Study on normal and otosclerotic bone cell cultures: an advance in understanding the pathogenesis of otosclerosis

The authors first reviewed the main theories concerning the pathogenesis of otosclerosis and studied the morphologic and functional characteristics of cell cultures derived from normal and otosclerotic bones. Light transmission and scanning electron microscopy did not permit definite identification of the cultured cells as predominantly osteoblasts, nor did these techniques show significant differences between cultured cells derived from normal and pathologic bone. Functional tests of the cell cultures proved more interesting. First, the bony nature of the cultured cells was demonstrated by studying the intracellular 45Ca++ uptake after stimulation with calcitonin and dybutryl-cAMP. Second, cell cultures derived from otosclerotic bone behaved differently from those derived from normal bone. Their peak uptake of calcium appeared later, and post-stimulatory values were higher, suggesting that cells derived from otosclerotic bone store a greater quantity of 45Ca++. Furthermore, after stimulation with calcitonin and propranolol, we observed an inhibition of the calcium uptake and decreased intracellular cAMP levels in normal bone cell cultures. In contrast, the cell cultures derived from otosclerotic bone exhibited an initial inhibition of calcium absorption followed by massive calcium penetration. The response of adenylate cyclase to the action of Mg++, Ca++, and F− ions was evaluated in cultures derived from normal bone, otosclerotic bone, and normal skin fibroblasts. The resulting data show that activation due to Mg++ is much lower in cultured cells derived from otosclerotic bone than in those from either normal bone or skin fibroblasts. No significant differences were found after Ca++ inhibition in any of the cell cultures. Moreover, in cell cultures derived from normal bone, F− ions induced a strong activation that was lower than the levels observed in cultures of otosclerotic bone or in normal fibroblasts. We hypothesize that an alteration at the calcitonin receptor site is responsible for the difference in calcium uptake and cAMP levels observed in the cells derived from otosclerotic bone as compared to those cultured from normal cells

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation

OBJECTIVE It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. METHODS We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior) with those without prior oral anticoagulation (OACnaive). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged) with those who continued the same anticoagulation as secondary prevention (OACunchanged). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine–Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71–84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2–12]). The median CHA2DS2‐Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65–74 years, sex category) was 5 (IQR = 4–6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient‐years of follow‐up, 289 patients had AIS (4.7% per year, 95% CI = 4.2–5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2–2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7–2.1, p = 0.415) compared with OACunchanged (n = 585). INTERPRETATION Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2DS2‐Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high‐risk patient group. ANN NEUROL 202

Risiken im Lebenszyklus: Theorie und Evidenz

Der einzelne Mensch ist im Lebensverlauf erheblichen biometrischen, ökonomischen, familiären und politischen Risiken ausgesetzt. Viele meinen, diese wären in den letzten Jahren größer geworden. Haben wir die richtigen Institutionen, um diese Risiken effizient abzudecken? Unter Institutionen verstehen wir individuelles Sparen, familiäre Hilfe, private Versicherungen und schließlich den Staat mit seinen Sozialversicherungen. Wo und wann funktionieren diese Institutionen? Wo und wann nicht? Was muss man tun, um sie zu verbessern? Wie sieht modernes "Social Risk Management" aus? Der erste Teil dieses Übersichtsbeitrags skizziert die wirtschaftstheoretischen Grundlagen des Sparverhaltens, der Portefeuillewahl und der Versicherungsnachfrage. Im Hauptteil werden die empirischen Befunde gesammelt, um im dritten Teil wirtschaftspolitische Schlussfolgerungen zu ziehen

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation

OBJECTIVE: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin-K-antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years. METHODS: Individual patient data analysis from 7 prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk. RESULTS: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR≥85y =0.65, 95%-CI [0.52, 0.81]) and <85 years (HR<85y =0.79, 95%-CI [0.66, 0.95]) in simple (pinteraction =0.129), adjusted (pinteraction =0.094) or weighted (pinteraction =0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and <85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1). INTERPRETATION: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old

Sensors and Rotordynamics Health Management Research for Aircraft Turbine Engines

Develop Advanced Sensor Technology and rotordynamic structural diagnostics to address existing Aviation Safety Propulsion Health Management needs as well as proactively begin to address anticipated safety issues for new technologies

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding