HISTOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Multilayer Approach.

PubMed

Li, Miaoling; Huisingh, Carrie; Messinger, Jeffrey; Dolz-Marco, Rosa; Ferrara, Daniela; Freund, K Bailey; Curcio, Christine A

2018-05-03

To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch membrane-choriocapillaris complex and associated extracellular deposits. Geographic atrophy was delimited by the external limiting membrane (ELM) descent towards Bruch membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Müller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch membrane thinned, and choriocapillaris density decreased. The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Müller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick

Imaging of thymic disorders

PubMed Central

Bogot, Naama R; Quint, Leslie E

2005-01-01

Evaluation of the thymus poses a challenge to the radiologist. In addition to age-related changes in thymic size, shape, and tissue composition, there is considerable variability in the normal adult thymic appearance within any age group. Many different types of disorders may affect the thymus, including hyperplasia, cysts, and benign and malignant neoplasms, both primary and secondary; clinical and imaging findings typical for each disease process are described in this article. Whereas computed tomography is the mainstay for imaging the thymus, other imaging modalities may occasionally provide additional structural or functional information. PMID:16361143

Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review).

PubMed

Yan, Fenggen; Mo, Xiumei; Liu, Junfeng; Ye, Siqi; Zeng, Xing; Chen, Dacan

2017-11-01

The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics.

Immunological Aging

EPA Science Inventory

Immunosenescence is associated with an increased incidence and severity of infections with common pathogens, neoplastic disease and autoimmunity. In general, aging is associated with a decline in function at the cellular level, rather than cell loss, although thymic atrophy and ...

Thymic involution in the suspended rat model for weightlessness - Decreased glucocorticoid receptor concentration

NASA Technical Reports Server (NTRS)

Steffen, J. M.; Musacchia, X. J.

1984-01-01

Hindlimb muscle atrophy, thymic involution and adrenal hypertrophy in rats during spaceflight can be simulated using suspension models. Skeletal muscle and thymus are sensitive to gluco-corticoids (GC), and previous studies have demonstrated that muscle atrophy in suspended rats is associated with increased GC receptor concentration. The objectives were to confirm thymic involution during suspension, and determine if involution correlated with increased GC receptor concentration. Seven days of antiorthostatic (AO) suspension of rats produced a significant (P less than 0.001) reduction in thymic wet weight not associated with an alteration of percent water content. GC receptor concentration (pmol/mg protein) decreased 20 percent (P less than 0.025) in thymus glands from 7 day AO suspended rats. Suspension, therefore, is associated with involution of the thymus, but this is not dependent upon AO positioning. Thymus GC receptor concentrations were depressed in 7-day suspended rats, in contrast with previous observations on skeletal muscle, suggesting that different mechanisms may underlie these responses.

Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

PubMed

Van Someren, Eus J W; Oosterman, J M; Van Harten, B; Vogels, R L; Gouw, A A; Weinstein, H C; Poggesi, A; Scheltens, Ph; Scherder, E J A

2018-06-01

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible. Copyright © 2018. Published by Elsevier Inc.

An Age-Associated Decline in Thymic Output Differs in Dog Breeds According to Their Longevity.

PubMed

Holder, Angela; Mella, Stephanie; Palmer, Donald B; Aspinall, Richard; Catchpole, Brian

2016-01-01

The age associated decline in immune function is preceded in mammals by a reduction in thymic output. Furthermore, there is increasing evidence of a link between immune competence and lifespan. One approach to determining thymic output is to quantify signal joint T cell receptor excision circles (sj-TRECs), a method which has been developed and used in several mammalian species. Life expectancy and the rate of aging vary in dogs depending upon their breed. In this study, we quantified sj-TRECs in blood samples from dogs of selected breeds to determine whether there was a relationship between longevity and thymic output. In Labrador retrievers, a breed with a median expected lifespan of 11 years, there was an age-associated decline in sj-TREC values, with the greatest decline occurring before 5 years of age, but with sj-TREC still detectable in some geriatric animals, over 13 years of age. In large short-lived breeds (Burnese mountain dogs, Great Danes and Dogue de Bordeaux), the decline in sj-TREC values began earlier in life, compared with small long-lived breeds (Jack Russell terriers and Yorkshire terriers), and the presence of animals with undetectable sj-TRECs occurred at a younger age in the short-lived breeds. The study findings suggest that age-associated changes in canine sj-TRECs are related to breed differences in longevity, and this research highlights the use of dogs as a potential model of immunosenescence.

Autofluorescence Lifetimes in Geographic Atrophy in Patients With Age-Related Macular Degeneration.

PubMed

Dysli, Chantal; Wolf, Sebastian; Zinkernagel, Martin S

2016-05-01

To investigate fluorescence lifetime characteristics in patients with geographic atrophy (GA) in eyes with age-related macular degeneration and to correlate the measurements with clinical data and optical coherence tomography (OCT) findings. Patients with GA were imaged with a fluorescence lifetime imaging ophthalmoscope. Retinal autofluorescence lifetimes were measured in a short and a long spectral channel (498-560 nm and 560-720 nm). Mean retinal fluorescence lifetimes were analyzed within GA and the surrounding retina, and data were correlated with best corrected visual acuity and OCT measurements. Fluorescence lifetime maps of 41 eyes of 41 patients (80 ± 7 years) with GA were analyzed. Mean lifetimes within areas of atrophy were prolonged by 624 ± 276 ps (+152%) in the short spectral channel and 418 ± 186 ps (+83%) in the long spectral channel compared to the surrounding tissue. Autofluorescence lifetime abnormalities in GA occurred with particular patterns, similar to those seen in fundus autofluorescence intensity images. Within the fovea short mean autofluorescence lifetimes were observed, presumably representing macular pigment. Short lifetimes were preserved even in the absence of foveal sparing but were decreased in patients with advanced retinal atrophy in OCT. Short lifetimes in the fovea correlated with better best corrected visual acuity in both spectral channels. This study established that autofluorescence lifetime changes in GA present with explicit patterns. We hypothesize that the short lifetimes seen within the atrophy may be used to estimate damage induced by atrophy and to monitor disease progression in the context of natural history or interventional therapeutic studies.

Leptin Selectively Augments Thymopoiesis in Leptin Deficiency and Lipopolysaccharide-Induced Thymic Atrophy1

PubMed Central

Hick, Ryan W.; Gruver, Amanda L.; Ventevogel, Melissa S.; Haynes, Barton F.; Sempowski, Gregory D.

2007-01-01

The thymus is a lymphoid organ that selects T cells for release to the peripheral immune system. Unfortunately, thymopoiesis is highly susceptible to damage by physiologic stressors and can contribute to immune deficiencies that occur in a variety of clinical settings. No treatment is currently available to protect the thymus from stress-induced involution. Leptin-deficient (ob/ob) mice have severe thymic atrophy and this finding suggests that this hormone is required for normal thymopoiesis. In this study, the ability of leptin to promote thymopoiesis in wild-type C57BL/6 and BALB/c mice, as well as in leptin-deficient (ob/ob) and endotoxin-stressed (Escherichia coli LPS) mice, was determined. Leptin administration induced weight loss and stimulated thymopoiesis in ob/ob mice, but did not stimulate thymopoiesis in wild-type C57BL/6 nor BALB/c mice. In endotoxin-stressed mice, however, leptin prevented LPS-induced thymus weight loss and stimulated TCRα gene rearrangement. Coadministration of leptin with LPS blunted endotoxin-induced systemic corticosterone response and production of proinflammatory cytokines. Thus, leptin has a selective thymostimulatory role in settings of leptin deficiency and endotoxin administration, and may be useful for protecting the thymus from damage and augmenting T cell reconstitution in these clinical states. PMID:16785512

Intestinal lymphangiectasia and thymic hypoplasia.

PubMed Central

Sorensen, R U; Halpin, T C; Abramowsky, C R; Hornick, D L; Miller, K M; Naylor, P; Incefy, G S

1985-01-01

We have evaluated the immunological abnormalities present in a 6 year old patient with primary intestinal and generalized lymphangiectasia confirmed by intestinal, lung and lymph node biopsies. Lymphocyte loss through the gut was confirmed by the detection of lymphocytes in her stool. An increased enteric protein loss was suggested by hypoproteinaemia, peripheral oedema, and a very short half-life for i.v. immune serum globulin (3 days). Lymphocyte subpopulation analysis revealed a selective loss of T lymphocytes, with a proportionally increased loss of the OKT4 positive helper/inducer subpopulation. Functionally, there was a decrease in proliferative responses to some mitogens and to allogeneic cells, and a lack of T cell help for in vitro B lymphocyte differentiation into immunoglobulin secreting cells. Natural killer function was normal. In this patient, a concomitant thymic deficiency was documented by failure to identify thymic tissue on a thymus biopsy and by an absence or decrease of the serum thymic factor (thymulin) and thymosin alpha 1. No compensatory lymphopoiesis was detected in the bone marrow. In an attempt to increase T lymphocyte development, the patient was treated with thymosin fraction 5. Daily treatment with this preparation resulted in a transient clinical improvement which could not be sustained on a weekly thymosin treatment schedule. However, lymphocyte numbers did not increase during this treatment. The findings in this patient support the notion that T lymphocytes are needed to stimulate thymic epithelium. In situations of excessive loss of long lived T lymphocytes a secondary thymic atrophy may occur and further contribute to the development of a deficiency in cell-mediated immunity. Images Fig. 1 Fig. 2 PMID:3971596

Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy*

PubMed Central

Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.; Murry, Daryl J.; Fox, Daniel K.; Bongers, Kale S.; Lira, Vitor A.; Meyerholz, David K.; Talley, John J.; Adams, Christopher M.

2015-01-01

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. PMID:26338703

Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy.

PubMed

Ebert, Scott M; Dyle, Michael C; Bullard, Steven A; Dierdorff, Jason M; Murry, Daryl J; Fox, Daniel K; Bongers, Kale S; Lira, Vitor A; Meyerholz, David K; Talley, John J; Adams, Christopher M

2015-10-16

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The Long-term Natural History of Geographic Atrophy from Age-Related Macular Degeneration

PubMed Central

Sunness, Janet S.; Margalit, Eyal; Srikumaran, Divya; Applegate, Carol A.; Tian, Yan; Perry, Daniel; Hawkins, Barbara S.; Bressler, Neil M.

2008-01-01

Purpose To report the enlargement rate of geographic atrophy (GA) over time, its relationship to size of atrophy at baseline and to prior enlargement rate, and the implications for designing future treatment trials for GA. Design Prospective natural history study of GA resulting from age-related macular degeneration. Participants Two hundred twelve eyes of 131 patients were included in the analysis. Methods Annual follow-up included stereo color fundus photographs. The areas of GA were identified and measured, and the rate of enlargement of the atrophy was assessed. Sample sizes for clinical trials using systemic treatment and uniocular treatment were determined. Main Outcome Measure Rate of enlargement of the atrophy. Results The median overall enlargement rate was 2.1 mm2/year (mean, 2.6 mm2/year). Eyes with larger areas of atrophy at baseline tended to have larger enlargement rates, but knowledge of prior rates of enlargement was the most significant factor in predicting subsequent enlargement rates. There was high concordance between the enlargement rates in the 2 eyes of patients with bilateral GA (correlation coefficient, 0.76). To detect a 25% reduction in enlargement rate for a systemic treatment (α, 0.05; power, 0.80; losses to follow-up, 15%), 153 patients each in a control and treatment group would be required for a trial with a 2-year follow-up period for each patient. For a uniocular treatment, 38 patients with bilateral GA would be required, with the untreated eye serving as a control for the treated eye. Conclusions Treatment trials for GA with an outcome variable of change in enlargement rate are feasible. PMID:17270676

Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration.

PubMed

Sadda, SriniVas R; Tuomi, Lisa L; Ding, Beiying; Fung, Anne E; Hopkins, J Jill

2018-06-01

To evaluate macular atrophy (MA) presence in the 24-month HARBOR study (NCT00891735) for neovascular age-related macular degeneration (AMD). Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial. Evaluable subjects (N = 1095) with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD treated with ranibizumab 0.5 mg or 2.0 mg monthly or pro re nata (PRN). Fluorescein angiograms (FAs) and color fundus photographs at baseline and months 3, 12, and 24 were retrospectively graded by masked graders for MA: well-defined areas of depigmentation with increased choroidal vessel visibility, diameter ≥250 μm, corresponding to flat areas of well-demarcated staining on FA, excluding atrophy associated with retinal pigment epithelium tears. Atrophy immediately within, adjacent, and nonadjacent to CNV lesions was included. Macular atrophy incidence, best-corrected visual acuity (BCVA). At baseline, MA was detected in 11.2% (123/1095) of study eyes. At month 24, 29.4% (229/778) of eyes without baseline atrophy had detectable MA. Eyes with and without baseline MA had significant mean BCVA gains from baseline at month 24 (letters [95% confidence interval]: +6.7 [4.1-9.3]; +9.1 [8.0-10.2], respectively). Among eyes with and without MA at month 24, mean month 24 BCVA was 62.0 [60.3-63.7] and 64.7 [63.2-66.3] letters, respectively. Baseline risk factors for month 24 MA presence included intraretinal cysts (hazard ratio [HR], 2.45 [1.76-3.42]) and fellow eye atrophy (HR, 2.02 [1.42-2.87]); subretinal fluid was associated with a lower MA risk (HR, 0.50 [0.33-0.74]). Ranibizumab dose was not associated with MA development. Monthly versus PRN treatment trended toward an association with MA (HR, 1.29 [0.99-1.68]), but was not statistically significant. New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24

Progression of Geographic Atrophy and Genotype in Age-Related Macular Degeneration

PubMed Central

Klein, Michael L.; Ferris, Frederick L.; Francis, Peter J.; Lindblad, Anne S.; Chew, Emily Y.; Hamon, Sara C.; Ott, Jurg

2009-01-01

Purpose To determine if genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Design Prospective analysis of participants in a randomized controlled clinical trial. Participants 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). Methods Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. Main Outcome Measures Genotype frequencies and change in cumulative area of GA. Results The mean growth rate of geographic atrophy for the 114 eyes was 1.79 mm2/year (range= 0.17–4.76 mm2/year). No association between growth rate and genotype was present for variants in the CFH, C2, C3, APOE, and TLR3genes. For the single nucleotide polymorphism (SNP) rs10490924 in LOC387715/ARMS2, there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared to the homozygous non-risk genotype (unadjusted p-value = 0.002; Bonferroni corrected p-value = 0.014) and for allelic association(Bonferroni corrected p-value = 0.011). Analyses of other measures of geographic atrophy progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. Conclusion GA growth rates calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, and TLR3 genes. There was a nominally statistically significant association

Characteristics of Incident Geographic Atrophy in the Complications of Age-related Macular Degeneration Prevention Trial

PubMed Central

Brader, Hilary Smolen; Ying, Gui-shuang; Martin, E. Revell; Maguire, Maureen G.

2013-01-01

Objective To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs). Design Retrospective cohort study within a larger clinical trial Participants Patients with bilateral large drusen who developed GA during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Methods Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients who developed GA in the untreated eye during 5-6 years of follow-up. Geographic atrophy was defined according to the Revised GA Criteria for identifying early GA23. Color-optimized fundus photographs were viewed concurrently with the FAs during grading. Main Outcome Measures Size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye. Results At presentation, the median total GA area was 0.26mm2 (0.1 Disc area). GA presented as a single lesion in 89 (78%) of eyes. The median distance from the fovea was 395μm. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250μm of the foveal center. Development of GA was associated with a mean decrease of 7 letters from the baseline visual acuity level compared to 1 letter among matched early age-related macular degeneration (AMD) eyes without GA. GA that formed in areas previously occupied by drusenoid pigment epithelial detachments (DPED) were on average larger (0.53 vs. 0.20 mm2; p=0.0001), more central (50 vs. 500 microns from the center of the fovea; p<0.0001), and associated with significantly worse visual outcome (20/50 vs. 20/25; p=0.0003) than GA with other drusen types as precursors. Conclusions Incident geographic atrophy most often appears on color fundus photographs and fluorescein angiograms as a small, singular, parafoveal lesion, though a large minority of lesions are

Prefrontal atrophy, disrupted NREM slow waves, and impaired hippocampal-dependent memory in aging

PubMed Central

Mander, Bryce A.; Rao, Vikram; Lu, Brandon; Saletin, Jared M.; Lindquist, John R.; Ancoli-Israel, Sonia; Jagust, William; Walker, Matthew P.

2014-01-01

Aging has independently been associated with regional brain atrophy, reduced non-rapid eye movement (NREM) slow-wave activity (SWA), and impaired long-term retention of episodic memories. However, that the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. Here, we show that age-related medial prefrontal cortex (mPFC) grey-matter atrophy is associated with reduced NREM SWA activity in older adults, the extent to which statistically mediates the impairment of overnight sleep-dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represent a novel contributing factor to age-related cognitive decline in later life. PMID:23354332

Characteristics of incident geographic atrophy in the complications of age-related macular degeneration prevention trial.

PubMed

Brader, Hilary Smolen; Ying, Gui-Shuang; Martin, E Revell; Maguire, Maureen G

2013-09-01

To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs). Retrospective cohort study within a larger clinical trial. Patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients in whom GA developed in the untreated eye during 5 to 6 years of follow-up. Geographic atrophy was defined according to the Revised GA Criteria for identifying early GA.(23) Color-optimized fundus photographs were viewed concurrently with the FAs during grading. Size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye. At presentation, the median total GA area was 0.26 mm(2) (0.1 disc area). Geographic atrophy presented as a single lesion in 89 (78%) eyes. The median distance from the fovea was 395 μm. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250 μm of the foveal center. Development of GA was associated with a mean decrease of 7 letters from the baseline VA level compared with 1 letter among matched early age-related macular degeneration eyes without GA. Geographic atrophy that formed in areas previously occupied by drusenoid pigment epithelial detachments on average were larger (0.53 vs. 0.20 mm(2); P = 0.0001), were more central (50 vs. 500 μm from the center of the fovea; P<0.0001), and were associated with significantly worse visual outcome (20/50 vs. 20/25; P = 0.0003) than GA with other drusen types as precursors. Incident GA most often appears on color fundus photographs and FAs as a small, singular, parafoveal lesion, although a large minority of lesions are subfoveal or multifocal at initial detection. The characteristics of incident GA

Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions.

PubMed

Kern, Kyle C; Wright, Clinton B; Bergfield, Kaitlin L; Fitzhugh, Megan C; Chen, Kewei; Moeller, James R; Nabizadeh, Nooshin; Elkind, Mitchell S V; Sacco, Ralph L; Stern, Yaakov; DeCarli, Charles S; Alexander, Gene E

2017-01-01

Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

Marek’s disease virus induces transient atrophy of cecal tonsils

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by an immunosupperessive alpha herpesvirus, Marek’s disease virus (MDV). Clinical signs of MD include bursal/thymic atrophy and neurological disorders. The cecal tonsils (CT) are the largest lymphoid aggregates of avia...

Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

PubMed

Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

2014-01-01

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

Marek’s disease virus induced transient atrophy of cecal tonsils

USDA-ARS?s Scientific Manuscript database

Although bursal and thymic atrophy associated with Marek’s disease (MD) is well established and characterized, the effect of Marek's disease virus (MDV) infection on lymphoid aggregates within the gut-associated lymphoid tissue (GALT) is not known. The cecal tonsils (CT) are the two largest lympho...

Patterns of brain atrophy associated with episodic memory and semantic fluency decline in aging.

PubMed

Pelletier, Amandine; Bernard, Charlotte; Dilharreguy, Bixente; Helmer, Catherine; Le Goff, Melanie; Chanraud, Sandra; Dartigues, Jean-François; Allard, Michèle; Amieva, Hélène; Catheline, Gwénaëlle

2017-03-09

The cerebral substratum of age-related cognitive decline was evaluated in an elderly-cohort followed for 12 years (n=306). Participants, free of dementia, received neuropsychological assessments every two years and an MRI exam at baseline and four years later. Cognitive decline was evaluated on two broadly used tests to detect dementia: the Free and Cued Selective Reminding Test (FCSRT), a verbal episodic memory task, and the Isaacs Set Test (IST), a semantic fluency task. Using voxel-based approach, the relationship between cognitive decline with 1/ baseline grey matter volumes and 2/ grey matter volume loss between the two scans was explored. Baseline volumes analysis revealed that FCSRT and IST declines were both associated with lower volumes of the medial temporal region. Volumes loss analysis confirmed that both declines are related to medial temporal lobe atrophy and revealed that FCSRT decline was specifically associated with atrophy of the posterior cingulate cortex whereas IST decline was specifically related to temporal pole atrophy. These results suggest that cognitive decline across aging is firstly related to structural modifications of the medial temporal lobe, followed by an atrophy in the posterior midline structures for episodic memory and an atrophy of the temporal pole for semantic fluency.

PROGNOSTIC VALUE OF SHAPE-DESCRIPTIVE FACTORS FOR THE PROGRESSION OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PubMed

Pfau, Maximilian; Lindner, Moritz; Goerdt, Lukas; Thiele, Sarah; Nadal, Jennifer; Schmid, Matthias; Schmitz-Valckenberg, Steffen; Sadda, SriniVas R; Holz, Frank G; Fleckenstein, Monika

2018-05-16

To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in geographic atrophy progression in previously unknown patients and 39.1% in patients with previous observation. These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

FSP1+ fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells

PubMed Central

Sun, Lina; Sun, Chenming; Liang, Zhanfeng; Li, Hongran; Chen, Lin; Luo, Haiying; Zhang, Hongmei; Ding, Pengbo; Sun, Xiaoning; Qin, Zhihai; Zhao, Yong

2015-01-01

Thymic epithelial cells (TECs) form a 3-dimentional network supporting thymocyte development and maturation. Besides epithelium and thymocytes, heterogeneous fibroblasts are essential components in maintaining thymic microenvironments. However, thymic fibroblast characteristics, development and function remain to be determined. We herein found that thymic non-hematopoietic CD45-FSP1+ cells represent a unique Fibroblast specific protein 1 (FSP1)—fibroblast-derived cell subset. Deletion of these cells in FSP1-TK transgenic mice caused thymus atrophy due to the loss of TECs, especially mature medullary TECs (MHCIIhigh, CD80+ and Aire+). In a cyclophosphamide-induced thymus injury and regeneration model, lack of non-hematopoietic CD45-FSP1+ fibroblast subpopulation significantly delayed thymus regeneration. In fact, thymic FSP1+ fibroblasts released more IL-6, FGF7 and FSP1 in the culture medium than their FSP1- counterparts. Further experiments showed that the FSP1 protein could directly enhance the proliferation and maturation of TECs in the in vitro culture systems. FSP1 knockout mice had significantly smaller thymus size and less TECs than their control. Collectively, our studies reveal that thymic CD45-FSP1+ cells are a subpopulation of fibroblasts, which is crucial for the maintenance and regeneration of TECs especially medullary TECs through providing IL-6, FGF7 and FSP1. PMID:26445893

Cellular mechanism of estrogen-induced thymic involution in wall lizard: caspase-dependent action.

PubMed

Hareramadas, Batchu; Rai, Umesh

2006-05-01

The present study, for the first time in an ectothermic vertebrate, demonstrates the cellular mechanism of estrogen-induced thymic involution. Ovariectomy in lizards during the preparatory phase of the reproductive cycle resulted in distinct differentiation of cortico-medullary regions and increase in cellularity, especially in the cortical region. The ovariectomy-induced changes were reversed following administration of 17-estradiol (E2), suggesting a primary role of E2 in causing thymic atrophy. To understand the cellular mechanism of E2-induced thymic atrophy, in vitro effect of E2 was investigated on thymocyte proliferation and apoptosis. E2 decreased the uptake of tritiated thymidine (3H-TdR) by thymocytes in a dose-dependent manner, suggesting that estrogen directly inhibits the thymocyte proliferation. Unlike proliferation, E2 did not have any direct effect on thymocyte apoptosis, as evident by DNA gel electrophoretic, flow cytometric or fluorescence microscopic studies. However, in the presence of thymic epithelial cell-rich stromal components (TEC), E2 treatment at low or high concentrations resulted in depolarization of plasma membrane, DNA fragmentation and decrease in DNA content. This suggests that E2 indirectly, through TEC-secreted factors, controls thymocyte apoptosis. Similar result was observed following fluorescence microscopy. The indirect effect of E2 was further ascertained with the findings that E2-pretreated TEC-conditioned medium accelerated the thymocyte apoptosis. Nevertheless, exposure of thymocytes to E2 was seen to be inevitable for the apoptotic action of TEC-secreted paracrine factors. In the presence of TEC, a positive reaction for caspase-3, -7 and -9 and enzyme substrate, poly(ADP-ribose) polymerase (PARP) in response to E2 suggests the caspase-dependent thymocyte apoptosis in the wall lizard Hemidactylus flaviviridis. Further, E2 was shown to act through genomic pathway, since the receptor antagonist tamoxifen and transcription

[Atrophy of the macula in the context of its wet, age-related degeneration : An inescapable consequence of anti-VEGF therapy?

PubMed

Garweg, J G

2016-12-01

Current understanding of the mechanisms that underlie the long-term consequences of anti-VEGF therapy in wet, age-related macular degeneration (AMD) is poor. Here, the impact of this treatment on the development of macular atrophy (MA) is discussed based on our current pathophysiological understanding. This review is based on a PubMed literature survey using the MeSH terms "wet AMD" and "macular atrophy" (151 hits) and limited to publications since 2013 (n = 90). Publications focussing on diagnostics and clinical course not in the context of therapy were excluded. Macular atrophy is defined herein as atrophy affecting the functionally relevant complex of photoreceptors, retinal pigmented epithelium (RPE), Bruch's membrane and choriocapillaris. Experimentally, a primary complete suppression of local VEGF leads to evident changes in the choriocapillaris, whereas its incomplete suppression exacerbates cell death of RPE and photoreceptors. Since pre-existing atrophic changes are already present at diagnosis, the role of anti-VEGF treatment cannot be separated from the spontaneous progression of AMD. The progression of MA appears to be faster under ranibizumab than bevacizumab, and likewise on a monthly rather than as-needed basis. Although MA progresses more rapidly under consequent therapy, visual function remains better. Hence, a functionally relevant progression of atrophy during the first five years of treatment would only be expected in pre-existing advanced MA. Despite doubts regarding the long-term safety of anti-VEGF therapy, it is the author's view that this is the only option to stabilise visual function. The impact of therapy-induced damage on the spontaneous progression of AMD and the biological status of the aging individual cannot be unequivocally assessed.

Alterations in intrinsic mitochondrial function with aging are fiber type-specific and do not explain differential atrophy between muscles.

PubMed

Picard, Martin; Ritchie, Darmyn; Thomas, Melissa M; Wright, Kathryn J; Hepple, Russell T

2011-12-01

To determine whether mitochondrial dysfunction is causally related to muscle atrophy with aging, we examined respiratory capacity, H(2) O(2) emission, and function of the mitochondrial permeability transition pore (mPTP) in permeabilized myofibers prepared from four rat muscles that span a range of fiber type and degree of age-related atrophy. Muscle atrophy with aging was greatest in fast-twitch gastrocnemius (Gas) muscle (-38%), intermediate in both the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (Sol) muscles (-21%), and non-existent in adductor longus (AL) muscle (+47%). In contrast, indices of mitochondrial dysfunction did not correspond to this differential degree of atrophy. Specifically, despite higher protein expression for oxidative phosphorylation (oxphos) system in fast Gas and EDL, state III respiratory capacity per myofiber wet weight was unchanged with aging, whereas the slow Sol showed proportional decreases in oxphos protein, citrate synthase activity, and state III respiration. Free radical leak (H(2) O(2) emission per O(2) flux) under state III respiration was higher with aging in the fast Gas, whereas state II free radical leak was higher in the slow AL. Only the fast muscles had impaired mPTP function with aging, with lower mitochondrial calcium retention capacity in EDL and shorter time to mPTP opening in Gas and EDL. Collectively, our results underscore that the age-related changes in muscle mitochondrial function depend largely upon fiber type and are unrelated to the severity of muscle atrophy, suggesting that intrinsic changes in mitochondrial function are unlikely to be causally involved in aging muscle atrophy. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Massive thymic hemorrhage and hemothorax occurring in utero.

PubMed

Gargano, Giancarlo; Paltrinieri, Anna Lucia; Gallo, Claudio; Di Pancrazio, Luciana; Roversi, Maria Federica; Ferrari, Fabrizio

2015-11-14

Thymic enlargement is a common and physiological finding in children and neonates' X-rays, but it is usually asymptomatic. Occasionally it can cause respiratory distress. In most cases the aetiology of this expansion remains unclear and it is diagnosed as a thymic hyperplasia. True thymic hyperplasia is defined as a gland expansion, both in size and weight, while maintaining normal microscopic architecture. Often it is a diagnosis of exclusion and prognosis is good. Thymic haemorrhage is an unusual condition related to high foetal and neonatal mortality. We report a case of spontaneous massive thymic haemorrhage in a newborn developing at birth acute respiratory distress associated with severe bilateral haemothorax. Thymic enlargement was evident after pleural evacuation and confirmed by radiographic, Computed Tomography (CT) images and Magnetic Resonance Imaging (MRI) sequences. The spontaneous resolution of this enlargement seen with CT scan and MRI sequences suggested a thymic haemorrhage; surgery was not necessary. Thymic haemorrhage should be considered in newborn infants with pleural effusion, mediastinal space enlargement and Respiratory Distress.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort.

