Hypoxic glioblastoma-cell-derived extracellular vesicles impair cGAS-STING activity in macrophages.

BACKGROUND: Solid tumors such as glioblastoma (GBM) exhibit hypoxic zones that are associated with poor prognosis and immunosuppression through multiple cell intrinsic mechanisms. However, release of extracellular vesicles (EVs) has the potential to transmit molecular cargos between cells. If hypoxic cancer cells use EVs to suppress functions of macrophages under adequate oxygenation, this could be an important underlying mechanism contributing to the immunosuppressive and immunologically cold tumor microenvironment of tumors such as GBM. METHODS: EVs were isolated by differential ultracentrifugation from GBM cell culture supernatant. EVs were thoroughly characterized by transmission and cryo-electron microscopy, nanoparticle tracking analysis (NTA), and EV marker expression by Western blot and fluorescent NTA. EV uptake by macrophage cells was observed using confocal microscopy. The transfer of miR-25/93 as an EV cargo to macrophages was confirmed by miRNA real-time qPCR. The impact of miR-25/93 on the polarization of recipient macrophages was shown by transcriptional analysis, cytokine secretion and functional assays using co-cultured T cells. RESULTS: We show that indirect effects of hypoxia can have immunosuppressive consequences through an EV and microRNA dependent mechanism active in both murine and human tumor and immune cells. Hypoxia enhanced EV release from GBM cells and upregulated expression of miR-25/93 both in cells and in EV cargos. Hypoxic GBM-derived EVs were taken up by macrophages and the miR-25/93 cargo was transferred, leading to impaired cGAS-STING pathway activation revealed by reduced type I IFN expression and secretion by macrophages. The EV-treated macrophages downregulated expression of M1 polarization-associated genes Cxcl9, Cxcl10 and Il12b, and had reduced capacity to attract activated T cells and to reactivate them to release IFN-γ, key components of an efficacious anti-tumor immune response. CONCLUSIONS: Our findings suggest a mechanism by which immunosuppressive consequences of hypoxia mediated via miRNA-25/93 can be exported from hypoxic GBM cells to normoxic macrophages via EVs, thereby contributing to more widespread T-cell mediated immunosuppression in the tumor microenvironment.

SPRTN is involved in hepatocellular carcinoma development through the ER stress response.

Endoplasmic reticulum (ER) stress, prompted by the accumulation of misfolded or unfolded proteins, triggers the activation of the unfolded protein response (UPR) pathway to restore ER homeostasis. This stress response is implicated in the development of hepatocellular carcinoma (HCC). A biallelic mutation in SPRTN is currently the only known single-gene mutation implicated in the early onset of HCC. However, the exact mechanism linking SPRTN mutations to HCC remains unclear. In our study, we analyzed SPRTN and UPR in 21 human HCC tissue samples using RT-qPCR, immunoblot, and immunohistochemistry. We found alterations in the expression levels of SPRTN and UPR-related genes and proteins in HCC samples. The impact of SPRTN on the ER stress response was assessed in SPRTN-depleted HepG2 cells through RNA sequencing, pull-down assay, comet assay, and mitotic index calculation. We demonstrated that SPRTN interacts with the UPR sensor GRP78. Furthermore, we observed a decrease in SPRTN levels during ER stress, and increased sensitivity to ER stress in SPRTN-depleted cells. These findings suggest an essential role for SPRTN in the ER stress response and provide new insights into HCC pathogenesis. This newly discovered function of SPRTN could significantly enhance our understanding and treatment of HCC.

Clinical and Cytogenetic Characteristics of Children With Leukemia 20-Year Retrospective Study.

