The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species.

Mitochondrial fission mediated by the GTPase dynamin-related protein 1 (Drp1) is an attractive drug target in numerous maladies that range from heart disease to neurodegenerative disorders. The compound mdivi-1 is widely reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate brain injury. Here, we show that mdivi-1 reversibly inhibits mitochondrial complex I-dependent O2 consumption and reverse electron transfer-mediated reactive oxygen species (ROS) production at concentrations (e.g., 50 µM) used to target mitochondrial fission. Respiratory inhibition is rescued by bypassing complex I using yeast NADH dehydrogenase Ndi1. Unexpectedly, respiratory impairment by mdivi-1 occurs without mitochondrial elongation, is not mimicked by Drp1 deletion, and is observed in Drp1-deficient fibroblasts. In addition, mdivi-1 poorly inhibits recombinant Drp1 GTPase activity (Ki > 1.2 mM). Overall, these results suggest that mdivi-1 is not a specific Drp1 inhibitor. The ability of mdivi-1 to reversibly inhibit complex I and modify mitochondrial ROS production may contribute to effects observed in disease models.

Cellular alterations in human traumatic brain injury: changes in mitochondrial morphology reflect regional levels of injury severity.

Mitochondrial dysfunction may be central to the pathophysiology of traumatic brain injury (TBI) and often can be recognized cytologically by changes in mitochondrial ultrastructure. This study is the first to broadly characterize and quantify mitochondrial morphologic alterations in surgically resected human TBI tissues from three contiguous cortical injury zones. These zones were designated as injury center (Near), periphery (Far), and Penumbra. Tissues from 22 patients with TBI with varying degrees of damage and time intervals from TBI to surgical tissue collection within the first week post-injury were rapidly fixed in the surgical suite and processed for electron microscopy. A large number of mitochondrial structural patterns were identified and divided into four survival categories: normal, normal reactive, reactive degenerating, and end-stage degenerating profiles. A tissue sample acquired at 38 hours post-injury was selected for detailed mitochondrial quantification, because it best exhibited the wide variation in cellular and mitochondrial changes consistently noted in all the other cases. The distribution of mitochondrial morphologic phenotypes varied significantly between the three injury zones and when compared with control cortical tissue obtained from an epilepsy lobectomy. This study is unique in its comparative quantification of the mitochondrial ultrastructural alterations at progressive distances from the center of injury in surviving TBI patients and in relation to control human cortex. These quantitative observations may be useful in guiding the translation of mitochondrial-based neuroprotective interventions to clinical implementation.

Quality indicators of fresh frozen plasma and platelet utilization.

OBJECTIVE: To determine the normative rates of expiration and wastage for units of fresh frozen plasma (FFP) and platelets (PLTs) in hospital communities throughout the United States, and to examine hospital blood bank practices associated with more desirable (lower) rates. DESIGN: In 3 separate studies, participants in the College of American Pathologists Q-Probes laboratory quality improvement program collected data retrospectively on the numbers of units of FFP and PLTs that expired (outdated) prior to being used and that were wasted due to mishandling. Participants also completed questionnaires describing their hospitals' and blood banks' laboratory and transfusion practices. SETTING AND PARTICIPANTS: One thousand six hundred thirty-nine public and private institutions, more than 80% of which were known to be located in the United States. MAIN OUTCOME MEASURES: Quality indicators of FFP and PLT utilization: the rates of expiration and wastage of units of FFP and PLTs. RESULTS: Participants submitted data on 8 981 796 units of FFP and PLTs. In all 3 studies, aggregate combined FFP and PLT expiration rates ranged from 5.8% to 6.4% and aggregate combined FFP and PLT wastage rates ranged from 2.0% to 2.5%. Among the top-performing 10% of participants (90th percentile and above), FFP and PLT expiration rates were 0.6% or lower and FFP and PLT wastage rates were 0.5% or lower. Among the bottom-performing 10% of participants (10th percentile and below), expiration rates were 13.8% or higher and wastage rates were 6.8% or higher. We were unable to associate selected hospital characteristics or blood bank practices with lower rates of FFP and PLT utilization. CONCLUSIONS: The rates of FFP and PLT expiration and wastage vary greatly among hospitals in the United States. Hospital blood bank personnel are capable of achieving FFP and PLT expiration and wastage rates below 1%.

Quality indicators of blood utilization: three College of American Pathologists Q-Probes studies of 12,288,404 red blood cell units in 1639 hospitals.

OBJECTIVES: To determine the normative rates of blood unit crossmatched to transfused (C:T) ratios, red blood cell (RBC) unit wastage, and RBC unit expiration that exist in hospital communities throughout the United States, and to examine hospital blood bank practices associated with more desirable (lower) rates. DESIGN: In 3 separate studies, participants in the College of American Pathologists Q-Probes laboratory quality improvement program collected data retrospectively on the number of transfusion crossmatches performed in their institutions and the number of RBC-containing units that were transfused into patients, the number of units that expired (outdated) prior to being utilized, and the number that were wasted due to mishandling. Participants also completed questionnaires describing their hospitals' and blood banks' laboratory and transfusion practices. SETTING AND PARTICIPANTS: One thousand six hundred thirty-nine public and private institutions, well more than 80% of which were known to be located in the United States. MAIN OUTCOME MEASURES: Quality indicators of blood utilization (namely, the C:T ratio, the rate of RBC unit expiration, and the rate of RBC unit wastage). RESULTS: Participants submitted data on 12,288,404 RBC unit transfusions. The C:T ratios were 1.5 or less in the top-performing 10% of participating institutions (90th percentile and above), 1.8 to 1.9 in the midrange of participating institutions (50th percentile), and 2.4 or greater in the bottom-performing 10% of participating institutions (10th percentile and below). Red blood cell unit expiration rates were 0.1% or less at the 90th percentile and above, 0.3% to 0.9% at the 50th percentile, and 3.5% or greater at the 10th percentile and below. Red blood cell unit wastage rates were 0.1% or less at the 90th percentile and above, 0.1% to 0.4% at the 50th percentile, and 0.7% or greater at the 10th percentile and below. Depending on which quality indicator was examined, lower values (ie, better performances) were found in institutions that had fewer than 200 hospital beds, no teaching programs, no on-site full-time medical directors of transfusion services, did not utilize maximum surgical blood order schedules, set C:T threshold goals of 2.0 or less, monitored categories of health care workers responsible for RBC wastage, monitored requests for RBC components by transfusion indication, did not accept short-dated units from blood distribution centers, and if they did accept short-dated units, were allowed to return those units to the distribution centers. CONCLUSIONS: Hospital blood bank personnel can achieve C:T ratios below 2.0, RBC unit expiration rates below 1.0%, and RBC unit wastage rates below 0.5%. Lower C:T ratios and/or RBC unit expiration rates were associated with blood bank personnel setting C:T thresholds of 2.0 or less, monitoring requests for blood components by transfusion indication criteria, monitoring categories of health care workers responsible for blood wastage, not accepting short-dated units from blood distribution centers, and if short-dated units were accepted, being allowed to return those units to the blood distribution center. These practices were not associated with lower blood wastage rates.