Modulating cardiac conduction during metabolic ischemia with perfusate sodium and calcium in guinea pig hearts.

We previously demonstrated that altering extracellular sodium (Nao) and calcium (Cao) can modulate a form of electrical communication between cardiomyocytes termed "ephaptic coupling" (EpC), especially during loss of gap junction coupling. We hypothesized that altering Nao and Cao modulates conduction velocity (CV) and arrhythmic burden during ischemia. Electrophysiology was quantified by optically mapping Langendorff-perfused guinea pig ventricles with modified Nao (147 or 155 mM) and Cao (1.25 or 2.0 mM) during 30 min of simulated metabolic ischemia (pH 6.5, anoxia, aglycemia). Gap junction-adjacent perinexal width ( WP), a candidate cardiac ephapse, and connexin (Cx)43 protein expression and Cx43 phosphorylation at S368 were quantified by transmission electron microscopy and Western immunoblot analysis, respectively. Metabolic ischemia slowed CV in hearts perfused with 147 mM Nao and 2.0 mM Cao; however, theoretically increasing EpC with 155 mM Nao was arrhythmogenic, and CV could not be measured. Reducing Cao to 1.25 mM expanded WP, as expected during ischemia, consistent with reduced EpC, but attenuated CV slowing while delaying arrhythmia onset. These results were further supported by osmotically reducing WP with albumin, which exacerbated CV slowing and increased early arrhythmias during ischemia, whereas mannitol expanded WP, permitted conduction, and delayed the onset of arrhythmias. Cx43 expression patterns during the various interventions insufficiently correlated with observed CV changes and arrhythmic burden. In conclusion, decreasing perfusate calcium during metabolic ischemia enhances perinexal expansion, attenuates conduction slowing, and delays arrhythmias. Thus, perinexal expansion may be cardioprotective during metabolic ischemia. NEW & NOTEWORTHY This study demonstrates, for the first time, that modulating perfusate ion composition can alter cardiac electrophysiology during simulated metabolic ischemia.

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells.

B cell lymphoma-6 (Bcl-6) is a transcriptional repressor that is required for the differentiation of T follicular helper (TFH) cell populations. Currently, the molecular mechanisms underlying the transcriptional regulation of Bcl-6 expression are unclear. In this study, we have identified the Ikaros zinc finger transcription factors Aiolos and Ikaros as novel regulators of Bcl-6. We found that increased expression of Bcl-6 in CD4+ Th cell populations correlated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Furthermore, overexpression of Aiolos or Ikaros, but not the related family member Eos, was sufficient to induce Bcl6 promoter activity. Intriguingly, STAT3, a known Bcl-6 transcriptional regulator, physically interacted with Aiolos to form a transcription factor complex capable of inducing the expression of Bcl6 and the TFH-associated cytokine receptor Il6ra Importantly, in vivo studies revealed that the expression of Aiolos was elevated in Ag-specific TFH cells compared with that observed in non-TFH effector Th cells generated in response to influenza infection. Collectively, these data describe a novel regulatory mechanism through which STAT3 and the Ikaros zinc finger transcription factors Aiolos and Ikaros cooperate to regulate Bcl-6 expression.

IL-7 signalling represses Bcl-6 and the TFH gene program.

The transcriptional repressor Bcl-6 is linked to the development of both CD4(+) T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6Rα and IL-7R. Exposure of this potentially bi-potent cell population to IL-6 favours the TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL-6Rα(+)IL-7R(+) CD4(+) T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity.

Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model.

SCOPE: The long-term effect of exposure to relevant dietary levels of genistein (GEN) on estrogen receptor-positive (ER+) human breast cancer (MCF-7) progression after GEN withdrawal in athymic mice xenograft model was studied. MATERIALS AND METHODS: Feeding studies were conducted to determine the estrogenic effect of diets on MCF-7 tumor growth: (1) implantation (19 weeks) and withdrawal (6 weeks) of 17ß-estradiol (E2 ); (2) dietary GEN 500 and 750 ppm during treatment/withdrawal for 23/10 and 15/9 weeks, respectively; and, (3) dietary soy protein isolate (SPI) containing GEN 180 ppm for 31/9 weeks of treatment/withdrawal. MCF-7 tumors grew fast in the presence of E2 implantation and abruptly regressed completely after E2 withdrawal. At different rates, dietary GEN alone (500 and 750 ppm) and GEN (180 ppm)-containing SPI stimulated MCF-7 tumor growth. After removal of the stimulus diet, tumors induced by 750 ppm GEN, but not 500 ppm GEN or SPI, regressed completely. The protein expression of epidermal growth factor receptor 2 (HER2) was higher in the GEN- and SPI-induced nonregressing (GINR) tumors compared to MCF-7 and E2 controls. CONCLUSION: Long-term consumption of low GEN doses (≤500 ppm) promotes MCF-7 tumor growth and results in GINR tumors with more aggressive and advanced growth phenotypes.

Effects of non-digestible carbohydrates on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice.

Non-digestible carbohydrates (NDC(4)) have been used as a low-calorie sweetener and prebiotics that stimulate the growth of certain intestinal bacteria that support healthy colon conditions. In this study, we examined the dietary effect of commercially available NDCs on estrogen receptor positive (ER+) human breast cancer. We conducted a feeding study of fructooligosaccharides (FOSs), Fibersol 2 (F2; digestion resistant maltodextrin), Hi-Maize (HM; high amylose cornstarch), and Frutafit (FF; a range of powdered inulins) (5% in diet, w/w) to evaluate their effects on the growth of ER(+) human breast cancer (MCF-7) tumors in the presence of 17ß-estradiol (E(2)) using an athymic xenograft model. F2, HM, and FOSs supplementation significantly reduced E(2)-stimulated MCF-7 tumor growth by inhibiting cellular proliferation (Ki-67) and increasing apoptosis (M30) in tumors. F2, HM, and FOSs treatments also lowered serum E(2) level and reduced uterine weight compared to the control diet. NDCs treatments downregulated relative mRNA expression of the E(2)-responsive gene markers pS2, bcl2, bcl-xL, and cyclin D1 in MCF-7 tumors. In conclusion, the NDC intake may have a protective effect against ER(+) tumors by inhibiting cellular proliferation and increasing apoptosis.

Estimated costs for uterine artery embolization and abdominal myomectomy for uterine leiomyomata: a comparative study at a single institution.

PURPOSE: To determine and compare the costs associated with uterine artery embolization (UAE) and abdominal myomectomy for the treatment of symptomatic leiomyomata. MATERIALS AND METHODS: Charge information was gathered and analyzed from 23 patients who underwent UAE and 17 who underwent abdominal myomectomy in a single institution. The mean charges for each procedure were calculated from the patients' billing data. Cost-to-charge ratios were applied to the mean charges to estimate costs. The work relative value units (RVUs) for all physician services for each procedure were calculated. These total work RVUs for each intervention were multiplied by the appropriate Medicare conversion factors to estimate a uniform physician fee. These costs were totaled and compared with use of the unpaired t test to estimate the cost difference between UAE and abdominal myomectomy. RESULTS: The estimated hospital cost for UAE was $3,193, which was significantly lower than the $5,598 estimated for abdominal myomectomy (P <.0001). The discrepancy was caused primarily by increased hospital care and operating room costs for abdominal myomectomy. The total professional costs were significantly higher for UAE ($2,220) than for abdominal myomectomy ($1,611) (P =.002). When all associated costs, including typical imaging costs, were considered, there was a trend toward lower costs for UAE ($6,708) compared to abdominal myomectomy ($7,630) (P =.086). CONCLUSION: UAE had lower procedure-related costs than abdominal myomectomy despite higher physician costs. When typical imaging costs were included, there was still a trend toward lower costs for UAE.

Complications after uterine artery embolization for leiomyomas.

OBJECTIVE: To determine the frequency and severity of complications that occur as a result of uterine artery embolization for leiomyomas. METHODS: As part of an ongoing study of outcome after uterine embolization, prospective data regarding complications that occurred in 400 consecutive patients were gathered. Each patient had a minimum of a 3-month interval from the procedure at the time of analysis. Each complication was categorized and graded as to severity and outcome using the complication classification developed by the Society of Cardiovascular and Interventional Radiology (SCVIR) and a modified set of The American College of Obstetricians and Gynecologists (ACOG) criteria for complications of hysterectomy and myomectomy. All adverse events that occurred during the follow-up period were included, including those that occurred after the 3-month minimum interval. Confidence intervals (CIs) were calculated for each complication. RESULTS: There were no deaths and no major permanent injuries. One patient required hysterectomy as a result of a complication, and one patient had an undiagnosed leiomyosarcoma. There were ten in-hospital complications and an additional 27 complications within the first 30 days, with 34 patients experiencing a periprocedural complication for a rate of 8.5% (95% CI 6.0%, 11.7%). There were five serious complications (SCVIR class D), comprising 1.25% (95% CI 0.3%, 2.5%) of the study group. Using ACOG definitions for perioperative complications, the overall morbidity was 5% (95% CI 3.1%, 7.7%). CONCLUSION: The short-term complication rate was low in women undergoing uterine embolization.