Acute leukemias are the most common malignant diseases in childhood. The aims of this retrospective cohort study were to investigate the frequency of cytogenetic abnormalities in acute pediatric leukemia; the correlation between cytogenetic abnormalities and 5-year survival; and the correlation between cytogenetic abnormalities and clinical and laboratory features. We included 105 patients; acute lymphoblastic leukemia (ALL) had 80.9% patients, B-cell lineage ALL (B-ALL) 84.7% of them, and T-cell lineage (T-ALL) 15.3%. The overall 5-year survival for B-ALL was 85.9% and for T-ALL was 84.6%. The most common cytogenetic abnormalities in patients with B-ALL were t(12;21)(p13.2;q22.1); ETV6-RUNX1 with 22.2% and hyperdiploidy with 19.4%. Our survival analysis showed that t(12;21)(p13.2;q22.1); ETV6-RUNX1 and t(1;19)(q23;p13.3); TCF3-PBX1 had the best 5-year survival with 100% of patients surviving, whereas t(v;11q23.3); KMT2A rearranged had the worst 5-year survival of just 33.3% of patients surviving after 5 years. We found no difference in 5-year survival in B-ALL when comparing clinical features. Acute myelogenous leukemia had 20 patients with 70.6% 5-year survival. The most common cytogenetic abnormality in acute myelogenous leukemia was t(8;21)(q21;q22.1); RUNX1-RUNX1T1 (20%). In conclusion, this study showed the correlation of different cytogenetic abnormalities with 5-year survival in B-ALL patients. Such correlation was not found when comparing clinical features and 5-year survival of patients with B-ALL. This emphasized the significance of cytogenetic analysis in pediatric leukemia.

Synthesis, Formulation and Characterization of Immunotherapeutic Glycosylated Dendrimer/cGAMP Complexes for CD206 Targeted Delivery to M2 Macrophages in Cold Tumors.

Anti-tumor responses can be achieved via the stimulation of the immune system, a therapeutic approach called cancer immunotherapy. Many solid tumor types are characterized by the presence of immune-suppressive tumor-associated macrophage (TAMs) cells within the tumor microenvironment (TME). Moreover, TAM infiltration is strongly associated with poor survival in solid cancer patients and hence a low responsiveness to cancer immunotherapy. Therefore, 2'3' Cyclic GMP-AMP (2'3' cGAMP) was employed for its ability to shift macrophages from pro-tumoral M2-like macrophages (TAM) to anti-tumoral M1. However, cGAMP transfection within macrophages is limited by the molecule's negative charge, poor stability and lack of targeting. To circumvent these barriers, we designed nanocarriers based on poly(amidoamine) dendrimers (PAMAM) grafted with D-glucuronic acid (Glu) for M2 mannose-mediated endocytosis. Two carriers were synthesized based on different dendrimers and complexed with cGAMP at different ratios. Orthogonal techniques were employed for synthesis (NMR, ninhydrin, and gravimetry), size (DLS, NTA, and AF4-DLS), charge (DLS and NTA), complexation (HPLC-UV and AF4-UV) and biocompatibility and toxicity (primary cells and hen egg chorioallantoic membrane model) evaluations in order to evaluate the best cGAMP carrier. The best formulation was selected for its low toxicity, biocompatibility, monodispersed distribution, affinity towards CD206 and ability to increase M1 (STAT1 and NOS2) and decrease M2 marker (MRC1) expression in macrophages.

Myocardial Scintigraphy in Diagnosing Cardiac Transthyretin Amyloidosis.

Myocardial scintigraphy with technetium-99m pyrophosphate is a minimally invasive technique that can distinguish between transthyretin amyloidosis (ATTR) and light-chain amyloidosis. We present a case in which it helped determine the amyloidosis type in a 74-year-old man with cardiac amyloidosis and multiple previous admissions for acute decompensated heart failure. The patient presented with increasing abdominal girth and bilateral lower extremity edema. His medical history also included atrial fibrillation, liver cirrhosis, hypertension, stage 3 chronic kidney disease, and peripheral vascular disease. We prescribed guideline-directed medical therapy for his acute decompensated heart failure with cardiorenal syndrome and his decompensated cirrhosis. Two years previously, a presumptive diagnosis of ATTR cardiomyopathy had been made on the basis of the patient's age, predominantly cardiac involvement, an unremarkable serum protein electrophoresis result, and an abnormal free κ/λ light-chain ratio of 2.24. Over the next year, the patient's clinical condition had worsened with the development of liver cirrhosis and peripheral neuropathy, and his free κ/λ light-chain ratio had become even more abnormal. At the current presentation, a technetium-99m pyrophosphate nuclear scintigram revealed a free κ/λ light-chain ratio of 1.52. This, combined with the patient's age and slow progression of primarily cardiac disease, supported the diagnosis of ATTR, and we prescribed tafamadis. This case suggests that technetium-99m pyrophosphate scintigraphy is valuable in definitively diagnosing ATTR cardiomyopathy and selecting patients who may benefit from disease-modifying therapy.

