Richard Oeckler

Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces

The gastrointestinal epithelial enterochromaffin (EC) cell synthesizes the vast majority of the bodys serotonin. As a specialized mechanosensor, the EC cell releases this serotonin in response to mechanical forces. However, the molecular mechanism of EC cell mechanotransduction is unknown. In the present study, we show, for the first time, that the mechanosensitive ion channel Piezo2 is specifically expressed by the human and mouse EC cells. Activation of Piezo2 by mechanical forces results in a characteristic ionic current, the release of serotonin and stimulation of gastrointestinal secretion. Piezo2 inhibition by drugs or molecular knockdown decreases mechanosensitive currents, serotonin release and downstream physiological effects. The results of the present study suggest that the mechanosensitive ion channel Piezo2 is specifically expressed by the EC cells of the human and mouse small bowel and that it is important for EC cell mechanotransduction.

TRIM72 modulates caveolar endocytosis in repair of lung cells.

Alveolar epithelial and endothelial cell injury is a major feature of the acute respiratory distress syndrome, in particular when in conjunction with ventilation therapies. Previously we showed [Kim SC, Kellett T, Wang S, Nishi M, Nagre N, Zhou B, Flodby P, Shilo K, Ghadiali SN, Takeshima H, Hubmayr RD, Zhao X. Am J Physiol Lung Cell Mol Physiol 307: L449-L459, 2014.] that tripartite motif protein 72 (TRIM72) is essential for amending alveolar epithelial cell injury. Here, we posit that TRIM72 improves cellular integrity through its interaction with caveolin 1 (Cav1). Our data show that, in primary type I alveolar epithelial cells, lack of TRIM72 led to significant reduction of Cav1 at the plasma membrane, accompanied by marked attenuation of caveolar endocytosis. Meanwhile, lentivirus-mediated overexpression of TRIM72 selectively increases caveolar endocytosis in rat lung epithelial cells, suggesting a functional association between these two. Further coimmunoprecipitation assays show that deletion of either functional domain of TRIM72, i.e., RING, B-box, coiled-coil, or PRY-SPRY, abolishes the physical interaction between TRIM72 and Cav1, suggesting that all theoretical domains of TRIM72 are required to forge a strong interaction between these two molecules. Moreover, in vivo studies showed that injurious ventilation-induced lung cell death was significantly increased in knockout (KO) TRIM72(KO) and Cav1(KO) lungs compared with wild-type controls and was particularly pronounced in double KO mutants. Apoptosis was accompanied by accentuation of gross lung injury manifestations in the TRIM72(KO) and Cav1(KO) mice. Our data show that TRIM72 directly and indirectly modulates caveolar endocytosis, an essential process involved in repair of lung epithelial cells through removal of plasma membrane wounds. Given TRIM72s role in endomembrane trafficking and cell repair, we consider this molecule an attractive therapeutic target for patients with injured lungs.

Effectiveness of hands-on tutoring and guided selfdirected learning versus self-directed learning alone to educate critical care fellows on mechanical ventilation - a pilot project

Background Physicians require extensive training to achieve proficiency in mechanical ventilator (MV) management of the critically ill patients. Guided self-directed learning (GSDL) is usually the method used to learn. However, it is unclear if this is the most proficient approach to teaching mechanical ventilation to critical care fellows. We, therefore, investigated whether critical care fellows achieve higher scores on standardized testing and report higher satisfaction after participating in a hands-on tutorial combined with GSDL compared to self-directed learning alone. Methods First-year Pulmonary and Critical Care Medicine (PCCM) fellows (n=6) and Critical Care Internal Medicine (CCIM) (n=8) fellows participated. Satisfaction was assessed using the Likert scale. MV knowledge assessment was performed by administering a standardized 25-question multiple choice pre- and posttest. For 2 weeks the CCIM fellows were exposed to GSDL, while the PCCM fellows received hands-on tutoring combined with GSDL. Results Ninety-three percentage (6 PCCM and 7 CCIM fellows, total of 13 fellows) completed all evaluations and were included in the final analysis. CCIM and PCCM fellows scored similarly in the pretest (64% vs. 52%, p=0.13). Following interventions, the posttest scores increased in both groups. However, no significant difference was observed based on the interventions (74% vs. 77%, p=0.39). The absolute improvement with the hands-on-tutoring and GSDL group was higher than GSDL alone (25% vs. 10%, p=0.07). Improved satisfaction scores were noted with hands-on tutoring. Conclusions Hands-on tutoring combined with GSDL and GSDL alone were both associated with an improvement in posttest scores. Absolute improvement in test and satisfaction scores both trended higher in the hands-on tutorial group combined with GSDL group.Background Physicians require extensive training to achieve proficiency in mechanical ventilator (MV) management of the critically ill patients. Guided self-directed learning (GSDL) is usually the method used to learn. However, it is unclear if this is the most proficient approach to teaching mechanical ventilation to critical care fellows. We, therefore, investigated whether critical care fellows achieve higher scores on standardized testing and report higher satisfaction after participating in a hands-on tutorial combined with GSDL compared to self-directed learning alone. Methods First-year Pulmonary and Critical Care Medicine (PCCM) fellows (n=6) and Critical Care Internal Medicine (CCIM) (n=8) fellows participated. Satisfaction was assessed using the Likert scale. MV knowledge assessment was performed by administering a standardized 25-question multiple choice pre- and posttest. For 2 weeks the CCIM fellows were exposed to GSDL, while the PCCM fellows received hands-on tutoring combined with GSDL. Results Ninety-three percentage (6 PCCM and 7 CCIM fellows, total of 13 fellows) completed all evaluations and were included in the final analysis. CCIM and PCCM fellows scored similarly in the pretest (64% vs. 52%, p=0.13). Following interventions, the posttest scores increased in both groups. However, no significant difference was observed based on the interventions (74% vs. 77%, p=0.39). The absolute improvement with the hands-on-tutoring and GSDL group was higher than GSDL alone (25% vs. 10%, p=0.07). Improved satisfaction scores were noted with hands-on tutoring. Conclusions Hands-on tutoring combined with GSDL and GSDL alone were both associated with an improvement in posttest scores. Absolute improvement in test and satisfaction scores both trended higher in the hands-on tutorial group combined with GSDL group.

