The rapid development of AmboVent: a simple yet sustainable ventilation solution for use in a pandemic.

INTRODUCTION: COVID-19 (SARS-CoV-2) emerged at the end of 2019, generating a rapidly evolving pandemic, raising serious global health implications. Among them was the fear of a mechanical ventilator shortage due to COVID-19's high contagion rate and pathophysiology. Fears of a ventilator shortage unleashed a wave of innovations. MATERIAL AND METHOD: This manuscript describes the AmboVent, a ventilator, rapidly developed with a sense of urgency, by a group of Israeli volunteers. RESULTS: Using a decentralized approach, we worked extensively and managed within ten days to create a working ventilator. It utilizes a 64-year-old technological concept, the bag valve mask (BVM), sometimes known by the proprietary name Ambu bag, which we transformed into an automatic, controlled, and feature-rich ventilator by endowing it with contemporary computing technology. CONCLUSIONS: Applying a functional rather than a commercial-oriented approach can result in the ad hoc development of lifesaving solutions during a rapidly spreading pandemic.

Transcutaneous functional electrical stimulation-a novel therapy for premature ejaculation: results of a proof of concept study.

Premature Ejaculation (PE) is a very common and disturbing sexual dysfunction in men. Currently available treatment modalities are associated with limited efficacy and low treatment adherence. In this prospective, single-blinded, self-controlled study, we evaluated the efficacy and safety of transcutaneous electrical stimulation (TES) for the treatment of (PE). We included 23 patients aged 20-60 (mean: 38.7) with lifelong PE. On the first visit, we delivered either TES or sham treatment to the perineum, based on the enrollment order. For stimulation, we used a commercial neuromuscular electrical stimulation device. The patients were invited for the second visit after at least 7 days for receiving the alternating treatment. During the treatment sessions, the patients were left alone in a privet silent room to masturbate and a stopwatch was used to measure their masturbation ejaculatory latency time (MELT). The patients also filled-out safety questionnaires after each visit and on each of the 3 following days. Of the 20 patients who completed the study, 17 (85%) experienced prolonged MELT under TES compared with the sham treatment. Mean MELT values increased 3.5-folds under TES (p = 0.0009). We demonstrated a significant increase in MELT in lifelong PE patients using TES. This therapeutic option may have the potential to become an on-demand treatment option for PE. Future studies with wireless devices are needed to confirm the efficacy and safety of this treatment concept during intercourse.

Transcutaneous neuromuscular electrical stimulation may be beneficial in the treatment of premature ejaculation.

Approximately 20-30% of sexually active men suffer from Premature Ejaculation (PE), but the pathophysiology still remains unclear and the current available treatments for PE are unsatisfying. Considering the role of rhythmic bulbospongiosus and ischiocavernosus Muscles contractions on the ejaculatory reflex, we hypothesize that weakening this muscles via inhibiting it's contractions by Application of Neuromuscular Electrical Stimulation prior to the planned sexual activity, may have a beneficial effect in the treatment of PE. Using miniaturized perineal on-demand stimulation device, in a home setting during sexual intercourse may become the first line of treatment for PE.

Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior.

BACKGROUND: The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node. METHODS AND RESULTS: We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs. CONCLUSIONS: This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power-law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial-compatible spontaneous cardiomyocytes from the patient's own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers.

Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells.

In view of the therapeutic potential of cardiomyocytes derived from induced pluripotent stem (iPS) cells (iPS-derived cardiomyocytes), in the present study we investigated in iPS-derived cardiomyocytes, the functional properties related to [Ca(2+) ](i) handling and contraction, the contribution of the sarcoplasmic reticulum (SR) Ca(2+) release to contraction and the b-adrenergic inotropic responsiveness. The two iPS clones investigated here were generated through infection of human foreskin fibroblasts (HFF) with retroviruses containing the four human genes: OCT4, Sox2, Klf4 and C-Myc. Our major findings showed that iPS-derived cardiomyocytes: (i) express cardiac specific RNA and proteins; (ii) exhibit negative force-frequency relations and mild (compared to adult) post-rest potentiation; (iii) respond to ryanodine and caffeine, albeit less than adult cardiomyocytes, and express the SR-Ca(2+) handling proteins ryanodine receptor and calsequestrin. Hence, this study demonstrates that in our cardiomyocytes clones differentiated from HFF-derived iPS, the functional properties related to excitation-contraction coupling, resemble in part those of adult cardiomyocytes.

TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements.

Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administration-approved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptotic-inducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-epsilon and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 microM, 24 h) prevented doxorubicin (0.5 microM, 24 h)-induced elevation of diastolic [Ca(2+)](i), the slowing of [Ca(2+)](i) relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase, Na(+)/Ca(2+) exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/dt(max)) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.

Gap junctional remodeling by hypoxia in cultured neonatal rat ventricular myocytes.

OBJECTIVES: Altered gap junctional coupling of ventricular myocytes plays an important role in arrhythmogenesis in ischemic heart disease. Since hypoxia is a major component of ischemia, we tested the hypothesis that hypoxia causes gap junctional remodeling accompanied by conduction disturbances. METHODS: Cultured neonatal rat ventricular myocytes were exposed to hypoxia (1% O(2)) for 15 min to 5 h, connexin43 (Cx43) expression was analyzed, and conduction velocity was measured using the Micro-Electrode Array data acquisition system. RESULTS: After 15 min of hypoxia, conduction velocity was unaffected, while total Cx43, including the phosphorylated and nonphosphorylated isoforms, was increased. After 5 h of hypoxia, total Cx43 protein was decreased by 50%, while the nonphosphorylated Cx43 isoform was unchanged. Confocal analyses yielded a 55% decrease in the gap junctional Cx43 fluorescence signal, a 55% decrease in gap junction number, and a 26% decrease in size. The changes in Cx43 were not accompanied by changes in mRNA levels. The reduction in Cx43 protein levels was associated with a approximately 20% decrease in conduction velocity compared to normoxic cultures. CONCLUSIONS: Short-term hypoxia (5 h) decreases Cx43 protein and conduction velocity, thereby contributing to the generation of an arrhythmogenic substrate.