+iTBS subjected to iTBS therapy after icv- saline solution. The RotaRod result showed that STZ did not alter motor function in rats. Eight arm radial maze test results showed that iTBS significantly improved cognitive impairment induced by STZ intoxication. Reactive gliosis in the hippocampus and periventricular area, manifested through elevated levels of Iba1 + and GFAP + /VIM + following icv-STZ, was ameliorated after iTBS treatment. Our research identifies iTBS as an effective therapeutic candidate against STZ-induced neurotoxicity and AD-like changes. The beneficial effects of iTBS on cognitive dysfunction might be due to targeting microglia and astrocytes, as they exert a protective role in neurodegenerative and neuroinflammatory diseases. The results could provoke translation into clinical practice as an early/add-on non-invasive therapeutic intervention for cognitive impairment in AD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Wound healing of acute full-thickness injuries and chronic non-healing ulcers leads to delayed wound closure, prolonged recovery period and hypertrophic scarring, generating a demand for an autologous cell therapy and a relevant pre-clinical research models for wound healing. In this study, an immunocompetent model for wound healing was employed using a syngeneic murine cell line of mesenchymal stem cells cultured from the mouse whisker hair follicle outer root sheath (named moMSCORS). moMSCORS were isolated using an air-liquid interface method, expanded in vitro and characterized according to the MSC definition criteria - cell viability, in vitro proliferation, MSC phenotype and multi-lineage differentiations. Moreover, upon applying moMSCORS in an in vivo full-thickness wound model in the syngeneic C57BL/6 mice, the treated wounds displayed different morphology to that of the untreated wound beds. Quantitative evaluation of angiogenesis, granulation and wound closure involving clinical scoring and software-based quantification indicated a lower degree of inflammation in the treated wounds. Histological staining of treated wounds by the means of H&E, Alcian Blue, PicroSirius Red and αSMA immune labelling showed lower cellularity, less collagen filaments as well as thinner dermal and epidermal layers compared with the untreated wounds, indicating a general reduction of hypertrophic scars. The decreased inflammation, accelerated wound closure and non-hypertrophic scarring, which were facilitated by moMSCORS, hereby address a common problem of hypertrophic scars and non-physiological tissue properties upon wound closure, and additionally offer an in vivo model for the autologous cell-based wound healing., (© 2021. The Author(s).)

Hydrogen sulfide (H 2 S) represents the third and the youngest member of the gaseous transmitters family. The dominant effect of H 2 S on isolated vessels is vasodilation. As the mechanism of H 2 S-induced relaxation in human vessels remains unclear, the present study aimed to investigate the effects of H 2 S donor, sodium hydrosulfide (NaHS), on isolated human saphenous vein (HSV) and to determine the mechanism of action. Our results showed that NaHS (1 µM-3 mM) induced a concentration-dependent relaxation of endothelium-intact HSV rings pre-contracted by phenylephrine. Pre-treatment with L-NAME, ODQ and KT5823 significantly inhibited NaHS-induced relaxation, while indomethacin induced partial inhibition. Among K + channel blockers, the combination of apamin and TRAM-34 significantly affected the relaxation produced by NaHS, while iberiotoxin and glibenclamide only reduced maximal relaxation of HSV. NaHS partially relaxed endothelium-intact rings pre-contracted by high K + , as well as phenylephrine-contracted rings in the presence of nifedipine. Additionally, the incubation of HSV rings with NaHS increased NO production. These results demonstrate that NaHS produces the concentration- and endothelium-dependent relaxation of isolated HSV. Vasorelaxation to NaHS probably involves activation of NO/cGMP/PKG pathway and partially prostacyclin. In addition, different K + channels subtypes, especially SK Ca and IK Ca , as well as BK Ca and K ATP channels in high concentrations of NaHS, probably participate in the NaHS-induced vasorelaxation., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Pseudoaneurysm of the ascending aorta (PAA) is a hazardous and potentially fatal cardiovascular disease. This condition is caused by the rupture of at least one layer of the vessel and contained by the remaining vascular layers or the surrounding mediastinal structures. We presented the surgical treatment of a patient with sepsis and large PAA and brachiocephalic trunk, which was compressing the brachiocephalic trunk leading to syncope.

Background: The study evaluated the cost of baroreflex activation therapy plus guideline directed therapy (BAT + GDT) compared to GDT alone for HF patients with reduced ejection fraction and New York Heart Association Class III or II (with a recent history of III). Baroreflex activation therapy (BAT) is delivered by an implantable device that stimulates the baroreceptors through an electrode attached to the outside of the carotid artery, which rebalances the autonomic nervous system to regain cardiovascular (CV) homeostasis. The BeAT-HF trial evaluated the safety and effectiveness of BAT., Methods: A cost impact model was developed from a U.S. health care payer or integrated delivery network perspective over a 3-year period for BAT + GDT versus GDT alone. Expected costs were calculated by utilizing 6-month data from the BeAT-HF trial and existing literature. HF hospitalization rates were extrapolated based on improvement in NT-proBNP., Results: At baseline the expected cost of BAT + GDT were $29,526 per patient more than GDT alone due to BAT device and implantation costs. After 3 years, the predicted cost per patient was $9521 less expensive for BAT + GDT versus GDT alone due to lower rates of significant HF hospitalizations, CV non-HF hospitalizations, and resource intensive late-stage procedures (LVADs and heart transplants) among the BAT + GDT group., Conclusions: BAT + GDT treatment becomes less costly than GDT alone beginning between years 1 and 2 and becomes less costly cumulatively between years 2 and 3, potentially providing significant savings over time. As additional BeAT-HF trial data become available, the model can be updated to show longer term effects.

Obesity, a global health problem nowadays, is a state of low-grade chronic inflammation of adipose tissue (AT) associated with increased adipocyte growth and proliferation and immune cell polarization towards an inflammatory phenotype within the stromal vascular fraction (SVF). Pro-inflammatory cells in the AT produce mediators of inflammation (IL-1β, TNF, macrophage migration inhibitory factor - MIF), thereby surpassing the anti-inflammatory response mediated by IL-10 and TGF-β, cytokines produced by regulatory T (Treg) cells. In this study we demonstrate that the absence of the pro-inflammatory cytokine MIF led to obesity and inflammation in the visceral AT (VAT) in 6 months old MIF -/- mice. Besides the increment of pro-inflammatory AT macrophages and the enhanced production of TNF and IL-1β, VAT of MIF -/- mice contained increased numbers of Treg cells. In situ proliferation of Treg cells did not differ between MIF -/- and wild type mice, but Treg cells isolated from the VAT of MIF-deficient mice, and not from the cervical lymph nodes, exhibited lower expression and production of IL-10 and TGF-β. Additionally, SVF cells had significantly lower levels of STAT3 and IL-33, altogether indicating that VAT Treg cells in MIF -/- mice, albeit abundantly present, are not fully functional. These results indicate that MIF is a new regulator of VAT Treg cell function, necessary for their immunosuppressive activities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The DIA-DB is a web server for the prediction of diabetes drugs that uses two different and complementary approaches: (a) comparison by shape similarity against a curated database of approved antidiabetic drugs and experimental small molecules and (b) inverse virtual screening of the input molecules chosen by the users against a set of therapeutic protein targets identified as key elements in diabetes. As a proof of concept DIA-DB was successfully applied in an integral workflow for the identification of the antidiabetic chemical profile in a complex crude plant extract. To this end, we conducted the extraction and LC-MS based chemical profile analysis of Sclerocarya birrea and subsequently utilized this data as input for our server. The server is open to all users, registration is not necessary, and a detailed report with the results of the prediction is sent to the user by email once calculations are completed. This is a novel public domain database and web server specific for diabetes drugs and can be accessed online through http://bio-hpc.eu/software/dia-db/.

