Importance of spatiotemporal heterogeneity of cellular restitution in mechanism of arrhythmogenic discordant alternans

BACKGROUND: Spatially discordant cellular alternans form a substrate for development of unidirectional block and ventricular fibrillation. However, the mechanisms responsible for discordant alternans remain poorly understood. Previous work suggests electrical restitution is critical to the development of alternans in single cells. OBJECTIVES: The purpose of this study was to investigate the hypothesis that spatial and temporal heterogeneities of restitution underlie the mechanism eliciting discordant alternans. METHODS: Steady-state pacing was used to elicit concordant cellular alternans in nine Langendorff-perfused guinea pig hearts. A single extrastimulus (S2) was applied every 51st beat following either the even or the odd beat of alternans. The cellular response to S2 was determined using optical mapping to generate action potential duration (APD) restitution curves from 256 ventricular sites for both the even and the odd beats. RESULTS: Restitution kinetics were temporally heterogeneous during alternans, as restitution curves between the even and the odd beats differed significantly. Temporal heterogeneity was quantified by the average separation of restitution between the two curves, or Delta-restitution. Delta-Restitution was spatially heterogeneous and proportional to the amount of alternans at a given ventricular site. A computer simulation based on the experimental results showed the mechanism of discordant alternans was dependent on both spatial and temporal heterogeneities of restitution. CONCLUSION: Both temporal and spatial heterogeneities of restitution exist during cellular alternans in the intact heart. Temporal heterogeneities of restitution, quantified by Delta-restitution, are proportional to the magnitude of cellular alternans. The combination of spatial and temporal heterogeneities of restitution may underlie the genesis of discordant alternans.     

Diagnosis and management of severe atherosclerosis of the ascending aorta and aortic arch during cardiac surgery: focus on aortic replacement

Objective: Severe atherosclerosis of the ascending aorta and arch frequently causes difficulties during heart operations, hindering surgical manoeuvres and potentially leading to systemic embolism. The aim of our study was to assess the safety and effectiveness of replacing the atherosclerotic ascending aorta in this setting. Methods: Aortic atherosclerosis was characterized by epiaortic ultrasonographic scanning in 90.1% of 1927 consecutive adult patients undergoing cardiac operations, and by computed tomographic chest scanning in selected cases. Thirty-six of the 152 patients requiring major derangements from our standard practice due to aortic atherosclerosis underwent replacement of the ascending aorta and constitute the study group. Replacement of the aorta was extended to the arch in 13 cases (36.1%). It was associated with single or multiple valve surgery in 34 patients (94.4%) and with coronary revascularization in 30 (83.3%). Two patients (5.6%) underwent coronary bypass grafting without valve surgery. A cryoablation procedure was associated in three patients with permanent atrial fibrillation. Deep hypothermic circulatory arrest was employed in 34 patients (94.4%), while proximal aortic disease allowed conventional distal crossclamping in 2 cases. The risk of operative mortality was estimated by the logistic EuroSCORE both with and withholding the variable ‘surgery of the thoracic aorta’. All survivors were followed-up for 1–41 months (16 ± 12). Results: Two patients died in the hospital (5.6%) and two during follow-up, for a cumulative survival of 91.3% and 85.6% at 1 and 3 years, respectively (hospital deaths included). The hospital death rate compared favourably with the expected estimates of 25.5% (p < 0.05) and 10.3% (p = 0.67) obtained by the EuroSCORE full model and without ‘aortic surgery’, respectively. In-hospital adverse neurologic events occurred in six patients (16.7%), including stroke in one patient (2.8%) and neurocognitive disturbances in five (13.9%), although they were all transient and cleared before discharge. Excess bleeding required re-exploration in four patients (11.1%), and one more patient underwent emergency grafting for acute postoperative coronary occlusion. Ten patients (38.5%) were intubated for longer than 24 h. Conclusion: Despite significant perioperative morbidity, replacement of the severely atherosclerotic aorta is worth consideration to avert expectedly higher death and stroke rates.     

Transient hypoparathyroidism following thyroidectomy: a prospective study and multivariate analysis of 604 consecutive patients.

OBJECTIVE: The purpose of this study was to identify the risk factors for postoperative transient hypoparathyroidism in a group of patients undergoing thyroid surgery. STUDY DESIGN: A prospective study was conducted on 604 patients undergoing thyroid surgery. SUBJECTS AND METHODS: Gender, final diagnosis, extent of resection, biology of pathology, intrathoracic involvement, surgery for recurrent multinodular goiter, and presence and number of parathyroid glands in a surgical specimen were analyzed as risk factors for postoperative transient hypoparathyroidism. The chi-square test and a logistic regression analysis were applied. RESULTS: On logistic regression analysis, only the extent of surgery constituted an independent variable for transient hypoparathyroidism (P = 0.001). CONCLUSION: The extent of surgery to central and/or lateral neck lymph nodes is responsible for a high rate of transient hypoparathyroidism owing to a high probability of unplanned parathyroidectomy or parathyroid gland devascularization.     

Application of phage display peptide library to autoimmune diabetes: identification of IA-2/ICA512bdc dominant autoantigenic epitopes

Autoantigenic epitope mapping represents a critical issue in autoimmune diseases. The islet tyrosine phosphatase-like protein IA-2/ICA512bdc is a major autoantigen in type 1 diabetes (IDDM), but the epitopes responsible for autoantibody binding have been only partially defined. The aim of our study was to identify ICA512bdc epitopes, and in particular mini-epitopes, utilizing a novel strategy for autoimmune diseases. The study was performed in three sequential steps: (1) construction of a lambda-phage surface-displayed ICA512bdc cDNA library with the methodology of tagged random priming with peptides displayed as a fusion to the C terminus of the capsid protein D; (2) affinity selection of the resulting library, followed by immunoscreening, enzyme-linked immunosorbent assay and sequence analysis of positive clones, and (3) radioimmunoprecipitation to detect autoantibodies to the selected clones. This strategy resulted in the identification of two epitopes (IA-2 residues 761 - 964 and 929 - 979), which were recognized by 100 % and 62.9 % ICA512bdc-positive IDDM patients, respectively. Interestingly, the larger clone was detected also by a proportion (16.7 %) of new onset ICA512bdc-negative patients, thus suggesting that this region contains not only the main autoantigenic repertoire of ICA512bdc molecule, but is able to detect IA-2 autoantibodies in even higher percentages of patients. In addition, this study showed the existence of multiple epitopes located in the C-terminal domain of the IA-2 protein, one of which is formed by the 50 C-terminal amino acids, and provided evidence that the strategy used represents a valid tool for identification of epitopes within autoantigenic molecules.     

Self-reported urogenital symptoms in postmenopausal women: Women's Health Initiative

OBJECTIVE: To examine the prevalence and correlates of self-reported urogenital symptoms (dryness, irritation or itching, discharge, dysuria) among postmenopausal women aged 50-79. DESIGN: A cross-sectional analysis based on n=98,705 women enrolled in the US-based Women's Health Initiative observational study and clinical trials. Urogenital symptoms, symptom severity (mild, moderate, severe), and all covariates were self-reported through questionnaires at enrollment. Prevalence rates of each urogenital symptom were examined and logistic regression was used to identify potential correlates. RESULTS: Prevalence rates for each symptom were: dryness, 27.0%; irritation or itching, 18.6%; discharge, 11.1%; and dysuria, 5.2%. Four factors were correlated with two or more symptoms: Hispanic ethnicity (adjusted odds ratio (AOR)=2.1-3.1 versus white women across all symptoms), obesity (AOR=2.2 severe discharge versus none, AOR=3.6 severe irritation/itching versus none), treated diabetes (pills or shots) compared to no diabetes (AOR=2.4 severe dysuria versus none, AOR=3.2 severe irritation/itching versus none), and vaginal cream HRT/ERT compared to those who never used HRT/ERT (AOR=4.4 severe dryness versus none, AOR=4.6 severe irritation/itching versus none). Factors not associated with the symptoms included sexual activity, age, years since menopause, current smoking, marital status, gravidity, and natural versus surgical menopause. CONCLUSIONS: This is the first report to document urogenital symptoms by race/ethnicity among an exclusively postmenopausal population. We found an elevated prevalence of urogenital symptoms among women who are Hispanic, obese, and/or diabetic. Confirmation of our findings in these subgroups, and, if confirmed, analysis on why these populations are at greater risk, are areas for future research.     

Vasculogenic mimicry has no prognostic significance in pT3 and pT4 cutaneous melanoma

The concept of vasculogenic mimicry has been introduced to define periodic acid-Schiff (PAS)-positive channels and loops lined by tumor cells, instead of endothelium, able to contribute to microcirculation in uveal melanomas. Previous studies have shown that the PAS-positive patterns are associated with a poor prognosis in uveal melanoma. The aim of the current study was to investigate whether vasculogenic mimicry has a prognostic impact in pT3 and pT4 cutaneous melanoma. Fifteen patients with pT3 and pT4 cutaneous melanoma who did not experience progression after 10 years of follow-up and 30 matched controls who underwent progression were selected. Tumor sections were stained with PAS reaction, omitting the nuclear counterstaining. For immunohistochemistry, sections were stained with CD31, CD105 (endoglin), and laminin. Differences in the distribution of the PAS-positive patterns and a series of clinicopathological variables were evaluated by the Pearson chi(2) and Mann-Whitney U tests. We observed PAS-positive linear sheets, arcs, elliptical loops, and networks encircling roundish to oval aggregates of melanoma cells. The overall distribution of the PAS-positive patterns did not match with the blood microvessels' architecture as detected by immunohistochemical analysis. No statistically significant differences in the distribution of PAS-positive patterns were found between cases and controls. The presence of a parallel pattern correlated significantly with thickness (P = 0.04), whereas an inverse correlation was found with vessel area (P = 0.05). In conclusion, our results suggest that there is a mismatch between vasculogenic mimicry and tumor angiogenesis and do not support any prognostic role of vasculogenic mimicry in thick cutaneous melanoma.     

Syndiospecific polymerization of styrene with the catalytic system [Ti2(OC2H5)8Cl]2Mg2(μ-Cl)2/methylaluminoxane compared with MgCl2-supported and unsupported Ti(OC2H5)4

As a part of our interest in the performance of [Ti₂(OC₂H₅)₈Cl]₂Mg₂(μ-Cl)₂ as Ziegler-Natta catalyst, the polymerization of styrene with a toluene solution of this compound and methyl-aluminoxane as cocatalyst was performed. It was found that the present catalytic system promotes the syndiospecific polymerization of styrene with high stereoregularity and the results were compared with those obtained with MgCl₂-supported or unsupported Ti(OC₂H₅)₄ catalysts. Determination of the titanium oxidation states and electron spin resonance (ESR) measurements both in the absence and in the presence of styrene were carried out for all the catalytic systems aimed at shedding some light on the nature of the active species.