Cardiobacterium hominis endocarditis incidentally diagnosed following an aortic valve replacement surgery.

Background: Cardiobacterum hominis (C. hominis) is the part of the HACEK group (Haemophilus spp, Actinobacillus spp, C. hominis, Eikenella, and Kingella spp) that accounts for the majority of the Gram-negative infective endocarditis cases. Historically, the fastidious characteristics of these microorganisms proved challenging to many clinicians. Advances in microbiological identification of culture-negative endocarditis; however, may be the reason for the rising incidence of these infections. Here, we report an incidentally diagnosed C. hominis endocarditis following an aortic valve replacement. Case report: A healthy 54-year-old gentleman presented after several months of generalized weakness and exertional intolerance. He was found to have a bicuspid aortic valve with regurgitation and underwent aortic valve replacement surgery. Intraoperatively, the patient was found to have a large perforation of the fused leaflet associated with abnormal pink tissue in the aortic valve area. The aortic valve tissue was cultured. Gram-negative rods were isolated 48 h later and were ultimately identified as C. hominis. He was successfully treated with 6 weeks of intravenous ceftriaxone with sterile blood cultures throughout the hospital stay. In retrospect, the patient's valve failure was likely secondary to subacute endocarditis from C. hominis complicated by leaflet perforation. Conclusion: C. hominis is a rare cause of infective endocarditis with an excellent prognosis when timely diagnosed and managed. By reporting this case, we wish to raise awareness of potential asymptomatic infection, particularly amongst patients with underlying native valve abnormalities, new leaflet perforation, and valve insufficiency.

"Heart in DRESS": Cardiac Manifestations, Treatment and Outcome of Patients with Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome: A Systematic Review.

Cardiac involvement in drug reaction with eosinophilia and systemic symptoms (DS) is rare but associated with high mortality. The aim of this research was to systematically review case reports by PRISMA guidelines in order to synthetize the knowledge of cardiac manifestations of DS. We identified 42 cases from 36 case reports. Women were two times more affected than men. Two-thirds of patients had cardiac manifestation in the initial phase of the disease, while in one-third of cases cardiac manifestations developed later (mean time of 70 ± 63 days). The most common inciting medications were minocycline (19%) and allopurinol (12%). In 17% of patients, the heart was the only internal organ affected, while the majority (83%) had at least one additional organ involved, most commonly the liver and the kidneys. Dyspnea (55%), cardiogenic shock (43%), chest pain (38%), and tachycardia (33%) were the most common cardiac signs and symptoms reported. Patients frequently had an abnormal ECG (71.4%), and a decrease in left ventricular ejection fraction was the most common echocardiographic finding (45%). Endomyocardial biopsy or histological examination at autopsy was performed in 52.4%, with the predominant finding being fulminant eosinophilic myocarditis with acute necrosis in 70% of those biopsied. All patients received immunosuppressive therapy with intravenous steroids, while non-responders were more likely to have received IVIG, cyclosporine, mycophenolate, and other steroid-sparing agents (60%). Gender and degree of left ventricular systolic dysfunction were not associated with outcomes, but short latency between drug exposure and the first DRESS symptom onset (<15 days) and older age (above 65 years) was associated with death. This underscores the potential importance of heightened awareness and early treatment.

IS A DECREASED NITRIC OXIDE CONCENTRATION AFTER TRIAMCINOLONE ACETONIDE INTRAVITREAL INJECTION ONE OF THE REASONS FOR INTRAOCULAR PRESSURE RISE?

Diabetic macular edema is the most common cause of vision loss in patients affected by diabetes mellitus. For eyes with persistent retinal thickening despite anti-VEGF therapy, treatment with intravitreal triamcinolone may be considered, especially in pseudophakic eyes. The aim of this study was to examine aqueous humor nitric oxide concentration changes in pseudophakic eyes with persistent diffuse diabetic macular edema after intravitreal injection of triamcinolone acetonide, as well as the potential impact of these changes on the intraocular pressure values. In 10 pseudophakic eyes with persistent diffuse diabetic macular edema, paracentesis of anterior chamber with aspiration of aqueous humor and nitric oxide concentration measurements were done on the day of the intravitreal application of 20 mg triamcinolone acetonide, and after 1, 3, 6 and 9 months. Also, we were recording intraocular pressure values before the intravitreal triamcinolone acetonide injection and during the next 9 months. One month after the intravitreal triamcinolone acetonide injection, we noticed a decrease of nitric oxide concentration (45.37±5.55 µmol/L) by 31.79% compared to the initial values (66.52±7.66 µmol/L). After that, nitric oxide concentrations began to rise slightly, and at the end of the ninth month the mean nitric oxide concentration was similar to that recorded at the beginning of the study. Intraocular pressure values had increasing trend one month after the intravitreal triamcinolone acetonide injection (23.70±4.08 mm Hg) compared to the initial values (16.21±1.55 mm Hg), but after nine months these values returned to normal levels. Decreased concentration of nitric oxide could be one of the reasons for increased intraocular pressure after intravitreal application of triamcinolone acetonide in the treatment of diffuse diabetic macular edema.

Feasibility and value of two-dimensional volumetric stress echocardiography.

BACKGROUND: Stroke volume response during stress is a major determinant of functional status in heart failure and can be measured by two-dimensional (2-D) volumetric stress echocardiography (SE). The present study hypothesis is that SE may identify mechanisms underlying the change in stroke volume by measuring preload reserve through end-diastolic volume (EDV) and left ventricular contractile reserve (LVCR) with systolic blood pressure and end-systolic volume (ESV). METHODS: We enrolled 4735 patients (age 63.6±11.3 years, 2800 male) referred to SE for known or suspected coronary artery disease (CAD) and/or heart failure (HF) in 21 SE laboratories in 8 countries. In addition to regional wall motion abnormalities (RWMA), force was measured at rest and peak stress as the ratio of systolic blood pressure by cuff sphygmomanometer/ESV by 2D with Simpson's or linear method. Abnormal values of LVCR (peak/rest) based on force were ≤1.10 for dipyridamole (N.=1992 patients) and adenosine (N.=18); ≤2.0 for exercise (N.=2087) or dobutamine (N.=638). RESULTS: Force-based LVCR was obtained in all 4735 patients. Lack of stroke volume increase during stress was due to either abnormal LVCR and/or blunted preload reserve, and 57% of patients with abnormal LVCR nevertheless showed increase in stroke volume. CONCLUSIONS: Volumetric SE is highly feasible with all stresses, and more frequently impaired in presence of ischemic RWMA, absence of viability and reduced coronary flow velocity reserve. It identifies an altered stroke volume response due to reduced preload and/or contractile reserve.

Formulation of Novel Liqueurs from Juice Industry Waste: Consumer Acceptance, Phenolic Profile and Preliminary Monitoring of Antioxidant Activity and Colour Changes During Storage.

RESEARCH BACKGROUND: Apple juice is one of the most popular and liked beverages worldwide. Due to the increased health consciousness among consumers, beetroot and chokeberry juices have also rising consumption trends. Despite representing a considerable percentage of the processed fruit and rich source of bioactive compounds, fruit pomace, remaining after juice production, has still been underutilised. Here, the possibility of using apple, beetroot and chokeberry pomace in liqueur formulations is investigated. EXPERIMENTAL APPROACH: Apple and chokeberry liqueurs were produced from apple and chokeberry pomace extracts, respectively. Apple/chokeberry and apple/beetroot liqueurs were obtained by combining apple pomace with chokeberry and beetroot pomace extracts in ratios 50:50 and 70:30, respectively. The sensory quality and acceptability of freshly prepared liqueurs were evaluated by experts and consumers. Sugars and phenolics were identified and quantified by high-performance anion-exchange chromatography with pulsed-amperometric detection (HPAEC-PAD) and high-performance liquid chromatography-diode array detection-tandem mass spectrometry (HPLC-DAD-MS/MS), respectively. Storability was preliminarily evaluated based on monitoring of total phenolic concentration, antioxidant activity and colour each month during 6 months of storage at 4 and 22 °C. RESULTS AND CONCLUSIONS: The expert and the consumer testing indicated that apple and chokeberry pomace could be used as raw materials without any flavour corrections while apple/beetroot pomace liqueur would require modification. High total phenolic content and antioxidant activity were found in all freshly prepared liqueurs, with chokeberry liqueur being by far superior. Among identified phenolics, ellagic acid and phlorizin were quantified as the most prominent, except in chokeberry liqueur, where phlorizin was not quantified. Despite the decrease in total phenolic concentration and antioxidant activity after 6 months, liqueurs still represented a rich source of phytochemicals. The highest phenolic compound retention and antioxidant activity maintenance were observed in chokeberry liqueur. Also, the appealing colour was retained despite the changes detected in chromatic characteristics. NOVELTY AND SCIENTIFIC CONTRIBUTION: The possibility of apple, beetroot and chokeberry pomace restoration into the food chain by the production of liqueurs has been demonstrated for the first time. Functional and sensorial properties of newly developed liqueurs indicated that the selected pomace represents the promising raw material for liqueur production. The applied approach represents a contribution to the circular economy in juice production.

