Hormonal basis of sex differences in anesthetic sensitivity.

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.

Henry Jacob Bigelow Inhaled Nitrous Oxide While an Undergraduate at Harvard College.

When teenaged Henry Jacob Bigelow was an undergraduate at Harvard College in 1833-1837, he prepared nitrous oxide gas for demonstrations to other students. Bigelow's son, William Sturgis Bigelow, related the claim, and there is an eyewitness account from Augustus Goddard Peabody, a fellow Harvard undergraduate with Bigelow. Peabody wrote to Henry David Thoreau about a nitrous frolic. College chemistry primed Bigelow to support the concept of inhaled surgical anesthesia when the idea came to Boston in 1845-1846. Bigelow's chemistry professor was John White Webster. According to Harvard alumnus Edward Everett Hale, in addition to demonstrating effects of nitrous oxide, Webster presciently treated two cases of carbon monoxide poisoning with copious volumes of synthetic oxygen gas. The career of Webster was inhibited by financial difficulties that were suspected to be contributory when he was convicted of the 1849 murder of physician George Parkman at the Harvard Medical School, then adjacent to Massachusetts General Hospital and its Ether Dome. Webster suffered the death penalty in 1850.

Spinal Cord Stimulation vs Conventional Therapies for the Treatment of Chronic Low Back and Leg Pain: A Systematic Review of Health Care Resource Utilization and Outcomes in the Last Decade.

OBJECTIVE: The purpose of this review is to critically appraise the literature for evidence supporting the health care resource utilization and cost-effectiveness of spinal cord stimulation (SCS) compared with conventional therapies (CTs) for chronic low back and leg pain. METHODS: The PubMed, MEDLINE, Embase, CINAHL, and Rehabilitation & Sports Medicine databases were searched for studies published from January 2008 through October 2018, using the following MeSH terms: "spinal cord stimulation," "chronic pain," "back pain," "patient readmission," "economics," and "costs and cost analysis." Additional sources were added based on bibliographies and consultation with experts. The following data were extracted and analyzed: demographic information, study design, objectives, sample sizes, outcome measures, SCS indications, complications, costs, readmissions, and resource utilization data. RESULTS: Of 204 studies screened, 11 studies met inclusion criteria, representing 31,439 SCS patients and 299,182 CT patients. The mean age was 53.5 years for SCS and 55.6 years for CT. In eight of 11 studies, SCS was associated with favorable outcomes and found to be more cost-effective than CT for chronic low back pain. Compared with CT, SCS resulted in shorter hospital stays and lower complication rates and health care costs at 90 days. SCS was associated with significant improvement in health-related quality of life, health status, and quality-adjusted life-years. CONCLUSIONS: For the treatment of chronic low back and leg pain, the majority of studies are of fair quality, with level 3 or 4 evidence in support of SCS as potentially more cost-effective than CT, with less resource expenditure but higher complication rates. SCS therapy may yet play a role in mitigating the financial burden associated with chronic low back and leg pain.

Divine's CO2 Absorber of 1867.

Chemist and inventor Silas R. Divine (1838-1912) sold ammonium nitrate and other anesthesia supplies in New York City. He offered a carbon dioxide absorber for the purpose of rebreathing nitrous oxide. Like his colleague Gardner Q. Colton, he denied the need for nitrous oxide to be supplemented with O2 gas.

George Washington Frost Mellen and Resuscitation with Nitrous Oxide in 1847.

In The Boston Medical and Surgical Journal of 1847 (later to be called The New England Journal of Medicine), Boston chemist George Washington Frost Mellen claimed that inhaled nitrous oxide gas supports human life in the manner of oxygen gas, and he proposed the use of nitrous oxide in resuscitation from drowning and from carbon monoxide poisoning. The claim was reprinted in at least one dental journal and was long cited as justification for the use of 100% nitrous oxide for inhaled anesthesia. Advocates included anesthesia pioneer and painless dentist Gardner Quincy Colton. Though misguided as to nitrous oxide, Mellen was a prominent member of the Boston community for the abolition of slavery.

Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis.

OBJECTIVE: To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer. METHODS: Published data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment. RESULTS: Thirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13-2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09-2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01-1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06-1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09-1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control. CONCLUSIONS: VEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.

Amygdala stimulation evokes time-varying synaptic responses in the gustatory cortex of anesthetized rats.

