Abstract Objective To evaluate outcomes after mitral valve repair. Methods Between May 1999 and June 2015, 446 patients underwent mitral valve repair. Isolated mitral valve annuloplasty was excluded. ...A total of 398 (89%) had degenerative valve disease. Mean follow-up was 5.5 ± 3.8 years. Postoperative echocardiograms were obtained in 334 patients (75%) at a mean of 24.3 ± 13.7 months. Results Survival was 97%, 96%, 95%, and 94% at 1, 3, 5, and 10 years. Risk factor analysis showed age >60 years and nondegenerative etiology predict death (hazard ratio, 2.91; 95% confidence interval, 1.06-8.02, P = .038; and hazard ratio, 1.87; 95% confidence interval, 1.16-3.02, P = .010, respectively). Considering competing risks due to mortality, the cumulative incidence of reoperation was 2.8%, 4.2%, 5.1%, and 9.6% at 1, 3, 5, and 10 years. Competing risk proportional hazard survival regression identified nondegenerative etiology and previous cardiac surgery as predictors of reoperation, and posterior repair was protective (all P < .05). Cumulative incidence of progression of mitral regurgitation (2 or more grades) with mortality as a competing risk was 4.7%, 10.5%, 21.0%, and 35.8% at 1, 3, 5, and 10 years. Patients with previous sternotomy, repair or coronary artery bypass grafting, and concurrent tricuspid valve procedure or isolated anterior leaflet repair were more likely to develop progression of mitral regurgitation (all P < .05), and posterior leaflet repair was protective ( P = .038). On multivariate analysis diabetes, previous coronary artery bypass grafting and concurrent tricuspid valve intervention predicted MR progression. Conclusions Mitral valve repair has excellent outcomes. Our results demonstrate failures appear to occur less in those who undergo posterior leaflet repair.
Introduction
Sporadic Creutzfeldt‐Jakob disease (sCJD) comprises multiple subtypes (MM1, MM2, MV1, MV2C, MV2K, VV1, and VV2) with distinct disease durations and spatiotemporal cascades of brain ...lesions. Our goal was to establish the ante mortem diagnosis of sCJD subtype, based on patient‐specific estimates of the spatiotemporal cascade of lesions detected by diffusion‐weighted magnetic resonance imaging (DWI).
Methods
We included 488 patients with autopsy‐confirmed diagnosis of sCJD subtype and 50 patients with exclusion of prion disease. We applied a discriminative event‐based model (DEBM) to infer the spatiotemporal cascades of lesions, derived from the DWI scores of 12 brain regions assigned by three neuroradiologists. Based on the DEBM cascades and the prion protein genotype at codon 129, we developed and validated a novel algorithm for the diagnosis of the sCJD subtype.
Results
Cascades of MM1, MM2, MV1, MV2C, and VV1 originated in the parietal cortex and, following subtype‐specific orderings of propagation, went toward the striatum, thalamus, and cerebellum; conversely, VV2 and MV2K cascades showed a striatum‐to‐cortex propagation. The proposed algorithm achieved 76.5% balanced accuracy for the sCJD subtype diagnosis, with low rater dependency (differences in accuracy of ± 1% among neuroradiologists).
Discussion
Ante mortem diagnosis of sCJD subtype is feasible with this novel data‐driven approach, and it may be valuable for patient prognostication, stratification in targeted clinical trials, and future therapeutics.
Highlights
Subtype diagnosis of sporadic Creutzfeldt‐Jakob disease (sCJD) is achievable with diffusion MRI.
Cascades of diffusion MRI abnormalities in the brain are subtype‐specific in sCJD.
We proposed a diagnostic algorithm based on cascades of diffusion MRI abnormalities and demonstrated that it is accurate.
Our method may aid early diagnosis, prognosis, stratification in clinical trials, and future therapeutics.
The present approach is applicable to other neurodegenerative diseases, enhancing the differential diagnoses.
To investigate the incidence of corticotroph hyperplasia (CH) or lymphocyte infiltration in the pituitary of patients with obesity.
The pituitary and adrenal glands from 161 adult autopsies performed ...between 2010 and 2019 at our institution were reviewed. The clinical history, body mass index (BMI), and cause of death were recorded. Routine hematoxylin and eosin staining, reticulin staining, and immunohistochemical staining for adrenocorticotropic hormone, CD3, and CD20 were performed. The results were analyzed using the Fisher and chi-square statistics. Decedents were separated into 4 groups based on BMI (kg/m
): (1) lean (BMI, <25.0), (2) overweight (BMI, 25.0-29.9), (3) obesity class I (BMI, 30.0-34.9), and (4) obesity classes II to III (BMI, >34.9).
CH/neoplasia was identified in 44 of 161 pituitary glands. Four (9.1%) of 53 lean patients had pituitary lesions, whereas 27.3% (12) of overweight, 22.7% (10) of obesity class I, and 40.9% (18) of obesity class II patients had hyperplasia (P < .0001). Small corticotroph tumors were identified in 15 patients; only 1 was a lean patient, and the tumor was associated with the Crooke hyaline change of nontumorous corticotrophs. The presence of CH and neoplasia was associated with adrenal cortical hyperplasia and lipid depletion. Microscopic foci of T and B lymphocytes were identified in the pituitaries of patients in each weight category; no independent association between BMI and lymphocyte inflammation was found.
Our data indicate an association between CH/neoplasia and obesity. It remains unclear whether obesity is the cause or effect of adrenocorticotropic hormone and cortisol excess.
Prion disease research and surveillance can be challenging due to the disease's difficulty to diagnose, rapid progression, and geographic dispersion. Improving accessibility through teleneurology ...could improve the ability to conduct these activities.
The aim of this study was to determine the feasibility of conducting teleneurology assessments for research and surveillance of prion diseases.
Participants were offered in-person visit, medical record review, or teleneurology assessment. Standardized histories and assessments evaluating cognition, functional ability, and neuropsychiatric symptoms were collected. Data regarding participants' satisfaction with teleneurology were collected.
From April 2017 to July 2018, the study received 114 referrals. 45 and 5 participants consented for the teleneurology and medical record review arms of the study, respectively. 29 subjects participated in at least one teleneurology visit. Participants expressed satisfaction with teleneurology and found it easy to participate. Some aspects of the examination were hindered or interrupted due to technological reasons.
We demonstrate the feasibility and preference of teleneurology as a modality in which subjects with prion disease can partake in clinical research. Technological aspects sometimes interfered with research assessments.
Amyloid angiopathy-associated intracerebral hemorrhage (ICH) comprises 12%-15% of lobar ICH in the elderly. This growing population has an increasing incidence of thrombolysis-related hemorrhages, ...causing the management of hemorrhages associated with cerebral amyloid angiopathy (CAA) to take center stage. A concise reference assimilating the pathology and management of this clinical entity does not exist. Amyloid angiopathy-associated hemorrhages are most often solitary, but the natural history often progresses to include multifocal and recurrent hemorrhages. Compared with other causes of ICH, patients with CAA-associated hemorrhages have a lower mortality rate but an increased risk of recurrence. Unlike hypertensive arteriolar hemorrhages that occur in penetrating subcortical vessels, CAA-associated hemorrhages are superficial in location due to preferential involvement of vessels in the cerebral cortex and meninges. This feature makes CAA-associated hemorrhages easier to access surgically. In this paper, the authors discuss 3 postulates regarding the pathogenesis of amyloid hemorrhages, as well as the established clinicopathological classification of amyloid angiopathy and CAA-associated ICH. Common inheritance patterns of familial CAA with hemorrhagic strokes are discussed along with the role of genetic screening in relatives of patients with CAA. The radiological characteristics of CAA are described with specific attention to CAA-associated microhemorrhages. The detection of these microhemorrhages may have important clinical implications on the administration of anticoagulation and antiplatelet therapy in patients with probable CAA. Poor patient outcome in CAA-associated ICH is associated with dementia, increasing age, hematoma volume and location, initial Glasgow Coma Scale score, and intraventricular extension. The surgical management strategies for amyloid hemorrhages are discussed with a review of published surgical case series and their outcomes with a special attention to postoperative hemorrhage.
Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain ...largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (
Ext1
+
/
−
) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography–mass spectrometry (LC–MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC–MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, ...mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers.
Background: Mechanism of prion adaptation and evolution has not been fully elucidated.
Results: Distinct human prion particles co-exist and undergo competitive selection during replication.
Conclusion: The process is governed by preferential replication of the least stable pathogenic conformers.
Significance: The spectrum of conformers in wild human prion isolates enables adaptation and evolution by selection of the progressively less stable and faster replicating subset.
The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) ...extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts.To investigate this phenomenon further, a cohort of 27 iCJD cases - 21 with adequate number of histopathological sections - originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrP
), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND).Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrP
with the exception of iCJD harboring the "MMi" phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients' younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD.In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other factors, including GH deficiency, cannot be discounted, our findings increase the mounting evidence that this pathology is acquired by a mechanism resembling that of prion diseases.
Controversy exists regarding the optimal extent of repair for type A aortic dissection. Our approach is to replace the ascending aorta, and only replace the aortic root or arch when intimal tears are ...present in those areas. We examined intermediate outcomes with this approach to acute type A aortic dissection repair.
Between March 2005 and October 2016, 195 patients underwent repair of acute type A aortic dissection. Repair was categorized by site of proximal and distal anastomosis and extent of repair. Mean follow-up was 31.0 ± 30.9 months. Kaplan-Meier analysis was used to assess survival. Multiple variable Cox proportional hazards modeling was utilized to identify factors associated with overall mortality.
Overall survival was 85.1%, 83.9%, 79.1%, and 74.4% at 6, 12, 36, and 60 months, respectively. Eight patients required reintervention. The cumulative incidence of aortic reintervention at 1 year with death as a competing outcome was 3.95%. Multiple variable regression analysis identified factors such as age, preoperative renal failure, concomitant thoracic endograft, postoperative myocardial infarction and sepsis, and need for extracorporeal membrane oxygenation as predictive of overall mortality. Neither proximal or distal extent of repair, nor need for reintervention affected overall survival (proximal: hazard ratio 1.63, 95% confidence interval: 0.75 to 3.51, p = 0.22; distal: hazard ratio 1.12, 95% confidence interval: 0.43 to 2.97, p = 0.81; reintervention: hazard ratio 0.03, 95% confidence interval: 0.002 to 0.490, p < 0.01).
A selective approach to root and arch repair in acute type A aortic dissection is safe. If aortic reintervention is needed, survival does not appear to be affected.
A Practical Primer on Prion Pathology Appleby, Brian S; Rhoads, Daniel D; Mente, Karin ...
Journal of neuropathology and experimental neurology,
05/2018, Letnik:
77, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Abstract
Prion diseases comprise a group of transmissible degenerative encephalopathies resulting from propagation of a misfolded cellular protein of uncertain function. As is generally the case with ...rare diseases, lack of institutional experience compromises individual familiarity with the varying, and apparently protean, manifestations of prion diseases, both clinically and pathologically. Coupled with the documented transmissibility of these diseases both within and between species, the Centers for Disease Control and Prevention (CDC) has established the National Prion Disease Pathology Surveillance Center to both aid with diagnosis of prion disease and to survey the United States for evidence of zoonotic transmission. We have assembled this primer with the hope that our accumulated experience will enable the neuropathological community to help the CDC "save lives and protect people."
PDF
