How Much Do Focal Infarcts Distort White Matter Lesions and Global Cerebral Atrophy Measures?

BACKGROUND: White matter lesions (WML) and brain atrophy are important biomarkers in stroke and dementia. Stroke lesions, either acute or old, symptomatic or silent, are common in older people. Such stroke lesions can have similar signals to WML and cerebrospinal fluid (CSF) on magnetic resonance (MR) images, and may be classified accidentally as WML or CSF by MR image processing algorithms, distorting WML and brain atrophy volume from the true volume. We evaluated the effect that acute or old stroke lesions at baseline, and new stroke lesions occurring during follow-up, could have on measurement of WML volume, cerebral atrophy and their longitudinal progression. METHODS: We used MR imaging data from patients who had originally presented with acute lacunar or minor cortical ischaemic stroke symptoms, recruited prospectively, who were scanned at baseline and about 3 years later. We measured WML and CSF volumes (ml) semi-automatically. We manually outlined the acute index stroke lesion (ISL), any old stroke lesions present at baseline, and new lesions appearing de novo during follow-up. We compared baseline and follow-up WML volume, cerebral atrophy and their longitudinal progression excluding and including the acute ISL, old and de novo stroke lesions. A non-parametric test (Wilcoxon's signed rank test) was used to compare the effects. RESULTS: Among 46 patients (mean age 72 years), 33 had an ISL visible on MR imaging (median volume 2.05 ml, IQR 0.88–8.88) and 7 of the 33 had old lacunes at baseline: WML volume was 8.54 ml (IQR 5.86–15.80) excluding versus 10.98 ml (IQR 6.91–24.86) including ISL (p < 0.001). At follow-up, median 39 months later (IQR 30–45), 3 patients had a de novo stroke lesion; total stroke lesion volume had decreased in 11 and increased in 22 patients: WML volume was 12.17 ml (IQR 8.54–19.86) excluding versus 14.79 ml (IQR 10.02–38.03) including total stroke lesions (p < 0.001). Including/excluding lacunes at baseline or follow-up also made small differences. Twenty-two of the 33 patients had tissue loss due to stroke lesions between baseline and follow-up, resulting in a net median brain tissue volume loss (i.e. atrophy) during follow-up of 24.49 ml (IQR 12.87–54.01) excluding versus 24.61 ml (IQR 15.54–54.04) including tissue loss due to stroke lesions (p < 0.001). Including stroke lesions in the WML volume added substantial noise, reduced statistical power, and thus increased sample size estimated for a clinical trial. CONCLUSIONS: Failure to exclude even small stroke lesions distorts WML volume, cerebral atrophy and their longitudinal progression measurements. This has important implications for design and sample size calculations for observational studies and randomised trials using WML volume, WML progression or brain atrophy as outcome measures. Improved methods of discriminating between stroke lesions and WML, and between tissue loss due to stroke lesions and true brain atrophy are required

Fluid flow in the osteocyte mechanical environment : a fluid-structure interaction approach

Osteocytes are believed to be the primary sensor of mechanical stimuli in bone, which orchestrate osteoblasts and osteoclasts to adapt bone structure and composition to meet physiological loading demands. Experimental studies to quantify the mechanical environment surrounding bone cells are challenging, and as such, computational and theoretical approaches have modelled either the solid or fluid environment of osteocytes to predict how these cells are stimulated in vivo. Osteocytes are an elastic cellular structure that deforms in response to the external fluid flow imposed by mechanical loading. This represents a most challenging multi-physics problem in which fluid and solid domains interact, and as such, no previous study has accounted for this complex behaviour. The objective of this study is to employ fluid–structure interaction (FSI) modelling to investigate the complex mechanical environment of osteocytes in vivo. Fluorescent staining of osteocytes was performed in order to visualise their native environment and develop geometrically accurate models of the osteocyte in vivo. By simulating loading levels representative of vigorous physiological activity (3,000με compression and 300 Pa pressure gradient), we predict average interstitial fluid velocities (∼60.5μ m/s ) and average maximum shear stresses (∼11 Pa ) surrounding osteocytes in vivo. Interestingly, these values occur in the canaliculi around the osteocyte cell processes and are within the range of stimuli known to stimulate osteogenic responses by osteoblastic cells in vitro. Significantly our results suggest that the greatest mechanical stimulation of the osteocyte occurs in the cell processes, which, cell culture studies have indicated, is the most mechanosensitive area of the cell. These are the first computational FSI models to simulate the complex multi-physics mechanical environment of osteocyte in vivo and provide a deeper understanding of bone mechanobiology

Cancer effects of formaldehyde: a proposal for an indoor air guideline value

Formaldehyde is a ubiquitous indoor air pollutant that is classified as “Carcinogenic to humans (Group 1)” (IARC, Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropanol-2-ol. IARC monographs on the evaluation of carcinogenic risks to humans, vol 88. World Health Organization, Lyon, pp 39–325, 2006). For nasal cancer in rats, the exposure–response relationship is highly non-linear, supporting a no-observed-adverse-effect level (NOAEL) that allows setting a guideline value. Epidemiological studies reported no increased incidence of nasopharyngeal cancer in humans below a mean level of 1 ppm and peak levels below 4 ppm, consistent with results from rat studies. Rat studies indicate that cytotoxicity-induced cell proliferation (NOAEL at 1 ppm) is a key mechanism in development of nasal cancer. However, the linear unit risk approach that is based on conservative (“worst-case”) considerations is also used for risk characterization of formaldehyde exposures. Lymphohematopoietic malignancies are not observed consistently in animal studies and if caused by formaldehyde in humans, they are high-dose phenomenons with non-linear exposure–response relationships. Apparently, these diseases are not reported in epidemiological studies at peak exposures below 2 ppm and average exposures below 0.5 ppm. At the similar airborne exposure levels in rodents, the nasal cancer effect is much more prominent than lymphohematopoietic malignancies. Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies. Departing from the rat studies, the guideline value of the WHO (Air quality guidelines for Europe, 2nd edn. World Health Organization, Regional Office for Europe, Copenhagen, pp 87–91, 2000), 0.08 ppm (0.1 mg m−3) formaldehyde, is considered preventive of carcinogenic effects in compliance with epidemiological findings

Tissue engineering of functional articular cartilage: the current status

Osteoarthritis is a degenerative joint disease characterized by pain and disability. It involves all ages and 70% of people aged >65 have some degree of osteoarthritis. Natural cartilage repair is limited because chondrocyte density and metabolism are low and cartilage has no blood supply. The results of joint-preserving treatment protocols such as debridement, mosaicplasty, perichondrium transplantation and autologous chondrocyte implantation vary largely and the average long-term result is unsatisfactory. One reason for limited clinical success is that most treatments require new cartilage to be formed at the site of a defect. However, the mechanical conditions at such sites are unfavorable for repair of the original damaged cartilage. Therefore, it is unlikely that healthy cartilage would form at these locations. The most promising method to circumvent this problem is to engineer mechanically stable cartilage ex vivo and to implant that into the damaged tissue area. This review outlines the issues related to the composition and functionality of tissue-engineered cartilage. In particular, the focus will be on the parameters cell source, signaling molecules, scaffolds and mechanical stimulation. In addition, the current status of tissue engineering of cartilage will be discussed, with the focus on extracellular matrix content, structure and its functionality

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding