Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described

LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy

Temporal Responses of a Low-Energy Meal Replacement Plan or Exercise Training on Cardiovascular Function and Fibro-Inflammatory Markers in People with Type 2 Diabetes—A Secondary Analysis of the “Diabetes Interventional Assessment of Slimming or Training to Lessen Inconspicuous Cardiovascular Dysfunction” Study

Background: This study assesses the temporal responses of cardiovascular function, fibro-inflammation, and glucometabolic profiles in asymptomatic adults with type 2 diabetes, following a low-energy meal replacement plan (MRP) or exercise training. Methods: Secondary analysis of DIASTOLIC: a randomised, open-label, blinded-endpoint trial of 12 weeks MRP (~810 kcal/day) or exercise training. Cardiac magnetic resonance, plasma fibroinflammatory, and metabolic markers were undertaken at baseline, 4, and 12 weeks. Results: Out of 24 participants in the MRP group and 22 in exercise training, 18 and 11 completed all three visits. MRP resulted in early (0–4 weeks) improvement in insulin resistance (HOMA-IR: 10.82 to 4.32), decrease in FABP-4 (4.87 ± 0.19 to 5.15 ± 0.32 mg/L), and improvement in left ventricular remodelling LV mass: volume (0.86 ± 0.14 to 0.78 ± 0.11), all with large effect sizes. MMP8 levels increased moderately at 4–12 weeks. Peak early diastolic strain rate (cPEDSR) initially decreased, then improved. Exercise training led to minor improvements in insulin resistance and MMP-8 levels, with no significant changes in cPEDSR or LV remodelling. Conclusions: MRP resulted in early improvements in insulin resistance, cardiac remodelling, and inflammation, but with an initial decrease in diastolic function, improving by 12 weeks. Exercise training showed minor early benefits in insulin resistance and inflammation, but no significant cardiac changes

An example of secondary fault activity along the North Anatolian Fault on the NE Marmara Sea Shelf, NW Turkey

Seismic data on the NE Marmara Sea Shelf indicate that a NNE-SSW-oriented buried basin and ridge system exist on the sub-marine extension of the Paleozoic Rocks delimited by the northern segment of the North Anatolian Fault (NS-NAF), while seismic and multi-beam bathymetric data imply that four NW-SE-oriented strike-slip faults also exist on the shelf area. Seismic data indicate that NW-SE-oriented strike-slip faults are the youngest structures that dissect the basin-ridge system. One of the NW-SE-oriented faults (F1) is aligned with a rupture of the North Anatolian Fault (NAF) cutting the northern slope of the Cinarcik Basin. This observation indicates that these faults have similar characteristics with the NS-NAF along the Marmara Sea. Therefore, they may have a secondary relation to the NAF since the principle deformation zone of the NAF follows the Marmara Trough in that region. The seismic energy recorded on these secondary faults is much less than that on the NAF in the Marmara Sea. These faults may, however, produce a large earthquake in the long term

Evaluating susceptibility of karst dolines (sinkholes) for collapse in Sango, Tennessee, USA

Dolines or sinkholes are earth depressions that develop in soluble rocks complexes such as limestone, dolomite, gypsum, anhydrite, and halite; dolines appear in a variety of shapes from nearly circular to complex structures with highly curved perimeters. The occurrence of dolines in the studied karst area is not random; they are the results of geomorphic, hydrologic and chemical processes that have caused partial subsidence, even total collapse of the land surface, when voids and caves are present in the bedrock and the regolith arch overbridging these voids is unstable. In the study area, the majority of collapses occur in the regolith (bedrock cover) that bridges voids in the bedrock. Because these collapsing dolines can damage property and cause even the loss of lives, there is a need to develop methods for evaluating karst hazards; such methods can be used by planners and practitioners for urban and economic development, especially in regions with a growing population. The purpose of this project is threefold: 1) to develop a karst feature database, 2) to investigate critical indicators associated with doline collapse, and 3) to design a doline susceptibility model for potential doline collapse based on external morphometric data. The study revealed the presence of short range spatial dependence in the distribution of the dolines’ morphometric parameters such as circularity, geographic orientation of the main doline axes and the length-to-width doline ratios; therefore, geostatistics can be used to spatially evaluate the susceptibility of the karst area for doline collapse using the probability of occurrence of these critical parameters. The partial susceptibility estimates were combined into final spatial probabilities enabling the identification of areas where undetected dolines may cause significant hazards