Gustatory stimuli are characterized by a specific hedonic value; they are either palatable or aversive. Hedonic value, along with other psychological dimensions of tastes, is coded in the time-course of gustatory cortex (GC) neural responses and appears to emerge via top-down modulation by the basolateral amygdala (BLA). While the importance of BLA in modulating gustatory cortical function has been well established, the nature of its input onto GC neurons is largely unknown. Somewhat conflicting results from extracellular recordings point to either excitatory or inhibitory effects. Here, we directly test the hypothesis that BLA can evoke time-varying - excitatory and inhibitory - synaptic responses in GC using in vivo intracellular recording techniques in urethane anesthetized rats. Electrical stimulation of BLA evoked a post-synaptic potential (PSP) in GC neurons that resulted from a combination of short and long latency components: an initial monosynaptic, glutamatergic potential followed by a multisynaptic, GABAergic hyperpolarization. As predicted by the dynamic nature of amygdala evoked potentials, trains of five BLA stimuli at rates that mimic physiological firing rates (5-40 Hz) evoke a combination of excitation and inhibition in GC cells. The magnitude of the different components varies depending on the frequency of stimulation, with summation of excitatory and inhibitory inputs reaching its maximum at higher frequencies. These experiments provide the first description of BLA synaptic inputs to GC and reveal that amygdalar afferents can modulate gustatory cortical network activity and its processing of sensory information via time-varying synaptic dynamics.

Elton Romeo Smilie, the not-quite discoverer of ether anesthesia.

Like William T.G. Morton, Elton Romeo Smilie (1819-1889) was raised in Massachusetts, attended medical school in New England, practiced dentistry there, strove for clinical invention, and moved to Boston. In October 1846, both announced that inhaled ethereal preparations achieved reversible insensibility in surgical patients. Smilie published a report in the Boston Med Surg J 3 wk before Bigelow used that forum to broadcast Morton's Ether Day. Smilie's preparation was an ethereal tincture of opium, and, as he mistakenly believed the opium to be volatile and important, he ceded priority to Morton for ether anesthesia. The two authors collaborated on chloroform, but Smilie soon headed off in the Gold Rush to California. It is tempting to speculate that Charles T. Jackson and Morton were indebted in part to Smilie.

The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression.

Proper neuronal function and several forms of synaptic plasticity are highly dependent on precise control of mRNA translation, particularly in dendrites. We find that eIF4AIII, a core exon junction complex (EJC) component loaded onto mRNAs by pre-mRNA splicing, is associated with neuronal mRNA granules and dendritic mRNAs. eIF4AIII knockdown markedly increases both synaptic strength and GLUR1 AMPA receptor abundance at synapses. eIF4AIII depletion also increases ARC, a protein required for maintenance of long-term potentiation; arc mRNA, one of the most abundant in dendrites, is a natural target for nonsense-mediated decay (NMD). Numerous new NMD candidates, some with potential to affect synaptic activity, were also identified computationally. Two models are presented for how translation-dependent decay pathways such as NMD might advantageously function as critical brakes for protein synthesis in cells such as neurons that are highly dependent on spatially and temporally restricted protein expression.

Hippocampal inactivation enhances taste learning.

Learning tasks are typically thought to be either hippocampal-dependent (impaired by hippocampal lesions) or hippocampal-independent (indifferent to hippocampal lesions). Here, we show that conditioned taste aversion (CTA) learning fits into neither of these categories. Rats were trained to avoid two taste stimuli, one novel and one familiar. Muscimol infused through surgically implanted intracranial cannulae temporarily inactivated the dorsal hippocampus during familiarization, subsequent CTA training, or both. As shown previously, hippocampal inactivation during familiarization enhanced the effect of that familiarization on learning (i.e., hippocampal inactivation enhanced latent inhibition of CTA); more novel and surprising, however, was the finding that hippocampal inactivation during training sessions strongly enhanced CTA learning itself. These phenomena were not caused by specific aspects of our infusion technique--muscimol infusions into the hippocampus during familiarization sessions did not cause CTAs, muscimol infusions into gustatory cortex caused the expected attenuation of CTA, and hippocampal inactivation caused the expected attenuation of spatial learning. Thus, we suggest that hippocampal memory processes interfere with the specific learning mechanisms underlying CTA, and more generally that multiple memory systems do not operate independently.

"Ask A Librarian": the experiences of four hospital libraries.

The librarians at four hospital libraries describe the electronic reference service, "Ask A Librarian," offered at their institutions. The hospitals are vastly different in size and in number of library staff, and offer the "Ask A Librarian" service to different clientele. The article illustrates that both large hospitals with a large library staff and small hospitals with a solo librarian and some volunteers can offer this type of service.