Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression.

Chronic wasting disease (CWD) is a prion disease of free-ranging and farmed cervids that is highly contagious because of extensive prion shedding and prion persistence in the environment. Previously, cellulose ether compounds (CEs) have been shown to significantly extend the survival of mice inoculated with mouse-adapted prion strains. In this study, we used CEs, TC-5RW, and 60SH-50, in vitro and in vivo to assess their efficacy to interfere with CWD prion propagation. In vitro, CEs inhibited CWD prion amplification in a dose-dependent manner. Transgenic mice over-expressing elk PrPC (tgElk) were injected subcutaneously with a single dose of either of the CEs, followed by intracerebral inoculation with different CWD isolates from white tailed deer, mule deer, or elk. All treated groups showed a prolonged survival of up to more than 30 % when compared to the control group regardless of the CWD isolate used for infection. The extended survival in the treated groups correlated with reduced proteinase K resistance of prions. Remarkably, passage of brain homogenates from treated or untreated animals in tgElk mice resulted in a prolonged life span of mice inoculated with homogenates from CE-treated mice (of + 17%) even in the absence of further treatment. Besides the delayed disease onset upon passage in TgElk mice, the reduced proteinase K resistance was maintained but less pronounced. Therefore, these compounds can be very useful in limiting the spread of CWD in captive and wild-ranging cervids.

Ether in the developing world: rethinking an abandoned agent.

BACKGROUND: The first true demonstration of ether as an inhalation anesthetic was on October 16, 1846 by William T.G. Morton, a Boston dentist. Ether has been replaced completely by newer inhalation agents and open drop delivery systems have been exchanged for complicated vaporizers and monitoring systems. Anesthesia in the developing world, however, where lack of financial stability has halted the development of the field, still closely resembles primitive anesthetics. DISCUSSION: In areas where resources are scarce, patients are often not given supplemental intraoperative analgesia. While halothane provides little analgesia, ether provides excellent intra-operative pain control that can extend for several hours into the postoperative period. An important barrier to the widespread use of ether is availability. With decreasing demand, production of the inexpensive inhalation agent has fallen. Ether is inexpensive to manufacture, and encouraging increased production at a local level would help developing nations to cut costs and become more self-sufficient.

The outlook of physician histories: J. Marion Sims and 'The Discovery of Anaesthesia'.

The fact that doctors have a long tradition of writing medical history to interpret and direct their profession is well established. But readers (particularly modern physician readers) can also understand physician-authored histories as offering commentary and analysis of the world beyond medicine. In this essay, we offer a reading (perhaps a modern one) of J. Marion Sims's 1877 article, 'The Discovery of Anaesthesia' which exemplifies the stance of looking both inward and outward from the medical field. We begin by discussing Sims, including the complicated legacy he left as a physician. Next, we review late 19th-century history with a focus on Reconstruction. Finally, we show how the modern reader can use Sims's article both to trace the first use of ether and nitrous oxide for surgical anaesthesia and to provide a window into the 19th-century medical profession and the post-Civil War period. Through this study, we hope to show how to read both medicine and the world around it in physician histories.

Special article: Horace Nelson MD, John Webster LDS--unrecognized Canadian anesthesia pioneers.

PURPOSE: The timing of the earliest reported ether anesthetics in early 1847, in regions to become Canada in July 1867, was examined using information from on-line and library-based sources. Previous authors had identified the first reported ether anesthetic given by a visiting American dentist in January 1847 in Saint John, New Brunswick. Nevertheless, they had reported three different anesthetics as the second occurrence - which would denote the first anesthetic given by a resident of Canada. PRINCIPAL FINDINGS: We confirmed that there were no reports of ether anesthetics being given in Canada before that reported on January 18, 1847 in Saint John. The information available for our review indicates that the second ether anesthetic, and the first by a Canadian, was given in Montreal by a dentist, Dr. John Horatio Webster, on February 20, 1847. The surgical assistant for that operation, Dr. Horace Nelson, later reported on animal and human experiments with ether, which he had led in Montreal starting in January 1847. CONCLUSION: Earlier authors, who may not have had access to the information now available, came to incorrect conclusions about the first ether anesthetic reported to have been given by a Canadian. Current information indicates that John Webster gave the first reported anesthetic in Montreal on February 20, 1847 following experiments with ether led by Horace Nelson. Both Webster and Nelson deserve recognition as Canadian anesthesia pioneers.

Correspondence by Charles T. Jackson containing the earliest known illustrations of a Morton ether inhaler.

A letter, dated December 1, 1846, from Charles T. Jackson, MD, to Josiah D. Whitney contains a previously unreported description of a Morton ether inhaler and the only known contemporaneous hand-drawn illustrations of this type of ether inhaler. This letter and 2 other known letters on ether anesthesia were probably carried from Boston, MA, to Liverpool, United Kingdom, on the same paddle steamer (Acadia) that carried the well-known letter from Jacob Bigelow, MD, to Francis Boott, MD.

Researches regarding the Morton ether inhaler at Massachusetts General Hospital, Boston.

The Morton ether inhaler in the possession of Massachusetts General Hospital, Boston, MA, was traced back to 1906 when the earliest known photograph of it was published. The authors believe that the inhaler was given by William T. G. Morton, MD, to J. Mason Warren, MD, in January 1847. The inhaler was acquired by the Warren Anatomical Museum at an unknown date, loaned to Massachusetts General Hospital in October 1946, and placed on permanent loan to Massachusetts General Hospital in April 1948. Many documents relating to the inhaler have disappeared, and it was only identified in 2009 as the inhaler that probably belonged to J. Mason Warren, MD. The inhaler is not believed to be the one that Morton used on October 16, 1846, at Massachusetts General Hospital. It is the only known example of a Morton ether inhaler with valves (excluding replicas or reproduction inhalers) and is probably of similar design to the inhaler that Morton used on October 16, 1846.

Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal.

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

[The development of vaporizers. A question of precise dose]. / Die Entwicklung des Vapors--Eine Frage der präzisen Dosierung.

Since the beginning of anaesthesia it was well known that anaesthetic agents administered by inhalation must be capable of existing in gaseous form. For vaporization various types tried to work accurately. Since oxygen was available there could be realized new concepts like the principles of injection or bubble through. With Copper Kettle (1948) for ether and chloroform and Draeger Vapor (1958) for Halothane accurate administration of volatile anaesthetics was available. Today vaporizers are part of anaesthetic machines.

Superior gallstone dissolubility and safety of tert-amyl ethyl ether over methyl-tertiary butyl ether.

BACKGROUND: The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE. AIM: To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity. METHODS: The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones. RESULTS: The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE. CONCLUSION: We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

The Perfect and Famous Anesthetic Known as Methyl in Boston in 1895.

Extravagant claims were made for proprietary dental anesthetics in Boston, MA, in the late 1800s. For instance, in 1883, Urial K. Mayo introduced an inhaled Vegetable Anaesthetic comprised of nitrous oxide that had been uselessly pretreated with botanical material. This misguided concept may have been inspired by homeopathy, but it was also in line with the earlier false belief of Elton R. Smilie, Charles T. Jackson, and William T.G. Morton that sulfuric ether could volatilize opium at room temperature. In 1895, the Dental Methyl Company advertised an agent they called Methyl, a supposedly perfect topical anesthetic for painless dental extraction. The active ingredient was probably chloroform. Anesthetic humbug did not cease in Boston on Ether Day of October 16, 1846.

Ether Anesthesia in the Austere Environment: An Exposure and Education.

Medical services in the austere and limited environment often require therapeutics and practices uncommon in modern times due to a lack of availability, affordability, or expertise in remote areas. In this setting, diethyl ether, or simply ether anesthesia, still serves a role today as an effective inhalation agent. An understanding of ether as an anesthetic not only illustrates the evolution in surgical anesthesia but also demonstrates ether's surviving function and durable use as a practical agent in developing nations. Although uncommon, it is not unseen, so a working knowledge should be understood if observation and advocacy for patients receiving this method of anesthesia are experienced.

A Newly Discovered Manuscript of Charles T. Jackson, MD, on the Preparation and Administration of Anesthetics for Humans and Animals.

A newly discovered handwritten manuscript of Charles T. Jackson, MD, contains instructions for the preparation and administration of sulfuric ether, information on Jackson's preferred mixture of ether and chloroform, an account of his experiments with other potential anesthetic agents, and his comments on etherizing cattle and other animals. Jackson's nine-page manuscript is believed to have been written in the autumn of 1851, around the time that he submitted his memorial on the discovery of etherization to Baron von Humboldt, and made a separate submission to the US Congress.

Sex differences in the traumatic stress response: the role of adult gonadal hormones.

BACKGROUND: Our previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones? METHODS: For the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined. RESULTS: We now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females. CONCLUSIONS: We propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.