Cortical theta burst stimulation (TBS) structured as intermittent (iTBS) and continuous (cTBS) could prevent the progression of the experimental autoimmune encephalomyelitis (EAE). The interplay of brain antioxidant defense systems against free radicals (FRs) overproduction induced by EAE, as well as during iTBS or cTBS, have not been entirely investigated. This study aimed to examine whether oxidative-nitrogen stress (ONS) is one of the underlying pathophysiological mechanisms of EAE, which may be changed in terms of health improvement by iTBS or cTBS. Dark Agouti strain female rats were tested for the effects of EAE and TBS. The rats were randomly divided into the control group, rats specifically immunized for EAE and nonspecifically immuno-stimulated with Complete Freund's adjuvant. TBS or sham TBS was applied to EAE rats from 14th-24th post-immunization day. Superoxide dismutase activity, levels of superoxide anion (O 2 •- ), lipid peroxidation, glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH), and thioredoxin reductase (TrxR) activity were analyzed in rat spinal cords homogenates. The severity of EAE clinical coincided with the climax of ONS. The most critical result refers to TrxR, which immensely responded against the applied stressors of the central nervous system (CNS), including immunization and TBS. We found that the compensatory neuroprotective role of TrxR upregulation is a positive feedback mechanism that reduces the harmfulness of ONS. iTBS and cTBS both modulate the biochemical environment against ONS at a distance from the area of stimulation, alleviating symptoms of EAE. The results of our study increase the understanding of FRs' interplay and the role of Trx/TrxR in ONS-associated neuroinflammatory diseases, such as EAE. Also, our results might help the development of new ideas for designing more effective medical treatment, combining neuropsychological with noninvasive neurostimulation-neuromodulation techniques to patients living with MS.

Background: Early identification of acute infections and sepsis remains an unmet medical need. While early detection and initiation of treatment reduces mortality, inappropriate treatment leads to adverse events and the development of antimicrobial resistance. Current diagnostic and prognostic solutions, including procalcitonin, lack required accuracy. A novel blood-based host response test, HostDx™ Sepsis by Inflammatix, Inc., assesses the likelihood of a bacterial infection, the likelihood of a viral infection, and the severity of the condition., Objectives: We estimated the economic impact of adopting HostDx Sepsis testing among patients with suspected acute respiratory tract infection (ARTI) in the emergency department (ED)., Methods: Our cost impact model estimated costs for adult ED patients with suspected ARTI under the standard of care versus with the adoption of HostDx Sepsis from the perspective of US payers. Included costs were those assumed to be associated with an episode of sepsis diagnosis, management, and treatment. Projected accuracies for test predictions, disease prevalence, and clinical parameters was derived from patient-level meta-analysis data of randomized trials, supplemented with published performance data for HostDx Sepsis. One-way sensitivity analysis was performed on key input parameters., Results: Compared to standard of care including procalcitonin, the superior test characteristics of HostDx Sepsis resulted in an average cost savings of approximately US$1974 per patient (-31.3%) exclusive of the cost of HostDx Sepsis. Reductions in hospital days (-0.80 days, -36.7%), antibiotic days (-1.49 days, -29.5%), and percent 30-day mortality (-1.67%, -13.64%) were driven by HostDx Sepsis providing fewer "noninformative" moderate risk predictions and more "certain" low- or high-risk predictions compared to standard of care, especially for patients who were not severely ill. These results were robust to changes in key parameters, including disease prevalence., Conclusions: Our model shows substantial savings associated with introduction of HostDx Sepsis among patients with ARTIs in EDs. These results need confirmation in interventional trials.

Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties. The present study was undertaken to assess the vasorelaxant effect of procyanidin B2 on isolated human saphenous vein (HSV) and its underlying mechanisms. Procyanidin B2 relaxed phenylephrine-induced contraction of HSV rings in concentration-dependent manner. The relaxation was dependent on the presence of endothelium and was strongly affected by l-NAME, hydroxocobalamin or ODQ, the inhibitors of NO/cGMP pathway. Indomethacin significantly affected only the relaxation produced by the highest concentrations of procyanidin B2. Apamin and TRAM-34 combination, in the presence of l-NAME and indomethacin, did not additionally decreased procyanidin B2-induced relaxation. In the presence of K + channel blockers, relaxation induced by procyanidin B2 was partially attenuated by 4-aminopyridine, significantly inhibited by glibenclamide and almost abolished by iberiotoxin. Procyanidin B2 also relaxed the contractions induced by phenylephrine or caffeine in Ca 2+ -free solution. Finally, nifedipine slightly, while thapsigargin strongly antagonized HSV relaxation. Our results indicate that procyanidin B2 induces endothelium-dependent relaxation of HSV, which results primarily from stimulation of NO production, as well K + channels opening, especially BK Ca , and partially K ATP and K V . Regulation of the intracellular Ca 2+ release and inhibition of Ca 2+ influx probably contribute to procyanidin B2-induced relaxation., Competing Interests: Declaration of Competing Interest The authors indicated no potential conflict of interest., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Type 1 diabetes (T1D) is a multifactorial autoimmune disease that develops as a consequence of macrophage- and T cell-dependent pancreatic β-cell death. Multiple approaches for induction of anti-inflammatory/regulatory mechanisms that would attenuate T1D have been utilized, with little or no beneficial effects. To achieve prolonged stimulation of regulatory immune cells, we orally introduced microparticles (MPs) loaded with all-trans retinoic acid (ATRA) and transforming growth factor-β (TGF-β) to C57BL/6 mice treated with multiple low doses of streptozotocin (MLDS) for T1D induction. Disease incidence was significantly lower in ATRA/TGF-β MPs-treated mice, as was the degree of immune cell infiltration into the pancreatic islets. In Peyer's patches (PP), ATRA/TGF-β MPs up-regulated tolerogenic dendritic cells (tolDCs) (CD11c + CD11b - CD103 + ), while the proportion of mature dendritic cells was not altered. This was accompanied by reduced Th1 and Th17 proportions and up-regulation of regulatory T cells (Tregs - CD4 + CD25 high FoxP3 + ). The immune cell composition in the pancreatic lymph nodes was similar to PP. Further, the proportion of effector Tbet + CD25 med cells was decreased, while the proportion of Tbet + Treg cells that specifically inhibit Th1 response was increased. Moreover, ATRA/TGF-β MPs treatment resulted in increased Treg proliferation and frequency of CTLA-4 + PD1 + and CD39 + IL-10 + Tregs, suggestive of their higher suppressive capacity. Reduced pancreatic infiltration may have been a consequence of lower cell capacity for matrix degradation. In conclusion, oral application of ATRA/TGF-β MPs ameliorated T1D through potentiation of tolDCs and Tregs, inhibition of Th1 response and prevention of the immune cell entrance into the islets., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: The purpose of this prospective randomized study was to compare the early and midterm outcomes of aortic valve replacement (AVR) through upper ministernotomy with conventional AVR through median sternotomy., Methods: One hundred patients undergoing elective AVR were randomized into two groups: the M group (upper ministernotomy group, n = 50) and the C group (conventional sternotomy group, n = 50). The operative data, major adverse outcomes, and postoperative variables were compared between the two groups of patients. A cross-sectional follow-up was performed 24.9 ± 5.8 months after surgery., Results: The aortic cross-clamp time and cardiopulmonary bypass time were significantly longer in the M group. Similar incidences of major cardiac, neurologic and renal complications were recorded in both groups. Two patients (4%) in the C group developed wound infections. The length of ICU stay was similar in both groups. The patients in the M group had a shorter hospital stay compared with the patients in the C group (7.6 ± 2 days vs 9.3 ± 4.8 days; P = 0.022). Follow-up revealed that the time period needed to reach full recovery was significantly shorter in the ministernotomy group (1.7 ± 1.2 months vs 2.8 ± 1.6 months; P = 0.001). Morbidity and mortality data did not differ between the two groups., Conclusions: There was no difference in the major outcomes between the patients who underwent upper ministernotomy and those who underwent full sternotomy. The benefits of the minimally invasive approach were the shorter hospital stay and significantly faster recovery of patients after discharge from the hospital., (© 2019 Wiley Periodicals, Inc.)

Introduction: Heart failure (HF) is a major public health concern, prevalent in millions of people worldwide. The most widely-used HF diagnostic method, echocardiography, incurs a decreased diagnostic accuracy for heart failure disease progression when patients are asymptomatic compared to those who are symptomatic. The purpose of this study is to conduct a cost-effectiveness analysis of heart failure diagnosis comparing echocardiography to a novel myocardial strain assessment (Fast-SENC), which utilizes cardiac-tagged magnetic resonance imaging., Methods: We develop two models, one from the perspective of payers and one from the perspective of purchasers (hospitals). The payer model is a cost-effectiveness model composed of a 1-year short-term model and a lifetime horizon model. The hospital/purchaser model is a cost impact model where expected costs are calculated by multiplying cost estimates of each subcomponent by the accompanying probability., Results: The payer model shows lower healthcare costs for Fast-SENC in comparison to ECHO ($24,647 vs. $39,097) and a lifetime savings of 37% when utilizing Fast-SENC. Similarly, the hospital model revealed that the total cost per HF patient visit is $184 for ECHO and $209 for Fast-SENC, which results in hospital contribution margins of $81 and $115, respectively., Conclusions: Fast-SENC is associated with higher quality-adjusted life years and lower accumulated expected healthcare costs than echocardiogram patients. Fast-SENC also shows a significant short-term and lifetime cost-savings difference and a higher hospital contribution margin when compared to echocardiography. These results suggest that early discovery of heart failure with methods like Fast-SENC can be cost-effective when followed by the appropriate treatment.

Aims: The purpose of this study is to assess the economic cost differences and the associated treatment resource changes between the developing coronary artery disease (CAD) diagnostic tool fast strain-encoded cardiac imaging (Fast-SENC) and the current commonly used stress test single-photon emission computed tomography (SPECT)., Materials and Methods: A "payer perspective" model was created first, consisting of long-term and short-term components that used a hypothetical cohort of patients of average age (60.8 years) presenting with chest pain and suspected CAD to assess cost-impact. A cost impact model was then built that assessed likely savings from a "hospital perspective" from substituting Fast-SENC for a portion of SPECTs assuming an average number of annual SPECT tests performed in US hospitals., Results: In the payer model, using Fast-SENC followed by coronary angiography (CA) and percutaneous coronary intervention (PCI) treatment when necessary is less costly than the SPECT method when considering both direct and indirect costs of testing. Expected costs of the Fast-SENC were between $2,510 and $2,632 per correct diagnosis, while expected costs for the SPECT were between $3,157 and $4,078. Fast-SENC reduced false positives by 50% and false negatives by 86%, generating additional cost savings. The hospital model showed total costs per CAD patient visit of $825 for SPECT and $376 for Fast-SENC., Limitations: Limitations of this study are that clinical data are sourced from other published clinical trials on how CAD diagnostic strategies impact clinical outcome, and that necessary assumptions were made which impact health outcomes., Conclusion: The lower cost, higher sensitivity and specificity rates, and faster, less burdensome process for detecting CAD patients make Fast-SENC a more capable and economically beneficial stress test than SPECT. The payer model and hospital model demonstrate an alignment between payer and provider economics as Fast-SENC provides monetary savings for patients and resource benefits for hospitals.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in expression of proteins engaged in the activity of excitatory and inhibitory systems, restores these functions and suppresses the progression of disability in experimental autoimmune encephalitis (EAE). The structural type of TMS, the arrangement as theta burst stimulation (TBS) has been applied as intermittent TBS (iTBS) and continuous TBS (cTBS) protocols to female adult DA rats. The animals were randomly divided into experimental groups: control group (C), group treated with complete Freund's adjuvant (CFA), experimental autoimmune encephalomyelitis (EAE) group, group treated with iTBS post EAE immunization (EAE + iTBS), group treated with cTBS post EAE immunization (EAE + cTBS), group of healthy animals treated with iTBS or cTBS. Therapeutic protocols of iTBS or cTBS in all EAE groups of animals were performed starting from 14 days post immunization (dpi), for 10 days with time point decapitation at 24 dpi. After decapitation, spinal cords were analysed for BDNF and Ki67 expression. The results revealed reduced BDNF expression in the rat's spinal cord of EAE animals in the stage of remission, which was associated with increased Ki67 and GFAP expressions. Decreased Iba 1 and BDNF expression, contrary to increased Iba 1 and Ki67 expression, suggests clustered microglia in the resolution phase of EAE. Enhanced GABA expression in spinal cord sections indicates higher GABA metabolic turnover, and also GAD activity in astrocytes, or prominent activity of GABAergic neurons. Both TBS protocols induced advance BDNF expression; amongst iTBS application provoked elevating of BDNF and stabilizing of GFAP and Ki67 expressions.

SPR cytometry entails the measurement of parameters from intact cells using the surface plasmon resonance (SPR) phenomenon. Specific real-time and label-free binding of living cells to sensor surfaces has been made possible through the availability of SPR imaging (SPRi) instruments and researchers have started to explore its potential in the last decade. Here we will discuss the mechanisms of detection and additionally describe the problems and issues of mammalian cells in SPR biosensing, both from our own experience and with information from the literature. Finally, we build on the knowledge and applications that has already materialized in this field to give a forecast of some exciting applications for SPRi cytometry.

Autoreactive, myelin-specific, CD4 + T cells have a central role in multiple sclerosis (MS) pathogenesis; however the exact phenotype characteristics of these cells remain elusive. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) expression has emerged as the main pathological signature of the encephalogenicity in both T and B cell compartment. In this review we have summarized the current data supporting GM-CSF relevance in MS pathophysiology, in the context of both immunomodulatory and neuroinflammatory processes; as well as the potential cellular sources of this stimulating factor, including different T and B cell subsets., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is a large unmet need for reliable biomarker measurement systems for clinical application. Such systems should meet challenging requirements for large scale use, including a large dynamic detection range, multiplexing capacity, and both high specificity and sensitivity. More importantly, these requirements need to apply to complex biological samples, which require extensive quality control. In this paper, we present the development of an enhancement detection cascade for surface plasmon resonance imaging (SPRi). The cascade applies an antibody sandwich assay, followed by neutravidin and a gold nanoparticle enhancement for quantitative biomarker measurements in small volumes of complex fluids. We present a feasibility study both in simple buffers and in spiked equine synovial fluid with four cytokines, IL-1β, IL-6, IFN-γ, and TNF-α. Our enhancement cascade leads to an antibody dependent improvement in sensitivity up to 40 000 times, resulting in a limit of detection as low as 50 fg/mL and a dynamic detection range of more than 7 logs. Additionally, measurements at these low concentrations are highly reliable with intra- and interassay CVs between 2% and 20%. We subsequently showed this assay is suitable for multiplex measurements with good specificity and limited cross-reactivity. Moreover, we demonstrated robust detection of IL-6 and IL-1β in spiked undiluted equine synovial fluid with small variation compared to buffer controls. In addition, the availability of real time measurements provides extensive quality control opportunities, essential for clinical applications. Therefore, we consider this method is suitable for broad application in SPRi for multiplex biomarker detection in both research and clinical settings.

Particulate adjuvants have shown increasing promise as effective, safe, and durable agents for the stimulation of immunity, or alternatively, the suppression of autoimmunity. Here we examined the potential of the adjuvant carbonyl iron (CI) for the modulation of organ-specific autoimmune disease-type 1 diabetes (T1D). T1D was induced by multiple low doses of streptozotocin (MLDS) that initiates beta cell death and triggers immune cell infiltration into the pancreatic islets. The results of this study indicate that the single in vivo application of CI to MLDS-treated DA rats, CBA/H mice, or C57BL/6 mice successfully counteracted the development of insulitis and hyperglycemia. The protective action was obtained either when CI was applied 7 days before, simultaneously with the first dose of streptozotocin, or 1 day after MLDS treatment. Ex vivo cell analysis of C57BL/6 mice showed that CI treatment reduced the proportion of proinflammatory F4/80 + CD40 + M1 macrophages and activated T lymphocytes in the spleen. Moreover, the treatment down-regulated the number of inflammatory CD4 + IFN-γ + cells in pancreatic lymph nodes, Peyer's patches, and pancreas-infiltrating mononuclear cells, while simultaneously potentiating proportion of CD4 + IL17 + cells. The regulatory arm of the immune system represented by CD3 + NK1.1 + (NKT) and CD4 + CD25 + FoxP3 + regulatory T cells was potentiated after CI treatment. In vitro analysis showed that CI down-regulated CD40 and CD80 expression on dendritic cells thus probably interfering with their antigen-presenting ability. In conclusion, particulate adjuvant CI seems to suppress the activation of the innate immune response, which further affects the adaptive immune response directed toward pancreatic beta cells., (© 2017 Wiley Periodicals, Inc.)

Macrophage migration inhibitory factor (MIF) is a multifunctional protein that is involved in the development of gut-related inflammation. To investigate the role of MIF in the function of the intestinal barrier, we have explored intestinal permeability and gut-associated immune response in MIF-deficient (MIF-KO) mice. The absence of MIF provoked impairment of tight and adherens epithelial junctions in the colon through the disturbance of E-cadherin, zonula occludens-1, occludin and claudin-2 expression, which lead to the increase of intestinal barrier permeability. In these circumstances the diversity and content of gut microbiota in MIF-KO mice was considerably different compared to wild type mice. This change in microbiota was accompanied by an increased intestinal IgA concentration and a higher production of pro-inflammatory cytokines TNF and IFN-γ in mesenteric lymph nodes of MIF-KO mice. The forced changes of microbiota executed by antibiotics prevented the "leakage" of the barrier in MIF-KO mice, probably through up-regulation of occludin expression and normalization of cellular pore diameters. In addition, cytokine secretion was normalized after the treatment with antibiotics. These results suggest that MIF participates in the maintenance of physiological microbiota diversity and immunosurveillance, which in turn enables the proper intestinal barrier function.

Background: Studies have shown that improvements in glycemic control are associated with avoidance or delayed onset of diabetes complications, improvements in health-related quality of life, and reductions in diabetes-related health care costs. Clinical practice guidelines recommend maintaining a hemoglobin A1c (HbA1c) level less than 7%, but among type 2 diabetes patients using insulin, two-thirds have HbA1c above 7% and one-third have HbA1c above 9%., Objectives: This study examined the use of insulin management services to enable patients to optimize insulin dosing to achieve HbA1c targets and subsequently reduce health care costs. Cost savings may be achieved through reduced complications and hospitalizations, as well as reduced outpatient, physician, and clinic costs. This study quantified the reduction in pharmaceutical expenses related to the use of an enhanced insulin management service to improve glycemic control., Methods: Two hundred seventeen insulin-reliant patients were enrolled in the d-Nav® Insulin Guidance Service through a participating insurance group. A prospective cost analysis was conducted using data from enrolled patients who completed the first 90 days of follow up., Results: Of the 192 patients who completed the 90-day study period, 54 (28.13%) were prescribed one or more expensive medications at baseline, but 45 (83.33%) of those patients were eligible for medication discontinuation after 90 days. At baseline, the annual cost of expensive medications per patient was $7564 (CI: $5191-$9938) and $1483 (CI: -$1463-$4429) at 90 days (p<0.001). Direct savings from medication elimination was estimated to be $145 per patient per month (PPPM) or $1736 per patient per year (PPPY) for all patients and $514 PPPM/$6172 PPPY for the target group. Patients that completed the 90-day period significantly reduced HbA1c levels from 9.37% (CI:7.72%-11.03%) at baseline to 7.71% (CI: 6.70%-8.73%) (p<0.001). A total of 170 (88.54%) patients had improved HbA1c at 90 days., Conclusions: Use of the insulin guidance service achieved improved glycemic control by optimizing insulin dosing, which enabled most patients using the service to reduce or eliminate the use of expensive diabetes medications. Further study is needed to assess the impact of optimized insulin dosing on other diabetes-related health care costs in a usual practice setting.

In this study, we aimed to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human saphenous vein (HSV), as a part of its cardioprotective action, and to define the mechanisms underlying this vasorelaxation. (-)-Epicatechin induced a concentration-dependent relaxation of HSV pre-contracted by phenylephrine. Among K + channel blockers, 4-aminopyridine, margatoxin, and iberiotoxin significantly inhibited relaxation of HSV, while glibenclamide considerably reduced effects of the high concentrations of (-)-epicatechin. Additionally, (-)-epicatechin relaxed contraction induced by 80 mM K + , whereas in the presence of nifedipine produced partial relaxation of HSV rings pre-contracted by phenylephrine. In Ca 2+ -free solution, (-)-epicatechin relaxed contraction induced by phenylephrine, but had no effect on contraction induced by caffeine. A sarcoplasmic reticulum Ca 2+ -ATPase inhibitor, thapsigargin, significantly reduced relaxation of HSV produced by (-)-epicatechin. These results demonstrate that (-)-epicatechin produces endothelium-independent relaxation of isolated HSV rings. Vasorelaxation to (-)-epicatechin probably involves activation of 4-aminopyridine- and margatoxin-sensitive K V channels, BK Ca channels, and at least partly, K ATP channels. In addition, not only the inhibition of extracellular Ca 2+ influx, but regulation of the intracellular Ca 2+ release, via inositol-trisphosphate receptors and reuptake into sarcoplasmic reticulum, via stimulation of Ca 2+ -ATPase, as well, most likely participate in (-)-epicatechin-induced relaxation of HSV., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose of the Study: Heat shock proteins (Hsp) are evolutionary conserved molecules with a chaperone role in cell survival. We hypothesized that cord blood concentrations of molecules reflecting fetal cardiac muscle insult, including Hsp, troponins cTnI and cTnT, and glycol-phosphorylase BB (GP-BB) would be elevated in pregnancies complicated by gestational diabetes (GDM) or preeclampsia (PIH) compared to healthy controls., Materials and Methods: Pregnant women admitted for delivery at >28 weeks were divided into four groups: healthy patients delivered vaginally (VAG), healthy patients delivered by c-section (CS), patients with PIH, and patients with GDM. Demographics, clinical characteristics, and cord blood concentrations of Hsp, troponins cTnI and cTnT, and GP-BB were compared between groups. Statistical analyses included t-test, Chi square, and Wilcoxon rank sum as appropriate., Results: cTnI concentrations were significantly higher in the PIH group compared to the GDM and VAG groups and they were higher in the CS group compared to the VAG group. Concentrations of Hsp70 were higher in the GDM group compared to the VAG and CS groups. Concentration of GP-BB was higher in the PIH group compared to the VAG group., Conclusions: GP-BB and cTNI are the most sensitive markers for PIH-related fetal myocyte injury as is Hsp70 in pregnancies complicated by GDM.

Objectives: Amyotrophic lateral sclerosis (ALS) is recognized as a progressive neurodegenerative disorder of unknown origin. Oxidative stress (OS) is considered as one of the most challenging hypothesis in the disease pathogenesis. The aim of this study was to contribute to the understanding of what extent there is involvement of OS in ALS., Patients and Methods: We assessed Advanced Oxidation Protein Products (AOPP) and total thiol (-SH) groups in cerebrospinal fluid (CSF) of 24 ALS patients (13 of them presented with spinal form while 11 patients had bulbar form) and 20 controls (CG)., Results: The obtained AOPP levels in ALS patients were higher than those in CG (p <0.001), while -SH groups showed lower values compared to CG (p<0.001). The AOPP values were higher in ALS patients with bulbar compared with ALS patients with common spinal manifestation (p<0.001). There were no differences in -SH group's levels among these different clinical forms (p>0.05). The negative correlation between AOPP and the levels of -SH groups was confirmed (p <0.01). Significant mild correlations between tested parameters and functional rating scale as well as disease progression index were recorded for both of tested parameters in spinal form of ALS (p<0.01)., Conclusion: The data presented here clearly support the fact that OS is involved in patophysiology of ALS, where oxidation of -SH groups represents an important aspect of protein oxidation. The CSF AOPP level and -SH groups may serve as potential useful biomarker for functional disorder and progression of the disease in the spinal form of ALS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Identification, enumeration, and characterization of extracellular vesicles (EVs) are hampered by the small size of EVs, a low refractive index, and low numbers of antigens on their surface., Methods: We investigated the potential of a 48-multiplex surface plasmon resonance imaging (SPRi) system to perform EV phenotyping. Antigen surface density of 11 antigens was measured on the human breast cancer cell lines HS578T, MCF7, and SKBR3 and their EVs by use of both SPRi and the widely used flow cytometry (FCM)., Results: For cells, the SPRi and FCM signals for antigen exposure correlated (R HS578T cells 2 = 0.66, R MCF7 cells 2 = 0.78, R SKBR3 cells 2 = 0.60). With regard to EVs, SPRi detected 31 out of 33 tested antibody-EV pairs, whereas our flow cytometer detected 5 antibody-EV pairs because of high blank and isotype control signals. For HS578T-derived EVs, the SPRi and FCM signals correlated (R 2 HS578T EVs = 0.98). However, on MCF7- and SKBR3-derived EVs, insufficient antigens were detected by our flow cytometer. To confirm that the SPRi responses correlated with mean antigen density on EVs, the SPRi responses of EVs were correlated with antigen density on parental cells as measured by FCM (R HS578T 2 = 0.77, R MCF7 2 = 0.49, R SKBR3 2 = 0.52)., Conclusions: SPRi responses correlate with mean antigen density. Moreover, SPRi detects lower antigen-exposure levels than FCM because SPRi measures an ensemble of EVs binding to the sensor surface, whereas FCM detects antigens of single EV., (© 2017 American Association for Clinical Chemistry.)

We investigated the impact of preoperative ultrasonography of the forearm circulation on radial artery conduit selection. Preoperative ultrasound of the forearm circulation was performed routinely in 536 patients planned for radial artery harvesting. The safety assessment of the harvest included the following algorithm of tests: the ultrasound, the Allen test, and pulse oximetry. The quality criteria that were used to exclude a radial artery from harvesting were small size of the artery, diffuse atherosclerosis, calcifications, and severe neointimal hyperplasia. The overall rejection rate due to safety reasons was 16.4%. Seventy-one (13.2%) radial arteries did not fulfill the conduit quality criteria and consequently these arteries were not harvested. In 13.4% of radial arteries, localized arterial wall disease was found in the distal third of the artery. The distal part of the artery was discarded and the rest was used as a conduit. Our results indicate that the ultrasound provides an accurate preoperative insight into the radial artery morphology, enabling selection of the arteries with favorable morphological features.