PubMed

Ryberg, C; Rostrup, E; Paulson, O B; Barkhof, F; Scheltens, P; van Straaten, E C W; van der Flier, W M; Fazekas, F; Schmidt, R; Ferro, J M; Baezner, H; Erkinjuntti, T; Jokinen, H; Wahlund, L-O; Poggesi, A; Pantoni, L; Inzitari, D; Waldemar, G

2011-08-15

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed. CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3 years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness). In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly. Copyright © 2011 Elsevier B.V. All rights reserved.

Designing clinical trials for age-related geographic atrophy of the macula: enrollment data from the geographic atrophy natural history study.

PubMed

Sunness, Janet S; Applegate, Carol A; Bressler, Neil M; Hawkins, Barbara S

2007-02-01

To derive information from the Geographic Atrophy (GA) Natural History Study that is relevant to recruiting patients and designing clinical trials for GA. A prospective natural history study with annual follow-up enrolled patients with GA and no choroidal neovascularization (CNV) in at least one eye. Characteristics of recruited and enrolled patients are analyzed, in the context of progression data from the study. The data show that GA from age-related macular degeneration (AMD) was seen in 82% of the referred patients, there was an attrition rate of 14%, and 60% of the patients with GA from AMD had bilateral GA without CNV. Within the 83 patients in the bilateral GA group with follow-up, 50 patients (60%) met both the proposed visual acuity and the proposed GA area criteria for a treatment trial in one or both eyes. These data should be helpful in planning future treatment trials for GA.

Administration of RANKL boosts thymic regeneration upon bone marrow transplantation.

PubMed

Lopes, Noella; Vachon, Hortense; Marie, Julien; Irla, Magali

2017-06-01

Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, we show that RANK ligand (RANKL) is upregulated in CD4 + thymocytes and lymphoid tissue inducer (LTi) cells during the early phase of thymic regeneration. Importantly, whereas RANKL neutralization alters TEC recovery after irradiation, ex vivo RANKL administration during BMT boosts the regeneration of TEC subsets including thymic epithelial progenitor-enriched cells, thymus homing of lymphoid progenitors, and de novo thymopoiesis. RANKL increases specifically in LTi cells, lymphotoxin α, which is critical for thymic regeneration. RANKL treatment, dependent on lymphotoxin α, is beneficial upon BMT in young and aged individuals. This study thus indicates that RANKL may be clinically useful to improve T-cell function recovery after BMT by controlling multiple facets of thymic regeneration. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

The International Thymic Malignancy Interest Group thymic initiative: a state-of-the-art study of thymic malignancies.

PubMed

Detterbeck, Frank; Korst, Robert

2014-01-01

Thymic malignancies are relatively rare tumors. A general lack of knowledge, misconceptions about benignancy, confusion about the definition of terms, and variability in reporting of outcomes have further hampered progress in these diseases. The International Thymic Malignancy Interest Group has emerged to counter these challenges and has brought together a worldwide multidisciplinary community determined to improve outcomes for these patients. Although the organization is young (initiated in 2010), major early accomplishments have created a foundation and infrastructure for scientific research. These include consensus definitions of terms, an unprecedented global database, development of practical clinical resources and, together with the International Association for the Study of Lung Cancer, development of proposals for the first formal stage classification of these malignant tumors. Many articles have been published or are under way, and a second phase of projects building on the early success is proceeding. The greatest accomplishment of the International Thymic Malignancy Interest Group lies in the establishment of an open culture of collaboration and the engagement of a broad group of individuals united by a common mission. It is a testament to what can be achieved, despite ongoing and inherent challenges, by determination and a collective effort. Copyright © 2014 Elsevier Inc. All rights reserved.

Gender effects on age-related changes in brain structure.

PubMed

Xu, J; Kobayashi, S; Yamaguchi, S; Iijima, K; Okada, K; Yamashita, K

2000-01-01

Previous reports have suggested that brain atrophy is associated with aging and that there are gender differences in brain atrophy with aging. These reports, however, neither exclude silent brain lesions in "healthy subjects" nor divide the brain into subregions. The aim of this study is to clarify the effect of gender on age-related changes in brain subregions by MR imaging. A computer-assisted system was used to calculate the brain matter area index (BMAI) of various regions of the brain from MR imaging of 331 subjects without brain lesions. There was significantly more brain atrophy with aging in the posterior parts of the right frontal lobe in male subjects than there was in female subjects. Age-related atrophy in the middle part of the right temporal lobe, the left basal ganglia, the parietal lobe, and the cerebellum also was found in male subjects, but not in female subjects. In the temporal lobe, thalamus, parieto-occipital lobe, and cerebellum, brain volume in the left hemisphere is significantly smaller than in the right hemisphere; sex and age did not affect the hemisphere differences of brain volume in these regions. The effect of gender on brain atrophy with aging varied in different subregions of the brain. There was more brain atrophy with aging in male subjects than in female subjects.

Thymic Carcinoma Management Patterns among International Thymic Malignancy Interest Group (ITMIG) Physicians with Consensus from the Thymic Carcinoma Working Group.

PubMed

Shepherd, Annemarie; Riely, Gregory; Detterbeck, Frank; Simone, Charles B; Ahmad, Usman; Huang, James; Korst, Robert; Rajan, Arun; Rimner, Andreas

2017-04-01

Thymic carcinomas are rare epithelial malignancies with limited data to guide management. To identify areas of agreement and variability in current clinical practice, a 16-question electronic survey was given to members of the International Thymic Malignancy Interest Group (ITMIG). Areas of controversy were discussed with the Thymic Carcinoma Working Group and consensus was achieved, as described. A total of 100 ITMIG members responded. There was general agreement regarding the role for multimodality therapy with definitive surgical resection in physically fit patients with advanced but resectable disease. Areas of controversy included the need for histologic confirmation before surgery, the role of adjuvant therapy, the optimal first-line chemotherapy regimen, and the recommended treatment course for marginally resectable disease with invasion into the great vessels, pericardium, and lungs. The results of the questionnaire provide a description of the management of thymic carcinoma by 100 ITMIG members with a specific interest or expertise in thymic malignancies. Although there was agreement in some areas, clinical practice appears to vary significantly. There is a great need for collaborative research to identify optimal evaluation and treatment strategies. Given the need for multimodality therapy in many cases, a multidisciplinary discussion of the management of patients with thymic carcinoma is critical. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development

PubMed Central

Pinto, Ana Isabel; Smith, Jennifer; Kissack, Miriam R.; Hogg, Karen G.; Green, E. Allison

2018-01-01

Type 1 diabetes (T1D) results from a coordinated autoimmune attack of insulin producing beta cells in the pancreas by the innate and adaptive immune systems, beta cell death being predominantly T cell-mediated. In addition to T cells, peripheral B cells are important in T1D progression. The thymus of mice and man also contains B cells, and lately they have been linked to central tolerance of T cells. The role of thymic B cells in T1D is undefined. Here, we show there are abnormalities in the thymic B cell compartment before beta cell destruction and T1D manifestation. Using non-obese diabetic (NOD) mice, we document that preceding T1D development, there is significant accumulation of thymic B cells-partly through in situ development- and the putative formation of ectopic germinal centers. In addition, in NOD mice we quantify thymic plasma cells and observe in situ binding of immunoglobulins to undefined antigens on a proportion of medullary thymic epithelial cells (mTECs). By contrast, no ectopic germinal centers or pronounced intrathymic autoantibodies are detectable in animals not genetically predisposed to developing T1D. Binding of autoantibodies to thymic stroma correlates with apoptosis of mTECs, including insulin-expressing cells. By contrast, apoptosis of mTECs was decreased by 50% in B cell-deficient NOD mice suggesting intrathymic autoantibodies may selectively target certain mTECs for destruction. Furthermore, we observe that these thymic B cell-associated events correlated with an increased prevalence of premature thymic emigration of T cells. Together, our data suggest that the thymus may be a principal autoimmune target in T1D and contributes to disease progression.

Images in pediatrics: the thymic sail sign and thymic wave sign.

PubMed

Alves, Nuno D; Sousa, Marta

2013-01-01

The authors present a radiographic image portraying the "thymic sail sign" and the "thymic wave sign," both normal findings in infant radiographs and present a short description of these signs. These are distinguished from pathologic findings such as the "spinnaker-sail sign" in pneumomediastinum.

Age-related changes in the thymus gland: CT-pathologic correlation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, A.V.; Korobkin, M.; Olanow, W.

1983-08-01

Recent reports suggest that computed tomography (CT) is useful for thymoma detection in patients with myasthenia gravis. However, that usefulness may be conditioned by the state of the normal thymus. To examine this concept, the CT findings in 64 consecutive patients with histologic confirmation of thymic status after thymectomy or thymic biopsy during mediastinal exploration were reviewed. The normal thymus has a bilobed, arrowhead-shaped cross section at all ages, with gradual focal or diffuse fatty infiltration of the parenchyma usually occurring between 20 and 40 years of age. A thymoma is usually a spherical or oval mass, often producing amore » focal, distinct bulge in the adjacent pleural reflection. The differentiation of thymoma from normal thymus should be possible in most patients if age-related changes in the normal gland are appreciated.« less

Thymic hormone containing cells. II. Evolution of cells containing the serum thymic factor (FTS or thymulin) in normal and autoimmune mice, as revealed by anti-FTS monoclonal antibodies. Relationship with Ia bearing cells.

PubMed Central

Savino, W; Dardenne, M; Bach, J F

1983-01-01

The number of thymic epithelial cells containing the serum thymic factor (FTS or thymulin), assessed by indirect immunofluorescence using an anti-FTS monoclonal antibody, was studied in the thymus of normal and autoimmune mice as a function of age. In normal mice the number of FTS+ cells was constant until the age of 6 months and then began to decline. In autoimmune strains, the age linked decline was premature being already significant at 10 weeks of age. These findings were paralleled by the age associated decline of FTS blood levels in all strains studied. Double labelling experiments showed that in both normal and autoimmune mice, FTS+ cells were Ia negative, suggesting that these cells belong to a specific subpopulation of the thymic epithelial reticulum. PMID:6345030

Thymoma and Thymic Carcinoma—Health Professional Version

Cancer.gov

Thymomas and thymic carcinomas are epithelial tumors of the thymus. A thymic epithelial tumor that exhibits cytologic atypia and histologic features no longer specific to the thymus is known as a thymic carcinoma. Find evidence-based information on thymoma and thymic carcinoma treatment.

Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer´s disease

PubMed Central

Grothe, Michel; Heinsen, Helmut; Teipel, Stefan J.

2013-01-01

Background The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer´s disease (AD). However, there is a controversy on how the cholinergic lesion in AD relates to early and incipient stages of the disease. In-vivo imaging studies on the structural integrity of the BFCS in normal and pathological aging are still rare. Methods We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of BF cholinergic nuclei to a large cross-sectional dataset of high-resolution MRI scans, covering the whole adult age-range (20–94 years; N=211) as well as patients with very mild AD (vmAD; CDR=0.5; N=69) and clinically manifest AD (AD; CDR=1; N=28). For comparison, we investigated hippocampus volume using automated volumetry. Results Volume of the BFCS declined from early adulthood on and atrophy aggravated in advanced age. Volume reductions in vmAD were most pronounced in posterior parts of the nucleus basalis Meynert, while in AD atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume. Conclusions Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in-vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathological aging. PMID:21816388

Acute respiratory failure revealing a multilocular thymic cyst in an infant: a case report.

PubMed

Asma, Bouziri; Ammar, Khaldi; Khaled, Menif; Najoua, Guandoura; Nejla, Ben Jaballah

2009-11-30

Multilocular thymic cysts are rare benign lesions of the neck and mediastinum that can occur at any age. In children, multilocular thymic cysts are usually symptomatic after the age of 2 years and produce few symptoms. We present an unusual case of a multilocular thymic cyst diagnosed in a 3-month-old girl and causing severe respiratory failure. A 3 month-old-girl, with a medical history of dyspnea and wheezing since the age of 20 days, presented in our pediatric intensive care unit for acute respiratory failure requiring mechanical ventilation. The chest radiograph showed thoracic distension without any other abnormalities. The diagnosis of severe asthma was initially suspected and the patient was treated by intravenous corticosteroids and continuous perfusion of salbutamol without any improvement. A chest tomography scan was performed and demonstrated an anterior mediastinal multiseptated cystic mass extending from the inferior face of the thyroid gland to the left cardiophrenic angle. Sternotomy and excision biopsy were planned urgently. The cystic mass was excised completely. The histopathological examination confirmed the diagnosis of a multilocular thymic cyst. The particularities of our observation are the occurrence of a multilocular thymic cyst in a young infant and its presentation by a severe acute respiratory failure mimicking asthma.

Thymoma and Thymic Carcinoma—Patient Version

Cancer.gov

Thymomas and thymic carcinomas are rare tumors that form in cells on the thymus. Thymomas grow slowly and rarely spread beyond the thymus. Thymic carcinoma grows faster, often spreads to other parts of the body, and is harder to treat. Start here to find information on thymoma and thymic carcinoma treatment.

Cardiorespiratory Fitness is Associated with Atrophy in Alzheimer’s and Aging Over Two Years

PubMed Central

Vidoni, Eric D.; Honea, Robyn A.; Billinger, Sandra A.; Swerdlow, Russel H.; Burns, Jeffrey M.

2011-01-01

We sought to describe change in cardiorespiratory (CR) fitness over 2 years in those with early–stage Alzheimer’s disease (AD) and nondemented aging and assess the relationship of CR fitness with cognitive decline, brain atrophy and dementia progression. Individuals with early-stage AD (n=37) and without dementia (n=53) attended clinical evaluations, cognitive and exercise tests, and MRI at baseline and 2 years later. CR fitness was lower in those with AD over the study period. Lower baseline CR fitness was associated with progression of dementia severity in AD. Declining CR fitness over 2 years was associated with brain atrophy in AD, especially in the parahippocampus. In nondemented participants, there was a trend for lower baseline fitness to be related to cognitive decline. Both lower baseline CR fitness and declining CR fitness over 2 years were associated with regional brain atrophy. We conclude that CR fitness is chronically reduced in those with AD. Further in those with AD, CR fitness is associated with progression of dementia severity and brain atrophy in AD, suggesting a link between progression of dementia severity and cardiorespiratory health. PMID:21531480

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study.

PubMed

Geerlings, M I; Sigurdsson, S; Eiriksdottir, G; Garcia, M E; Harris, T B; Sigurdsson, T; Gudnason, V; Launer, L J

2013-02-01

To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. Within the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 4354 persons (mean age 76 ± 5 years, 58% women) without dementia had a 1.5-T brain magnetic resonance imaging (MRI) scan. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI). Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy [B = -1.25%, 95% confidence interval (CI) -2.05 to -0.44], including more gray- and white-matter atrophy in most lobes, and also more atrophy of the hippocampus and thalamus. Participants with current, first-onset MDD also had more brain atrophy (B = -1.62%, 95% CI -3.30 to 0.05) whereas those remitted did not (B = 0.06%, 95% CI -0.54 to 0.66). In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD was associated with widespread gray- and white-matter brain atrophy. Prospective studies should examine whether MDD is a consequence of, or contributes to, brain volume loss and development of dementia.

Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF.

PubMed

Choi, K-J; Zhang, S-N; Choi, I-K; Kim, J-S; Yun, C-O

2012-07-01

Interleukin (IL)-12 and granulocyte-monocyte colony-stimulating factor (GM-CSF) have recently been used as immunotherapeutic agents in cancer gene therapy. IL-12 and GM-CSF have differential roles in the antitumor immune response, as IL-12 targets T, NK and natural killer T (NKT) cells and GM-CSF principally targets antigen-presenting cells (APCs). To strengthen the therapeutic efficacy of these two cytokines, we generated an oncolytic adenovirus (Ad), Ad-ΔB7/IL12/GMCSF, coexpressing IL-12 and GM-CSF. Using a murine B16-F10 syngeneic tumor model, we show that Ad-ΔB7/IL12/GMCSF promoted antitumor responses and increased survival compared with an oncolytic Ad expressing IL-12 or GM-CSF alone (Ad-ΔB7/IL12 or Ad-ΔB7/GMCSF, respectively). By measuring cytotoxic T lymphocyte activity and interferon-γ production, we show that the enhanced therapeutic effect was mediated by the induction of immune cell cytotoxicity. In situ delivery of Ad-ΔB7/IL12/GMCSF resulted in massive infiltration of CD4(+) T cells, CD8(+) T cells, NK cells and CD86(+) APCs into the tissue surrounding the necrotic area of the tumor. Moreover, GM-CSF effectively promoted antitumor immune memory, which was significantly augmented by IL-12. Lastly, IL12-expressing oncolytic Ads prevented tumor-induced thymic atrophy and was associated with reduced apoptosis and increased proliferation in the thymus. Taken together, these data demonstrate that an oncolytic Ad coexpressing IL-12 and GM-CSF is a potential therapeutic tool for the treatment of cancer.

Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25.

PubMed

Gossens, Klaus; Naus, Silvia; Corbel, Stephane Y; Lin, Shujun; Rossi, Fabio M V; Kast, Jürgen; Ziltener, Hermann J

2009-04-13

Thymic T cell progenitor (TCP) importation is a periodic, gated event that is dependent on the expression of functional P-selectin ligands on TCPs. Occupancy of intrathymic TCP niches is believed to negatively regulate TCP importation, but the nature of this feedback mechanism is not yet resolved. We show that P-selectin and CCL25 are periodically expressed in the thymus and are essential parts of the thymic gate-keeping mechanism. Periodicity of thymic TCP receptivity and the size of the earliest intrathymic TCP pool were dependent on the presence of functional P-selectin ligand on TCPs. Furthermore, we show that the numbers of peripheral blood lymphocytes directly affected thymic P-selectin expression and TCP receptivity. We identified sphingosine-1-phosphate (S1P) as one feedback signal that could mediate influence of the peripheral lymphocyte pool on thymic TCP receptivity. Our findings suggest a model whereby thymic TCP importation is controlled by both early thymic niche occupancy and the peripheral lymphocyte pool via S1P.

Optical Coherence Tomography Angiography Reveals Mature, Tangled Vascular Networks in Eyes With Neovascular Age-Related Macular Degeneration Showing Resistance to Geographic Atrophy.

PubMed

Dansingani, Kunal K; Freund, K Bailey

2015-10-01

To demonstrate a vascular pattern seen on optical coherence tomography angiography (OCTA) that appears to correlate with reduced rates of geographic atrophy (GA) in eyes receiving long-term anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). Non-consecutive, retrospective cohort study. Patients were included if they had received more than 50 anti-VEGF injections during a period of at least 4 years for neovascular AMD in at least one eye, with absence or minimal progression of GA. Clinical charts and imaging were reviewed retrospectively; study eyes underwent OCTA. Nine eyes of eight patients were included. Mean age was 82 years, and mean follow-up of study eyes 9.1 years; study eyes received a mean of 65.8 injections. OCTA revealed tangled networks of neovessels associated with type 1 lesions. With prolonged anti-VEGF treatment, GA appears to occur less commonly in eyes with type 1 neovascularization. OCTA shows mature tangled vessels with substantial flow within type 1 lesions. Mature, tangled networks may be associated with a decreased likelihood of developing GA despite the presence of choriocapillaris atrophy. Copyright 2015, SLACK Incorporated.

Thymic involution in the suspended rat - Adrenal hypertrophy and glucocorticoid receptor content

NASA Technical Reports Server (NTRS)

Steffen, J. M.; Musacchia, X. J.

1986-01-01

The relationship between thymic involution and adrenal hypertrophy is studied. The thymus, adrenal glands, and tissue water content are evaluated in male Sprague rats suspended in antiorthostatic (AO) or orthostatic (O) positions. A 50 percent decrease in the wet weight of the thymus and hypertrophy of the adrenal glands are observed during the seven days of AO suspension. After seven days of recovery the thymus weight is increased to control level; however, the hypertrophy of the adrenal glands remains unchanged. Thymic and renal responses in O postioned rats are similar to AO reactions. Thymic glucocorticoid (GC) receptor concentrations in the rats are analyzed; a 20 percent decrease in GC receptor site concentration, which is related to thymic involution, is detected in both AO and O rats. It is concluded that there is a temporal correlation between thymic involution and adrenal hypertrophy, which is not affected by AO positioning, and thymic involution is not associated with an increased sensitivity to GC.

Early metabolic crisis-related brain atrophy and cognition in traumatic brain injury.

PubMed

Wright, Matthew J; McArthur, David L; Alger, Jeffry R; Van Horn, Jack; Irimia, Andrei; Filippou, Maria; Glenn, Thomas C; Hovda, David A; Vespa, Paul

2013-09-01

Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as 'frontal-temporal' in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis-related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.

GEOGRAPHIC ATROPHY: Semantic Considerations and Literature Review.

PubMed

Schmitz-Valckenberg, Steffen; Sadda, Srinivas; Staurenghi, Giovanni; Chew, Emily Y; Fleckenstein, Monika; Holz, Frank G

2016-12-01

There is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term "geographic atrophy." Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals. We reviewed the nominal definition of the term "geographic atrophy" and conducted a search of the ophthalmologic literature focusing on preceding terminologies and the first citations of the term "geographic atrophy" secondary to age-related macular degeneration. According to the nominal definition, the term "geography" stands for a detailed description of the surface features of a specific region, indicating its relative position. However, it does not necessarily imply that the borders of the region must be sharply demarcated or related to any anatomical structures. The term "geographical areas of atrophy" was initially cited in the 1960s in the ophthalmologic literature in the context of uveitic eye disease and shortly thereafter also for the description of variants of "senile macular degeneration." However, no direct explanation could be found in the literature as to why the terms "geographical" and "geographic" were chosen. Presumably the terms were used as the atrophic regions resembled the map of a continent or well-defined country borders on thematic geographical maps. With the evolution of the terminology, the commonly used adjunct "of the retinal pigment epithelium" was frequently omitted and solely the term "geographic atrophy" prevailed for the nonexudative late-stage of age-related macular degeneration itself. Along with the quantification of atrophic areas, based on different imaging modalities and the use of both manual and semiautomated approaches, various and inconsistent definitions for the minimal lesion diameter or size of atrophic lesions have also emerged. Reconsideration of the application of the term "geographic atrophy" in the context of age-related macular

Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26.

PubMed

Lindblad, Anne S; Lloyd, Patricia C; Clemons, Traci E; Gensler, Gary R; Ferris, Frederick L; Klein, Michael L; Armstrong, Jane R

2009-09-01

To characterize progression of geographic atrophy (GA) associated with age-related macular degeneration in AREDS as measured by digitized fundus photographs. Fundus photographs from 181 of 4757 AREDS participants with a GA area of at least 0.5 disc areas at baseline or from participants who developed bilateral GA during follow-up were scanned, digitized, and evaluated longitudinally. Geographic atrophy area was determined using planimetry. Rates of progression from noncentral to central GA and of vision loss following development of central GA included the entire AREDS cohort. Median initial lesion size was 4.3 mm(2). Average change in digital area of GA from baseline was 2.03 mm(2) (standard error of the mean, 0.24 mm(2)) at 1 year, 3.78 mm(2) (0.24 mm(2)) at 2 years, 5.93 mm(2) (0.34 mm(2)) at 3 years, and 1.78 mm(2) (0.086 mm(2)) per year overall. Median time to developing central GA after any GA diagnosis was 2.5 years (95% confidence interval, 2.0-3.0). Average visual acuity decreased by 3.7 letters at first documentation of central GA, and by 22 letters at year 5. Growth of GA area can be reliably measured using standard fundus photographs that are digitized and subsequently graded at a reading center. Development of GA is associated with subsequent further growth of GA, development of central GA, and loss in central vision.

Thymic Dendritic Cells Are Primary Targets for the Oncogenic Virus SL3-3

PubMed Central

Uittenbogaart, Christel H.; Law, Wendy; Leenen, Pieter J. M.; Bristol, Gregory; van Ewijk, Willem; Hays, Esther F.

1998-01-01

The murine retrovirus SL3-3 causes malignant transformation of thymocytes and thymic lymphoma in mice of the AKR and NFS strains when they are inoculated neonatally. The objective of the present study was to identify the primary target cells for the virus in the thymuses of these mice. Immunohistochemical studies of the thymus after neonatal inoculation of the SL3-3 virus showed that cells expressing the viral envelope glycoprotein (gp70+ cells) were first seen at 2 weeks of age. These virus-expressing cells were found in the cortex and at the corticomedullary junction in both mouse strains. The gp70+ cells had the morphology and immunophenotype of dendritic cells. They lacked macrophage-specific antigens. Cell separation studies showed that bright gp70+ cells were detected in a fraction enriched for dendritic cells. At 3 weeks of age, macrophages also expressed gp70. At that time, both gp70+ dendritic cells and macrophages were found at the corticomedullary junction and in foci in the thymic cortex. At no time during this 3-week period was the virus expressed in cortical and medullary epithelial cells or in thymic lymphoid cells. Infectious cell center assays indicated that cells expressing infectious virus were present in small numbers at 2 weeks after inoculation but increased at 5 weeks of age by several orders of magnitude, indicating virus spread to the thymic lymphoid cells. Thus, at 2 weeks after neonatal inoculation of SL3-3, thymic dendritic cells are the first cells to express the virus. At 3 weeks of age, macrophages also express the virus. In subsequent weeks, the virus spreads to the thymocytes. This pathway of virus expression in the thymus allows the inevitable provirus integration in a thymocyte that results in a clonal lymphoma. PMID:9811752

Thymic hormone containing cells. III. Evidence for a feed-back regulation of the secretion of the serum thymic factor (FTS) by thymic epithelial cells.

PubMed Central

Savino, W; Dardenne, M; Bach, J F

1983-01-01

Cells containing the serum thymic factor (FTS), as measured by indirect immunofluorescence, were studied in mice either FTS depleted by injection of anti-FTS monoclonal antibodies or immunization against FTS coupled to bovine serum albumin (FTS-BSA), or FTS enriched by multiple injections of synthetic thymulin (FTS-Zn). Injections of thymulin did not significantly depress FTS secretion. Conversely, long term elimination of FTS from peripheral blood caused a great increase in the thymic intracellular content of FTS, as evidenced by the higher number of FTS containing cells observed with immunofluorescence. These data could provide the first evidence of a feed-back control of thymic endocrine function. PMID:6683135

Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression

PubMed Central

Garfin, Phillip M.; Min, Dullei; Bryson, Jerrod L.; Serwold, Thomas; Edris, Badreddin; Blackburn, Clare C.; Richie, Ellen R.; Weinberg, Kenneth I.; Manley, Nancy R.; Viatour, Patrick

2013-01-01

Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow–independent mechanism, identifying a novel pathway to target to increase thymic function in patients. PMID:23669396

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study

PubMed Central

Geerlings, Mirjam I.; Sigurdsson, Sigurdur; Eiriksdottir, Gudny; Garcia, Melissa E.; Harris, Tamara B.; Sigurdsson, Thordur; Gudnason, Vilmundur; Launer, Lenore J.

2014-01-01

Background To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. Methods Within the population-based AGES-Reykjavik Study 4,354 persons (mean age 76±5 years, 58% women) without dementia had a 1.5Tesla brain MRI. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the MINI International Neuropsychiatric Interview. Results Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy (B=−1.25%; 95%CI −2.05 to −0.44%), including more gray and white matter atrophy in most lobes as well as more atrophy of the hippocampus and thalamus. Participants with current, first onset, MDD also had more brain atrophy (B=−1.62%; 95%CI −3.30 to 0.05%), while those remitted did not (B=0.06%; 95%CI −0.54 to 0.66%). Conclusion In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD, was associated with widespread gray and white matter brain atrophy. Prospective studies should examine whether MDD is a consequence of or contributes to brain volume loss and development of dementia. PMID:22647536

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

PubMed Central

Wertheimer, Tobias; Velardi, Enrico; Tsai, Jennifer; Cooper, Kirsten; Xiao, Shiyun; Kloss, Christopher C.; Ottmüller, Katja J.; Mokhtari, Zeinab; Brede, Christian; deRoos, Paul; Kinsella, Sinéad; Palikuqi, Brisa; Ginsberg, Michael; Young, Lauren F.; Kreines, Fabiana; Lieberman, Sophia R.; Lazrak, Amina; Guo, Peipei; Malard, Florent; Smith, Odette M.; Shono, Yusuke; Jenq, Robert R.; Hanash, Alan M.; Nolan, Daniel J.; Butler, Jason M.; Beilhack, Andreas; Manley, Nancy R.; Rafii, Shahin; Dudakov, Jarrod A; van den Brink, Marcel RM

2018-01-01

The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. Here we show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration, via their production of BMP4. ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signalling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance and regeneration; and its downstream targets such as Dll4, itself a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity. PMID:29330161

Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice

PubMed Central

Deguise, Marc-Olivier; De Repentigny, Yves; McFall, Emily; Auclair, Nicole; Sad, Subash

2017-01-01

Abstract Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis. PMID:28108555

THE PATHOPHYSIOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION AND THE COMPLEMENT PATHWAY AS A THERAPEUTIC TARGET

PubMed Central

Schmidt-Erfurth, Ursula; van Lookeren Campagne, Menno; Henry, Erin C.; Brittain, Christopher

2017-01-01

Purpose: Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To date, there are no approved therapeutics for GA treatment; however, several are in clinical trials. This review focuses on the pathophysiology of GA, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade. Methods: Primary literature search on PubMed for GA, complement cascade in age-related macular degeneration. ClinicalTrials.gov was searched for natural history studies in GA and clinical trials of drugs targeting the complement cascade for GA. Results: Cumulative damage to the retina by aging, environmental stress, and other factors triggers inflammation via multiple pathways, including the complement cascade. When regulatory components in these pathways are compromised, as with several GA-linked genetic risk factors in the complement cascade, chronic inflammation can ultimately lead to the retinal cell death characteristic of GA. Complement inhibition has been identified as a key candidate for therapeutic intervention, and drugs targeting the complement pathway are currently in clinical trials. Conclusion: The complement cascade is a strategic target for GA therapy. Further research, including on natural history and genetics, is crucial to expand the understanding of GA pathophysiology and identify effective therapeutic targets. PMID:27902638

Clinical Endpoints for the Study of Geographic Atrophy Secondary to Age-Related Macular Degeneration

PubMed Central

Sadda, SriniVas R.; Chakravarthy, Usha; Birch, David G.; Staurenghi, Giovanni; Henry, Erin C.; Brittain, Christopher

2017-01-01

Purpose To summarize the recent literature describing the application of modern technologies in the study of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Methods Review of the literature describing the terms and definitions used to describe GA, imaging modalities used to capture and measure GA, and the tests of visual function and functional deficits that occur in patients with GA. Results In this paper we describe the evolution of the definitions used to describe GA. We compare imaging modalities used in the characterization of GA, report on the sensitivity and specificity of the techniques where data exist, and describe the correlations between these various modes of capturing the presence of GA. We review the functional tests that have been used in patients with GA, and critically examine their ability to detect and quantify visual deficits. Conclusion Ophthalmologists and retina specialists now have a wide range of assessments available for the functional and anatomic characterization of GA in patients with AMD. To date, studies have been limited by their unimodal approach and we recommend that future studies of GA use multimodal imaging. We also suggest strategies for the optimal functional testing of patients with GA. PMID:27652913

Apatinib treatment in extensive metastatic advanced thymic carcinoma.