Acute Heart Failure Due to Aluminum Phosphide Poisoning.

Aluminum phosphide (ALP) is a pesticide agent and infrequent culprit of accidental poisoning. We present a case of severe reversible cardiomyopathy and left ventricular apical thrombus in a patient who worked as an exterminator and had ALP poisoning.

Functional Assessment of Myocardial Bridging With Conventional and Diastolic Fractional Flow Reserve: Vasodilator Versus Inotropic Provocation.

Background Functional assessment of myocardial bridging (MB) remains clinically challenging because of the dynamic nature of the extravascular coronary compression with a certain degree of intraluminal coronary reduction. The aim of our study was to assess performance and diagnostic value of diastolic-fractional flow reserve (d-FFR) during dobutamine provocation versus conventional-FFR during adenosine provocation with exercise-induced myocardial ischemia as reference. Methods and Results This prospective study includes 60 symptomatic patients (45 men, mean age 57±9 years) with MB on the left anterior descending artery and systolic compression ≥50% diameter stenosis. Patients were evaluated by exercise stress-echocardiography test, and both conventional-FFR and d-FFR in the distal segment of left anterior descending artery during intravenous infusion of adenosine (140 µg/kg per minute) and dobutamine (10-50 µg/kg per minute), separately. Exercise-stress-echocardiography test was positive for myocardial ischemia in 19/60 patients (32%). Conventional-FFR during adenosine and peak dobutamine had similar values (0.84±0.04 versus 0.84±0.06, P=0.852), but d-FFR during peak dobutamine was significantly lower than d-FFR during adenosine (0.76±0.08 versus 0.79±0.08, P=0.018). Diastolic-FFR during peak dobutamine was significantly lower in the exercise-stress-echocardiography test -positive group compared with the exercise- stress-echocardiography test -negative group (0.70±0.07 versus 0.79±0.06, P<0.001), but not during adenosine (0.79±0.07 versus 0.78±0.09, P=0.613). Among physiological indices, d-FFR during peak dobutamine was the only independent predictor of functionally significant MB (odds ratio, 0.870; 95% CI, 0.767-0.986, P=0.03). Receiver-operating characteristics curve analysis identifies the optimal d-FFR during peak dobutamine cut-off ≤0.76 (area under curve, 0.927; 95% CI, 0.833-1.000; P<0.001) with a sensitivity, specificity, and positive and negative predictive value of 95%, 95%, 90%, and 98%, respectively, for identifying MB associated with stress-induced ischemia. Conclusions Diastolic-FFR, but not conventional-FFR, during inotropic stimulation with high-dose dobutamine, in comparison to vasodilatation with adenosine, provides more reliable functional significance of MB in relation to stress-induced myocardial ischemia.

Evaluation of novel green walnut liqueur as a source of antioxidants: Multi-method approach.