The aim of the present study was to investigate and characterize vasorelaxant effect of procyanidin B2 on human internal mammary artery (HIMA) as one of the mechanisms of its protective effect against vascular risk. Procyanidin B2 induced strong concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Pretreatment with L-NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2-induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K + channel blockers, iberiotoxin, a selective blocker of large conductance Ca 2+ -activated K + channels (BK Ca ), abolished procyanidin B2-induced relaxation, glibenclamide, a selective ATP-sensitive K + (K ATP ) channels blocker, induced partial inhibition, while 4-aminopyridine, a blocker of voltage-gated K + (K V ) channels, and TRAM-34, an inhibitor of intermediate-conductance Ca 2+ -activated K + (IK Ca ) channels, slightly reduced maximal relaxation of HIMA. Further, procyanidin B2 relaxed contraction induced by phenylephrine in Ca 2+ -free Krebs solution, but had no effect on contraction induced by caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca 2+ -ATPase inhibitor, significantly reduced relaxation of HIMA produced by procyanidin B2. These results demonstrate that procyanidin B2 produces endothelium-dependent relaxation of HIMA pre-contracted by phenylephrine. This effect is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BK Ca and K ATP , as well as K V and IK Ca channels in high concentrations of procyanidin B2., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The proportion of outpatient surgeries performed in physician offices has been increasing over time, raising concern about the impact on outcomes., Objective: To use a private insurance claims database to compare 7-day and 30-day hospitalization rates following relatively complex outpatient surgical procedures across physician offices, freestanding ambulatory surgery centers (ASCs), and hospital outpatient departments (HOPDs)., Methods: A multivariable logistic regression model was used to compare the risk-adjusted probability of hospitalization among patients after any of the 88 study outpatient procedures at physician offices, ASCs, and HOPDs over 2008-2012 in Florida., Results: Risk-adjusted hospitalization rates were higher following procedures performed in physician offices compared with ASCs for all procedures grouped together, for most procedures grouped by type, and for many individual procedures., Conclusions: Hospitalizations following surgery were more likely for procedures performed in physician offices compared with ASCs, which highlights the need for ongoing research on the safety and efficacy of office-based surgery., Competing Interests: DECLARATION OF CONFLICTING INTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosures and Ethics As a requirement of publication, author(s) have provided to the publisher signed confirmation of compliance with legal and ethical obligations including, but not limited to the, following: authorship and contributorship, conflicts of interest, privacy and confidentiality, and (where applicable) protection of human and animal research subjects. The authors have read and confirmed their agreement with the ICMJE authorship and conflict of interest criteria. The authors have also confirmed that this article is unique and not under consideration or published in any other publication, and that they have permission from rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest.

Background: Cost-impact models have indicated that in the USA, the use of antibiotic stewardship protocols based on procalcitonin (PCT) levels for patients with suspected acute respiratory tract infection results in cost savings. Our objective was to assess the cost impact of adopting PCT testing among patients with acute respiratory infections (ARI) from the perspective of a typical hospital system in urban China., Methods: To conduct an economic evaluation of PCT testing versus usual care we built a cost-impact model based on a previously published patient-level meta-analysis data of randomized trials including Chinese sites. The data were adapted to the China setting by applying the results to mean lengths of stay, costs, and practice patterns typically found in China. We estimated the annual ARI visit rate for the typical hospital system (assumed to be 1650 beds) and ARI diagnosis., Results: In the inpatient setting, the costs of PCT-guided care compared to usual care for a cohort of 16,405 confirmed ARI patients was almost 1.1 million Chinese yuan (CNY), compared to almost 1.8 million CNY for usual care, resulting in net savings of 721,563 CNY to a typical urban Chinese hospital system for 2015. In the ICU and outpatient settings, savings were 250,699 CNY and 2.4 million CNY, respectively. The overall annual net savings of PCT-guided care was nearly 3.4 million CNY., Conclusions: Substantial savings are associated with PCT protocols of ARI across common China hospital treatment settings mainly by direct reduction in unnecessary antibiotic utilization.

Bovine colostrum is a rich source of nutrients and immunologically active components that play a role in conveying passive immunity to the offspring, protection and maturation of new-born's gastrointestinal tract. Colostrum has exerted positive effects in diseases affecting gastrointestinal tract, as well as type 2 diabetes (T2D). However, health-promoting effects in type 1 diabetes have not been reported. The aim of this study was to investigate therapeutic value of oral administration of standardized bovine colostrum derivative (SBCD) in three models of type 1 diabetes (T1D): spontaneously developed T1D in NOD mice and BB-DP rats, and in chemically induced T1D in C57BL/6 mice with multiple low doses of streptozotocin (MLDS). SBCD was administered per os and the disease development was evaluated by weekly measurement of blood glucose and by histological analyses of the pancreas. SBCD administration prevented diabetes development in all three models, as indicated by euglicaemia. Ex vivo analysis of cytokine expression and production in the spleen and mesenteric lymph nodes (MLN) in MLDS challenged mice revealed a strong modulation of the immune response. In the MLN cells SBCD disrupted harmful Th17 response induced by MLDS. Expression of Th1 signature cytokine IFN-γ was down-regulated in MLN cells of SBCD-treated mice, while IL-4 secretion (Th2 cytokine) was up-regulated in comparison to diabetic group. Modulation of the immune response seen in the MLN protruded to the spleen, giving overall less infiltration of immune cells to the pancreas. SBCD acted on immune cells and halted (auto) aggression towards pancreatic beta cells. Moreover, SBCD induced beta cell proliferation. Hence, this derivative could be tested in diabetes and other similar diseases with aberrant immune response., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Oxidative stress plays important roles in the pathophysiology of acute myocardial infarction (AMI). The aim of this study was to investigate the correlation of the oxidative stress status and matrix metalloproteinase activity in AMI patients in comparison to controls. This study included 136 subjects: 68 patients with AMI (42 males/26 females; mean age 58.5 ± 10.5 years) and 68 controls (37 males/29 females; mean age 60.2 ± 12.4 years). Gelatinases A and B were assayed using gelatin zymography, enzyme activities were obtained spectrophotometrically. Gelatinase A and B activities were increased in the AMI patients' group compared to the control. Activities of serum superoxide dismutase (SOD) and xanthine oxidase (XO) were significantly higher in AMI patients (106.53 ± 23.45 U/l, P < 0.001 and 158.18 ± 29.59 U/l, P < 0.001) than in the control group (55.99 ± 10.79 U/l and 79.81 ± 7.93 U/l). The activity of catalase (CAT) in the sera of AMI patients was lower (271.31 ± 7.53 U/l, P < 0.005) than in the control group (305.94 ± 97.28 U/l). Plasma glutathione peroxidase (GPx) and glutathione reductase (GR) in AMI patients were significantly higher (582.47 ± 184.81 U/l, P < 0.001 and 59.64 ± 21.88 U/l, P < 0.001) than in the control group (275.32 ± 104.69 U/l and 47.71 ± 20.05 U/l). The present findings demonstrate activation of gelatinases A and B and oxidative stress markers in the early stage of AMI. Gelatinases, detected at high levels in AMI patients only, indicate their noticeable predisposition for becoming additional biomarkers of the early phase of AMI.

