A possible role of the ATP-sensitive potassium ion channel in determining the duration of spike-bursts in mouse pancreatic β-cells

AbstractThe pancreatic β-cell displays an electrical activity consisting of spike bursts and silent phases at glucose concentrations of about 10 mM. The mechanism of initial depolarization induced by glucose is well defined. However, the mechanism inducing the silent phase has not been fully elucidated. In the present study, the possibility of involvement of ATP-sensitive K+ channels in repolarization was examined using the patch-clamp technique in the cell-attached recording configuration. Ouabain (0.1 mM), an inhibitor of Na+/K+-ATPase, caused a complete suppression of ATP-sensitive K+ channel activity followed by typical biphasic current deflections, which were due to action potentials. The channel activity was also inhibited by removal of K+ from a perifusion solution. Furthermore, the activity of ATP-sensitive K+ channels was markedly inhibited either by replacement of external NaCl with LiCl or by addition of amiloride (0.2 mM), a blocker of Na+/H+ antiport. Addition of L-type Ca2+ channel blockers such as Nifedipine or Mn2+ induced the complete suppression of K+ channel activity. These findings strongly suggest that a fall in ATP consumption results in sustained depolarization, and that the repolarizations interposed between spike-bursts under normal ionic conditions are due to the periodical fall of ATP concentration brought about by periodical acceleration of ATP consumption at Na+/K+-pumps. It is concluded that the elevation of intracellular Na+ concentration as a consequence of accelerated Na+/Ca2+-countertransport during the period of spike-burst enhances ATP consumption, leading to a fall in ATP concentration which is responsible for termination of spike-burst and initiation of repolarization

Identification of cardiac progenitors that survive in the ischemic human heart after ventricular myocyte death.

Atypically-shaped cardiomyocytes (ACMs) are beating heart cells identified in the cultures of cardiomyocyte-removed fractions obtained from adult mouse hearts. Since ACMs spontaneously develop into beating cells in the absence of hormones or chemicals, these cells are likely to be a type of cardiac progenitors rather than stem cells. "Native ACMs" are found as small interstitial cells among ventricular myocytes that co-express cellular prion protein (PrP) and cardiac troponin T (cTnT) in mouse and human heart tissues. However, the endogenous behavior of human ACMs is unclear. In the present study, we demonstrate that PrP(+) cTnT(+) cells are present in the human heart tissue with myocardial infarction (MI). These cells were mainly found in the border of necrotic cardiomyocytes caused by infarcts and also in the hibernating myocardium subjected to the chronic ischemia. The ratio of PrP(+) cTnT(+) cells to the total cells observed in the normal heart tissue section of mouse and human was estimated to range from 0.3-0.8%. Notably, living human PrP(+) cTnT(+) cells were identified in the cultures obtained at pathological autopsy despite exposure to lethal ischemic conditions for hours after death. These findings suggest that ACMs could survive in the ischemic human heart and develop into a sub-population of cardiac myocytes

COVID-19 vaccine effectiveness against severe COVID-19 requiring oxygen therapy, invasive mechanical ventilation, and death in Japan: A multicenter case-control study (MOTIVATE study).

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron