Periods of differing mortality distribution during the first year after acute myocardial infarction

The mortality rate after acute myocardial infarction (AMI) has generally been modeled by a single exponential function. The present study was undertaken to determine, in 3 different populations, whether or not periods exist during the first year after AMI which have mortality distributions that differ from this pattern. The 3 patient populations included San Diego (346 patients, 71 deaths), Vancouver (704 patients, 146 deaths), and Copenhagen (1,140 patients, 262 deaths). Hospital admission was within 24 hours of the onset of symptoms, and patients dying within the first 24 hours after hospital admission or of noncardiac or unknown causes were not analyzed. The mortality between 2 and 21 days in the combined data base was 11.4% (range 10.9 to 11.7) and from 3 weeks to 1 year 10.5% (range 9.0 to 11.3). A high degree of similarity was noted among the shapes of the 3 survival curves. The hypothesis of an exponential mortality rate during the entire first year was rejected. Using a special statistic, changepoints at days 17,23, and 24 in the 3 populations (21 days for the combined data base) were identified and used thereafter to divide the year into 2 separate periods of mortality within which exponentiality for the mortality rate was not rejected. The point by which exactly 50% of deaths had occurred was day 19, with 75% of deaths occurring by day 100. These data further define the natural history after AMI and indicate optimal follow-up periods for short- and longer-term management strategies based on risk assessment or trials of risk reduction after AMI.     

Peroxynitrite formation and sinusoidal endothelial cell injury during acetaminophen-induced hepatotoxicity in mice

INTRODUCTION: Vascular injury and accumulation of red blood cells in the space of Disse (hemorrhage) is a characteristic feature of acetaminophen hepatotoxicity. However, the mechanism of nonparenchymal cell injury is unclear. Therefore, the objective was to investigate if either Kupffer cells or intracellular events in endothelial cells are responsible for the cell damage. RESULTS: Acetaminophen treatment (300 mg/kg) caused vascular nitrotyrosine staining within 1 h. Vascular injury (hemorrhage) occurred between 2 and 4 h. This paralleled the time course of parenchymal cell injury as shown by the increase in plasma alanine aminotransferase activities. Inactivation of Kupffer cells by gadolinium chloride (10 mg/kg) had no significant effect on vascular nitrotyrosine staining, hemorrhage or parenchymal cell injury. In contrast, treatment with allopurinol (100 mg/kg), which prevented mitochondrial injury in hepatocytes, strongly attenuated vascular nitrotyrosine staining and injury. CONCLUSIONS: Our data do not support the hypothesis that acetaminophen-induced superoxide release leading to vascular peroxynitrite formation and endothelial cell injury is caused by activated Kupffer cells. In contrast, the protective effect of allopurinol treatment suggests that, similar to the mechanism in parenchymal cells, mitochondrial oxidant stress and peroxynitrite formation in sinusoidal endothelial cells may be critical for vascular injury after acetaminophen overdose.     

OCT evaluation of the internal adaptation of ceramic veneers depending on preparation design and ceramic thickness

ObjectivesIn-vitro evaluation of the influence of preparation design and thickness of ceramic veneers on the interfacial bond using optical coherence tomography (OCT).MethodsSixty-four central incisors were randomly assigned to four preparation designs differing from no to complete dentine exposure (n = 16 each): non-prep (NP), minimal-invasive (MI, no dentine exposure), semi-invasive (SI, 50% dentine) and invasive (I, 100% dentine). Ceramic veneers (IPS InLine Veneer) of two thicknesses (0.2?0.5 mm (T1) and > 0.5–1.2 mm (T2)) were etched, silanized, and adhesively luted (Optibond FL, Variolink Veneer). After water storage (37 °C, 21d), thermocycling (2000 cycles, 5°-55 °C), and mechanical loading (2 + 1 million cycles, 50 + 100 N) specimens were imaged by spectral-domain OCT (Telesto II, Thorlabs). Adhesive defects at the ceramic-composite and tooth-composite interfaces were quantified on 35 equidistantly distributed OCT B-scans (length, %). Statistical differences were verified with Wilcoxon-/Mann-Whitney-U-test (α = 0.05).ResultsAdhesive defects appeared in all groups at both interfaces, albeit to differing extents (0.1 – 31.7%). NP and MI veneers showed no significant differences at the interfaces (p_i > 0.05). In groups, SI and I, significantly more adhesive defects appeared at the tooth-composite compared to the veneer-composite interface (p_i ≤ 0.039). The following preparation designs and veneer thicknesses showed differences (p_i ≤ 0.021): Veneer-composite: NP-T1 < I-T1, MI-T1 < I-T1, I-T1 > I-T2; Tooth-composite: NP-T1 < SI-T1, NP-T1 < I-T1, NP-T2 > MI-T2, MI-T1 < SI-T1, MI-T1 < I-T1, SI-T1 < I-T1, MI-T2 < SI-T2, MI-T2 < I-T2.SignificanceThe interface adhesion of ceramic veneers was influenced by the preparation design and the veneer thickness. A ceramic thickness of at least 0.5 mm and a preparation without exposing dentine is advantageous for the interfacial bond.     

Comparison of volumetric bone mineral density in the operated and contralateral knee after anterior cruciate ligament and reconstruction: A 1‐year follow‐up study using peripheral quantitative computed tomography

The purpose of this study was to quantify changes in volumetric bone mineral density (vBMD) in the tibial plateau of the operated and contralateral leg measured using peripheral quantitative computed tomography (pQCT) before and 3, 6, and 12 months after anterior cruciate ligament (ACL) reconstruction. The ACL was reconstructed with a hamstring tendon autograft using press‐fit fixation. pQCT measurements of the proximal tibia were obtained in 61 patients after ACL reconstruction, and total, cortical, and trabecular vBMD were calculated. vBMD in the operated leg decreased from baseline to 3 months (?12% [total], ?11% [cortical], and ?12.6% [trabecular]; p < 0.001) and remained below baseline for 12 months after surgery (6 months: ?9.5%, ?9.4%, and ?9.6%, p < 0.001; 12 months: ?8%, ?5%, and ?11%, p < 0.001). vBMD in the contralateral leg was slightly reduced only 6 months after surgery. Including age and sex as covariates into the analysis did not affect the results. ACL reconstruction contributed to loss in bone mineral density within the first year after surgery. The role of factors such as time of weight‐bearing, joint mechanics, post‐traumatic inflammatory reactions, or genetic predisposition in modulating the development of posttraumatic knee osteoarthritis after ACL injury should be further elucidated. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1804–1810, 2015.

     

Different steroids co-regulate long-term expansion versus terminal differentiation in primary human erythroid progenitors

Outgrowth, long-term self-renewal, and terminal maturation of human erythroid progenitors derived from umbilical cord blood in serum-free medium can be modulated by steroid hormones. Homogeneous erythroid cultures, as characterized by flow cytometry and dependence on a specific mixture of physiologic proliferation factors, were obtained within 8 days from a starting population of mature and immature mononuclear cells. Due to previous results in mouse and chicken erythroblasts, the proliferation-promoting effect of glucocorticoids was not unexpected. Surprisingly, however, androgen had a positive effect on the sustained expansion of human female but not male erythroid progenitors. Under optimal conditions, sustained proliferation of erythroid progenitors resulted in a more than 10(9)-fold expansion within 60 days. Terminal erythroid maturation was significantly improved by adding human serum and thyroid hormone (3,5,3'-triiodothyronine [T3]) to the differentiation medium. This resulted in highly synchronous differentiation of the cells toward enucleated erythrocytes within 6 days, accompanied by massive size decrease and hemoglobin accumulation to levels comparable to those in peripheral blood erythrocytes. Thus, obviously, different ligand-activated nuclear hormone receptors massively influence the decision between self-renewal and terminal maturation in the human erythroid compartment.     

Shear stress-induced up-regulation of the intermediate-conductance Ca(2+)-activated K(+) channel in human endothelium

OBJECTIVE: Wall shear stress associated with blood flow is a major stimuli for generation of endothelial vasodilating and antithrombotic factors and it also regulates endothelial gene expression. Activation of endothelial intermediate-conductance Ca(2+)-activated K(+) channels (IK(Ca)) is important for the control of endothelial function by inducing cell hyperpolarization and thus generation of the endothelium-derived hyperpolarizing factor. In the present study we tested whether the IK(Ca) encoding IKCa1 gene is regulated by laminar shear stress (LSS). METHODS: Human umbilical vein endothelial cells (HUVEC) were subjected to LSS with a magnitude of 0.5-15 dyn/cm(2) and time intervals of 2-24 h in a flow cone apparatus. Expression of the IKCa1 gene and IK(Ca)-functions were determined by using real time RT-PCR and patch-clamp techniques. RESULTS: A short 2-4 h-or long 24 h-exposure to a LSS with a low (venous) magnitude of 0.5 dyn/cm(2) had no effect on IKCa1 expression levels. An exposure for 2 and 4 h to LSS with an intermediate magnitude of 5 dyn/cm(2) was also ineffective, whereas an exposure for 24 h induced a significant threefold up-regulation of IKCa1 expression levels. An exposure to LSS with a higher (arterial) magnitude of 15 dyn/cm(2), resulted in an eightfold up-regulation of IKCa1 expression levels after a 4 h-exposure and a fourfold increase of IKCa1 expression levels at 24 h. The increased IKCa1 expression levels following exposure to high levels of LSS resulted in enhanced IK(Ca) whole-cell currents and in an increased hyperpolarization of the endothelium in response to ATP and the IK(Ca) opener 1-EBIO. Inhibition of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK) kinase 1/2 (MEK/ERK) pathway by PD98059 prevented the LSS-induced up-regulation of IKCa1 expression levels and IK(Ca) whole-cell currents indicating that augmentation of IKCa1 expression levels is mediated by the LSS-induced activation of the MEK/ERK pathway. CONCLUSION: Long term exposure to LSS up-regulates expression and function of endothelial IK(Ca). This increase might represent a new important mechanism in endothelial adaptation to altered hemodynamics.     

Guidelines for empiric antimicrobial prescribing in community-acquired pneumonia

Empiric antimicrobial prescribing for community-acquired pneumonia remains a challenge, despite the availability of treatment guidelines. A number of key differences exist between North American and European guidelines, mainly in the outpatient setting. The North American approach is to use initial antimicrobial therapy, which provides coverage for Streptococcus pneumoniae plus atypical pathogens. Europeans tend to focus on providing pneumococcal coverage with less emphasis on covering for an atypical pathogen. Ambulatory patients without comorbidity are more likely to receive macrolide therapy in North America, whereas in Europe these patients would probably receive a beta-lactam agent. Major issues that are fundamental to this difference include the importance of providing therapy for atypical pathogens and the clinical significance of macrolide-resistant S pneumoniae. Prospective data are required to evaluate which of these two approaches offers clinical superiority.     

Continuous complete remission in adult patients with acute lymphocytic leukaemia at a median observation of 12 years after autologous bone marrow transplantation

We report our long-term experience with autologous bone marrow transplantation (ABMT) for 32 adult patients with acute lymphocytic leukaemia (ALL) in second or later remission (CR), or in first CR but with high-risk. Bone marrow was purged with mafosfamide (n = 25) or with immunomagnetic beads and monoclonal antibodies (n = 7). Retrospective analysis showed that 12 out of 32 patients were in continuous complete remission (CCR) at a median of 143 months (range 66-181 months). A plateau was reached at 50 months and the disease-free and overall survival rates were both 37.5%. It was notable that durable CCR could be achieved for patients in second (three out of nine) or third (one out of six) CR. ABMT could produce durable CCR and the long-term outcome compared favourably with those reported for allogeneic transplantation.