Nitrite reacts with deoxyhemoglobin to form nitric oxide (NO) and methemoglobin. Though this reaction is experimentally associated with NO generation and vasodilation, kinetic analysis suggests that NO should not be able to escape inactivation in the erythrocyte. We have discovered that products of the nitrite-hemoglobin reaction generate dinitrogen trioxide (N2O3) via a novel reaction of NO and nitrite-bound methemoglobin. The oxygen-bound form of nitrite-methemoglobin shows a degree of ferrous nitrogen dioxide (Fe(II)-NO2*) character, so it may rapidly react with NO to form N2O3. N2O3 partitions in lipid, homolyzes to NO and readily nitrosates thiols, all of which are common pathways for NO escape from the erythrocyte. These results reveal a fundamental heme globin- and nitrite-catalyzed chemical reaction pathway to N2O3, NO and S-nitrosothiol that could form the basis of in vivo nitrite-dependent signaling. Because the reaction redox-cycles (that is, regenerates ferrous heme) and the nitrite-methemoglobin intermediate is not observable by electron paramagnetic resonance spectroscopy, this reaction has been 'invisible' to experimentalists over the last 100 years.

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Insulin resistance has been associated with higher plasma amino acid (AA) concentrations, but majority of studies have used indirect measures of insulin resistance. Our main objective was to define the relationship between plasma AA concentrations and a direct measure of insulin resistance in women and men. This was a cross-sectional study of 182 nondiabetic individuals (118 women and 64 men) who had measurement of 24 AAs and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. Fourteen out of 24 AA concentrations were significantly (P < 0.05) higher in men than women; only glycine was lower in men. Majority of these AAs were positively associated with SSPG; only glycine concentration was negatively associated. Glutamic acid, isoleucine, leucine, and tyrosine concentrations had the strongest correlation with SSPG (r ≥ 0.4, P < 0.001). The degree of association was similar in women and men, independent of obesity, and similar to traditional markers of insulin resistance (e.g., glucose, triglyceride, high-density lipoprotein cholesterol). Compared with women, men tended to have a more unfavorable AA profile with higher concentration of AAs associated with insulin resistance and less glycine. However, the strength of association between a direct measurement of insulin resistance and AA concentrations were similar between sexes and equivalent to several traditional markers of insulin resistance.

Objective: Individuals with substance use disorders have a high prevalence of smoking cigarettes. Hospitalization represents an opportunity to deliver concurrent treatment for tobacco and other substances. Using a sequential explanatory mixed methods design, we characterized practices and perspectives of patients and physicians about smoking cessation counseling during inpatient addiction medicine consultations. Methods: We abstracted data from 694 consecutive inpatient addiction consult notes to quantify how often physicians addressed tobacco dependence using the guideline-recommended 5As framework. We conducted semi-structured interviews with 9 addiction medicine physicians and 20 hospitalized smokers with substance use disorders. We analyzed transcripts to explore physicians' and patients' perspectives on smoking cessation conversations during inpatient addiction consultations, physician-perceived barriers and facilitators to engaging inpatients in tobacco treatment, and strategies to improve tobacco treatment in this context. Results: 75.5% (522/694) of hospitalized substance use disorder patients were current smokers. Among smokers, 20.9% (109/522) were offered nicotine replacement while hospitalized, but only 5.4% (28/522) received the full guideline-recommended 5As. Patients and physicians reported minimal discussion about tobacco addiction during hospitalization. Physicians cited tobacco not being an immediate health threat and the perception that quitting tobacco is not a priority to patients as barriers, often limiting thorough counseling to patients with smoking-related admissions. Physicians and patients offered strategies to integrate treatment of tobacco dependence and other substances. Conclusions: Inpatient addiction consultations represent a missed opportunity to counsel patients with substance use disorders to quit smoking. System-level changes are needed to coordinate treatment of tobacco and other drug dependence in hospitalized smokers.