The Emerging Role of Sirtuin 1 in Cellular Metabolism, Diabetes Mellitus, Diabetic Kidney Disease and Hypertension.

Despite diagnostic and therapeutic approaches, diabetic kidney disease (DKD) is the most common cause of end-stage renal disease worldwide. Sirtuins, a group of nicotinamid adenine dinucleotide (NAD) dependent enzymes, can deacetylase target enzymes that regulate a wide variety of cellular processes regarding protein, carbohydrate and lipid metabolism, mitochondrial homeostasis and programmed cell death mechanisms including autophagy and apoptosis. Among sirtuins, sirtuin 1 (SIRT1) has been the most studied one in the pathogenesis and progression of DKD. In recent years, the relation between SIRT1 and hypertension was also evaluated.In the present review, we aimed to represent the mechanisms of SIRT1 in glucose and lipid metabolism and in the pathogenesis of diabetes mellitus. We also sought to highlight the emerging role of SIRT1 in the pathogenesis and treatment of DKD and hypertension.

Using the LigaSure vessel sealing device in the large uterus at laparoscopic hysterectomy.

OBJECTIVE: To compare intraoperative hemorrhage and other operative parameters between patients with large and small weighted uterus who underwent laparoscopic hysterectomy (LH). MATERIALS AND METHODS: Forty-six patients intending to have LH were divided into two groups according to uterine weight (group 1 > 300 grams vs. group 2 < 299 grams). Intraoperative blood loss, operating time, periopera- tive complications, and duration of hospitalization were compared. RESULTS: Intraoperative blood loss was significantly higher in the large uterus group (group 1); 350 (227-454) ml vs. 250 (182-320) ml (p < 0.001). However, it was not significantly different between the groups in the laparoscopy step. Mean operating time was 90 (77-103) minutes and 80 (62-98) minutes in groups 1 and 2, respectively (p < 0.001) revealing ten-minute delay in group 1. Similarly, this was also not significantly different in the laparoscopy step. No significant differences were found between two groups; in terms of hemoglobin concentration decrease, major and minor complications, and hospitalization duration. CONCLUSION: The authors conclude that LigaSure can be safely used for LH in patients with a large uterus.

ENerGetIcs in hypertrophic cardiomyopathy: traNslation between MRI, PET and cardiac myofilament function (ENGINE study).

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM. METHODS: Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group. ENDPOINTS: Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.

Evaluation of biventricular myocardial performance index in patients with Behçet's disease.

OBJECTIVE: The global function of both left ventricular (LV) and right ventricular (RV) functions were compared in patients with Behçet's disease (BD) versus healthy controls. METHODS: Biventricular function was evaluated by measurement of the myocardial performance index (MPI) evaluated from tissue Doppler echocardiographic measurements in 24 BD patients and was compared with measurements in 24 age- and sex-matched healthy controls. RESULTS: Significantly higher MPI values were associated with ventricular dysfunction. The study demonstrated impaired RV function in patients with BD compared with healthy controls, whereas normal LV function was observed both in patients with BD and in healthy controls. CONCLUSION: Early noninvasive evaluation of the properties of BD during the asymptomatic phase of this inflammatory disease may have prognostic value in the management of patients.

Magnetism and correlations in fractionally filled degenerate shells of graphene quantum dots.

We show that the ground state and magnetization of the macroscopically degenerate shell of electronic states in triangular gated graphene quantum dots depends on the filling fraction of the shell. The effect of degeneracy, finite size, and electron-electron interactions are treated nonperturbatively using a combination of density functional theory, tight-binding, Hartree-Fock and configuration interaction methods. We show that electronic correlations play a crucial role in determining the nature of the ground state as a function of filling fraction of the degenerate shell at the Fermi level. We find that the half-filled charge neutral shell leads to full spin polarization but this magnetic moment can be completely destroyed by adding a single electron.

Absence of contralateral suppression of transiently evoked otoacoustic emissions in fibromyalgia syndrome.

OBJECTIVE: To assess contralateral suppression of transiently evoked otoacoustic emissions in patients with fibromyalgia syndrome and normal hearing. METHODS: Twenty-four female patients with fibromyalgia syndrome and 24 healthy female controls with normal hearing were assessed using pure tone audiometry and transiently evoked otoacoustic emissions. RESULTS: All patients with fibromyalgia syndrome and all controls had normal hearing on pure tone audiometry. In the patients with fibromyalgia syndrome, the mean transiently evoked otoacoustic emission amplitude was 15.5 +/- 4.8 dB. The mean transiently evoked otoacoustic emission amplitudes after contralateral suppression was 15.5 +/- 4.9 dB. There was no statistically significant difference between the transiently evoked otoacoustic emission amplitudes measured before and after contralateral suppression (p > 0.05). In the controls, the mean transiently evoked otoacoustic emission amplitude was 12 +/- 5 dB. The mean transiently evoked otoacoustic emission amplitudes after contralateral suppression was 11 +/- 4.7 dB. There was a statistically significant decrease in transiently evoked otoacoustic emission amplitudes after contralateral suppression (p < 0.01). CONCLUSION: The mechanisms related to contralateral suppression of transiently evoked otoacoustic emissions seem dysfunctional in fibromyalgia syndrome. This dysfunction may be at the brain stem level, where the medial superior olivary complex is located, or at the synapses of medial superior olivary complex fibres with the outer hair cells in the cochlea. Demonstration of lack of contralateral suppression of transiently evoked otoacoustic emissions can be used as a diagnostic tool in patients with fibromyalgia syndrome.

Atypical hemolytic uremic syndrome.

The pathogenesis of atypical uremic syndrome (HUS), which is rarely encountered in childhood, is poorly understood and its mortality and morbidity rates are high. A wide variety of therapeutic approaches has been attempted and the literature contains numerous conflicting reports about the results of these approaches. In a case diagnosed as recurrent atypical HUS, pulse methyl prednisolone, fresh frozen plasma infusions and plasma exchange transfusion were used at different stages of the disease with satisfactory response.

Inhibition of pulmonary metastases of B16 melanoma with irradiated tumor cells and BCG.

When the tumor-bearing leg of C57BL/6J mice was amputated 16 days after SC inoculation of 10(6)B16 melanoma cells, all the amputated mice died of pulmonary metastases. Transfer of lungs from the amputated to normal syngeneic mice revealed tumor cells in the lungs just after amputation. Repeated weekly injections of BCG and irradiated tumor cells, beginning 24 h after amputation of the tumor-bearing limb, prolonged the survival only of mice presensitized to BCG. Injections of BCG or irradiated melanoma cells alone, or neuraminidase- and mitomycin C-treated tumor cells or of Levamisole had no effect, but injections of ConA-coated tumor cells slightly prolonged the survival of the amputated mice. Both BCG and B16 cells induced humoral and cell-mediated immunity but there was no cross-reactivity between BCG and B16 cells.

Inhibition of a mouse hepatoma by the alkylating agent Trenimon linked to immunoglobulins.

Trenimon was conjugated in active alkylating form to rabbit anti-mouse H6 hepatoma globulin (AHG) with retention of antibody activity. H6 hepatoma-inoculated mice were given various combinations of conjugates, free Trenimon, and unconjugated immunoglobulins in daily injections for 5 days. Linkage of Trenimon to immunoglobulins reduced systemic toxicity of the drug, with comparative retention of its antitumor activity. The antitumor action of Trenimon was potentiated by AHG irrespective of whether the drug was directly linked to AHG or free AHG was administered along with Trenimon linked to normal rabbit globulin (NRG). In vitro, Trenimon bound to AHG was less inhibitory to hepatoma cells than free Trenimon, but more inhibitory than Trenimon-NRG conjugates. There was no significant endocytosis of conjugates by the hepatoma cells. This suggests that unlike free Trenimon, the target molecules of Trenimon-immunoglobulin conjugates are not intracellular DNA but are located on the surface of the hepatoma cells.

Immunochemotherapy of malignant melanoma with chlorambucil-bound antimelanoma globulins: preliminary results in patients with disseminated disease.

Thirteen consecutive patients with inoperable recurrent malignant melanoma were treated by immunochemotherapy with the use of chlorambucil noncovalently bound to goat or rabbit antihuman melanoma globulins. The next consecutive 11 patients fulfilling the criteria for admission into this study were treated with chemotherapy only, i.e., dimethyltriazenoimidazole carboxamide (DTIC). Follow-up was for a minimum of 29 months or until death. Two patients showing an objective response to immunochemotherapy had disease confined to lymph nodes and cutaneous sites; 5 others showed stabilization of cutaneous, nodal, and visceral disease, and 6 patients showed progression of their disease. The median survival of the responders and stabilizers was 20 months, but only 3.5 months for patients with disease progression. None of the 11 patients treated with DTIC had objective tumor regression, and all died within 11 months of the start of treatment with a median survival of 3 months. Immunochemotherapy significantly prolonged the survival compared to that in the DTIC-treated group (P less than 0.05). No hematologic or renal toxicity was detected after immunochemotherapy, but 2 patients in this group developed anaphylactic reactions. Skin reactivity tests to dinitrochlorobenzene and purified protein derivative were of no prognostic value

In vivo suppression of EL 4 lymphomas by rabbit antitumor sera.

Three of more than 50 batches of rabbit antisera raised against the mouse EL 4 lymphoma could inhibit the growth of the tumor in the syngeneic C57BL/6J mice either after exposure of the tumor cells to the antitumor globulin (ATG) in vitro or after the administration of ATG in mice preinoculated with various numbers of EL 4 cells, even though the ATG was not cytotoxic to the tumor cells in the presence of complement. The outcome of immunotherapy with ATG in tumor-bearing C57BL/6J mice depended on the tumor load, the interval between tumor inoculation and the institution of therapy, the total dose, and the schedule of administration of ATG. Complete tumor suppression could be obtained in a proportion of mice preinoculated with 10(5) EL 4 cells, i.e., 10(4) times more than the minimum number of EL 4 cells necessary for 100% tumor takes. Whole-body irradiation (400 rads) or complement depletion of tumor host by cobra venom factor had no effect on tumor suppression by ATG. No evidence of immunity against the EL 4 lymphoma could be detected in EL 4-bearing mice that survived after serotherapy. Anti-EL 4 sera raised in goats and goat and rabbit antisera raised against a lymphoma in the AKR mice have, so far, failed to show any tumor inhibition.

Active immunoprophylaxis and immunotherapy in two mouse lymphoma models.

Injections of appropriate numbers of irradiated tumor cells produced antibodies against tumor cell-surface antigen(s) in both syngeneic tumor models studied: the early transplant generations of the spontaneous L2 lymphoma in AKR/J mice and the chemically induced EL 4 lymphoma in C57BL/6J mice. No antibody was detected in normal or nonimmunized tumor-bearing mice. Tumor inhibitory or enhancing activity was not demonstrated by these antibodies. Immunoprophylaxis or cell-mediated immunity against the L2 lymphoma was not observed after injections of irradiated L2 cells and/or BCG into AKR mice. However, injections of irradiated EL 4 cells alone were effective in immunoprophylaxis against as many as 10(6) EL 4 cells and in immunotherapy against 10(2) EL 4 cells per mouse. The addition of BCG injections made immunotherapy with irradiated EL 4 cells effective against a load of 10(4) EL 4 cells/mouse, though BCG alone was not effective for immunoprophylaxis against EL 4 cells. Resistance to EL 4 could be transferred with viable syngeneic peritoneal or nucleated spleen cells. In both tumor models, an ongoing delayed hypersensitivity reaction to BCG alone apparently did not inhibit bystander tumor cells even when tumor cells were mixed before inoculation with viable BCG. In neither tumor model were concanavalin A-coated tumor cells more potent for immunoprophylaxis than were irradiated tumor cells alone.

Suppression of an AKR lymphoma by antibody and chlorambucil.

A cell-surface localizing xenogeneic antibody against an AKR mouse lymphoma of spontaneous origin could be bound to chlorambucil without interference with either the alkylating activity of chlorambucil or the immunologic reactivity of the antibody. Exposure of the lymphoma cells to chlorambucil-bound antibody caused greater tumor inhibition both in vitro and vivo than did the synergistic effect of exposure seperately to the antibody and chlorambucil.

Antibody as carrier of 131I in cancer diagnosis and treatment.

Cell-surface localizing heterologous antibodies against mouse EL4 lymphoma, Ehrlich ascites carcinoma, and several human malignant tumors could be bound to varying amounts of 131I without interfering with the reactivity of these antibodies with their respective tumor cells. Exposure of the mouse tumor cells to radio-iodinated antitumor antibodies in vitro, or the injection of radio-iodinated antitumor antibodies into mice preinoculated with tumor cells resulted in either partial or complete tumor inhibition depending upon the amount of 131I activity carried by the antibodies. Injection of comparable amounts of the immunoglobulin alone or of 131I bound to normal globulin did not cause any tumor inhibition. Intraperitoneally injected radio-iodinated anti-EL4 antibody was found to localize preferentially in the subcutaneous transplants of EL4 lymphoma. Similar localization of intravenously injected radio-iodinated antibodies was observed in the metastases of two cancer patients.