PubMed

He, Y; Liu, S; E, M; Wang, C; Shi, M; Liu, G; Abiyasi, N

2018-01-01

Apatinib is a novel oral, anti-tumor, angiogenic-targeting drug that can selectively target vascular endothelial growth factor receptor-2 (VEGFR-2). In clinical trials, this new tyrosine kinase inhibitor (TKI) has been shown to be an effective and safe treatment for a variety of malignancies. Currently, there is a lack of studies of patients with thymic carcinoma; therefore, we present a case of advanced thymic carcinoma treated with apatinib after chemotherapy failure with multiple lung metastases. This patient has been taking a dose of 500 mg of apatinib per day, and his efficacy has achieved partial response (PR), according to the RECIST 1.1 standard, and progression-free survival (PFS) is 6.3 months at this point. Apatinib will continue as his maintenance treatment. During the treatment, drug-related toxicity and side effects were tolerable. Thus, apatinib may be a meaningful option for the treatment of advanced metastatic thymic carcinoma after chemotherapy failure.

Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe.

PubMed

Nho, Kwangsik; Saykin, Andrew J; Nelson, Peter T

2016-01-01

Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

Effects of age and inactivity due to prolonged bed rest on atrophy of trunk muscles.

PubMed

Ikezoe, Tome; Mori, Natsuko; Nakamura, Masatoshi; Ichihashi, Noriaki

2012-01-01

This study investigated the effects of age and inactivity due to being chronically bedridden on atrophy of trunk muscles. The subjects comprised 33 young women (young group) and 41 elderly women who resided in nursing homes or chronic care institutions. The elderly subjects were divided into two groups: independent elderly group who were able to perform activities of daily living involving walking independently (n = 28) and dependent elderly group who were chronically bedridden (n = 13). The thickness of the following six trunk muscles was measured by B-mode ultrasound: the rectus abdominis, external oblique, internal oblique, transversus abdominis, thoracic erector spinae (longissimus) and lumbar multifidus muscles. All muscles except for the transversus abdominis and lumbar multifidus muscles were significantly thinner in the independent elderly group compared with those in the young group. The thicknesses of all muscles in the dependent elderly group was significantly smaller than that in the young group, whereas there were no differences between the dependent elderly and independent elderly groups in the muscle thicknesses of the rectus abdominis and internal oblique muscles. In conclusion, our results suggest that: (1) age-related atrophy compared with young women was less in the deep antigravity trunk muscles than the superficial muscles in the independent elderly women; (2) atrophy associated with chronic bed rest was more marked in the antigravity muscles, such as the back and transversus abdominis.

Ghrelin promotes thymopoiesis during aging

PubMed Central

Dixit, Vishwa Deep; Yang, Hyunwon; Sun, Yuxiang; Weeraratna, Ashani T.; Youm, Yun-Hee; Smith, Roy G.; Taub, Dennis D.

2007-01-01

The decline in adaptive immunity, T lymphocyte output, and the contraction of the TCR repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow–derived Lin–Sca1+cKit+ cells, while ghrelin- and growth hormone secretagogue receptor–deficient (GHS-R–deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice. Our findings demonstrate what we believe to be a novel role for ghrelin and its receptor in thymic biology and suggest a possible therapeutic benefit of harnessing this pathway in the reconstitution of thymic function in immunocompromised subjects. PMID:17823656

Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.

PubMed

Danis, Ronald P; Lavine, Jeremy A; Domalpally, Amitha

2015-01-01

Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular-associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this

Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects

PubMed Central

Danis, Ronald P; Lavine, Jeremy A; Domalpally, Amitha

2015-01-01

Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular-associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this

MACULAR ATROPHY FINDINGS BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY COMPARED WITH FUNDUS AUTOFLUORESCENCE IN TREATED EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PubMed

Takasago, Yukari; Shiragami, Chieko; Kobayashi, Mamoru; Osaka, Rie; Ono, Aoi; Yamashita, Ayana; Tsujikawa, Akitaka; Hirooka, Kazuyuki

2017-11-28

To compare the areas of choriocapillaris (CC) nonperfusion and macular atrophy (MA) in treated exudative age-related macular degeneration. This was a prospective, observational, cross-sectional study. Forty-four eyes exhibiting MA (42 patients with age-related macular degeneration), with a dry macula, underwent fundus autofluorescence and optical coherence tomography angiography. The area of MA detected by fundus autofluorescence and CC nonperfusion detected by optical coherence tomography angiography was measured using image analysis software. The rates of concordance between the MA and CC nonperfusion areas were calculated. We qualitatively and quantitatively compared the areas of MA and CC nonperfusion in age-related macular degeneration eyes. The mean areas of MA and CC nonperfusion were 5.95 ± 4.50 mm and 10.66 ± 7.05 mm, respectively (paired t-test, P < 0.001). In 39 eyes (88.6%), the CC nonperfusion area was larger than the MA area, and the mean CC nonperfusion area was significantly larger than the mean MA area. Fundus autofluorescence matching optical coherence tomography angiography showed that the CC nonperfusion area was almost included in the MA area. The mean concordance rate for the MA area inside the CC nonperfusion area was 87.7 ± 13.9%. The MA and CC nonperfusion areas markedly overlapped. The area of CC nonperfusion correlated with the MA area. Choroidal ischemia might be involved in the pathogenesis of MA in treated age-related macular degeneration.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

General Information about Thymoma and Thymic Carcinoma

MedlinePlus

... and Thymic Carcinoma Treatment (PDQ®)–Patient Version General Information About Thymoma and Thymic Carcinoma Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

Imaging Characteristics of Pathologically Proven Thymic Hyperplasia: Identifying Features That Can Differentiate True From Lymphoid Hyperplasia

PubMed Central

Araki, Tetsuro; Sholl, Lynette M.; Gerbaudo, Victor H.; Hatabu, Hiroto; Nishino, Mizuki

2014-01-01

OBJECTIVE The purpose of this article is to investigate the imaging characteristics of pathologically proven thymic hyperplasia and to identify features that can differentiate true hyperplasia from lymphoid hyperplasia. MATERIALS AND METHODS Thirty-one patients (nine men and 22 women; age range, 20–68 years) with pathologically confirmed thymic hyperplasia (18 true and 13 lymphoid) who underwent preoperative CT (n = 27), PET/CT (n = 5), or MRI (n = 6) were studied. The length and thickness of each thymic lobe and the transverse and anterior-posterior diameters and attenuation of the thymus were measured on CT. Thymic morphologic features and heterogeneity on CT and chemical shift on MRI were evaluated. Maximum standardized uptake values were measured on PET. Imaging features between true and lymphoid hyperplasia were compared. RESULTS No significant differences were observed between true and lymphoid hyperplasia in terms of thymic length, thickness, diameters, morphologic features, and other qualitative features (p > 0.16). The length, thickness, and diameters of thymic hyperplasia were significantly larger than the mean values of normal glands in the corresponding age group (p < 0.001). CT attenuation of lymphoid hyperplasia was significantly higher than that of true hyperplasia among 15 patients with contrast-enhanced CT (median, 47.9 vs 31.4 HU; Wilcoxon p = 0.03). The receiver operating characteristic analysis yielded greater than 41.2 HU as the optimal threshold for differentiating lymphoid hyperplasia from true hyperplasia, with 83% sensitivity and 89% specificity. A decrease of signal intensity on opposed-phase images was present in all four cases with in- and opposed-phase imaging. The mean maximum standardized uptake value was 2.66. CONCLUSION CT attenuation of the thymus was significantly higher in lymphoid hyperplasia than in true hyperplasia, with an optimal threshold of greater than 41.2 HU in this cohort of patients with pathologically confirmed

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration.

PubMed

Wertheimer, Tobias; Velardi, Enrico; Tsai, Jennifer; Cooper, Kirsten; Xiao, Shiyun; Kloss, Christopher C; Ottmüller, Katja J; Mokhtari, Zeinab; Brede, Christian; deRoos, Paul; Kinsella, Sinéad; Palikuqi, Brisa; Ginsberg, Michael; Young, Lauren F; Kreines, Fabiana; Lieberman, Sophia R; Lazrak, Amina; Guo, Peipei; Malard, Florent; Smith, Odette M; Shono, Yusuke; Jenq, Robert R; Hanash, Alan M; Nolan, Daniel J; Butler, Jason M; Beilhack, Andreas; Manley, Nancy R; Rafii, Shahin; Dudakov, Jarrod A; van den Brink, Marcel R M

2018-01-12

The thymus is not only extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood, and this capacity diminishes considerably with age. We show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration via their production of bone morphogenetic protein 4 (BMP4) ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signaling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1 , a key transcription factor involved in TEC development, maintenance, and regeneration, and its downstream targets such as Dll4 , a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Soluble Klotho and Brain Atrophy in Alcoholism.

PubMed

González-Reimers, Emilio; Romero-Acevedo, Lucía; Espelosín-Ortega, Elisa; Martín-González, M Candelaria; Quintero-Platt, Geraldine; Abreu-González, Pedro; José de-la-Vega-Prieto, María; Martínez-Martínez, Daniel; Santolaria-Fernández, Francisco

2018-05-26

Fibroblast growth factor (FGF-23) and α-Klotho (Klotho) levels may be altered in inflammatory conditions, possibly as compensatory mechanisms. Klotho exerts a protective effect on neurodegeneration and improves learning and cognition. No data exist about the association of Klotho and FGF-23 levels with brain atrophy observed in alcoholics. The aim of this study is to explore these relationships. FGF-23 and Klotho levels are altered in inflammation, possibly as compensatory mechanisms. Klotho enhances learning, but its role in ethanol-mediated brain atrophy is unknown. We found higher FGF-23 and lower Klotho levels in 131 alcoholics compared with 41 controls. Among cirrhotics, Klotho was higher and inversely related to brain atrophy. The study was performed on 131 alcoholic patients (54 cirrhotics) and 41 age- and sex-matched controls, in whom a brain computed tomography (CT) was performed and several indices were calculated. Marked brain atrophy was observed among patients when compared with controls. Patients also showed higher FGF-23 and lower Klotho values. However, among cirrhotics, Klotho values were higher. Klotho was inversely related to brain atrophy (for instance, ventricular index (ρ = -0.23, P = 0.008)), especially in cirrhotics. Klotho was also directly related to tumor necrosis factor (TNF) alpha (ρ = 0.22; P = 0.026) and inversely to transforming growth factor (TGF)-β (ρ = -0.34; P = 0.002), but not to C-reactive protein (CRP) or malondialdehyde levels. FGF-23 was also higher among cirrhotics but showed no association with CT indices. Klotho showed higher values among cirrhotics, and was inversely related to brain atrophy. FGF-23, although high among patients, especially cirrhotics, did not show any association with brain atrophy. Some inflammatory markers or cytokines, such as CRP or TGF-β were related to brain atrophy.

Toll-Like Receptor-3 and Geographic Atrophy in Age-Related Macular Degeneration

PubMed Central

Yang, Zhenglin; Stratton, Charity; Francis, Peter J.; Kleinman, Mark E.; Tan, Perciliz L.; Gibbs, Daniel; Tong, Zongzhong; Chen, Haoyu; Constantine, Ryan; Yang, Xian; Chen, Yuhong; Zeng, Jiexi; Davey, Lisa; Ma, Xiang; Hau, Vincent S.; Wang, Chi; Harmon, Jennifer; Buehler, Jeanette; Pearson, Erik; Patel, Shrena; Kaminoh, Yuuki; Watkins, Scott; Luo, Ling; Zabriskie, Norman A.; Bernstein, Paul S.; Cho, Wongil; Schwager, Andrea; Hinton, David R; Klein, Michael L; Hamon, Sara C.; Simmons, Emily; Yu, Beifeng; Campochiaro, Betsy; Sunness, Janet S.; Campochiaro, Peter; Jorde, Lynn; Parmigiani, Giovanni; Zack, Donald J.; Katsanis, Nicholas; Ambati, Jayakrishna; Zhang, Kang

2008-01-01

BACKGROUND Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. Advanced AMD is comprised of geographic atrophy (GA) and choroidal neovascularization (CNV). Specific genetic variants that predispose for GA are largely unknown. METHODS We tested (i) for association between the functional toll-like receptor-3 (TLR3) variant rs3775291 (L412F) and AMD in European Americans and (ii) the effect of TLR3 L and F variants on the viability of human retinal pigment epithelium (RPE) cells in vitro and on RPE cell apoptosis in wildtype and Tlr3−/− mice. RESULTS The F variant (or T allele at single nucleotide polymorphism at rs3775291) was associated with protection against GA (P=0.005); this association was replicated in two independent GA case-control series (P=5.43×10−4 and P=0.002, respectively. We observed no association between TLR3 variants and CNV. The rs377291 variant is probably critical to the function of TLR3, because a prototypic TLR3 ligand induced cell death and apoptosis in human RPE cells with the LL genotype to a greater extent than it did RPE cells with the LF genotype. Moreover, the ligand induced more RPE cell death and apoptosis in wild-type than in Tlr3−/− mice. CONCLUSIONS The TLR3 412F variant confers protection against GA, probably by suppressing RPE cell death. Given that double stranded RNA can activate TLR3-mediated apoptosis, our results suggest a possible role for viral dsRNA transcripts in the development of GA and raise awareness of potential toxicity induced by short interfering RNA (siRNA) therapeutics in the eye. PMID:18753640

Thymic Stromal-Cell Abnormalities and Dysregulated T-Cell Development in IL-2-Deficient Mice

PubMed Central

Reya, Tannishtha; Bassiri, Hamid; Biancaniello, Renée

1998-01-01

The role that interleukin-2 (IL-2) plays in T-cell development is not known. To address this issue, we have investigated the nature of the abnormal thymic development and autoimmune disorders that occurs in IL-2-deficient (IL-2–/–) mice. After 4 to 5 weeks of birth, IL-2–/– mice progressively develop a thymic disorder resulting in the disruption of thymocyte maturation. This disorder is characterized by a dramatic reduction in cellularity, the selective loss of immature CD4-8- (double negative; DN) and CD4+8+ (double positive; DP) thymocytes and defects in the thymic stromal-cell compartment. Immunohistochemical staining of sections of thymuses from specific pathogen-free and germ-free IL-2–/– mice of various ages showed a progressive ,loss of cortical epithelial cells, MHC class II-expressing cells, monocytes, and macrophages. Reduced numbers of macrophages were apparent as early as week after birth. Since IL-2–/– thymocyte progenitor populations could mature normally on transfer into a normal thymus, the thymic defect in IL-2–/– mice appears to be due to abnormalities among thymic stromal cells. These results underscore the role of IL-2 in maintaining functional microenvironments that are necessary to support thymocyte growth, development, and selection. PMID:9814585

Evaluation of Geographic Atrophy from Color Photographs and Fundus Autofluorescence Images: Age-Related Eye Disease Study 2 Report Number 11.

PubMed

Domalpally, Amitha; Danis, Ronald; Agrón, Elvira; Blodi, Barbara; Clemons, Traci; Chew, Emily

2016-11-01

To compare measurements of area of geographic atrophy (GA) and change in GA area from color photographs and fundus autofluorescence (FAF) images. The Age-Related Eye Disease Study 2 (AREDS2) was a prospective multicenter randomized clinical trial evaluating progression of dry age-related macular degeneration (AMD) using color photographs at annual visits over a 5-year study period. The FAF images were acquired in a subset of participants who joined the FAF ancillary study at any of the annual visits over the study period. The AREDS2 FAF ancillary study included 8070 corresponding color and FAF visits of 2202 participants with variable follow-up. Corresponding color and FAF images were independently evaluated at a central reading center for GA area measurement, lesion growth, and involvement of the macula center. Presence, area, growth rate of GA, and involvement of center of macula from color and FAF images. Hypoautofluorescence was visible in 2048 visits (25.4%). Agreement for the presence of GA between the 2 modalities had a kappa of 0.79, with 23% of visits with hypoautofluorescence not presenting with GA on color photographs. Percentage agreement for GA presence ranged from 43% at baseline to 81% at year 5 with improving agreement over time. The mean difference in GA area between the 2 modalities was 0.5 mm 2 , with larger areas on FAF. Growth rate of GA was 1.45 mm 2 from color photographs and 1.43 mm 2 from FAF images. The center of the macula was involved in 51% of color photographs and 56% with FAF images. Geographic atrophy may be detected earlier by the use of FAF images, but over the course of the study, the 2 modalities become comparable. Progression of GA area is comparable between color photographs and FAF images, but evaluating involvement of the center of the macula may differ, probably because of macular pigmentation blocking autofluorescence. Copyright © 2016 American Academy of Ophthalmology. All rights reserved.

Hippocampal Sclerosis of Aging, a Common Alzheimer’s Disease ‘Mimic’: Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe

PubMed Central

Nho, Kwangsik; Saykin, Andrew J.; Nelson, Peter T.

2016-01-01

Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer’s disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (~50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer’s disease contribution to atrophy outside of the hippocampus in older adults. PMID:27003218

Methylation and expression profiles of MGMT gene in thymic epithelial tumors.

PubMed

Mokhtar, Mohamed; Kondo, Kazuya; Namura, Toshiaki; Ali, Abdellah H K; Fujita, Yui; Takai, Chikako; Takizawa, Hiromitsu; Nakagawa, Yasushi; Toba, Hiroaki; Kajiura, Koichiro; Yoshida, Mitsuteru; Kawakami, Gyokei; Sakiyama, Shoji; Tangoku, Akira

2014-02-01

A key challenge in diagnosis and treatment of thymic epithelial tumors (TET) is in improving our understanding of the genetic and epigenetic changes of these relatively rare tumors. Methylation specific PCR (MSP) and immunohistochemistry were applied to 66 TET to profile the methylation status of DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) and its protein expression in TET to clarify the association between MGMT status and clinicopathological features, response to chemotherapy and overall survival. MGMT methylation was significantly more frequent in thymic carcinoma than in thymoma (17/23, 74% versus 13/44, 29%; P<0.001). Loss of expression of MGMT protein was significantly more frequent in thymic carcinoma than in thymoma (20/23, 87% versus 10/44, 23%; P<0.0001). There is a significant correlation between of MGMT methylation and loss of its protein expression (P<0.0003). MGMT methylation and loss of expression were significantly more frequent in advanced thymic epithelial tumors (III/IV) than in early tumors (I/II). MGMT methylation plays a soul role in development of TET, especially in thymic carcinoma. Therefore, translation of our results from basic molecular research to clinical practice may have important implication for considering MGMT methylation as a marker and a target of future therapies in TET. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway

PubMed Central

Fan, Jingjing; Yang, Xiaoqi; Li, Jie; Shu, Ziyang; Dai, Jun; Liu, Xingran; Li, Biao; Jia, Shaohui; Kou, Xianjuan; Yang, Yi; Chen, Ning

2017-01-01

The quality control of skeletal muscle is a continuous requirement throughout the lifetime, although its functions and quality present as a declining trend during aging process. Dysfunctional or deficient autophagy and excessive apoptosis may contribute to the atrophy of senescent skeletal muscle. Spermidine, as a natural polyamine, can be involved in important cellular functions for lifespan extension and stress resistance in several model organisms through activating autophagy. Similarly, cellular autophagic responses to exercise have also been extensively investigated. In the present study, in order to confirm the mitigation or amelioration of skeletal muscle atrophy in aging rats through spermidine coupled with exercise intervention and explore corresponding mechanisms, the rat model with aging-related atrophy of skeletal muscle was established by intraperitoneal injection of D-galactose (D-gal) (200 mg/kgd), and model rats were subjected to the intervention with spermidine (5 mg/kgd) or swimming (60 min/d, 5 d/wk) or combination for 42 days. Spermidine coupled with exercise could attenuate D-gal-induced aging-related atrophy of skeletal muscle through induced autophagy and reduced apoptosis with characteristics of more autophagosomes, activated mitophagy, enhanced mitochondrial quality, alleviated cell shrinkage, and less swollen mitochondria under transmission scanning microscopic observation. Meanwhile, spermidine coupled with exercise could induce autophagy through activating AMPK-FOXO3a signal pathway with characterization of increased Beclin1 and LC3-II/LC3-I ratio, up-regulated anti-apoptotic Bcl-2, down-regulated pro-apoptotic Bax and caspase-3, as well as activated AMPK and FOXO3a. Therefore, spermidine combined with exercise can execute the prevention or treatment of D-gal-induced aging-related skeletal muscle atrophy through enhanced autophagy and reduced apoptosis mediated by AMPK-FOXO3a signal pathway. PMID:28407698

Age-dependent atrophy and microgravity travel: what do they have in common?

PubMed

Wang, E

1999-01-01

Space travel and extending human lifespan are two of the many advances of the twentieth century. However, both of these scientific wonders exact a price for their gains; i.e. deleterious effects on normal physiological processes. For example, both old age and prolonged microgravity travel are associated with atrophy in heart, muscle, and bone. The underlying signal transduction pathways, the control mechanisms for the processes of proliferation, differentiation, and apoptosis, may prove to be similarly altered in both old age and microgravity travel. We suggest that the mechanical events involved in space travel provide a telescopic compression of lifespan changes in these tissues; if so, space travel provides an excellent opportunity to investigate how long-term degeneration occurs on Earth. With the aid of biochip technology for multi-factorial analysis, a platform can be generated to create therapeutic modalities to contain, retard, reduce, or prevent this tissue atrophy, either in space or on Earth.

A Prospective Phase II Study of Cisplatin and Cremophor EL-Free Paclitaxel (Genexol-PM) in Patients with Unresectable Thymic Epithelial Tumors.

PubMed

Kim, Hae Su; Lee, Ji Yun; Lim, Sung Hee; Sun, Jong-Mu; Lee, Se Hoon; Ahn, Jin Seok; Park, Keunchil; Moon, Seung Hwan; Ahn, Myung-Ju

2015-12-01

We conducted a prospective phase II study of cisplatin plus cremophor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors to determine the efficacy and tolerability of the combination therapy. Patients were treated with cisplatin (70 mg/m) and Genexol-PM (230 mg/m) on day 1 of a 3-week cycle as first-line palliative chemotherapy. The primary end point of this study was objective response rate, and the secondary end points included toxicity, progression-free survival (PFS), overall survival, correlation between early 18F-fluorodeoxyglucose positron emission tomography/computed tomography response and PFS, and correlation between baseline flurododeoxyglucose uptake and histology. Forty-two patients with unresectable thymoma (n = 14) or thymic carcinoma (n = 28) were enrolled between May 2012 and October 2014. The median age was 59 years (range: 25-77) and 30 patients (71%) were male, and 39 patients (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range: 1-6). For 40 assessable patients, the objective response rate was 62.5% (95% confidence interval [CI]: 47.6-77.4) with rates of 46% (95% CI: 23.3-76.9) for advanced thymoma (n = 13) and 70% (95% CI: 52.0-82.1) for thymic carcinoma (n = 27). With a median follow-up of 15.5 months, the median PFS for all 42 patients was 9.8 months (11.4 months for thymoma versus 8.1 months for thymic carcinoma). The 2-year overall survival was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Eight patients (19%) experienced grade 2 hypersensitivity reactions. There was no correlation between early positron emission tomography response and PFS, but tumor histology (thymoma versus thymic carcinoma) was correlated with SUVmax before chemotherapy. These data suggest that combination of cisplatin and Genexol-PM is highly effective and

The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies.

PubMed

Detterbeck, Frank C; Asamura, Hisao; Crowley, John; Falkson, Conrad; Giaccone, Giuseppe; Giroux, Dori; Huang, James; Kim, Jhingook; Kondo, Kazuya; Lucchi, Marco; Marino, Mirella; Marom, Edith M; Nicholson, Andrew; Okumura, Meinoshin; Ruffini, Enrico; van Schil, Paul; Stratton, Kelly

2013-12-01

The lack of an official-stage classification system for thymic malignancies is an issue that hampers progress in this rare disease. A collaborative effort by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group is underway to develop proposals for such a system. A database of more than 10,000 cases worldwide has been assembled to provide a solid basis for analysis. This report outlines the structure of the effort and the process that has been designed.

ADAPTIVE OPTICS IMAGING OF FOVEAL SPARING IN GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PubMed

Querques, Giuseppe; Kamami-Levy, Cynthia; Georges, Anouk; Pedinielli, Alexandre; Capuano, Vittorio; Blanco-Garavito, Rocio; Poulon, Fanny; Souied, Eric H

2016-02-01

To describe adaptive optics (AO) imaging of foveal sparing in geographic atrophy (GA) secondary to age-related macular degeneration. Flood-illumination AO infrared (IR) fundus images were obtained in four consecutive patients with GA using an AO retinal camera (rtx1; Imagine Eyes). Adaptive optics IR images were overlaid with confocal scanning laser ophthalmoscope near-IR autofluorescence images to allow direct correlation of en face AO features with areas of foveal sparing. Adaptive optics appearance of GA and foveal sparing, preservation of functional photoreceptors, and cone densities in areas of foveal sparing were investigated. In 5 eyes of 4 patients (all female; mean age 74.2 ± 11.9 years), a total of 5 images, sized 4° × 4°, of foveal sparing visualized on confocal scanning laser ophthalmoscope near-IR autofluorescence were investigated by AO imaging. En face AO images revealed GA as regions of inhomogeneous hyperreflectivity with irregularly dispersed hyporeflective clumps. By direct comparison with adjacent regions of GA, foveal sparing appeared as well-demarcated areas of reduced reflectivity with less hyporeflective clumps (mean 14.2 vs. 3.2; P = 0.03). Of note, in these areas, en face AO IR images revealed cone photoreceptors as hyperreflective dots over the background reflectivity (mean cone density 3,271 ± 1,109 cones per square millimeter). Microperimetry demonstrated residual function in areas of foveal sparing detected by confocal scanning laser ophthalmoscope near-IR autofluorescence. Adaptive optics allows the appreciation of differences in reflectivity between regions of GA and foveal sparing. Preservation of functional cone photoreceptors was demonstrated on en face AO IR images in areas of foveal sparing detected by confocal scanning laser ophthalmoscope near-IR autofluorescence.

Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns.

PubMed

Habes, M; Janowitz, D; Erus, G; Toledo, J B; Resnick, S M; Doshi, J; Van der Auwera, S; Wittfeld, K; Hegenscheid, K; Hosten, N; Biffar, R; Homuth, G; Völzke, H; Grabe, H J; Hoffmann, W; Davatzikos, C

2016-04-05

We systematically compared structural imaging patterns of advanced brain aging (ABA) in the general-population, herein defined as significant deviation from typical BA to those found in Alzheimer disease (AD). The hypothesis that ABA would show different patterns of structural change compared with those found in AD was tested via advanced pattern analysis methods. In particular, magnetic resonance images of 2705 participants from the Study of Health in Pomerania (aged 20-90 years) were analyzed using an index that captures aging atrophy patterns (Spatial Pattern of Atrophy for Recognition of BA (SPARE-BA)), and an index previously shown to capture atrophy patterns found in clinical AD (Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease (SPARE-AD)). We studied the association between these indices and risk factors, including an AD polygenic risk score. Finally, we compared the ABA-associated atrophy with typical AD-like patterns. We observed that SPARE-BA had significant association with: smoking (P<0.05), anti-hypertensive (P<0.05), anti-diabetic drug use (men P<0.05, women P=0.06) and waist circumference for the male cohort (P<0.05), after adjusting for age. Subjects with ABA had spatially extensive gray matter loss in the frontal, parietal and temporal lobes (false-discovery-rate-corrected q<0.001). ABA patterns of atrophy were partially overlapping with, but notably deviating from those typically found in AD. Subjects with ABA had higher SPARE-AD values; largely due to the partial spatial overlap of associated patterns in temporal regions. The AD polygenic risk score was significantly associated with SPARE-AD but not with SPARE-BA. Our findings suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD.

Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART).

PubMed

Josephs, Keith A; Murray, Melissa E; Tosakulwong, Nirubol; Whitwell, Jennifer L; Knopman, David S; Machulda, Mary M; Weigand, Stephen D; Boeve, Bradley F; Kantarci, Kejal; Petrucelli, Leonard; Lowe, Val J; Jack, Clifford R; Petersen, Ronald C; Parisi, Joseph E; Dickson, Dennis W

2017-05-01

We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82-92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8%) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (r = 0.32, p = 0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer's disease of the old.

[Geographic atrophy imaging using fundus autofluorescence method].

PubMed

Dolar-Szczasny, Joanna; Święch-Zubilewicz, Anna; Mackiewicz, Jerzy

2015-01-01

Geographic atrophy is a manifestation of the advanced age-related macular degeneration and form of irreversible atrophy of retinal pigment epithelium and photoreceptor layer. Early detection of changes and the ability to evaluate disease progression accurately constitute a key problem in diagnosis and treatment planning. Fundus autofluorescence is a relatively new imaging method considered nowadays to be the best in diagnosis and observing the natural or treatment-altered course of disease. High resolution images showing the 3D distribution of retinal pigment epithelium autofluorescence as lipofuscin index can be obtained owing to the launch of the confocal scanning laser ophthalmoscope.

Fiber atrophy and hypertrophy in skeletal muscles of late middle-aged Fischer 344 x Brown Norway F1-hybrid rats.

PubMed

Hepple, Russell T; Ross, Karen D; Rempfer, Amanda B

2004-02-01

We examined young adult and late middle-aged male rats to test the hypothesis that gastrocnemius (a locomotor muscle) demonstrates reduced fiber size with aging, whereas soleus (a postural muscle) demonstrates atrophy of some fibers and compensatory hypertrophy in other fibers. Although body mass was greater in late middle-aged animals, mass was reduced in gastrocnemius but not soleus muscle. In another group of animals, physical activity was reduced by 34% in late middle-aged animals. Whereas mean fiber size was lower in gastrocnemius of late middle-aged animals, it was not different in soleus. Histograms revealed atrophied fibers (/=8000 micro m(2)) in soleus with aging. Atrophied fibers often demonstrated no subsarcolemmal mitochondrial staining, suggesting denervation, whereas hypertrophied fibers often demonstrated cytochrome oxidase deficiency, suggesting mitochondrial dysfunction. These results underscore the divergent influences (e.g., physical inactivity, denervation, mitochondrial dysfunction) affecting fiber size with aging.

DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration.

PubMed

Osada, Masako; Jardine, Logan; Misir, Ruth; Andl, Thomas; Millar, Sarah E; Pezzano, Mark

2010-02-08

Thymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus. Here we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+) Foxn1(+) and Aire(+) TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments. Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated

Mutational status of EGFR and KIT in thymoma and thymic carcinoma.

PubMed

Yoh, Kiyotaka; Nishiwaki, Yutaka; Ishii, Genichiro; Goto, Koichi; Kubota, Kaoru; Ohmatsu, Hironobu; Niho, Seiji; Nagai, Kanji; Saijo, Nagahiro

2008-12-01

This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein.

Thymic size in uninfected infants born to HIV-positive mothers and fed with pasteurized human milk.

PubMed

Jeppesen, D; Hasselbalch, H; Ersbøll, A K; Heilmann, C; Valerius, N H

2003-06-01

To examine the size of the thymus in uninfected infants born to HIV-positive mothers and to study the effects of feeding by human donor milk on the size of the thymus in these infants. The absolute and relative thymic size was assessed by sonography as thymic index (Ti), and the Ti/weight-ratio (Ti/w) at birth and at 4 mo of age in 12 healthy uninfected infants born to HlV-infected mothers. All infants were exclusively fed pasteurized donor milk. The results were compared with those obtained from a previous cohort of exclusively breastfed, partially breastfed and exclusively formula-fed infants. At birth the Ti was reduced in infants born to HIV-infected mothers in comparison with that in control infants but this difference disappeared when their birthweights were taken into consideration (Ti/w-ratio). At 4 mo of age the geometric mean Ti of infants fed donor milk was 23.8 and the mean Ti/w-ratio was 4.2. Compared with those of exclusively breastfed infants, the Ti and Ti/w-ratio of infants fed donor milk were significantly reduced (p < 0.01). The Ti/w-ratio increased in donor-milk-fed infants compared with that in the formula-fed infants (p = 0.02). At birth the size of the thymus was smaller in uninfected infants of HIV-positive mothers compared with infants of HIV-negative mothers but when birthweight was taken into account this difference disappeared. Feeding by human donor milk seemed to result in an increased size of the thymus at 4 mo of age compared with thymic size in infants that were exclusively formula fed.

Homeostatic Signals do not Drive Post-thymic T cell Maturation

PubMed Central

Houston, Evan G.; Boursalian, Tamar E.; Fink, Pamela J.

2012-01-01

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3-week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell’s responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property. PMID:22398309

Diffusion-weighted MR imaging in thymic epithelial tumors: correlation with World Health Organization classification and clinical staging.

PubMed

Abdel Razek, Ahmed Abdel Khalek; Khairy, Mohamed; Nada, Nadia

2014-10-01

To assess thymic epithelial tumors with diffusion-weighted magnetic resonance (MR) imaging. Informed consent from patients and institutional review board approval were obtained. Prospective study was conducted on 30 consecutive patients (21 men and nine women; age range, 35-71 years) with thymic epithelial tumors. They underwent true fast imaging with steady-state precession and single-shot echo-planar diffusion-weighted MR imaging of the mediastinum with b values of 0, 400, and 800 sec/mm(2). Apparent diffusion coefficient (ADC) of the thymic epithelial tumors was calculated by the same observer at two settings and was correlated with World Health Organization classification and clinical staging. There was significant difference in longest diameter (P = .001) and necrotic part of the tumor (P = .014) between low-risk thymoma, high-risk thymoma, and thymic carcinoma. Mean ADC value of both readings of thymic epithelial tumors (n = 30) was 1.24 × 10(-3) mm(2)/sec and 1.22 × 10(-3) mm(2)/sec, with good intraobserver agreement (κ = 0.732). There was significant difference in both readings (P = .01 and .20) of low-risk thymoma (1.30 × 10(-3) mm(2)/sec and 1.29 × 10(-3) mm(2)/sec), high-risk thymoma (1.16 × 10(-3) mm(2)/sec and 1.14 × 10(-3) mm(2)/sec), and thymic carcinoma (1.18 × 10(-3) mm(2)/sec and 1.06 × 10(-3) mm(2)/sec). Cutoff ADC values of both readings used to differentiate low-risk thymoma from high-risk thymoma and thymic carcinoma were 1.25 and 1.22 × 10(-3) mm(2)/sec with area under the curve of 0.804 and 0.851, respectively. There was significant difference in both readings of ADC value of early (stage I, II) and advanced stages (stage III, IV) of thymic epithelial tumors (P = .006 and .005, respectively). ADC value is a noninvasive, reliable, and reproducible imaging parameter that may help to assess and characterize thymic epithelial tumors. © RSNA, 2014.

Optical Coherence Tomography Reflective Drusen Substructures Predict Progression to Geographic Atrophy in Age-related Macular Degeneration.

PubMed

Veerappan, Malini; El-Hage-Sleiman, Abdul-Karim M; Tai, Vincent; Chiu, Stephanie J; Winter, Katrina P; Stinnett, Sandra S; Hwang, Thomas S; Hubbard, G Baker; Michelson, Michelle; Gunther, Randall; Wong, Wai T; Chew, Emily Y; Toth, Cynthia A

2016-12-01

Structural and compositional heterogeneity within drusen comprising lipids, carbohydrates, and proteins have been previously described. We sought to detect and define phenotypic patterns of drusen heterogeneity in the form of optical coherence tomography-reflective drusen substructures (ODS) and examine their associations with age-related macular degeneration (AMD)-related features and AMD progression. Retrospective analysis in a prospective study. Patients with intermediate AMD (n = 349) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) ancillary spectral-domain optical coherence tomography (SD OCT) study. Baseline SD OCT scans of 1 eye per patient were analyzed for the presence of ODS. Cross-sectional and longitudinal associations of ODS presence with AMD-related features visible on SD OCT and color photographs, including drusen volume, geographic atrophy (GA), and preatrophic features, were evaluated for the entire macular region. Similar associations were also made locally within a 0.5-mm-diameter region around individual ODS and corresponding control region without ODS in the same eye. Preatrophy SD OCT changes and GA, central GA, and choroidal neovascularization (CNV) from color photographs. Four phenotypic subtypes of ODS were defined: low reflective cores, high reflective cores, conical debris, and split drusen. Among the 349 participants, there were 307 eligible eyes and 74 (24%) had at least 1 ODS. The ODS at baseline were associated with (1) greater macular drusen volume at baseline (P < 0.001), (2) development of preatrophic changes at year 2 (P = 0.001-0.01), and (3) development of macular GA (P = 0.005) and preatrophic changes at year 3 (P = 0.002-0.008), but not development of CNV. The ODS at baseline in a local region were associated with (1) presence of preatrophy changes at baseline (P = 0.02-0.03) and (2) development of preatrophy changes at years 2 and 3 within the region (P = 0.008-0.05). Optical coherence tomography

Thymic pathology and cardiac myxomas: Coincidence or a closer relationship?

PubMed

Moraitis, Sotirios D; Agrafiotis, Apostolos C; Pappas, Dimitrios; Pothitakis, Chrysovalantis; Stergianni, Maria; Koukis, Ioannis

2018-04-30

Myxomas are the most common benign cardiac tumors and are located more frequently in the left atrium. In the literature there are cases describing the coexistence of thymic tumors and cardiac myxomas. In the case reported herein, during the resection of a cardiac myxoma, an enlarged thymus gland was encountered and resected. The histological exam revealed a thymic hyperplasia. The aim of this case study is to assess the need of conducting further studies in order to identify a common histological pathway between thymic lesions and cardiac myxomas. The diagnosis of a cardiac myxoma could justify a further workup of the anterior mediastinum in order not to overlook a lesion of thymic origin.

A meta-analysis on progressive atrophy in intractable temporal lobe epilepsy

PubMed Central

Caciagli, Lorenzo; Bernasconi, Andrea; Wiebe, Samuel; Koepp, Matthias J.; Bernasconi, Neda

2017-01-01

Objective: It remains unclear whether drug-resistant temporal lobe epilepsy (TLE) is associated with cumulative brain damage, with no expert consensus and no quantitative syntheses of the available evidence. Methods: We conducted a systematic review and meta-analysis of MRI studies on progressive atrophy, searching PubMed and Ovid MEDLINE databases for cross-sectional and longitudinal quantitative MRI studies on drug-resistant TLE. Results: We screened 2,976 records and assessed eligibility of 248 full-text articles. Forty-two articles met the inclusion criteria for quantitative evaluation. We observed a predominance of cross-sectional studies, use of different clinical indices of progression, and high heterogeneity in age-control procedures. Meta-analysis of 18/1 cross-sectional/longitudinal studies on hippocampal atrophy (n = 979 patients) yielded a pooled effect size of r = −0.42 for ipsilateral atrophy related to epilepsy duration (95% confidence interval [CI] −0.51 to −0.32; p < 0.0001; I2 = 65.22%) and r = −0.35 related to seizure frequency (95% CI −0.47 to −0.22; p < 0.0001; I2 = 61.97%). Sensitivity analyses did not change the results. Narrative synthesis of 25/3 cross-sectional/longitudinal studies on whole brain atrophy (n = 1,504 patients) indicated that >80% of articles reported duration-related progression in extratemporal cortical and subcortical regions. Detailed analysis of study design features yielded low to moderate levels of evidence for progressive atrophy across studies, mainly due to dominance of cross-sectional over longitudinal investigations, use of diverse measures of seizure estimates, and absence of consistent age control procedures. Conclusions: While the neuroimaging literature is overall suggestive of progressive atrophy in drug-resistant TLE, published studies have employed rather weak designs to directly demonstrate it. Longitudinal multicohort studies are needed to unequivocally differentiate aging from disease

Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways

PubMed Central

Lee, Jun Ho; Patel, Kalpesh; Tae, Hyun Jin; Lustig, Ana; Kim, Jie Wan; Mattson, Mark P.; Taub, Dennis D.

2014-01-01

Thymic atrophy occurs during normal aging, and is accelerated by exposure to chronic stressors that elevate glucocorticoid levelsand impair the naïve T cell output. The orexigenic hormone ghrelin was recently shown to attenuate age-associated thymic atrophy. Here, we report that ghrelin enhances the proliferation of murine CD4+ primary T cells and a CD4+ T-cell line. Ghrelin induced activation of the ERK1/2 and Akt signaling pathways, via upstream activation of phosphatidylinositol-3-kinase and protein kinase C, to enhance T-cell proliferation. Moreover, ghrelin induced expression of the cell cycle proteins cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2) and retinoblastoma phosphorylation. Finally, ghrelin activated the above-mentioned signaling pathways and stimulated thymocyte proliferation in young and older mice in vivo. PMID:25447526

Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease.

PubMed

Dudakov, Jarrod A; Mertelsmann, Anna M; O'Connor, Margaret H; Jenq, Robert R; Velardi, Enrico; Young, Lauren F; Smith, Odette M; Boyd, Richard L; van den Brink, Marcel R M; Hanash, Alan M

2017-08-17

Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity posttransplant. Manipulation of the ILC-IL-22-TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency. © 2017 by The American Society of Hematology.

MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging.

PubMed

Lustgarten, Michael S; Jang, Youngmok C; Liu, Yuhong; Qi, Wenbo; Qin, Yuejuan; Dahia, Patricia L; Shi, Yun; Bhattacharya, Arunabh; Muller, Florian L; Shimizu, Takahiko; Shirasawa, Takuji; Richardson, Arlan; Van Remmen, Holly

2011-06-01

In a previous study, we reported that a deficiency in MnSOD activity (approximately 80% reduction) targeted to type IIB skeletal muscle fibers was sufficient to elevate oxidative stress and to reduce muscle function in young adult mice (TnIFastCreSod2(fl/fl) mice). In this study, we used TnIFastCreSod2(fl/fl) mice to examine the effect of elevated oxidative stress on mitochondrial function and to test the hypothesis that elevated oxidative stress and decreased mitochondrial function over the lifespan of the TnIFastCreSod2(fl/fl) mice would be sufficient to accelerate muscle atrophy associated with aging. We found that mitochondrial function is reduced in both young and old TnIFastCreSod2(fl/fl) mice, when compared with control mice. Complex II activity is reduced by 47% in young and by approximately 90% in old TnIFastCreSod2(fl/fl) mice, and was found to be associated with reduced levels of the catalytic subunits for complex II, SDHA and SDHB. Complex II-linked mitochondrial respiration is reduced by approximately 70% in young TnIFastCreSod2(fl/fl) mice. Complex II-linked mitochondrial Adenosine-Tri-Phosphate (ATP) production is reduced by 39% in young and was found to be almost completely absent in old TnIFastCreSod2(fl/fl) mice. Furthermore, in old TnIFastCreSod2(fl/fl) mice, aconitase activity is almost completely abolished; mitochondrial superoxide release remains > 2-fold elevated; and oxidative damage (measured as F(2) - isoprostanes) is increased by 30% relative to age-matched controls. These data show that despite elevated skeletal muscle-specific mitochondrial oxidative stress, oxidative damage, and complex II-linked mitochondrial dysfunction, age-related muscle atrophy was not accelerated in old TnIFastCreSod2(fl/fl) mice, suggesting mitochondrial oxidative stress may not be causal for age-related muscle atrophy. No claim to original US government works. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates

PubMed Central

Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

2017-01-01

Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=−0.62) or septum (rs=−0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes. PMID:28039490

Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates.

