Molecular basis for the thiol sensitivity of insulin-degrading enzyme

Insulin-degrading enzyme (IDE) is a ubiquitous zinc-metalloprotease that hydrolyzes several pathophysiologically relevant peptides, including insulin and the amyloid beta-protein (Abeta). IDE is inhibited irreversibly by compounds that covalently modify cysteine residues, a mechanism that could be operative in the etiology of type 2 diabetes mellitus (DM2) or Alzheimer's disease (AD). However, despite prior investigation, the molecular basis underlying the sensitivity of IDE to thiol-alkylating agents has not been elucidated. To address this topic, we conducted a comprehensive mutational analysis of the 13 cysteine residues within IDE. Our analysis implicates C178, C812, and C819 as the principal residues conferring thiol sensitivity. The involvement of C812 and C819, residues quite distant from the catalytic zinc atom, provides functional evidence that the active site of IDE comprises two separate domains that are operational only in close apposition. Structural analysis and other evidence predict that alkylation of C812 and C819 disrupts substrate binding, whereas alkylation of C178 interferes with the apposition of active-site domains and subtly repositions zinc-binding residues. Unexpectedly, alkylation of C590 was found to activate hydrolysis of Abeta significantly, while having no effect on insulin, demonstrating that chemical modulation of IDE can be both bidirectional and highly substrate selective. Our findings resolve a long-standing riddle about the basic enzymology of IDE with important implications for the etiology of DM2 and AD. Moreover, this work uncovers key details about the mechanistic basis of the unusual substrate selectivity of IDE that may aid the development of pharmacological agents or IDE mutants with therapeutic value.     

Radial Access Optimization in the Nascent Post‐Adoption Era

• Post‐procedural upper extremity dysfunction (UED) remains one of the few potential questions about the overall benefits of the transradial approach (TRA) to endovascular procedures compared to femoral (TFA).
• Data on UED is limited, but the most comprehensive study curiously shows similar incidence of post‐procedural UED with TFA as TRA.
• The effects of trAnsRadial perCUtaneouS coronary intervention on upper extremity function (ARCUS) study will investigate whether patient characteristics influence radial access outcomes such as UED.
• ARCUS may herald a post‐radial‐adoption era of more detailed strategies for radial access optimization, typical of a maturing technology.

     

Value of Posterior and Right Ventricular Leads in Comparison to the Standard 12-Lead Electrocardiogram in Evaluation of ST-Segment Elevation in Suspected Acute Myocardial Infarction

In this multicenter prospective trial, we studied posterior (V₇ to V₉) and right ventricular (V₄R to V₆R) leads to assess their accuracy compared with standard 12-lead electrocardiograms (ECGs) for the diagnosis of acute myocardial infarction (AMI). Patients aged >34 years with suspected AMI received posterior and right ventricular leads immediately after the initial 12-lead ECG. ST elevation of 0.1 mV in 2 leads was blindly determined and inter-rater reliability estimated. AMI was diagnosed by World Health Organization criteria. The diagnostic value of nonstandard leads was determined when 12-lead ST elevation was absent and present and multivariate stepwise regression analysis was also performed. Of 533 study patients, 64.7% (345 of 533) had AMI and 24.8% received thrombolytic therapy. Posterior and right ventricular leads increased sensitivity for AMI by 8.4% (

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) but decreased specificity by 7.0% (

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). The likelihood ratios of a positive test for 12, 12 + posterior, and 12 + right ventricular ECGs were 6.4, 5.6, and 4.5, respectively. Increased AMI rates (positive predictive values) were found when ST elevation was present on 6 nonstandard leads (69.1%), on 12 leads only (88.4%), and on both 6 and 12 leads (96.8%; p <0.001). Treatment rates with thrombolytic therapy increased in parallel with this electrocardiographic gradient. Logistic regression analysis showed that 4 leads were independently predictive of AMI (p <0.001): leads I, II, V₃, V₅R; V₉ approached statistical significance (

