Allogeneic Cell Combination Therapy Ameliorates Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF. METHODS AND RESULTS: Yorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness. CONCLUSIONS: Intra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.

Heat-Up Colloidal Synthesis of Shape-Controlled Cu-Se-S Nanostructures-Role of Precursor and Surfactant Reactivity and Performance in N2 Electroreduction.

Copper selenide-sulfide nanostructures were synthesized using metal-organic chemical routes in the presence of Cu- and Se-precursors as well as S-containing compounds. Our goal was first to examine if the initial Cu/Se 1:1 molar proportion in the starting reagents would always lead to equiatomic composition in the final product, depending on other synthesis parameters which affect the reagents reactivity. Such reaction conditions were the types of precursors, surfactants and other reagents, as well as the synthesis temperature. The use of 'hot-injection' processes was avoided, focusing on 'non-injection' ones; that is, only heat-up protocols were employed, which have the advantage of simple operation and scalability. All reagents were mixed at room temperature followed by further heating to a selected high temperature. It was found that for samples with particles of bigger size and anisotropic shape the CuSe composition was favored, whereas particles with smaller size and spherical shape possessed a Cu2-xSe phase, especially when no sulfur was present. Apart from elemental Se, Al2Se3 was used as an efficient selenium source for the first time for the acquisition of copper selenide nanostructures. The use of dodecanethiol in the presence of trioctylphosphine and elemental Se promoted the incorporation of sulfur in the materials crystal lattice, leading to Cu-Se-S compositions. A variety of techniques were used to characterize the formed nanomaterials such as XRD, TEM, HRTEM, STEM-EDX, AFM and UV-Vis-NIR. Promising results, especially for thin anisotropic nanoplates for use as electrocatalysts in nitrogen reduction reaction (NRR), were obtained.

A case report of a ruptured Meckel's diverticulum with ectopic gastric and pancreatic tissue with negative computed tomography.

INTRODUCTION: A Meckel's diverticulum is a rare but known cause of an acute abdomen and can often be confused for acute appendicitis on physical examination. It is caused by an incomplete closure of the omphalomesenteric duct. It is present in 2% of the population and only 2% of those patients are symptomatic. CASE PRESENTATION: This is the case of a sixty-four-year-old male presented to the surgical clinic at request of his primary care physician with concern for acute appendicitis. The patient had a CT A/P with IV contrast performed two days prior to his office visit for the same pain which was non-diagnostic. The patient was taken to the operating room and found to have Meckel's Diverticulitis which was managed by laparoscopic hand-assisted small bowel resection and anastomosis. The patient had an uncomplicated postoperative course. Pathology demonstrated ulcerated gastric mucosa and pancreatic tissue. DISCUSSION: Symptomatic Meckel's diverticulum is managed with small bowel resection versus diverticulectomy based on characteristics of the diverticulum. The most common type of ectopic tissue is gastric followed by pancreatic. It is rare to find both types of tissue together. CONCLUSION: This case describes an unusual case of a rare acute surgical pathology with non-diagnostic imaging and labs. This case also describes an exceedingly rare histopathology of a Meckel's Diverticulum with the presence of both ectopic gastric and pancreatic tissues.

Facing Seawater Splitting Challenges by Regeneration with Ni-Mo-Fe Bifunctional Electrocatalyst for Hydrogen and Oxygen Evolution.