In this study, a novel green walnut liqueur (GWL) based on green walnuts, as the main ingredient, with the addition of fruits, aromatic plants, chocolate and honey, was produced at the pilot-scale. Antioxidant activity (AO) of the obtained GWL was determined using multiple AO assays in parallel, standard spectrophotometric (FC, DPPH and FRAP) and recently developed electrochemical ones, HydroxoPerhydroxoMercury(II) Complex and Mercury Reduction Antioxidant Power, and compared to similar commercial alcoholic beverages. Characterization of the GWL in terms of volatile and polyphenolic components was performed using SPE-GC-MS and HPLC-DAD-MS/MS, respectively. Sensory quality assessment was performed by experts in the field of sensory analysis of alcoholic beverages, using a scoring method. According to all AO assays applied, AO activity and total phenolics content of GWL were superior in comparison to commercial spirits considered. The volatile fraction of GWL was mainly composed of eugenol, α-terpineol and vanillin, while the most prevalent phenolic compounds were gallic (5.054 mg/L) and chlorogenic acid (1.307 mg/L) and flavonoids such as catechine (0.882 mg/L), quercetin (0.499 mg/L) and its sugar-conjugated derivatives, quercetin 3-O-glucoside (0.774 mg/L) and quercetin-3-O-rhamnoside (0.614 mg/L). Gallic acid is the major contributor to total AO activity, especially determined by DPPH and FRAP, followed by catechine, quercetin and chlorogenic acid. Among the terpenoids, contribution of eugenol to total AO activity is estimated as the highest. Excellent sensory quality (18.52 of maximum 20 scores) was ascribed to GWL. Consequently, the presence of bioactive compounds and high AO activity of GWL, in addition to high sensory quality score, indicates a high market potential for this high-value product.

The Effects of Newly Synthesized Platinum(IV) Complexes on Cytotoxicity and Radiosensitization of Human Tumour Cells In Vitro.

AIM: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines. MATERIALS AND METHODS: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays. RESULTS: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis. CONCLUSION: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.

Bioactivity and Sensory Properties of Probiotic Yogurt Fortified with Apple Pomace Flour.

To meet the demand for new functional foods in line with the trend of sustainable development, a novel probiotic yogurt fortified with 1%, 3%, and 5% apple pomace flour (APF) added immediately after inoculation with Lactobacillus acidophilus, Streptococcus thermophilus, and Bifidobacterium bifidum was developed. Upon fermentation in the presence of APF, a number of probiotic strains remained within the required range, while the syneresis of enriched yogurts was reduced up to 1.8 times in comparison to the control. Supernatants (i.e., extracted whey) obtained from yogurts with 1%, 3%, and 5% APF respectively had 1.4-, 1.8-, and 2.3-fold higher total phenolic content (TPC) than the control, 3.3-, 4.7-, and 8.0-fold higher radical scavenging (DPPH), and 1.3-, 1.6-, and 1.7-fold higher reducing activity (FRAP). Also, probiotic yogurt supernatants (3% and 5%) inhibited colon cancer cells' viability (HCT 116, 12% and 17%; SW-620, 13% and 19%, respectively). The highest firmness, cohesiveness, and viscosity index values, and the highest scores for color and taste, were obtained for yogurt with 3% APF, indicating that this is the optimal APF amount for the production of novel yogurt with functional properties.

Clinicopathological manifestations of myocarditis in a heart failure population.

Myocarditis continues to present challenges in diagnosis and management. The goal of this study is to determine the occurrence and manifestations of myocarditis in a heart failure (HF) population. The analyzed patients had acute or persistent HF and were referred over a 6-year period to a quaternary HF center for advanced HF therapies including mechanical circulatory support, left ventricular assist device (LVAD) implantation, and/or heart transplantation. The histopathological diagnosis of myocarditis was made based on the presence of an inflammatory infiltrate of the myocardium, typically with associated cardiomyocyte (CMC) damage, combined as indicated with immunohistochemical and molecular biology characterization. The pathological findings were correlated with a panel of clinical parameters and clinical course of the patients. Myocarditis was identified in 36 patients, with initial diagnoses made in 10 (40%) of 25 by endomyocardial biopsy (EMB), 1 by atrial biopsy (maze procedure), 7 (2.1%) of 331 at LVAD implantation, and 18 (7.8%) of 229 in the explanted heart. There were 20 cases of lymphocytic myocarditis, 4 cases of giant cell myocarditis, 3 cases of eosinophilic myocarditis, and 9 cases of lymphohistocytic with granulomas myocarditis - cardiac sarcoidosis. EMB was performed in 25 patients and was positive in 10 (40%) of cases. Myocarditis was found in 23 explanted hearts including 18 cases de novo and 5 cases with a previously positive specimen. Of the 23 explanted hearts, 21 were nonischemic cardiomyopathy and 2 were ischemic cardiomyopathy. Our findings show that, in patients presenting to a quaternary medical center, myocarditis can be manifest as acute HF as well as a complicating factor in chronic HF.

