Gentamicin Rapidly Inhibits Mitochondrial Metabolism in High-Frequency Cochlear Outer Hair Cells

Aminoglycosides (AG), including gentamicin (GM), are the most frequently used antibiotics in the world and are proposed to cause irreversible cochlear damage and hearing loss (HL) in 1/4 of the patients receiving these life-saving drugs. Akin to the results of AG ototoxicity studies, high-frequency, basal turn outer hair cells (OHCs) preferentially succumb to multiple HL pathologies while inner hair cells (IHCs) are much more resilient. To determine if endogenous differences in IHC and OHC mitochondrial metabolism dictate differential sensitivities to AG-induced HL, IHC- and OHC-specific changes in mitochondrial reduced nicotinamide adenine dinucleotide (NADH) fluorescence during acute (1 h) GM treatment were compared. GM-mediated decreases in NADH fluorescence and succinate dehydrogenase activity were observed shortly after GM application. High-frequency basal turn OHCs were found to be metabolically biased to rapidly respond to alterations in their microenvironment including GM and elevated glucose exposures. These metabolic biases may predispose high-frequency OHCs to preferentially produce cell-damaging reactive oxygen species during traumatic challenge. Noise-induced and age-related HL pathologies share key characteristics with AG ototoxicity, including preferential OHC loss and reactive oxygen species production. Data from this report highlight the need to address the role of mitochondrial metabolism in regulating AG ototoxicity and the need to illuminate how fundamental differences in IHC and OHC metabolism may dictate differences in HC fate during multiple HL pathologies

MILLER'S ANESTHESIA

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Predicting mortality in acute respiratory distress syndrome: circulatory system knows best.

peer reviewe

Transfusion-related acute lung injury: a review. Chest

Transfusion-related acute lung injury (TRALI) is an underreported complication of transfusion therapy, and it is the third most common cause of transfusion-associated death. TRALI is defined as noncardiogenic pulmonary edema temporally related to transfusion therapy. The diagnosis of TRALI relies on excluding other diagnoses such as sepsis, volume overload, and cardiogenic pulmonary edema. Supportive diagnostic evidence includes identifying neutrophil or human leukocyte antigen (HLA) antibodies in the donor or recipient plasma. All plasma-containing blood products have been implicated in TRALI, with the majority of cases linked to whole blood, packed RBCs, platelets, and fresh-frozen plasma. The pathogenesis of TRALI may be explained by a "two-hit" hypothesis, with the first "hit" being a predisposing inflammatory condition commonly present in the operating room or ICU. The second hit may involve the passive transfer of neutrophil or HLA antibodies from the donor or the transfusion of biologically active lipids from older, cellular blood products. Treatment is supportive, with a prognosis substantially better than most causes of clinical acute lung injury. ( CHEST 2004; 126:249 -258) Key words: ARDS; lung injury; pulmonary edema; transfusion; transfusion-related acute lung injury Abbreviations: ALI ϭ acute lung injury; FDA ϭ Food and Drug Administration; Fio 2 ϭ fraction of inspired oxygen; HLA ϭ human leukocyte antigen; PRBC ϭ packed RBC; TRALI ϭ transfusion-related acute lung injury T ransfusion-related acute lung injury (TRALI) was first coined by Popovsky et al 1 in 1983 to refer to noncardiogenic pulmonary edema complicating transfusion therapy. The syndrome had previously been referred to as pulmonary hypersensitivity reaction, 2,3 allergic pulmonary edema, 4 noncardiogenic pulmonary edema, 5-7 and pulmonary leukoagglutinin reaction. 8 Barnard 9 in 1951 described the first case of fatal pulmonary edema accompanying transfusion therapy. Brittingham 10 in 1957 was the first to initially shed light on the pathogenesis of TRALI. He transfused a strong leukoagglutinin to a volunteer who developed bilateral pulmonary infiltrates. This review will summarize the clinical features of TRALI and highlight potential mechanisms that may precipitate acute lung injury (ALI) and the ARDS. Definition and Clinical Presentation TRALI is defined as noncardiogenic pulmonary edema temporally related to the transfusion of blood products. The development of TRALI has been associated with all plasma-containing blood products, but most commonly involves whole blood, packed RBCs (PRBCs), fresh-frozen plasma, and platelets. TRALI has also occurred after the transfusion of cryoprecipitate and IV Ig. 11

Predicting mortality in the intensive care unit: a comparison of the University Health Consortium expected probability of mortality and the Mortality Prediction Model III.

BackgroundQuality benchmarks are increasingly being used to compare the delivery of healthcare, and may affect reimbursement in the future. The University Health Consortium (UHC) expected probability of mortality (EPM) is one such quality benchmark. Although the UHC EPM is used to compare quality across UHC members, it has not been prospectively validated in the critically ill. We aimed to define the performance characteristics of the UHC EPM in the critically ill and compare its ability to predict mortality with the Mortality Prediction Model III (MPM-III).MethodsThe first 100 consecutive adult patients discharged from the hospital (including deaths) each quarter from January 1, 2009 until September 30, 2011 that had an intensive care unit (ICU) stay were included. We assessed model discrimination, calibration, and overall performance, and compared the two models using Bland-Altman plots.ResultsEight hundred ninety-one patients were included. Both the UHC EPM and the MPM-III had excellent performance (Brier score 0.05 and 0.06, respectively). The area under the curve was good for both models (UHC 0.90, MPM-III 0.87, p = 0.28). Goodness of fit was statistically significant for both models (UHC p = 0.002, MPM-III p = 0.0003), but improved with logit transformation (UHC p = 0.41; MPM-III p = 0.07). The Bland-Altman plot showed good agreement at extremes of mortality, but agreement diverged as mortality approached 50 %.ConclusionsThe UHC EPM exhibited excellent overall performance, calibration, and discrimination, and performed similarly to the MPM-III. Correlation between the two models was poor due to divergence when mortality was maximally uncertain