Issues in modern bone histomorphometry

This review reports on proceedings of a bone histomorphometry session conducted at the Fortieth International IBMS Sun Valley Skeletal Tissue Biology Workshop held on August 1, 2010. The session was prompted by recent technical problems encountered in conducting histomorphometry on bone biopsies from humans and animals treated with anti-remodeling agents such as bisphosphonates and RANKL antibodies. These agents reduce remodeling substantially, and thus cause problems in calculating bone remodeling dynamics using in vivo fluorochrome labeling. The tissue specimens often contain few or no fluorochrome labels, and thus create statistical and other problems in analyzing variables such as mineral apposition rates, mineralizing surface and bone formation rates. The conference attendees discussed these problems and their resolutions, and the proceedings reported here summarize their discussions and recommendations

Why Acute Ischemic Stroke Patients in the United States Use or Do Not Use Emergency Medical Services Transport? Findings of an Inpatient Survey

Background Patients with acute ischemic stroke (AIS) who use emergency medical services (EMS) receive quicker reperfusion treatment which, in turn, mitigates post-stroke disability. However, nationally only 59% use EMS. We examined why AIS patients use or do not use EMS. Methods During 2016–2018, a convenience sample of AIS patients admitted to a primary stroke center in South Carolina were surveyed during hospitalization if they were medically fit, available for survey when contacted, and consented to participate. The survey was programed into EpiInfo with skip patterns to minimize survey burden and self-administered on a touchscreen computer. Survey questions covered symptom characteristics, knowledge of stroke and EMS importance, subjective reactions, role of bystanders and financial factors. Descriptive and multiple regression analyses were performed. Results Of 108 inpatients surveyed (out of 1179 AIS admissions), 49% were male, 44% African American, mean age 63.5 years, 59% mild strokes, 75 (69%) arrived by EMS, 33% were unaware of any stroke symptom prior to stroke, and 75% were unaware of the importance of EMS use for good outcome. Significant factors that influenced EMS use decisions (identified by regression analysis adjusting for stroke severity) were: prior familiarity with stroke (self or family/friend with stroke) adjusted odds ratio, 5.0 (95% confidence interval, 1.6, 15.1), perceiving symptoms as relevant for self and indicating possible stroke, 26.3 (7.6, 91.1), and bystander discouragement to call 911, 0.1 (0.01,0.7). Further, all 27 patients who knew the importance of EMS had used EMS. All patients whose physician office advised actions other than calling EMS at symptom onset, did not use EMS. Conclusion Systematic stroke education of patients with stroke-relevant comorbidities and life-style risk factors, and public health educational programs may increase EMS use and mitigate post-stroke disability

Why Acute Ischemic Stroke Patients in the United States Use or Do Not Use Emergency Medical Services Transport? Findings of an Inpatient Survey

Background: Patients with acute ischemic stroke (AIS) who use emergency medical services (EMS) receive quicker reperfusion treatment which, in turn, mitigates post-stroke disability. However, nationally only 59% use EMS. We examined why AIS patients use or do not use EMS. Methods: During 2016–2018, a convenience sample of AIS patients admitted to a primary stroke center in South Carolina were surveyed during hospitalization if they were medically fit, available for survey when contacted, and consented to participate. The survey was programed into EpiInfo with skip patterns to minimize survey burden and self-administered on a touchscreen computer. Survey questions covered symptom characteristics, knowledge of stroke and EMS importance, subjective reactions, role of bystanders and financial factors. Descriptive and multiple regression analyses were performed. Results: Of 108 inpatients surveyed (out of 1179 AIS admissions), 49% were male, 44% African American, mean age 63.5 years, 59% mild strokes, 75 (69%) arrived by EMS, 33% were unaware of any stroke symptom prior to stroke, and 75% were unaware of the importance of EMS use for good outcome. Significant factors that influenced EMS use decisions (identified by regression analysis adjusting for stroke severity) were: prior familiarity with stroke (self or family/friend with stroke) adjusted odds ratio, 5.0 (95% confidence interval, 1.6, 15.1), perceiving symptoms as relevant for self and indicating possible stroke, 26.3 (7.6, 91.1), and bystander discouragement to call 911, 0.1 (0.01, 0.7). Further, all 27 patients who knew the importance of EMS had used EMS. All patients whose physician office advised actions other than calling EMS at symptom onset, did not use EMS. Conclusion: Systematic stroke education of patients with stroke-relevant comorbidities and life-style risk factors, and public health educational programs may increase EMS use and mitigate post-stroke disability

Effects of heat treatment on the atomic structure and surface energy of rutile and anatase TiO2 nanoparticles under vacuum and water environments

Nanomaterials have become a widely used group of materials in many chemical engineering applications owing to their ability to provide an enhanced level of functional properties compared to their crystalline and bulk counterparts. Here we report fundamental level advancements on how the anatase and rutile phase of TiO2 nanoparticles chemo-thermally respond between room temperature and the melting temperature under both vacuum and water environments. The current study is based on using molecular dynamics (MD) simulations. We present results on the equilibrium crystal morphology of these phases, structural and surface energy of TiO2 nanoparticles in the size range of 2-6 nm under different temperatures. Thermodynamic and structural properties, in the form of potential energy and Radial Distribution Functions (RDF’s) respectively, are calculated for both forms of TiO2 nanoparticles. The temperature associated with the melting transition increased with an increase in the particle size in both the phases. The potential energy change associated with the melting transition for anatase was seen to be less than that for rutile nanoparticles. Also the temperature at which the RDF’s began to stretch and broaden was observed to be lower for the case of anatase than rutile, suggesting that rutile attains the most thermal stable phase for the nano particle sizes considered in this study. Structural changes in anatase and rutile nanoparticles under different temperatures revealed that non-spherical (rod-like) rutile nanoparticles tend to be thermodynamically more stable. Surface energy influences the shape of TiO2 nanoparticles at different temperatures. The increase in the surface energy of nanoparticles under vacuum when compared with that of water environment is higher for the anatase phase than the rutile phase of nanoparticle sizes studied here. The fundamental level simulation results reported here provide a strong platform for potentially accounting for the effects of atomic-scale phase characteristics of TiO2 nanoparticles and surface energy under different temperature fields in nano processing applications and related multi-scale modelling approaches in future

Comparison of Pharmacological Modulation of APP Metabolism in Primary Chicken Telencephalic Neurons and in a Human Neuroglioma Cell Line

Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases and the formation of Aβ peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aβ formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a β-secretase inhibitor (β-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination

Objective Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. Methods We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. Results Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). Conclusions In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022Peer reviewe

Evolving strategies for cancer and autoimmunity:back to the future

Although current thinking has focused on genetic variation between individuals and environmental influences as underpinning susceptibility to both autoimmunity and cancer, an alternative view is that human susceptibility to these diseases is a consequence of the way the immune system evolved. It is important to remember that the immunological genes that we inherit and the systems that they control were shaped by the drive for reproductive success rather than for individual survival. It is our view that human susceptibility to autoimmunity and cancer is the evolutionarily acceptable side effect of the immune adaptations that evolved in early placental mammals to accommodate a fundamental change in reproductive strategy. Studies of immune function in mammals show that high affinity antibodies and CD4 memory, along with its regulation, co-evolved with placentation. By dissection of the immunologically active genes and proteins that evolved to regulate this step change in the mammalian immune system, clues have emerged that may reveal ways of de-tuning both effector and regulatory arms of the immune system to abrogate autoimmune responses whilst preserving protection against infection. Paradoxically, it appears that such a detuned and deregulated immune system is much better equipped to mount anti-tumor immune responses against cancers