Cell-based tolerogenic therapy is a promising approach for the treatment of autoimmune diseases and transplant rejection. Regulatory T cells and tolerogenic dendritic cells have been particularly explored in the treatment of various autoimmune disorders in experimental models of disease. Although some of these cells have already been tested in a limited number of clinical trials, there is still a need for preclinical research on tolerogenic cells in animal models of autoimmunity. This review will focus on the relevance of data obtained from studies in experimental animal models for the use of tolerogenic cell-based therapy in humans. Also, perspectives for further improvement of tolerogenic cell preparation towards enhanced suppressive activity and stability of the cells will be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: Th-17 cells have been exclusively referred to inflammatory events in multiple sclerosis (MS), while their importance in the development of glutamate excitotoxicity and the consequent neurodegeneration has been a completely unexplored concept. Accordingly, the objective of our study was to assess IL-17A effect on astrocyte ability to metabolize and release glutamate, considering that astrocytes had the central role in glutamate homeostasis., Methods: By using primary rat astrocyte cultures, astrocyte ability to uptake glutamate was estimated by the alterations of glutamate transporters (GLAST and GLT-1) expression, whereas changes in glutamine synthetase expression were used to estimate the ability to metabolize glutamate. Gene expression was determined by real time polymerase chain reaction (rtPCR). IL-17A effect on astrocyte ability to produce glutamate was investigated directly, by measuring the level of released glutamate using high performance liquid chromatography (HPLC)., Results: Lower concentrations of IL-17A reduced the expressions of both glutamate transporters and glutamine synthetase; however, this effect was lost when IL-17A was applied in a higher dose. IL-17A did not significantly modify glutamate release from astrocyte in basal conditions, but following Ca 2+ stimulation, as well as Ca 2+ removal from the culture medium, IL-17A stimulated glutamate release in dose-dependent manner., Conclusion: Together, these results support that IL-17A could promote glutamate excitotoxicity by decreasing astrocyte ability to uptake and convert glutamate to non-toxic glutamine, but also by stimulating Ca 2+ dependent glutamate release. Such interactions between IL-17A and glutamate excitotoxicity implicate the potential link between inflammation and neurodegeneration during MS pathogenesis, and identify astrocytes as a potential target in achieving neuroprotective effects in MS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Considering the contradictory literature data about the role of nitric oxide (NO) in colon carcinogenesis, the purpose of this study was to examine the changes of L-arginine metabolites in colon cancer and surrounding tissue as possible molecular markers of tumor behavior after surgery and the possibility of NO synthesis modulation in new individualized therapeutic strategies., Methods: The study encompassed 50 patients who underwent surgery for colorectal cancer (CRC). The three tissue specimens were taken by surgery (tumor, adjacent and healthy tissue) and the concentrations of NO2+NO3, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were determined in the tissue specimens., Results: The results proved higher NO2+NO3 concentrations in adjacent tissue compared to the tumor, implicating high angiogenic potential of the tumor-surrounding tissue, which could have clinical importance in the assessment of the probability of tumor local recurrence and metastasis. Increased ADMA concentrations in tumor tissue associated with low NO levels, could lead to new therapeutic strategies directed to the use of inhibitors of NO synthesis as ideal candidates for molecular therapy of CRC. ADMA concentration in adjacent tissue was an independent predictor of distant metastasis., Conclusions: The obtained results suggest that determination of the examined biomarkers in CRC and adjacent tissue samples could give useful information about tumor proliferative and angiogenic potential, which in turn could enable individualization of therapy and the choice of proper adjuvant therapy in patients with CRC.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in expression of proteins engaged in activity of excitatory and inhibitory systems as well as redox homeostasis. Our aim was to investigate the effect of single (SS) and repeated session (RS) of intermittent and continuous theta-burst stimulation (iTBS; cTBS) on the expression of vesicular and plasmatic glutamate transporters 1 (vGluT1 and GLT-1), glial fibrillary acidic protein (GFAP) and influence on oxidative status in rats cerebellar tissue and plasma. Redox state parameters in cerebellar tissue and plasma were assessed 24 h after single and 48 h after the last TBS session. Molecular changes were examined by immunofluorescence. Stimulation significantly increased thiol groups (SH) in tissue of SS iTBS group, and decreased in iTBS RS. Activity of glucose-6-phosphate-dehydrogenase (G6PD) was increased markedly in cTBS RS. Immunoreactivity of vGluT1 in cTBS RS decreased, while GLT-1 increased in cTBS SS and cTBS RS, compared to control. Present study gives insight in molecular and biochemical mechanisms by which iTBS and cTBS exerts its effects on rats cerebellar cortex., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although current evidence mainly suggests immunopathogenesis of demyelination and neurodegeneration in multiple sclerosis (MS), there are results which document the importance of other factors, such as oxidative stress and its mediated injuries. The oxidative stress intensity in axonal damage during acute demyelination is little known. We performed this study as a cross-sectional biomarker validation study in order to evaluate the parameters of axonal damage (phosphorylated neurofilaments heavy chain (pNF-H)) and oxidative stress (8-hydroxy-2'-deoxyguanosine (8-OHdG)) in plasma of patients with initial and relapsing-remitting demyelination attacks, defined as clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS); and the correlations between these parameters and biological (index of blood brain barrier (BBB) permeability), clinical (index of disease progression), and radiological (T1-Gd-enhancing lesion volume) activities of disease. Both parameters were increased in CIS and RRMS compared to control subjects (p < 0.05). The positive correlations were observed between 8-OHdG values and index of BBB permeability, clinical severity of disease, and demyelinated brain lesion volume, in CIS group (r > 0.50; p < 0.05). Similar correlations were obtained between pNF-H values and the above parameters, as well as the index of disease progression, in RRMS group (r > 0.30; p < 0.05). There was a significant correlation between values of 8-OHdG and pNF-H only in CIS group, r = 0.52, p < 0.05. While the plasma values of 8-OHdG reflect the degree of acute demyelination in CIS, pNF-H values reflect that in RRMS. The obtained results must be reevaluated in similar prospective studies related to their prognostic values.

Introduction: Perianal fistula is usually of cryptoglandular origin, namely it results from inflammation of the anal glands. The main challenge in its management is how to resolve a fistula but avoid its recurrence as well as incontinence, which is even a bigger problem. Several treatment methods have been described and they all focus on cutting the anal sphincter and "opening" the fistula, placing the seton, plug technique, creating a mucosal advancement flap, injecting medical occlusive agents or using a combination of methods. In 2007 a method of managing a fistula by ligation of the intersphincteric fistula tract was described. The procedure is still getting a wider application., Case Report: A 60-year old male patient had had a fistula for 30 years. He underwent incision of perianal abscess on multiple occasions resulting in multiple scars in the gluteus area. The diagnosis revealed a high transsphincteric fistula. The inner ostium was diagnosed by injecting hydrogen-peroxide and by probing. The patient's general condition was satisfactory. For the first time the ligation of intersphincteric fistula tract procedure was applied in our regional hospital. Under general anesthesia, in a lithotomy position, the ligation of intersphincteric fistula tract procedure was successfully performed in approximately 30 minutes. The external opening of the fistula and the scars were widely excised. The postoperative course was uneventful. After 6 months there was no recurrence., Conclusion: The ligation of intersphincteric fistula tract procedure for transsphincteric fistulae can be a treatment of choice in all hospitals treating colorectal patients because the incontinence risk is low, and the disease is curable at a high percentage.

Type 1 diabetes (T1D) is an autoimmune disease that develops as a consequence of pancreatic β-cell death induced by proinflammatory mediators. Because Origanum vulgare L. ssp. hirtum (Greek oregano) contains antiinflammatory molecules, we hypothesized that it might be beneficial for the treatment of T1D. An ethyl acetate extract of oregano (EAO) was prepared from the leaves by a polar extraction method. Phytochemical composition was determined by liquid chromatography-UV diode array coupled to ion-trap mass spectrometry with electrospray ionization interface (LC/DAD/ESI-MS(n) ). In vitro immunomodulatory effect of EAO was estimated by measuring proliferation (MTT) or cytokine secretion (ELISA) from immune cells. Diabetes was induced by multiple low doses of streptozotocin (MLDS) in male C57BL/6 mice and EAO was administered intraperitoneally for 10 d. Determination of cellular composition (flow cytometry) and cytokine production (ELISA) was performed on 12th d after diabetes induction. EAO suppressed the function of both macrophages and lymphocytes in vitro. In vivo, EAO treatment significantly preserved pancreatic islets and reduced diabetes incidence in MLDS-challenged mice. Besides down-modulatory effect on macrophages, EAO reduced the number of total CD4(+) and activated CD4(+) CD25(+) T cells. Furthermore, EAO affected the number of T helper 1 (Th1) and T helper 17 (Th17) cells through downregulation of their key transcription factors T-bet and RORγT. Because EAO treatment protects mice from development of hyperglycemia by reducing proinflammatory macrophage/Th1/Th17 response, this plant extract could represent a basis for future diabetes therapy., (© 2016 Institute of Food Technologists®)

There are many opened questions about the precocious role of oxidative stress in the physiopathology of the early stage of transitory ischemic attack (TIA) and defined focal brain ischemia, as well as about its correlation with clinical severity, short-lasting and clinical outcome prediction in these conditions. The study evaluates the values of glutathione (GSH), glutathione peroxidase, and superoxide dismutase (SOD) in hemolysates and total thiol content (-SH), advanced oxidation protein products (AOPP), SOD, and malondialdehyde (MDA) in plasma, in TIA and stroke patients in the early stage of their neurological onset. The results are interpreted in view of the potential relationship between tested parameters and clinical severity and clinical outcome prediction. Better hemolysates' and total antioxidant profile with higher values of AOPP were observed in TIA compared to stroke patients (p < 0.05). The stroke patients with initially better clinical presentation showed better antioxidant profile with lower values of AOPP (p < 0.05). In TIA patients, this was observed for GSH, -SH content, and AOPP (p < 0.05), which correlated with a short risk for stroke occurrence in this group (p < 0.01). Beyond MDA values, all tested parameters showed correlation with clinical outcome in stroke patients (p < 0.05). The measurement of oxidative stress in TIA and stroke patients would be important for identifying patients' subgroups which might receive supporting therapy providing better neurological recovery and clinical outcome. That approach might give us an additional view of a short-lasting risk of stroke occurrence after TIA, and its clinical outcome and prognosis.

The presence of tumor cells in blood is predictive of short survival in several cancers and their isolation and characterization can guide toward the use of more effective treatments. These circulating tumor cells (CTC) are, however, extremely rare and require a technology that is sufficiently sensitive and specific to identify CTC against a background of billions of blood cells. Immuno-capture of cells expressing the epithelial cell adhesion molecule (EpCAM) are frequently used to enrich CTC from blood. The choice of bio conjugation strategy and antibody clone is crucial for adequate cell capture but is poorly understood. In this study, we determined the binding affinity constants and epitope binding of the EpCAM antibodies VU1D-9, HO-3, EpAb3-5, and MJ-37 by surface plasmon resonance imaging (SPRi). Glass surfaces were coated using a poly(acrylic acid) based coating and functionalized with anti-EpCAM antibodies. Binding of cells from the breast carcinoma cell line (SKBR-3) to the functionalized surfaces were compared. Although EpAb3-5 displayed the highest binding affinity HO-3 captured the highest amount of cells. Hence we report differences in the performance of the different antibodies and more importantly that the choice of antibody to capture CTC should be based on multiple assays.

Purpose: This study was aimed to evaluate the meaningfulness of the MRI Score WORMS (Whole Organ Magnetic Resonance Imaging), the arthroscopic WOAKS (Whole Organ Arthroscopic Knee Score) and the result of NIRS (near-infrared spectroscopy) measurements., Materials and Methods: A total of 49 patients with knee pain (> 3 months) underwent MRI with a standardised protocol. In the results the WORMS was calculated. The WOAKS was calculated from the results of an arthroscopic evaluation. In the same procedure, NIRS measurements were performed in the identical 14 regions of interest. From these measurements, the WOAKS&#95;NIRS was calculated., Results: The highest grade of degeneration in all evaluations was found in the patella. The medial compartment showed moderate lesions compared with the lateral compartment. The relative WORMS was only 3.7 % (95 % CI 2.8-4.6; 0-15.6 %). During arthroscopy, we calculated a mean WOAKS of 15.2 % (95 % CI 13.2-17.2; 5-39 %). The degree of joint degeneration was highest in NIRS measurements. The mean WOAKS&#95;NIRS was 50.9 % (95 % CI 48.1-53.7 %). These differences are significant (p < 0.001)., Conclusion: The methods to detect early cartilage degenerations in MRI are flawed. Thus in our patients, we detected a full grade of degeneration in only 3.7 % of the patients. Arthroscopy mostly gives higher damage within the knee joint. The initial stages of cartilage lesion are usually undetectable. Spectroscopy has the best sensitivity for the evaluation of early degeneration within the hyaline cartilage. The clinical relevance of our results is still unclear. Further outcome studies are needed., (Georg Thieme Verlag KG Stuttgart · New York.)

This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning.