The Thioredoxin System Reduces Protein Persulfide Intermediates Formed during the Synthesis of Thio-Cofactors in Bacillus subtilis.

The biosynthesis of Fe-S clusters and other thio-cofactors requires the participation of redox agents. A shared feature in these pathways is the formation of transient protein persulfides, which are susceptible to reduction by artificial reducing agents commonly used in reactions in vitro. These agents modulate the reactivity and catalytic efficiency of biosynthetic reactions and, in some cases, skew the enzymes' kinetic behavior, bypassing sulfur acceptors known to be critical for the functionality of these pathways in vivo. Here, we provide kinetic evidence for the selective reactivity of the Bacillus subtilis Trx (thioredoxin) system toward protein-bound persulfide intermediates. Our results demonstrate that the redox flux of the Trx system modulates the rate of sulfide production in cysteine desulfurase assays. Likewise, the activity of the Trx system is dependent on the rate of persulfide formation, suggesting the occurrence of coupled reaction schemes between both enzymatic systems in vitro. Inactivation of TrxA (thioredoxin) or TrxR (thioredoxin reductase) impairs the activity of Fe-S enzymes in B. subtilis, indicating the involvement of the Trx system in Fe-S cluster metabolism. Surprisingly, biochemical characterization of TrxA reveals that this enzyme is able to coordinate Fe-S species, resulting in the loss of its reductase activity. The inactivation of TrxA through the coordination of a labile cluster, combined with its proposed role as a physiological reducing agent in sulfur transfer pathways, suggests a model for redox regulation. These findings provide a potential link between redox regulation and Fe-S metabolism.

Serotonin Syndrome After Prolonged Remifentanil and Propofol Infusion for Craniotomy: A Case Report.

Serotonin syndrome (SS) is a life-threatening condition caused by serotonergic medications. We describe a unique case of SS likely caused by prolonged exposure to propofol and remifentanil alone. A young male presented for vestibular schwannoma resection. Several hours into the case, the patient demonstrated hyperthermia and hemodynamic instability, followed by clonus, rigidity, shivering, and tachycardia after emergence. SS was diagnosed using Hunter's criteria and improved with supportive measures. While the patient endorsed a history of methamphetamine use, his urine drug screen was negative. The possibility of SS should be considered when administering propofol and remifentanil, particularly with prolonged infusions.

Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia.

BACKGROUND: Thromboembolic disease secondary to complicated carotid atherosclerotic plaque is a major cause of cerebral ischemia. Clinical management relies on the detection of significant (>70%) carotid stenosis. A large proportion of patients suffer irreversible cerebral ischemia as a result of lesser degrees of stenosis. Diagnostic techniques that can identify nonstenotic high-risk plaque would therefore be beneficial. High-risk plaque is defined histologically if it contains hemorrhage/thrombus. Magnetic resonance direct thrombus imaging (MRDTI) is capable of detecting methemoglobin within intraplaque hemorrhage. We assessed this as a marker of complicated plaque and compared its accuracy with histological examination of surgical endarterectomy specimens. METHODS AND RESULTS: Sixty-three patients underwent successful MRDTI and endarterectomy with histological examination. Of these, 44 were histologically defined as complicated (type VI plaque). MRDTI demonstrated 3 false-positive and 7 false-negative results, giving a sensitivity and specificity of 84%, negative predictive value of 70%, and positive predictive value of 93%. The interobserver (kappa=0.75) and intraobserver (kappa=0.9) agreement for reading MRDTI scans was good. CONCLUSIONS: MRDTI of the carotid vessels in patients with cerebral ischemia is an accurate means of identifying histologically confirmed complicated plaque. The high contrast generated by short T1 species within the plaque allows for ease of interpretation, making this technique highly applicable in the research and clinical setting for the investigation of carotid atherosclerotic disease.

Prevalence of complicated carotid atheroma as detected by magnetic resonance direct thrombus imaging in patients with suspected carotid artery stenosis and previous acute cerebral ischemia.

BACKGROUND: It is recognized that complicated plaque largely accounts for the morbidity and mortality from atherosclerosis. Ideally, investigation of symptomatic and asymptomatic patients would identify atheromatous plaques independently of stenosis. We have previously shown that a magnetic resonance direct thrombus imaging (MRDTI) technique demonstrates complicated atheroma as high signal within the carotid arterial wall. We used this technique to examine the prevalence of complicated carotid plaque in vivo in the ipsilateral arteries of recently symptomatic patients with suspected carotid artery stenosis and to compare this with their contralateral arteries and with those of healthy age- and sex-matched controls. METHODS AND RESULTS: The carotid arteries of 120 patients with suspected severe carotid artery stenosis and previous acute cerebral ischemia were imaged using MRDTI, as were 28 control arteries. High signal was not seen in any control artery. However, there was a 60% prevalence of high signal, suggestive of complicated plaque in the patients' ipsilateral arteries. The prevalence of high signal was significantly greater in the patients' ipsilateral vessels compared with the contralateral, asymptomatic side (60% versus 36%, chi2 P<0.001), particularly for vessels of only moderate stenosis. CONCLUSIONS: MRDTI high signal suggestive of complicated plaque is prevalent in the ipsilateral carotid arteries of patients with carotid stenosis and recent cerebral ischemic events. MRDTI has a potential role in identifying "at risk" plaque, studying atherogenesis and the effects of plaque-modifying strategies.