Angiotensin II inhibits growth of cultured embryonic renomedullary interstitial cells through the AT2 receptor

Angiotensin II inhibits growth of cultured embryonic renomedullary interstitial cells through the AT2 receptor. The high abundance of angiotensin II (Ang II) AT2, relative to the AT1 receptor subtype in developing kidneys may be related to their potential as mediators of cell growth, although little evidence exists to support this concept. Renomedullary interstitial cells (RMICs) differentiate early in embryonic kidneys and are important in subsequent nephron development. These cells have been shown in vivo to possess AT2 binding sites, although the functional significance of these sites remains unknown. The aim of the current investigation was to examine the actions of Ang II on cultured embryonic renomedullary interstitial cells (ERMICs). 125I-[Sar1, Ile8]Ang II specifically bound to AT1 and AT2 receptors on ERMICs, and their mRNAs were detected by reverse transcription—polymerase chain reaction (RT-PCR). Angiotensin II (10−6M) increased intracellular IP3 concentrations at 20 seconds, and decreased intracellular cAMP concentrations after 10 minutes. Angiotensin II (10−6M) induced an increase in [3H]thymidine incorporation, mediated through the AT1 receptor subtype. Basic fibroblast growth factor (bFGF; 20 ng/ml) also increased 3[H]thymidine incorporation after 24 hours of treatment, an effect that was attenuated by subsequent addition of Ang II (10−6M). This antiproliferative action of Ang II was blocked by PD 123319 (10−6M), an AT2 receptor antagonist, and was not affected by losartan (10−6M), an AT1 receptor antagonist. These results indicate a dual role for Ang II in regulating ERMIC mitogenesis: a growth stimulating effect mediated by the AT1 receptor subtype, and an antiproliferative effect mediated by the AT2 receptor subtype

Impact of maternal obesity and diabetes on long-term health of the offspring.

The initial observations of David Barker, popularly known as the “Barker hypothesis” or “developmental origins of health and disease,” show that being born with low birth weight, as a result of intrauterine growth restriction produced by maternal undernutrition, is associated with a number of chronic diseases later in life [1]. Subsequently, studies show that it is not just intrauterine growth restriction, but also exposure to any other adverse factor during fetal and/or early postnatal development that can increase susceptibility to a number of chronic diseases later in life including cardiovascular and renal disease, hypertension, type 2 diabetes, certain forms of cancer, osteoporosis, Parkinson’s disease, dementia, and polycystic ovary syndrome [2–4

Obesity hypoventilation syndrome treated with non-invasive ventilation:Is a switch to CPAP therapy feasible?

Background and objective: Obesity hypoventilation syndrome (OHS) can be treated with either continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) therapy; the device choice has important economic and operational implications. Methods: This multicentre interventional trial investigated the safety and short-term efficacy of switching stable OHS patients who were on successful NIV therapy for ≥3 months to CPAP therapy. Patients underwent an autotitrating CPAP night under polysomnography (PSG); if the ensuing parameters were acceptable, they were sent home on a fixed CPAP for a 4–6-week period. It was hypothesized that blood gas analysis, PSG parameters and lung function tests would remain unchanged. Results: A total of 42 OHS patients were recruited, of whom 37 patients were switched to CPAP therapy. All patients had a history of severe obstructive sleep apnoea syndrome; chronic obstructive pulmonary disease (COPD) (Global Initiative for Obstructive Lung Disease (GOLD) I/II) was present in 52%. Regarding the primary outcome, 30 of 42 patients (71%, 95% CI: 55–84%) maintained daytime partial pressure of carbon dioxide (PaCO2) levels ≤45 mm Hg after the home CPAP period. There was no further impairment in quality of life, sleep parameters or lung function. Interestingly, 24 patients (65%) preferred CPAP as their long-term therapy, despite the high pressure levels used (mean: 13.8 ± 1.8 mbar). After the CPAP period, 7 of 37 patients were categorized as CPAP failure, albeit only due to mild hypercapnia (mean: 47.9 ± 2.7 mm Hg). Conclusion: It is feasible to switch most stable OHS patients from NIV to CPAP therapy, a step that could significantly reduce health-related costs. The auto-adjusted CPAP device, used in combination with the analysis of the PSG and capnometry, is a valid titration method in OHS patients

Cross-cultural color-odor associations

Colors and odors are associated; for instance, people typically match the smell of strawberries to the color pink or red. These associations are forms of crossmodal correspondences. Recently, there has been discussion about the extent to which these correspondences arise for structural reasons (i.e., an inherent mapping between color and odor), statistical reasons (i.e., covariance in experience), and/or semantically-mediated reasons (i.e., stemming from language). The present study probed this question by testing color-odor correspondences in 6 different cultural groups (Dutch, Netherlands-residing-Chinese, German, Malay, Malaysian-Chinese, and US residents), using the same set of 14 odors and asking participants to make congruent and incongruent color choices for each odor. We found consistent patterns in color choices for each odor within each culture, showing that participants were making non-random color-odor matches. We used representational dissimilarity analysis to probe for variations in the patterns of color-odor associations across cultures; we found that US and German participants had the most similar patterns of associations, followed by German and Malay participants. The largest group differences were between Malay and Netherlands-resident Chinese participants and between Dutch and Malaysian-Chinese participants. We conclude that culture plays a role in color-odor crossmodal associations, which likely arise, at least in part, through experience

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Vasoactive Hormones and the Diabetic Kidney

Diabetic nephropathy is the single most common cause of end-stage renal disease (ESRD) and accounts for significant morbidity and mortality. While the incidence of ESRD increased dramatically in the 1980s and 1990s, the U.S. Renal Data System (USRDS) 2005 Annual Data Report shows that 338 out of every million Americans had kidney failure in 2003, down slightly from 340 per million in 2002. This report shows that the numbers of people developing ESRD have stabilized despite the persistent increase in the number of people diagnosed with type 2 diabetes mellitus (T2DM). These data attest to both the efficacy of the currently available therapeutic regimens for the treatment of ESRD as well as better overall patient care. Unfortunately, these encouraging statistics do not apply to all patients. According to the USRDS report, the most marked ESRD decrease was seen in young Caucasian men (<40 years of age), while in other patient groups, particularly African Americans, ESRD has not changed much at all. These observations suggest that more in-depth studies, addressing specific issues, such as race, are needed to understand the disease process fully in order to create novel therapeutic strategies to eradicate the disease completely in all patient populations