Alterations in cardiac function in women with severe preeclampsia: return to normal in one year after delivery?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. In peri-partum period women with preeclampsia have demonstrated signs of subtle left ventricular (LV) dysfunction. However, there is still controversy if these changes persist or improve late after delivery. Purpose. To evaluate LV dimensions and function in severe preeclamptic women and healthy controls immediately post-delivery and 1 year postpartum. Methods. The study population comprised 24 women with severe preeclampsia and 15 healthy term controls. All women underwent standard and speckle-tracking echocardiography to assess myocardial function and deformation parameters 1 day after delivery and 1 year postpartum. To examine the impact of preload and afterload on myocardial function LV end-diastolic volume and systolic blood pressure were used accordingly. Results. On day 1 post-delivery women with severe preeclampsia were exposed to increased afterload with significantly higher systolic blood pressure compared to controls (147 [136-157] in preeclamptic vs. 112 [102-118] mmHg in control group, p &amp;lt; 0.001). Similarly, preeclamptic women had also higher preload demonstrated with larger LV end-diastolic volume (114 [100-128] vs. 95 [92-102] ml, p = 0.003) and left atrial volume index (36 [33-38] vs. 32 [29-36] ml/m2, p = 0.02) than control group. Among other geometric parameters difference in LV mass index was observed between groups (preeclamptic group: (81 [70-96] vs. control group: 66 [61-74] g/m2, p = 0.01). Global systolic parameters (LV ejection fraction and global longitudinal strain) did not differ between groups; however, peak systolic myocardial velocity (s’) was significantly lower in preeclamptic compared to control group (7.6 [6.5-8.1] vs. 8.0 [7.5-8.9] cm/s, p = 0.02) immediately post-delivery. Diastolic function differed between groups with significantly higher E/e’ ratio in preeclamptic women than controls (8.7 [7.6-10.0] vs. 6.9 [6.4-7.8] p = 0.01) one day post-delivery. One year after delivery both groups had normal and similar arterial blood pressure and there were no differences in geometric, systolic and diastolic function parameters between groups (Figure A-D).  Conclusions. Our results showed that women with severe preeclampsia had subtle cardiac dysfunction immediately post-delivery compared to healthy controls and recovered completely in one year after delivery. Subtle cardiac dysfunction in preeclampsia immediately post-delivery seemed to be related or unmasked by pronounced changes in loading conditions, which resolved in mid-term postpartum period. Long-term follow-up with larger study population is needed to identify subgroup of women who have persistent subclinical cardiac alterations and experience cardiovascular events later in life. Abstract Figure </jats:sec

Left ventricular strain analysis-the importance of being expert

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf - Background Myocardial strain imaging using speckle-tracking echocardiography is widely used in both research and clinics. Left ventricular global longitudinal strain (GLS) has proven to be a reproducible and useful tool in clinical practice.  However, data about the variability in global and segmental strain among novice are limited. Purpose The aim of this study was to evaluate how the variability of strain measurements depends on the experience of the physician performing the analysis. Furthermore, we tried to assess how image quality and presence of pathology influence the diagnostic performance of the analysis. Methods Twenty novice (no or limited experiences with strain analysis) and 5 experts analysed offline 3 cases: a healthy adult and a patient with ischemic cardiomyopathy, both with high image quality, and a healthy adult with suboptimal image quality (insufficient tracking in two segments). Frame rates were 65, 51, and 70 fps, respectively. Left ventricular GLS and segmental longitudinal peak systolic strain were quantified using the automated function imaging protocol from vendor-specific offline analysis software. The absolute difference in GLS and segmental strain between each novice readers and experts was calculated. Mean strain measurements from the experts were used as a comparator. Results Absolute values of GLS ranged from -13.6% to -20.1% in the novice group, while GLS ranged from -15.6% to -18.8% in the expert group. The absolute difference in GLS was significantly higher in the novice group compared to the expert group (P &amp;lt; 0.001). Absolute differences in GLS varied significantly among cases, with low variability in healthy adult with high image quality (Panel A) and with significantly higher variability between novices and experts in case with suboptimal image quality and ischemic cardiomyopathy (Panel B-C). The absolute differences in segmental longitudinal peak systolic strain were up to 11.9% strain unit in novice group and up to 6,8% strain unit in experts (P &amp;lt; 0.001 between groups). In novice group, highest absolute differences in segmental strain were observed in the region with suboptimal tracking and in infarct region in patient with ischemic cardiomyopathy (Panel D-E). Conclusion Left ventricular strain analysis by a reader with no or limited experiences severely affects the diagnostic potential of this method. Significant variability in strain measurements should be considered especially in cases with suboptimal image quality and in cases with regional left ventricular pathology. Abstract Figure. </jats:sec