A Fast pH-Switchable and Self-Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model

Co-registration of cortical magnetic stimulation and functional magnetic resonance imaging

FUNCTIONAL magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are noninvasive techniques recently used to investigate cortical motor physiology. However, these modalities measure different phenomena, and in studies of human motor control they have given inconsistent results. We have developed a reproducible technique which co-registers TMS and fMRI, using a frameless method. In four normal subjects, the TMS map and fMRI activation were present on the primary motor cortex contralateral to the target hand, with some extension into primary sensory cortex. fMRI activation alone was also present in the medial motor cortex bilaterally and in the sensori-motor cortex ipsilateral to the target hand. This technique allows a more comprehensive evaluation of the physiologic events involved in motor control

Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip

Extracellular vesicles (EVs) derived from various stem cell sources induce cardioprotective effects during ischemia-reperfusion injury (IRI). These have been attributed mainly to the antiapoptotic, proangiogenic, microRNA (miRNA) cargo within the stem cell-derived EVs. However, the mechanisms of EV-mediated endothelial signaling to cardiomyocytes, as well as their therapeutic potential toward ischemic myocardial injury, are not clear. EV content beyond miRNA that may contribute to cardioprotection has not been fully illuminated. This study characterized the protein cargo of human vascular endothelial EVs (EEVs) to identify lead cardioactive proteins and assessed the effect of EEVs on human laminar cardiac tissues (hlCTs) exposed to IRI. We mapped the protein content of human vascular EEVs and identified proteins that were previously associated with cellular metabolism, redox state, and calcium handling, among other processes. Analysis of the protein landscape of human cardiomyocytes revealed corresponding modifications induced by EEV treatment. To assess their human-specific cardioprotection in vitro, we developed a human heart-on-a-chip IRI assay using human stem cell-derived, engineered cardiac tissues. We found that EEVs alleviated cardiac cell death as well as the loss in contractile capacity during and after simulated IRI in an uptake- and dose-dependent manner. Moreover, we found that EEVs increased the respiratory capacity of normoxic cardiomyocytes. These results suggest that vascular EEVs rescue hlCTs exposed to IRI possibly by supplementing injured myocytes with cargo that supports multiple metabolic and salvage pathways and therefore may serve as a multitargeted therapy for IRI

IVF culture medium affects post-natal weight in humans during the first 2 years of life

Is post-natal growth during the first 2 years of life in IVF singletons affected by type of medium used for culturing human embryos during an IVF treatment? The in vitro culture of human embryos in medium from Cook resulted in singletons with a lower weight during the first 2 years of life compared with singletons born after embryo culture in medium from Vitrolife. In a previous study, we reported that type of medium used for culturing human IVF embryos during the first few days after fertilization until fresh embryo transfer significantly affects fetal growth and consequently birthweight of the resulting singletons. From July 2003 to December 2006, a total of 1432 IVF treatment cycles with fresh embryo transfer were randomly allocated to have all embryos cultured in medium from Vitrolife AB (n = 715) or from Cook (n = 717). Two years after delivery, questionnaires were sent to the parents of all children requesting data about weight, height and head circumference around 1, 2, 3, 4, 6, 7.5, 9, 11, 14, 18 and 24 months of age. These measurements were collected as part of the children's health programme at municipal infant welfare centres in the Netherlands by health professionals unaware of this study. Patients requiring donor oocytes or applying for PGD were excluded from the study. From the 294 live born singletons that fulfilled our inclusion criteria, 29 were lost to follow-up. The remaining 265 singletons (Cook group: 117, Vitrolife group: 148) were included in the analysis. Data analysis included linear regression, to compare cross-sectionally weight standard deviation score (SDS), height SDS and head circumference, and the first order Berkey-Reed model for a longitudinal analysis of the growth data. Singletons in the Vitrolife group were heavier during the first 2 years of life compared with singletons in the Cook group. Cross-sectional analyses showed that adjusted weight SDS differed between groups at 1 (0.35 ± 0.14, P = 0.010), 2 (0.39 ± 0.14, P = 0.006), 3 (0.35 ± 0.14, P = 0.011), 4 (0.30 ± 0.13, P = 0.020), 11 (0.28 ± 0.13, P = 0.036), 14 (0.32 ± 0.13, P = 0.014) and 24 (0.39 ± 0.15, P = 0.011) months of age, while adjusted height SDS was only significantly different at 1 (0.21 ± 0.11, P = 0.048) month of age. Head circumference was similar between the two groups at all ages. Longitudinal analyses showed that both post-natal weight (P = 0.005) and height (P = 0.031) differed between the groups throughout the first 2 years of life, while the growth velocity was not significantly different between the two groups. Factors that might influence post-natal growth were included in the analysis; however, it was not possible to include all such factors, for example childhood diseases or nutrition, as this information was not available. The effect of culture medium during the first few days after fertilization on prenatal growth and birthweight persists during the first 2 years of life. This suggests that the human embryo is sensitive to its very early environment, and that the culture medium used in IVF may have lasting consequences. Further monitoring of the long-term growth, development and health of IVF children is therefore warranted. W.V. was funded with an unrestricted research grant from the Stichting Fertility Foundation. The authors declare no conflict of interest. Not applicabl

Regret around fertility choices is decreased with pre-treatment counseling in gynecologic cancer patients

PURPOSE: Data have demonstrated an association between regret and lack of fertility counseling among patients undergoing treatment for non-gynecologic cancers. We sought to determine if fertility-related regret is reduced with pre-treatment counseling or fertility-sparing surgery (FSS) in patients with gynecologic cancers. METHODS: A cross-sectional survey was administered to 593 reproductive-age survivors (18-40 years old at diagnosis) of localized cervix, ovarian, or endometrial cancers that were eligible for FSS. A validated Decision Regret Score was used to evaluate regret in patients. RESULTS: 470 women completed the survey. Forty-six percent received pre-treatment counseling about treatment's effects on fertility. Having received counseling (adjusted ß-coefficient of −1.24, 95% CI=−2.29-−0.18, p=0.02), satisfactory counseling (adjusted ß-coefficient of −2.71, 95% CI=−3.86–−1.57, p<0.001) and FSS (adjusted ß-coefficient of −1.26, 95% CI=−2.39-−0.14, p=0.03) were associated with lower regret post-treatment, after adjusting for age. Time since diagnosis, prior parity, socioeconomic status and cancer type were not associated with regret (p>0.05). While 50% of women reported desiring more children after diagnosis, desire for children after treatment was associated with increased regret (adjusted ß-coefficient of 3.97, 95% CI=2.92-5.02, p<0.001). CONCLUSIONS: Though less than half of study participants received counseling about the effect of cancer treatment on future fertility, both fertility counseling and FSS were associated with decreased regret in reproductive-aged women with gynecologic cancers. Desire for more children after treatment was associated with increased regret. IMPLICATIONS FOR CANCER SURVIVORS: Inquiring about fertility desires and providing counseling regarding reproductive outcomes following cancer treatment should be implemented as part of the treatment process