No abstract

Our previous results run counter to the hypothesis that S-nitrosohemoglobin (SNO-Hb) serves as an in vivo reservoir for NO from which NO release is allosterically linked to oxygen release. We show here that SNO-Hb undergoes reductive decomposition in erythrocytes, whereas it is stable in purified solutions and in erythrocyte lysates treated with an oxidant such as ferricyanide. Using an extensively validated methodology that eliminates background nitrite and stabilizes erythrocyte S-nitrosothiols, we find the levels of SNO-Hb in the basal human circulation, including red cell membrane fractions, were 46 ؎ 17 nM in human arterial erythrocytes and 69 ؎ 11 nM in venous erythrocytes, incompatible with the postulated reservoir function of SNO-Hb. Moreover, we performed experiments on human red blood cells in which we elevated the levels of SNO-Hb to 10,000 times the normal in vivo levels. The elevated levels of intra-erythrocytic SNO-Hb fell rapidly, independent of oxygen tension and hemoglobin saturation. Most of the NO released during this process was oxidized to nitrate. A fraction (25%) was exported as S-nitrosothiol, but this fraction was not increased at low oxygen tensions that favor the deoxy (T-state) conformation of Hb. Results of these studies show that, within the redoxactive erythrocyte environment, the ␤-globin cysteine 93 is maintained in a reduced state, necessary for normal oxygen affinity, and incapable of oxygen-linked NO storage and delivery.Nitric oxide (NO) is a soluble gas that is continuously synthesized in endothelial cells and is a critical endogenous vasodilator (1-3). Although it is generally believed that endothelium-derived NO is the primary determinant of NO-mediated control of basal blood flow in humans (4, 5), considerable recent interest and controversy have focused on the role of intravascular NO-derived molecules that could stabilize NO bioactivity and contribute to blood flow and oxygen delivery. Such molecules include high and low molecular weight S-nitrosothiols in plasma (6 -10) and nitrite (4, 11). In addition, NO reacts reversibly with hemoglobin to form an NO-heme adduct, ironnitrosyl-hemoglobin (HbFe II NO), 1 and can also nitrosate a surface thiol on cysteine 93 of the ␤-globin chain to form S-nitrosohemoglobin (SNO-Hb). The potential role of S-nitrosated hemoglobin as an NO transporter is particularly appealing, because the environment of ␤-cysteine 93 is sensitive to the R 7 T conformational equilibrium of hemoglobin. The conformational transition from the R-to T-state could thus promote the allosteric delivery of both oxygen and NO to regions with low oxygen tension. Two central observations supporting this SNO-Hb hypothesis are reports of observed arterial-venous gradients of SNO-Hb in the rat (suggesting a dynamic cycle) and evidence that delivery of oxygen and NO are allosterically coupled events (12-14).However, the evidence for a dynamic cycle is brought into question by widely varying reports for the basal levels of intracellular SNO-Hb in arterial and venous bloo...

Level 3: Individuals who meet these criteria and are considering observation should be counseled regarding probability of successful hearing preservation based on the following prognostic data: the most consistent prognostic features associated with maintenance of serviceable hearing are good preoperative word recognition and/or pure tone thresholds with variable cut-points reported, as well as nongrowth of the tumor. Tumor size at the time of diagnosis, age, and sex do not predict future development of nonserviceable hearing during observation.  The full guideline can be found at: https://www.cns.org/guidelines/guidelines-manage-ment-patients-vestibular-schwannoma/chapter_3.

Autoimmune inner ear disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hearing loss. Hearing loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1β was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1β expression or release in response to dexamethasone, as compared with nonresponders. IL-1β has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1β and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1β concentration, suggesting that IL-1β expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1β. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1β release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1β into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1β release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1β release, suggesting that IL-1β blockade may be a viable therapy for these patients.

Transcuprein is a high-affinity copper carrier in the plasma that is involved in the initial distribution of copper entering the blood from the digestive tract. To identify and obtain cDNA for this protein, it was purified from rat plasma by size exclusion and copper-chelate affinity chromatography, and amino acid sequences were obtained. These revealed a 190-kDa glycosylated protein identified as the macroglobulin alpha(1)-inhibitor III, the main macroglobulin of rodent blood plasma. Albumin (65 kDa) copurified in variable amounts and was concluded to be a contaminant (although it can transiently bind the macroglobulin). The main macroglobulin in human blood plasma (alpha(2)-macroglobulin), which is homologous to alpha(1)-inhibitor III, also bound copper tightly. Expression of alpha(1)I3 (transcuprein) mRNA by the liver was examined in rats with and without copper deficiency, using quantitative polymerase chain reaction methodology and Northern blot analysis. Protein expression was examined by Western blotting. Deficient rats with 40% less ceruloplasmin oxidase activity and liver copper concentrations expressed about twice as much alpha(1)I3 mRNA, but circulating levels of transcuprein did not differ. Iron deficiency, which increased liver copper concentrations by threefold, reduced transcuprein mRNA expression and circulating levels of transcuprein relative to what occurred in rats with normal or excess iron. We conclude that transcupreins are specific macroglobulins that not only carry zinc but also carry transport copper in the blood, and that their expression can be modulated by copper and iron availability.

Our findings of elevated ICP and BMI in patients presenting with spontaneous CSF otorrhea are consistent with previous reports in the literature. The percentage of patients that underwent CSF diversion procedures was high at 53% and represents an aggressive stance in managing elevated ICP in a population that may be at risk for subsequent leaks.

Background The association between spontaneous skull base cerebrospinal fluid (CSF) leaks and idiopathic intracranial hypertension (IIH) has been suggested, but its significance remains unclear. Objective To estimate the prevalence of IIH in spontaneous skull base CSF leak patients. Methods Systematic collection of demographics, neuro-ophthalmic and magnetic resonance imaging evaluation of spontaneous skull base CSF leak patients seen pre- and post-leak repair in one neuro-ophthalmology service. Patients with preexisting IIH were diagnosed with definite IIH if adequate documentation was provided; otherwise, they were categorized with presumed IIH. Classic radiographic signs of intracranial hypertension and bilateral transverse venous sinus stenosis were recorded. Results Thirty six patients were included (age [interquartile range]: 50 [45;54] years; 94% women; body mass index: 36.8 [30.5;39.9] kg/m2), among whom six (16.7%, [95% confidence interval, CI]: [6.4;32.8]) had a preexisting diagnosis of definite or presumed IIH. Of the remaining 30 patients, four (13.3%, 95%CI: [3.8;30.7]) had optic nerve head changes suggesting previously undiagnosed IIH, while one was newly diagnosed with definite IIH at initial consultation. One out of 29 patients with normal findings of the optic nerve head at presentation developed new onset papilledema following surgery (3.4%, 95%CI: [0.1;17.8]) and was ultimately diagnosed with definite IIH. Overall, the prevalence of definite IIH was 19.4% (95%CI: [8.2;36.0]). Conclusion Striking demographic overlap exists between IIH patients and those with spontaneous CSF leak. Definite IIH was present in approximately 20% of our patients. However, its true prevalence is likely higher than identified by using classic criteria. We therefore hypothesize that an active CSF leak serves as an auto-diversion for CSF, thereby “treating” the intracranial hypertension and eliminating characteristic signs and symptoms at initial presentation.

Level 3: It is recommended that MRI be used to evaluate patients with a sudden sensorineural hearing loss. However, this practice is low yielding in terms of vestibular schwannoma diagnosis (<3%).  The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_2.