Therapeutic Ultrasound in Cardiovascular Medicine.

An advantage of therapeutic ultrasound (US) is the ability to cause controlled biological effects noninvasively. Depending on the magnitude and frequency of exposure parameters, US can interact in different ways with a variety of biological tissues. The development and clinical utility of therapeutic US techniques are now rapidly growing, especially with regard to the application of US pulses for cardiac pacing and the potential treatment of cardiovascular diseases. This review outlines the basic principles of US-based therapy in cardiology, including the acoustic properties of the cardiovascular tissue, and the use of US in therapeutic cardiovascular medicine.

Change in grip strength, hang time, and knot tying speed after 24 hours of endurance rock climbing.

Background: Non-professional climbers are increasingly attempting long routes in a single day. Many suffer injury or rely on search and rescue teams when they become too fatigued to finish. Predicting fatigue is difficult, and existing studies have only studied climbers over durations less than an hour, while many outdoor multipitch climbs require more than an hour of climbing. Objectives: To determine how strength, endurance, and dexterity reflect fatigue after 24 h of continuous climbing. Methods: Volunteer competitors completed measurements of grip strength, static hang time to failure, and time to tie a figure-eight follow-through knot. Measurements were taken during the registration period before the competition and again within an hour after the competition ended. Measurements were compared using the paired t-test. Subgroup analysis was applied to competitors by division. Linear regression was applied to determine the relationship between vertical feet climbed and the number of routes climbed during the competition on each metric. Results: Thirty-six total climbers (average age 29.4 years old) completed pre- and post-competition measurements. After 24 h of climbing (n = 36), mean grip strength decreased by 14.3-15 lbs or 14.7%-15.1% (p < 0.001) and static hang time decreased by 54.2 s or 71.2% (p < 0.001). There was no significant change in time to tie a figure-eight-follow-through knot. Grip strength and hang time decreases were significant in climbers with outdoor redpoints of 5.10a and above. Hang time decreased by 5.4 s per 1,000 vertical feet climbed (p = 0.044). Conclusion: Climbers can expect to experience a 14.7%-15.1% decrease in grip strength and 71.2% decrease in static hang time after 24 h of continuous climbing. These changes may make it difficult to climb consistently over a long objective, and climbers can use these measures at home to train for longer climbing routes. Future studies on shorter climbing intervals can help determine rates of decline in performance measures.

Conformational switches that control the TEC kinase - PLCγ signaling axis.

Cell surface receptors such as the T-cell receptor (TCR) and B-cell receptor (BCR) engage with external stimuli to transmit information into the cell and initiate a cascade of signaling events that lead to gene expression that drives the immune response. At the heart of controlling T- and B-cell cell signaling, phospholipase Cγ hydrolyzes membrane associated PIP2, leading to generation of the second messengers IP3 and DAG. These small molecules trigger mobilization of intracellular Ca2+ and promote transcription factor transport into the nucleus launching the adaptive immune response. The TEC family kinases are responsible for phosphorylating and activating PLCγ, and our group aims to understand mechanisms that regulate immune cell signal transduction by focusing on this kinase/phospholipase axis in T-cells and B-cells. Here, we review the current molecular level understanding of how the TEC kinases (ITK and BTK) and PLCγ1/2 are autoinhibited prior to activation of cell surface receptors, how TEC kinases are activated to specifically recognize the PLCγ substrate, and how conformational changes induced by phosphorylation trigger PLCγ activation.

Spontaneous Loculated Bilateral Hydropneumothoraces in a Patient with Recent COVID-19 Infection.

A 53-year-old male presented to the emergency room with chest pain, shortness of breath, and back pain. He had recently recovered from COVID-19 infection and returned home on room air. Chest imaging showed bilateral hydropneumothoraces that were not present on the imaging performed during his prior admission three weeks ago. The patient was treated with bilateral chest tube drainage and oxygen support and responded well to treatment. This case represents a unique occurrence of spontaneous loculated bilateral hydropneumothoraces in the context of recent clinical recovery from COVID-19 infection requiring inpatient treatment. This case highlights the importance of an awareness of a potential sequela of COVID-19 that may occur even after presumed clinical recovery.

The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance.

Mutations in PLCγ, a substrate of the tyrosine kinase BTK, are often found in patients who develop resistance to the BTK inhibitor Ibrutinib. However, the mechanisms by which these PLCγ mutations cause Ibrutinib resistance are unclear. Under normal signaling conditions, BTK mediated phosphorylation of Y783 within the PLCγ cSH2-linker promotes the intramolecular association of this site with the adjacent cSH2 domain resulting in active PLCγ. Thus, the cSH2-linker region in the center of the regulatory gamma specific array (γSA) of PLCγ is a key feature controlling PLCγ activity. Even in the unphosphorylated state this linker exists in a conformational equilibrium between free and bound to the cSH2 domain. The position of this equilibrium is optimized within the properly regulated PLCγ enzyme but may be altered in the context of mutations. We therefore assessed the conformational status of four resistance associated mutations within the PLCγ γSA and find that they each alter the conformational equilibrium of the γSA leading to a shift toward active PLCγ. Interestingly, two distinct modes of mutation induced activation are revealed by this panel of Ibrutinib resistance mutations. These findings, along with the recently determined structure of fully autoinhibited PLCγ, provide new insight into the nature of the conformational change that occurs within the γSA regulatory region to affect PLCγ activation. Improving our mechanistic understanding of how B cell signaling escapes Ibrutinib treatment via mutations in PLCγ will aid in the development of strategies to counter drug resistance.