'Yours Sincerely, Barney': Ralph Waters, Barindra Sircar, and the Training of an International Anesthesiologist.

In 1936, Ralph Milton Waters accepted a proposal to train an Indian physician who could return home and become the first native anesthesiologist in the subcontinent. Waters founded the United States' first anesthesiology residency in 1927 and in 1937 welcomed Barindra Sircar, MBBS, to the University of Wisconsin in Madison. Sircar trained with Waters for two years and did further training with Robert Macintosh and Ivan Magill. He became one of the first specialty-trained anesthesiologists in India and founded the Indian Society of Anaesthesiologists. Fifty-six letters between Sircar and Waters are preserved in the University of Wisconsin archives. The men corresponded until at least 1949, when Waters retired and the archive ends. Sircar's letters were always signed with the nickname he received as a resident: "Yours Sincerely, Barney."

Mode of action of triflumezopyrim: A novel mesoionic insecticide which inhibits the nicotinic acetylcholine receptor.

Triflumezopyrim, a newly commercialized molecule from DuPont Crop Protection, belongs to the novel class of mesoionic insecticides. This study characterizes the biochemical and physiological action of this novel insecticide. Using membranes from the aphid, Myzus persicae, triflumezopyrim was found to displace (3)H-imidacloprid with a Ki value of 43 nM with competitive binding results indicating that triflumezopyrim binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR). In voltage clamp studies using dissociated Periplaneta americana neurons, triflumezopyrim inhibits nAChR currents with an IC50 of 0.6 nM. Activation of nAChR currents was minimal and required concentrations ≥100 µM. Xenopus oocytes expressing chimeric nAChRs (Drosophila α2/chick ß2) showed similar inhibitory effects from triflumezopyrim. In P. americana neurons, co-application experiments with acetylcholine reveal the inhibitory action of triflumezopyrim to be rapid and prolonged in nature. Such physiological action is distinct from other insecticides in IRAC Group 4 in which the toxicological mode of action is attributed to nAChR agonism. Mesoionic insecticides act via inhibition of the orthosteric binding site of the nAChR despite previous beliefs that such action would translate to poor insect control. Triflumezopyrim is the first commercialized insecticide from this class and provides outstanding control of hoppers, including the brown planthopper, Nilaparvata lugens, which is already displaying strong resistance to neonicotinoids such as imidacloprid.

Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.

Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 µg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

4-Azolylphenyl isoxazoline insecticides acting at the GABA gated chloride channel.

Isoxazoline insecticides have been shown to be potent blockers of insect GABA receptors with excellent activity on a broad pest range, including Lepidoptera and Hemiptera. Herein we report on the synthesis, biological activity and mode-of-action for a class of 4-heterocyclic aryl isoxazoline insecticides.

Military anesthesia trainees in WWII at the University of Wisconsin: their training, careers, and contributions.

The emerging medical specialty of anesthesiology experienced significant advances in the decade prior to World War II but had limited numbers of formally trained practitioners. With war looming, a subcommittee of the National Research Council, chaired by Ralph M. Waters, MD., was charged with ensuring sufficient numbers of anesthesiologists for military service. A 12-week course was developed to train military physicians at academic institutions across the country, including the Wisconsin General Hospital. A total of 17 officers were trained in Madison between September 1942 and December 1943. Notably, Virgil K. Stoelting, the future chair of anesthesiology at Indiana University, was a member of this group.A rigorous schedule of study and clinical work ensured the officers learned to administer anesthesia safely while using a variety of techniques. Their leadership and contributions in the military and after the war contributed significantly to the further growth of anesthesiology.

Opportunities and responsibilities for pharmacists on short-term medical mission teams.

BACKGROUND: American medical mission teams commonly travel to developing countries for short-term provision of clinical services. Although medications play an important role in the work of these teams, how to plan and organize a mission field pharmacy has been seldom described in the literature. OBJECTIVE: To describe pharmacist participation in medical mission work. SUMMARY: Global standards and policies, as well as traditional best practices, should be applied to the selection, acquisition, use, and disposition of medications taken into a host country. This report describes the roles and responsibilities of pharmacists in planning and organizing a mission pharmacy and in delivering quality pharmacy services in the field. CONCLUSION: Pharmacists have an important contribution to make to medical mission teams. Pharmacist knowledge of drug products, regulatory issues, medication storage, dispensing, patient consultation, therapeutic substitution, and pharmacy organization and workflow is ideally suited for mission field work.

Using failure mode and effects analysis to plan implementation of smart i.v. pump technology.

PURPOSE: Failure mode and effects analysis (FMEA) was used to evaluate a smart i.v. pump as it was implemented into a redesigned medication-use process. SUMMARY: A multidisciplinary team conducted a FMEA to guide the implementation of a smart i.v. pump that was designed to prevent pump programming errors. The smart i.v. pump was equipped with a dose-error reduction system that included a pre-defined drug library in which dosage limits were set for each medication. Monitoring for potential failures and errors occurred for three months postimplementation of FMEA. Specific measures were used to determine the success of the actions that were implemented as a result of the FMEA. The FMEA process at the hospital identified key failure modes in the medication process with the use of the old and new pumps, and actions were taken to avoid errors and adverse events. I.V. pump software and hardware design changes were also recommended. Thirteen of the 18 failure modes reported in practice after pump implementation had been identified by the team. A beneficial outcome of FMEA was the development of a multidisciplinary team that provided the infrastructure for safe technology implementation and effective event investigation after implementation. With the continual updating of i.v. pump software and hardware after implementation, FMEA can be an important starting place for safe technology choice and implementation and can produce site experts to follow technology and process changes over time. CONCLUSION: FMEA was useful in identifying potential problems in the medication-use process with the implementation of new smart i.v. pumps. Monitoring for system failures and errors after implementation remains necessary.

Treatment of pain crisis at end of life from severe lower extremity venous outflow obstruction with hyperalgesia and allodynia.

Pain crisis in metastatic disease can be a therapeutic dilemma when differing mechanisms contribute to severe hyperalgesia and neuropathic pain. We discuss clinical presentation and management of excruciating pain from severe lower limb venous outflow obstruction in an opioid tolerant, terminally ill patient with locally invasive and metastatic adenocarcinoma of the cervix. This case illustrates how pain crises at end of life can be successfully managed by using a rational, complementary, multimodal approach. Key points include possible mechanisms of pain from venous outflow obstruction, benefit of hyperbaric subarachnoid bupivacaine, opioid rotation to methadone, and use of ketamine by mouth.