New herbal bitter liqueur with high antioxidant activity and lower sugar content: innovative approach to liqueurs formulations.

Herbal liqueurs are spirits with numerous functional properties, due to the presence of bioactive extractable compounds deriving from herbs. The aim of this study was to obtain new herbal bitter liqueur (HBL) on the basis of twelve selected bitter and aromatic plants extracts, with an optimal sensory profile for consumer acceptance. Also, the determination of optimal sugar content in HBL was done. Furthermore, antioxidant (AO) capacity and total phenolic content (TPC) of HBL was evaluated and compared to similar commercial herbal spirits. Among five tested formulations, assessed by 9-point hedonic scale, HBL with the ratio of bitter and aromatic plants 1:4 was the most acceptable. Ideal concentration of sugar in HBL, determined using a just-about-right scale, was found to be 80.32 g/l of sucrose, which is approximately 20% less than the minimum stipulated by European Union Regulation and several times lower than in the majority of commercial liqueurs. Obtained result indicates the possibility of sugar reduction in liqueurs, and suggests the need to carry out sensory analysis before production of these high-calorie beverages. Radical scavenging ability against DPPH and ABTS radicals, as well as ferric reducing antioxidant power and TPC of HBL were convincingly superior in comparison to similar commercial herbal alcoholic beverages. High correlation coefficients between TPC and other assays applied strongly support the significant role of the polyphenols in the total AO capacity of the HBL and other tested commercial herbal spirits. Headspace GC/MS revealed that the most abundant terpenes were menthone (3.75%), eucalyptol (3.42%) and menthol (3.10%), whereas methanol was present in a small amount (4.97 mg/l).

Prognostic Value of Preserved Coronary Flow Velocity Reserve by Noninvasive Transthoracic Doppler Echocardiography in Patients With Angiographically Intermediate Left Main Stenosis.

BACKGROUND: The potential of angiography to evaluate the hemodynamic severity of a left main coronary artery (LM) stenosis is limited. Noninvasive transthoracic Doppler echocardiographic coronary flow velocity reserve (CFVR) evaluation of intermediate coronary stenosis has demonstrated remarkably high negative prognostic value. The aim of this study was to assess clinical outcomes in patients with angiographically intermediate LM stenosis and preserved CFVR (>2.0) as evaluated by transthoracic Doppler echocardiographic CFVR. METHODS: The initial study population included 102 patients with intermediate coronary stenosis of the LM referred for transthoracic Doppler echocardiographic CFVR assessment. Peak diastolic CFVR measurements were performed in the distal segment of the left anterior descending coronary artery after intravenous adenosine (140 µg/kg/min), and CFVR was calculated as the ratio between maximal hyperemic and baseline coronary flow velocity. Nineteen patients had impaired CFVR (≤2.0) and were excluded from further analysis, as well as two patients with poor acoustic windows. The final group consisted of 81 patients (mean age, 60 ± 9 years; 76 men) evaluated for adverse cardiac events including death, myocardial infarction, and revascularization. RESULTS: Mean follow-up duration was 62 ± 26 months. Mean CFVR was 2.4 ± 0.4. Total event-free survival was 75 of 81 (92.6%), as six patients were referred for revascularization (five patients with coronary artery bypass grafting, one patient with percutaneous coronary intervention). There were no documented myocardial infarctions or cardiovascular deaths in the follow-up period. CONCLUSIONS: In patients with angiographically intermediate and equivocal LM stenosis and preserved CFVR values of >2.0, revascularization can be safely deferred.

Cardiac sarcoidosis presenting as arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular aneurysms: a case report.

A 70-year old Caucasian man with recurrent ventricular tachycardia and progressive biventricular failure attributed to arrhythmogenic right ventricular cardiomyopathy/dysplasia was evaluated for heart transplantation. Cardiac ventriculography revealed an abnormal left ventricle with five saccular aneurysms. Heart transplantation was performed. Pathology of the explanted heart showed multifocal sarcoid granulomas. Replacement fibrosis was widespread in both ventricles and associated with saccular aneurysms. No genetic basis was identified. Thus, the evidence suggested progressive cardiac sarcoidosis caused this patient's unusual condition.