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). The standard ECG is not optimal for detecting ST-segment elevation in AMI, but its accuracy is only modestly improved by the addition of posterior and right ventricular leads.In this multicenter prospective trial, 0.1 mV of ST-segment elevation in posterior (V₇ to V₉) and right ventricular (V₄R to V₆R) leads was found to increase the sensitivity of the electrocardiogram for acute myocardial infarction by 8.4% (

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), but decrease specificity by 7.0% (

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); logistic regression analysis showed that 4 leads were predictive of AMI at p <0.001: I, II, V₃, V₅; V₉ approached statistical significance (

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). The standard electrocardiogram is not optimal for detecting ST elevation in acute myocardial infarction, but its accuracy is only modestly improved by the addition of posterior and right ventricular leads.     

Triage decisions for emergency department patients with chest pain

OBJECTIVE: To determine whether physicians’ risk attitudes correlate with their triage decisions for emergency department patients with acute chest pain. DESIGN: Cohort. SETTING: The emergency department of a university teaching hospital. PATIENTS: Patients presenting to the emergency department with a chief complaint of acute chest pain. PHYSICIANS: All physicians who were primarily responsible for the emergency department triage of at least one patient with acute chest pain from July 1990 to July 1991. METHODS: The physicians’ risk attitudes were assessed by two methods: 1) a new, six-question risk-taking scale adapted from the Jackson Personality Index (JPI), and 2) the Stress from Uncertainty Scale (SUS). RESULTS: The physicians who had high risk-taking scores (“risk seekers”) admitted only 31% of the patients they evaluated, compared with admission rates of 44% for the medium scorers and 53% for the physicians who had low risk-taking scores (“risk avoiders”), p<0.001. After adjustment for clinical factors, the patients triaged by the risk-seeking physicians had half the odds of admission [odds ratio (OR) 0.51, 95% confidence interval (95% CI) 0.27 to 0.97], and the patients triaged by the risk-avoiding physicians had nearly twice the odds of admission (OR 1.83, 95% CI 1.10 to 3.03) of the patients triaged by the medium-risk scoring physicians. The SUS did not correlate significantly with admission rates. Of the 92 patients released home by the risk-seeking physicians, 91 (99%) were known to be alive four to six weeks afterwards and one was lost to follow-up; among the 66 patients released by the risk-avoiding physicians, 64 (97%) were known to be alive at four to six weeks, one was lost to follow-up, and one died of ischemic heart disease during a subsequent hospitalization (p=NS). CONCLUSIONS: The physicians’ risk attitudes as measured by a brief risk-taking scale correlated significantly with then-rates of admission for emergency department patients with acute chest pain. These data do not suggest that the risk-seeking physicians achieved lower admission rates by releasing more patients who needed to be in the hospital, but an adequate evaluation of the appropriateness of triage decisions of risk-seeking and risk-avoiding physicians will require further study.     

Who talks to physicians about mental health and substance abuse problems?

This is an analysis of data from the NIMH-sponsored Epidemiologic Catchment Area community-based study, investigating who reported discussing mental health or substance abuse problems with nonpsychiatric physicians. Data were from 7,092 respondents in four sites, all of whom had received care only in the nonpsychiatric sector in the previous six months. A multiple logistic model found that those individuals who had psychiatric disorders, and female, middle-aged, and Hispanic respondents, were more likely to have discussed emotional or mental health problems with their physicians. Respondents with alcohol abuse and substance abuse disorders did not report any more discussion of mental health problems than did respondents without alcohol or substance abuse disorders. Only 36% of the respondents who said they had discussed mental health problems were found to have psychiatric disorders by the Diagnostic Interview Survey (DIS), but many of those without disorders reported more anxiety symptoms. An analysis was done to predict which respondents with DIS-defined psychiatric disorders did not report discussing mental health problems with their nonpsychiatric physicians. Those less than 35 years of age, those older than 65 years of age, males, and those with only one recent visit to a provider were statistically at high risk for not discussing their psychiatric problems.