Hydrogen, produced by water splitting, has been proposed as one of the main green energy vectors of the future if produced from renewable energy sources. However, to substitute fossil fuels, large amounts of pure water are necessary, scarce in many world regions. In this work, we fabricate efficient and earth-abundant electrodes, study the challenges of using real seawater, and propose an electrode regeneration method to face undesired salt deposition. Ni-Mo-Fe trimetallic electrocatalyst is deposited on non-expensive graphitic carbon felts both for hydrogen (HER) and oxygen evolution reactions (OER) in seawater and alkaline seawater. Cl- pitting and the chlorine oxidation reaction are suppressed on these substrates and alkalinized electrolyte. Precipitations on the electrodes, mainly CaCO3 , originating from seawater-dissolved components have been studied, and a simple regeneration technique is proposed to rapidly dissolve undesired deposited CaCO3 in acidified seawater. Under alkaline conditions, Ni-Mo-Fe-based catalyst is found to reconfigure, under cathodic bias, into Ni-Mo-Fe alloy with a cubic crystalline structure and Ni : Fe(OH)2 redeposits whereas, under anodic bias, it is transformed into a follicular Ni:FeOOH structure. High productivities over 300 mA cm-2 and voltages down to 1.59 V@10 mA cm-2 for the overall water splitting reaction have been shown, and electrodes are found stable for over 24 h without decay in alkaline seawater conditions and with energy efficiency higher than 61.5 % which makes seawater splitting promising and economically feasible.

Metastatic lobular carcinoma of the breast found incidentally on pathology following cholecystectomy for chronic cholecystitis: A case report.

BACKGROUND: Traditional oncologic pattern of spread of breast cancer is metastasis to axillary lymph nodes, lung, liver and bone (Doval et al., 2006 [1]). Here we present a case of unknown synchronous breast cancer in a patient that was revealed on histopathologic assessment following elective cholecystectomy. CASE SUMMARY: A 57 year old female presented for an elective laparoscopic cholecystectomy secondary to biliary colic. Histopathologic assessment of the gallbladder revealed metastatic adenocarcinoma with signet ring features, consistent with metastatic lobular carcinoma. The patient went on to have a complete oncologic workup that revealed invasive ductal carcinoma with components of high grade ductal carcinoma in situ in the left breast, lobular carcinoma in the right breast, and metastatic lobular carcinoma to left and right axillary lymph nodes as well as diffuse osseous metastatic disease. CONCLUSIONS: Metastatic disease to the gallbladder found incidentally on elective cholecystectomy is a rare presentation of synchronous breast cancer.

Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction.

Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

BACKGROUND: The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). OBJECTIVES: This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. METHODS: Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. RESULTS: Both ACCT and allo-MSCs reduced scar size by -11.1 ± 4.8% (p = 0.012) and -9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. CONCLUSIONS: ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy.

BACKGROUND: Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit(+) cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. OBJECTIVES: To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. METHODS: Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. RESULTS: Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. CONCLUSIONS: These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy.

BACKGROUND: Growth hormone-releasing hormone agonists (GHRH-As) stimulate cardiac repair following myocardial infarction (MI) in rats through the activation of the GHRH signaling pathway within the heart. We tested the hypothesis that the administration of GHRH-As prevents ventricular remodeling in a swine subacute MI model. METHODS AND RESULTS: Twelve female Yorkshire swine (25 to 30 kg) underwent transient occlusion of the left anterior descending coronary artery (MI). Two weeks post MI, swine were randomized to receive injections of either 30 µg/kg GHRH-A (MR-409) (GHRH-A group; n=6) or vehicle (placebo group; n=6). Cardiac magnetic resonance imaging and pressure-volume loops were obtained at multiple time points. Infarct, border, and remote (noninfarcted) zones were assessed for GHRH receptor by immunohistochemistry. Four weeks of GHRH-A treatment resulted in reduced scar mass (GHRH-A: -21.9 ± 6.42%; P=0.02; placebo: 10.9 ± 5.88%; P=0.25; 2-way ANOVA; P=0.003), and scar size (percentage of left ventricular mass) (GHRH-A: -38.38 ± 4.63; P=0.0002; placebo: -14.56 ± 6.92; P=0.16; 2-way ANOVA; P=0.02). This was accompanied by improved diastolic strain. Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure-volume analysis. GHRH receptors were abundant in cardiac tissue, with a greater density in the border zone of the GHRH-A group compared with the placebo group. CONCLUSIONS: Daily subcutaneous administration of GHRH-A is feasible and safe in a large animal model of subacute ischemic cardiomyopathy. Furthermore, GHRH-A therapy significantly reduced infarct size and improved diastolic strain, suggesting a local activation of the GHRH pathway leading to the reparative process.