A Skeptical Perspective on High-Flow Nasal Cannula in the Treatment of Acute Hypoxemic Respiratory Failure

The delivery of oxygen, whether as treatment for hypoxemia or supportive adjunct in shock or surgery, is a mainstay of modern medical therapy, yet conventional oxygen therapy, delivered either by nasal cannula or face mask, remains limited by the high oxygen delivery demand of the acute and

794: IMPROVING PRIMARY TEAM PRESENCE AND PARTICIPATION DURING RAPID RESPONSE TEAM ACTIVATIONS

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The Hidden Consequences of Ventilator Management Decisions

In the following perspective, we will highlight seemingly remote, downstream consequences of common ventilator management decisions. For example, a change in PEEP may alter venous return, blood pressure, cardiac output, arterial and venous blood gas tensions, metabolic rate, respiratory sensations, breathing pattern, and the work of breathing. If providers consider any of these changes dangerous or maladaptive, they may initiate additional interventions in the form of vasoactive agents, intravenous fluids, and/or sedatives, all of which have their own risk/benefit profile. The approach to such co-interventions is rarely addressed even in well-designed large clinical trials. Therefore, it is often impossible to infer intervention-specific mechanisms of action and/or identify the phenotype of responders and nonresponders in such trials. On the flip side, in preclinical research intended to uncover mechanisms, experimental animals are rarely treated the way a critically ill patient would be. For respiratory therapists, this knowledge gap stresses the imperative to think beyond the lungs and to communicate ventilator management decisions with all members of the healthcare team.

Expanded spectrum of antineutrophil cytoplasmic antibody–negative vasculitis involving vessels from capillaries to medium‐sized arteries

The patient was admitted to a local hospital 2 weeks priorfor a 3-month duration of weight loss, generalized weak-ness, and progressive lower extremity pain. The symptomsstarted gradually, without any notable antecedent event.He felt weak, lost appetite, and developed intermittent drycough and pain in the lower extremities, initially in thethighs, and progressed to bilateral legs. In a matter ofmonths, his health deteriorated from being physically ac-tive and independent to mostly bedridden.Evaluation at the local hospital revealed low-grade fever(37.9°C), mild hypertension (140–150/90 mm Hg), multi-ple new lung nodules on a contrast-enhanced chest andabdominal computed tomography (CT) scan, and an ele-vated serum creatinine concentration of 2.6 mg/dl (fromhis baseline of 0.9 mg/dl approximately 6 months ago)with microscopic hematuria. Screening for hepatitis B andC, antinuclear antibodies, complements, and antineutro-phil cytoplasmic antibody (ANCA) panel (myeloperoxi-dase [MPO] and proteinase 3) was negative. His erythro-cyte sedimentation rate (ESR) was 49 mm/hour (referencerange 0–25). A transbronchial biopsy sample of severallung nodules showed no evidence of malignancy or activeinfection and was interpreted as nondiagnostic. For hislower extremity pain, he was empirically treated withintravenous (IV) immunoglobulin for possible Guillain-Barre´ syndrome. The treatment was discontinued 4 dayslater after an electromyogram sample revealed primaryaxonal sensory motor peripheral neuropathy. His kidneydysfunction worsened following intravenous contrast ex-posure for the CT scan; his serum creatinine level rose to3.4 mg/dl. He underwent a left kidney percutaneous bi-opsythatwasreadaspossiblecrescenticglomerulonephri-tis. IV methylprednisolone, 500 mg once daily, was initi-ated. During his hospital stay, the patient developedepisodic confusion. A spinal tap was performed andshowed no abnormality, nor evidence of syphilis or WestNile virus infection. Two days following the initiation ofIV methylprednisolone, his condition further deterioratedwith worsening extremity weakness to the point that hecould not ambulate with assistance and mental confusion.He was then transferred to our institution.