Patients with diabetes and peripheral neuropathy have a 25% risk of developing a foot ulcer, and these can lead to soft tissue infections that worsen and result in osteomyelitis. While Charcot ...neuroarthropathy is not as common as osteomyelitis, it is often misdiagnosed as osteomyelitis.
Three patients presented with diabetes, neuropathy, and foot ulcers. They underwent prophylactic surgery but later developed swelling at the surgical sites. Radiographs showed fragmentations that caused concern about osteomyelitis. The authors maintained diagnoses of Charcot neuroarthropathy and treated the patients with immobilization and offloading. All patients resolved the fragmentations without antibiotics or surgery.
While Charcot neuroarthropathy and osteomyelitis have similar signs and symptoms, understanding the similarities and differences between the conditions can aid providers in appropriate wound management.
The logarithmic nature of the allometric equation suggests that metabolic rate scaling is related to some fractal properties of the organism. Two universal models have been proposed, based on (1) the ...fractal design of the vasculature and (2) the fractal nature of the 'total effective surface' of mitochondria and capillaries. According to these models, basal and maximal metabolic rates must scale as M3/4. This is not what we find. In 34 eutherian mammalian species (body mass Mb ranging from 7 g to 500 kg) we found VO2max to scale with the 0.872 (+/-0.029) power of body mass, which is significantly different from 3/4 power scaling. Integrated structure-function studies on a subset of eleven species (Mb 20 g to 450 kg) show that the variation of VO2max with body size is tightly associated with the total volume of mitochondria and of the locomotor musculature capillaries. In athletic species the higher VO2max is linked to proportionally larger mitochondrial and capillary volumes. As a result, VO2max is linearly related to both total mitochondrial and capillary erythrocyte volumes, as well as to their surface areas. Consequently, the allometric variation of maximal metabolic rate is directly related to the scaling of the total effective surfaces of mitochondria and capillaries, thus confirming the basic conjecture of the second fractal models but refuting the arguments for 3/4 power scaling. We conclude that the scaling of maximal metabolic rate is determined by the energy needs of the cells active during maximal work. The vascular supply network is adapted to the needs of the cells at their working limit. We conjecture that the optimization of the arterial tree by fractal design is the result rather than the cause of the evolution of metabolic rate scaling. The remaining question is why the energy needs of locomotion scale with the 0.872 or 7/8 power of body mass.
► Dose dependent increase in FK506 binding protein 5 (Fkbp5) and decrease in DNA methyltransferase 1 (Dnmt1) expression by dexamethasone. ► Site-specific loss of methylation of Fkbp5 in pituitary ...cell line and hippocampus. ► Glucocorticoid-induced epigenetic activity in hippocampus enriched in dentate gyrus.
Glucocorticoids may play a significant role in the etiology of neuropsychiatric illnesses. Abnormalities in plasma cortisol levels, glucocorticoid sensitivity, and HPA-axis function often accompany clinical symptoms of stress-related illnesses such as PTSD and depression. Of particular interest are genetic association studies that link single nucleotide polymorphisms of HPA-axis genes with illnesses only in the context of an early-life trauma exposure such as child abuse. These studies suggest that dysregulation of HPA-axis function can have lasting repercussions in shaping mood and anxiety, long after termination of the traumatic experience. As persistent glucocorticoid-induced loss of DNA methylation in FK506 binding protein 5 (Fkbp5) was previously observed in the hippocampus and blood and in the neuronal cell line HT-22, we asked whether these epigenetic alterations occur in non-neuronal, HPA-axis relevant cells. We used the pituitary adenoma cell line AtT-20 to demonstrate that the intronic enhancer region of Fkbp5 undergoes loss of DNA methylation in response to dexamethasone treatment in a dose-dependent manner. We also focused on the mouse hippocampal dentate gyrus to test whether these changes would be enriched in a region implicated in the HPA-axis stress response, neurogenesis, and synaptic plasticity. We observed an increase in enrichment of DNA methylation loss in the dentate gyrus, as compared to whole hippocampal tissues that were similarly treated with glucocorticoids. We then asked whether DNA methyltransferase 1 (Dnmt1), a methyltransferase enzyme involved in maintaining DNA methylation following cell division, is involved in the observed epigenetic alterations. We found a dose-dependent decrease of Dnmt1 expression in the AtT-20 cells following dexamethasone treatment, and a similar decrease in corticosterone-treated mouse hippocampus. Taken together, we provide evidence that these glucocorticoid-induced epigenetic alterations have a broader validity in non-neuronal cells and that they may involve the DNA methylation machinery.
Quantitative assessment of the lung microstructure using standard stereological methods such as volume fractions of tissue, alveolar surface area, or number of alveoli, are essential for ...understanding the state of normal and diseased lung. These measures are traditionally obtained from histological sections of the lung tissue, a process that ultimately destroys the three-dimensional (3-D) anatomy of the tissue. In comparison, a novel X-ray-based imaging method that allows nondestructive sectioning and imaging of fixed lungs at multiple resolutions can overcome this limitation. Scanning of the whole lung at high resolution and subsequent regional sampling at ultrahigh resolution without physically dissecting the organ allows the application of design-based stereology for assessment of the whole lung structure. Here we validate multiple stereological estimates performed on micro-computed tomography (μCT) images by comparing them with those obtained via conventional histology on the same mouse lungs. We explore and discuss the potentials and limitations of the two approaches. Histological examination offers higher resolution and the qualitative differentiation of tissues by staining, but ultimately loses 3-D tissue relationships, whereas μCT allows for the integration of morphometric data with the spatial complexity of lung structure. However, μCT has limited resolution satisfactory for the sterological estimates presented in this study but not for differentiation of tissues. We conclude that introducing stereological methods in μCT studies adds value by providing quantitative information on internal structures while not curtailing more complex approaches to the study of lung architecture in the context of physiological or pathological studies.
1 Institute of Anatomy, University of Bern, Bern, Switzerland; and 2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
Quantitative data on lung ...structure are essential to set up structure-function models for assessing the functional performance of the lung or to make statistically valid comparisons in experimental morphology, physiology, or pathology. The methods of choice for microscopy-based lung morphometry are those of stereology, the science of quantitative characterization of irregular three-dimensional objects on the basis of measurements made on two-dimensional sections. From a practical perspective, stereology is an assumption-free set of methods of unbiased sampling with geometric probes, based on a solid mathematical foundation. Here, we discuss the pitfalls of lung morphometry and present solutions, from specimen preparation to the sampling scheme in multiple stages, for obtaining unbiased estimates of morphometric parameters such as volumes, surfaces, lengths, and numbers. This is demonstrated on various examples. Stereological methods are accurate, efficient, simple, and transparent; the precision of the estimates depends on the size and distribution of the sample. For obtaining quantitative data on lung structure at all microscopic levels, state-of-the-art stereology is the gold standard.
sampling; quantitative microscopy; structure
Address for reprint requests and other correspondence: M. Ochs, Institute of Anatomy, Univ. of Bern, Baltzerstrasse 2, CH-3000 Bern 9, Switzerland (e-mail: M.Ochs{at}ana.unibe.ch )
Chronic stress resulting from prolonged exposure to negative life events increases the risk of mood and anxiety disorders. Although chronic stress can change gene expression relevant for behavior, ...molecular regulators of this change have not been fully determined. One process that could play a role is DNA methylation, an epigenetic process whereby a methyl group is added onto nucleotides, predominantly cytosine in the CpG context, and which can be induced by chronic stress. It is unknown to what extent chronic social defeat, a model of human social stress, influences DNA methylation patterns across the genome. Our study addressed this question by using a targeted-capture approach called Methyl-Seq to investigate DNA methylation patterns of the dentate gyrus at putative regulatory regions across the mouse genome from mice exposed to 14 days of social defeat. Findings were replicated in independent cohorts by bisulfite-pyrosequencing. Two differentially methylated regions (DMRs) were identified. One DMR was located at intron 9 of Drosha, and it showed reduced methylation in stressed mice. This observation replicated in one of two independent cohorts. A second DMR was identified at an intergenic region of chromosome X, and methylation in this region was increased in stressed mice. This methylation difference replicated in two independent cohorts and in Major Depressive Disorder (MDD) postmortem brains. These results highlight a region not previously known to be differentially methylated by chronic social defeat stress and which may be involved in MDD.
Maximal metabolic rate (MMR) of mammals scales differently from basal metabolic rate (BMR). This is first shown by scrutinizing data reported on exercise-induced
V
̇
O
2
max in 34 eutherian mammalian ...species covering a body mass range of 7
g–500
kg.
V
̇
O
2
max was found to scale with the 0.872 (±0.029, 95% confidence limits 0.813–0.932) power of body mass which is significantly different from the 3/4 power reported for basal metabolic rate. The aerobic scope is higher in athletic than non-athletic species, and it is also higher in large than in small species. Integrated structure-function studies on a subset of 11 species (body mass 20
g–450
kg) show that the variation of
V
̇
O
2
max with body size is tightly associated with the aerobic capacity of the locomotor musculature: the scaling exponents for
V
̇
O
2
max, the total volume of mitochondria, and the volume of capillaries are nearly identical. The higher
V
̇
O
2
max of athletic species is tightly linked to proportionally larger mitochondrial and capillary volumes in animals of the same size class. As a result
V
̇
O
2
max is linearly related to both total mitochondrial and capillary erythrocyte volumes. We conclude that the scaling of maximal metabolic rate is explained by features and mechanisms different from those determining basal metabolic rate.
PDF
