The Sodium/Proton Exchanger NHE8 Regulates Late Endosomal Morphology and Function

The pH and lumenal environment of intracellular organelles is considered essential for protein sorting and trafficking through the cell. We provide the first evidence that a mammalian sodium (potassium)/proton exchanger, NHE8, plays a key role in the control of protein trafficking and endosome morphology

How do pharmacists select antimicrobials? A model of pharmacists’ therapeutic reasoning processes

INTRODUCTIONClinicians engage in clinical reasoning, comprised of both diagnostic and therapeutic components, when caring for patients. While diagnostic reasoning has been extensively investigated, relatively few studies have examined how clinicians make treatment decisions. Recent work has explored how physicians engage in therapeutic reasoning while selecting antimicrobials. However, understanding pharmacists’ antimicrobial reasoning is equally important due to their role in ensuring appropriate antimicrobial use. Therefore, we aimed to further our understanding of antimicrobial reasoning in pharmacists and compare their reasoning processes to physicians.METHODSWith a postpositivist orientation and using a general qualitative approach, we conducted semi‐structured interviews with hospital‐based pharmacists specializing in infectious diseases or other hospital‐based specialties. Participants narrated their thought processes while selecting antimicrobials for three case vignettes. We analyzed transcripts iteratively using a code book from a prior study of antimicrobial reasoning in physicians as a sensitizing framework.RESULTSParticipants included 11 pharmacists (5 infectious diseases and 6 noninfectious diseases pharmacists). Overall, participants’ responses reflected a three‐step reasoning process: Naming the Syndrome, Delineating Pathogens, and Selecting the Antimicrobial. Patient‐, syndrome‐, and system‐based factors interacted with drug characteristics to influence the selection of specific antimicrobial regimens.CONCLUSIONWe identified a framework for pharmacists’ antimicrobial therapeutic reasoning similar to physicians’ reasoning, with some nuances that may be attributable to the pharmacists’ role in medication review and antimicrobial stewardship. Application of this framework has the potential to aid in teaching, improve multidisciplinary care, and provide a framework for interprofessional communication.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172005/1/jac51580.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172005/2/jac51580_am.pd

Challenges and advances in the medical treatment of granulomatous amebic encephalitis.

Granulomatous amebic encephalitis, caused by the free-living amebae Balamuthia mandrillaris or Acanthamoeba species, is a rare and deadly infectious syndrome with a current mortality rate of >90%. Much work remains to define the optimal treatment for these infections. Here, we provide a comprehensive overview of the supporting evidence behind antimicrobials currently recommended by the Centers for Disease Control and Prevention (CDC) with updated statistics on survival rates and medication usage from the CDC Free-Living Ameba Database. We also discuss promising treatments, especially the emerging therapeutic agent nitroxoline, and provide recommendations for the next steps in this area

Challenges and advances in the medical treatment of granulomatous amebic encephalitis

Granulomatous amebic encephalitis, caused by the free-living amebae Balamuthia mandrillaris or Acanthamoeba species, is a rare and deadly infectious syndrome with a current mortality rate of >90%. Much work remains to define the optimal treatment for these infections. Here, we provide a comprehensive overview of the supporting evidence behind antimicrobials currently recommended by the Centers for Disease Control and Prevention (CDC) with updated statistics on survival rates and medication usage from the CDC Free-Living Ameba Database. We also discuss promising treatments, especially the emerging therapeutic agent nitroxoline, and provide recommendations for the next steps in this area

A Comprehensive Survey of Infectious Diseases Curriculum Among US Pharmacy Schools

Objective. To describe what and how infectious diseases (ID) topics are taught in US schools of pharmacy and summarize pharmacy faculty members' and students' perceived successes and challenges in teaching and learning about ID. Methods. A 23-item survey instrument was distributed electronically to ID faculty members at 137 US pharmacy schools. Data collected included curricular hours and format, topics covered, active-learning strategies, and curricular successes and concerns. Results. Surveys were collected from 106 schools (77% response rate). Infectious diseases curricula were allotted a median of 60 (IQR=40) hours of classroom time. Respondents dedicated 33% of curriculum hours to ID fundamentals and 66% to disease states. Greater than 94% of schools taught all tier one ID topics from the 2016 American College of Clinical Pharmacy Pharmacotherapy Didactic Curriculum Toolkit. Curricula were primarily delivered through traditional lectures rather than active learning (75% vs 25% of classroom time, respectively). The median number of active-learning strategies used was four (IQR=3). The most common active-learning modalities used either consistently or frequently were patient case application (98%) and audience response systems (76%). The most common successes cited by faculty members were implementation of active learning, the "real-world" applicability of the ID topics, and the breadth of topics and topic exposure covered in the curriculum. The most common concerns were a lack of time to cover material and the amount of material covered. Conclusion. Increased communication and collaboration between ID educators is warranted to increase consistency of ID education and distribution of educational innovations

sj-docx-1-tai-10.1177_20499361241228340 – Supplemental material for Challenges and advances in the medical treatment of granulomatous amebic encephalitis

Supplemental material, sj-docx-1-tai-10.1177_20499361241228340 for Challenges and advances in the medical treatment of granulomatous amebic encephalitis by Natasha Spottiswoode, Julia C. Haston, Natasha W. Hanners, Katherine Gruenberg, Annie Kim, Joseph L. DeRisi and Michael R. Wilson in Therapeutic Advances in Infectious Disease</p

Acetaminophen inhibits cytochrome c redox cycling induced lipid peroxidation

Cytochrome (cyt) c can uncouple from the respiratory chain following mitochondrial stress and catalyze lipid peroxidation. Accumulating evidence shows that this phenomenon impairs mitochondrial respiratory function and also initiates the apoptotic cascade. Therefore, under certain conditions a pharmacological approach that can inhibit cyt c catalyzed lipid peroxidation may be beneficial. We recently showed that acetaminophen (ApAP) at normal pharmacologic concentrations can prevent hemoprotein-catalyzed lipid peroxidation in vitro and in vivo by reducing ferryl heme to its ferric state. We report here, for the first time, that ApAP inhibits cytochrome c-catalyzed oxidation of unsaturated free fatty acids and also the mitochondrial phospholipid, cardiolipin. Using isolated mitochondria, we also showed that ApAP inhibits cardiolipin oxidation induced by the pro-apoptotic protein, tBid. We found that the IC(50) of the inhibition of cardiolipin oxidation by ApAP is similar in both intact isolated mitochondria and cardiolipin liposomes, suggesting that ApAP penetrates well into the mitochondria. Together with our previous results, the findings presented herein suggest that ApAP is a pleiotropic inhibitor of peroxidase catalyzed lipid peroxidation. Our study also provides a potentially novel pharmacological approach for inhibiting the cascade of events that can result from redox cycling of cyt c

Annexin A2 Regulates Phagocytosis of Photoreceptor Outer Segments in the Mouse Retina

The daily phagocytosis of shed photoreceptor outer segments by pigment epithelial cells is critical for the maintenance of the retina. In a subtractive polymerase chain reaction analysis, we found that functional differentiation of human ARPE19 retinal pigment epithelial (RPE) cells is accompanied by up-regulation of annexin (anx) A2, a major Src substrate and regulator of membrane–cytoskeleton dynamics. Here, we show that anx A2 is recruited to the nascent phagocytic cup in vitro and in vivo and that it fully dissociates once the phagosome is internalized. In ARPE19 cells depleted of anx A2 by using small interfering RNA and in ANX A2−/− mice the phagocytosis of outer segments was impaired, and in ANX A2−/− mice there was an accumulation of phagocytosed outer segments in the RPE apical processes, indicative of retarded phagosome transport. We show that anx A2 is tyrosine phosphorylated at the onset of phagocytosis and that the synchronized activation of focal adhesion kinase and c-Src is abnormal in ANX A2−/− mice. These findings reveal that anx A2 is involved in the circadian regulation of outer segment phagocytosis, and they provide new insight into the protein machinery that regulates phagocytic function in RPE cells

Essential Role of hIST1 in Cytokinesis

The last steps of multivesicular body (MVB) formation, human immunodeficiency virus (HIV)-1 budding and cytokinesis require a functional endosomal sorting complex required for transport (ESCRT) machinery to facilitate topologically equivalent membrane fission events. Increased sodium tolerance (IST) 1, a new positive modulator of the ESCRT pathway, has been described recently, but an essential function of this highly conserved protein has not been identified. Here, we describe the previously uncharacterized KIAA0174 as the human homologue of IST1 (hIST1), and we report its conserved interaction with VPS4, CHMP1A/B, and LIP5. We also identify a microtubule interacting and transport (MIT) domain interacting motif (MIM) in hIST1 that is necessary for its interaction with VPS4, LIP5 and other MIT domain-containing proteins, namely, MITD1, AMSH, UBPY, and Spastin. Importantly, hIST1 is essential for cytokinesis in mammalian cells but not for HIV-1 budding, thus providing a novel mechanism of functional diversification of the ESCRT machinery. Last, we show that the hIST1 MIM activity is essential for cytokinesis, suggesting possible mechanisms to explain the role of hIST1 in the last step of mammalian cell division