PubMed

Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

2016-12-28

Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus , spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (r s =0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (r s =0.56) and hippocampus (r s =-0.62) or septum (r s =-0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes.

Homeostatic signals do not drive post-thymic T cell maturation.

PubMed

Houston, Evan G; Boursalian, Tamar E; Fink, Pamela J

2012-01-01

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3 week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell's responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property. Copyright © 2012 Elsevier Inc. All rights reserved.

Cortical and subcortical atrophy in Alzheimer disease: parallel atrophy of thalamus and hippocampus.

PubMed

Štěpán-Buksakowska, Irena; Szabó, Nikoletta; Hořínek, Daniel; Tóth, Eszter; Hort, Jakub; Warner, Joshua; Charvát, František; Vécsei, László; Roček, Miloslav; Kincses, Zsigmond T

2014-01-01

Brain atrophy is a key imaging hallmark of Alzheimer disease (AD). In this study, we carried out an integrative evaluation of AD-related atrophy. Twelve patients with AD and 13 healthy controls were enrolled. We conducted a cross-sectional analysis of total brain tissue volumes with SIENAX. Localized gray matter atrophy was identified with optimized voxel-wise morphometry (FSL-VBM), and subcortical atrophy was evaluated by active shape model implemented in FMRIB's Integrated Registration Segmentation Toolkit. SIENAX analysis demonstrated total brain atrophy in AD patients; voxel-based morphometry analysis showed atrophy in the bilateral mediotemporal regions and in the posterior brain regions. In addition, regarding the diminished volumes of thalami and hippocampi in AD patients, subsequent vertex analysis of the segmented structures indicated shrinkage of the bilateral anterior thalami and the left medial hippocampus. Interestingly, the volume of the thalami and hippocampi were highly correlated with the volume of the thalami and amygdalae on both sides in AD patients, but not in healthy controls. This complex structural information proved useful in the detailed interpretation of AD-related neurodegenerative process, as the multilevel approach showed both global and local atrophy on cortical and subcortical levels. Most importantly, our results raise the possibility that subcortical structure atrophy is not independent in AD patients.

The relation between Glasgow Coma Scale score and later cerebral atrophy in paediatric traumatic brain injury.

PubMed

Ghosh, Alokananda; Wilde, Elisabeth A; Hunter, Jill V; Bigler, Erin D; Chu, Zili; Li, Xiaoqi; Vasquez, Ana C; Menefee, Deleene; Yallampalli, Ragini; Levin, Harvey S

2009-03-01

To examine initial Glasgow Coma Scale (GCS) score and its relationship with later cerebral atrophy in children with traumatic brain injury (TBI) using Quantitative Magnetic Resonance Imaging (QMRI) at 4 months post-injury. It was hypothesized that a lower GCS score would predict later generalized atrophy. As a guide in assessing paediatric TBI patients, the probability of developing chronic cerebral atrophy was determined based on the initial GCS score. The probability model used data from 45 paediatric patients (mean age = 13.6) with mild-to-severe TBI and 41 paediatric (mean age = 12.4) orthopaedically-injured children. This study found a 24% increase in the odds of developing an abnormal ventricle-to-brain ratio (VBR) and a 27% increase in the odds of developing reduced white matter percentage on neuroimaging with each numerical drop in GCS score. Logistic regression models with cut-offs determined by normative QMRI data confirmed that a lower initial GCS score predicts later atrophy. GCS is a commonly used measure of injury severity. It has proven to be a prognostic indicator of cognitive recovery and functional outcome and is also predictive of later parenchymal change.

Micronodular thymic neoplasms: case series and literature review with emphasis on the spectrum of differentiation.

PubMed

Mneimneh, Wadad S; Gökmen-Polar, Yesim; Kesler, Kenneth A; Loehrer, Patrick J; Badve, Sunil

2015-11-01

We report nine cases of micronodular thymoma with lymphoid B-cell hyperplasia and one case of micronodular thymic carcinoma with lymphoid hyperplasia from our institution. For a better understanding of these rare tumors, clinical records, and histological features of these cases were reviewed, with detailed review of additional 64 literature cases of micronodular thymic neoplasms. The joint analysis identified 64 cases of micronodular thymoma with lymphoid B-cell hyperplasia and 9 cases of micronodular thymic carcinoma with lymphoid hyperplasia. Both groups revealed slight male predilection, with male:female ratio of 1.3:1 and 5:4, and occurred at >40 years of age, with a mean of 64 (41-83) and 62 (42-78) years, respectively. Myasthenia gravis was noted in 3/64 (5%) and 1/9 (11%) patients, respectively. Other systemic, disimmune, or hematologic disorders were noted in 6/64 (9%) and 1/9 (11%) patients, respectively. Components of conventional thymoma were reported in 11/64 (17%) micronodular thymomas with lymphoid B-cell hyperplasia, with transitional morphology between the two components in most of them. Cellular morphology was predominantly spindle in micronodular thymoma with lymphoid B-cell hyperplasia when specified (30/43), and epithelioid in micronodular thymic carcinoma with lymphoid hyperplasia (6/9), and cytological atypia was more encountered in the latter. Dedifferentiation/transformation from micronodular thymoma with lymphoid B-cell hyperplasia to micronodular thymic carcinoma with lymphoid hyperplasia seems to occur in a small subset of cases. Three cases of micronodular thymomas with lymphoid B-cell hyperplasia were described with co-existent low-grade B-cell lymphomas. Follow-up data were available for 30 micronodular thymomas with lymphoid B-cell hyperplasia and 6 micronodular thymic carcinomas with lymphoid hyperplasia, with a mean of 47 (0.2-180) months and 23 (3-39) months, respectively. Patients were alive without disease, except for five

[Indication and procedure of video-assisted thoracoscopic surgery to thymic disease].

PubMed

Matsumura, Yuji; Kondo, Takashi

2006-07-01

We retrospective reviewed minimally invasive video-assisted thoracoscopic surgery (VATS) to thymic diseases. These procedures were performed using intercostal and infrasternal approach with a sternum-elevator. Indications of this method are benign thymic lesions [mature teratoma, thymic cyst and myasthenia gravis (MG)] and small thymoma (non-invasive Masaoka stage I-II, less than 5 cm in diameter and nontouching to the left brachiocephalic vein). Fifty patients underwent VATS for 13 hemithymectomies (7 thymomas, 5 mature teratomas and 1 thymic cyst) and 37 extended thymectomies (25 nonthymomatous MGs and 12 thymomatous MGs). Conversion to sternotomy was required in 3 cases of nonthymomatous MG because of bleeding from thymic vein in 1 case and pleural adhesion in 2 cases. Four cases of thymomatous MG were successfully treated with partial lung resection and/or small pericardial resection by VATS. New bipolar vessel sealing system (LigaSure V) is safer and more useful than metal clip and ultrasonic coagulator in VATS for thymic vein sealing, extraction of upper poles of thymus and incision of mediastinal pleura near phrenic nerve. VATS thymectomy should be useful from the standpoint of less invasive, less pain, rapid recovery, and good cosmetic results.

A hybrid segmentation approach for geographic atrophy in fundus auto-fluorescence images for diagnosis of age-related macular degeneration.

PubMed

Lee, Noah; Laine, Andrew F; Smith, R Theodore

2007-01-01

Fundus auto-fluorescence (FAF) images with hypo-fluorescence indicate geographic atrophy (GA) of the retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Manual quantification of GA is time consuming and prone to inter- and intra-observer variability. Automatic quantification is important for determining disease progression and facilitating clinical diagnosis of AMD. In this paper we describe a hybrid segmentation method for GA quantification by identifying hypo-fluorescent GA regions from other interfering retinal vessel structures. First, we employ background illumination correction exploiting a non-linear adaptive smoothing operator. Then, we use the level set framework to perform segmentation of hypo-fluorescent areas. Finally, we present an energy function combining morphological scale-space analysis with a geometric model-based approach to perform segmentation refinement of false positive hypo- fluorescent areas due to interfering retinal structures. The clinically apparent areas of hypo-fluorescence were drawn by an expert grader and compared on a pixel by pixel basis to our segmentation results. The mean sensitivity and specificity of the ROC analysis were 0.89 and 0.98%.

Thymoma and Thymic Carcinoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Thymoma and thymic carcinoma treatment options include surgery, radiation therapy, chemotherapy, chemoradiation, and corticosteroids. Get detailed information about treatment of newly diagnosed and recurrent thymoma and thymic cancer in this summary for clinicians.

A longitudinal study of brain atrophy over two years in community-dwelling older individuals.

PubMed

Jiang, Jiyang; Sachdev, Perminder; Lipnicki, Darren M; Zhang, Haobo; Liu, Tao; Zhu, Wanlin; Suo, Chao; Zhuang, Lin; Crawford, John; Reppermund, Simone; Trollor, Julian; Brodaty, Henry; Wen, Wei

2014-02-01

Most previous neuroimaging studies of age-related brain structural changes in older individuals have been cross-sectional and/or restricted to clinical samples. The present study of 345 community-dwelling non-demented individuals aged 70-90years aimed to examine age-related brain volumetric changes over two years. T1-weighted magnetic resonance imaging scans were obtained at baseline and at 2-year follow-up and analyzed using the FMRIB Software Library and FreeSurfer to investigate cortical thickness and shape and volumetric changes of subcortical structures. The results showed significant atrophy across much of the cerebral cortex with bilateral transverse temporal regions shrinking the fastest. Atrophy was also found in a number of subcortical structures, including the CA1 and subiculum subfields of the hippocampus. In some regions, such as left and right entorhinal cortices, right hippocampus and right precentral area, the rate of atrophy increased with age. Our analysis also showed that rostral middle frontal regions were thicker bilaterally in older participants, which may indicate its ability to compensate for medial temporal lobe atrophy. Compared to men, women had thicker cortical regions but greater rates of cortical atrophy. Women also had smaller subcortical structures. A longer period of education was associated with greater thickness in a number of cortical regions. Our results suggest a pattern of brain atrophy with non-demented people that resembles a less extreme form of the changes associated with Alzheimer's disease (AD). © 2013 Elsevier Inc. All rights reserved.

Forever Young(er): potential age-defying effects of long-term meditation on gray matter atrophy

PubMed Central

Luders, Eileen; Cherbuin, Nicolas; Kurth, Florian

2015-01-01

While overall life expectancy has been increasing, the human brain still begins deteriorating after the first two decades of life and continues degrading further with increasing age. Thus, techniques that diminish the negative impact of aging on the brain are desirable. Existing research, although scarce, suggests meditation to be an attractive candidate in the quest for an accessible and inexpensive, efficacious remedy. Here, we examined the link between age and cerebral gray matter re-analyzing a large sample (n = 100) of long-term meditators and control subjects aged between 24 and 77 years. When correlating global and local gray matter with age, we detected negative correlations within both controls and meditators, suggesting a decline over time. However, the slopes of the regression lines were steeper and the correlation coefficients were stronger in controls than in meditators. Moreover, the age-affected brain regions were much more extended in controls than in meditators, with significant group-by-age interactions in numerous clusters throughout the brain. Altogether, these findings seem to suggest less age-related gray matter atrophy in long-term meditation practitioners. PMID:25653628

Risk factors for choroidal neovascularization and geographic atrophy in the complications of age-related macular degeneration prevention trial.

PubMed

2008-09-01

To determine risk factors for choroidal neovascularization (CNV) and of geographic atrophy (GA) in eyes with large drusen. Cohort study within a multicenter, randomized clinical trial of laser treatment for the prevention of vision loss from advanced age-related macular degeneration. One thousand fifty-two participants with 10 or more large drusen (>or=125 microm) and visual acuity of 20/40 or better in each eye. At baseline, participants provided a brief medical history. Trained readers evaluated baseline color photographs for drusen characteristics and pigmentary abnormalities. One eye of each participant was assigned to laser treatment and the contralateral eye was assigned to observation. The Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Reading Center readers identified CNV and endpoint GA from color photographs and fluorescein angiograms obtained during follow-up visits scheduled for 5 or 6 years. Estimates of relative risks (RRs) and 95% confidence intervals (CIs) were obtained from survival analyses of observed and treated eyes, considered separately and combined. Development of CNV and of endpoint GA. Choroidal neovascularization developed in 141 observed eyes and 141 treated eyes, including 57 patients affected bilaterally. Statistically significant risk factors for CNV in the multivariate model for all eyes were older age (RR, 2.81 [95% CI, 1.33-5.94] for >79 years vs. 50-59 years), cigarette smoking (RR, 1.98 [95% CI, 1.16-3.39] for current vs. never), and focal hyperpigmentation (RR, 1.84 [95% CI, 1.22-2.76] for >or=250 microm vs. none). Among eyes free of GA at baseline, endpoint GA developed in 61 observed eyes and in 58 treated eyes, including 29 patients affected bilaterally. Statistically significant risk factors for GA in the multivariate model for all eyes were older age (RR, 6.39 [95% CI, 1.64-24.9] for >79 years vs. 50-59 years), greater retinal area covered by drusen (RR, 5.10 [95% CI, 2.57-10.1] for >or=25% vs

HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration.

PubMed

Cameron, D Joshua; Yang, Zhenglin; Gibbs, Daniel; Chen, Haoyu; Kaminoh, Yuuki; Jorgensen, Adam; Zeng, Jiexi; Luo, Ling; Brinton, Eric; Brinton, Gregory; Brand, John M; Bernstein, Paul S; Zabriskie, Norman A; Tang, Shibo; Constantine, Ryan; Tong, Zongzhong; Zhang, Kang

2007-05-02

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two types of degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA. This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.

B cells regulate thymic CD8+T cell differentiation in lupus-prone mice.

PubMed

Xing, Chen; Zhu, Gaizhi; Xiao, He; Fang, Ying; Liu, Xiaoling; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Shen, Beifen; Li, Yan; Ma, Ning; Wang, Renxi

2017-10-27

Previous studies have shown that under normal physiological conditions thymic B cells play a critical function in T cell negative selection. We tested the effect of thymic B cells on thymic T-cell differentiation in autoimmune diseases including systemic lupus erythematosus (SLE). We found that thymic B cells and CD8 - CD4 + and CD4 - CD8 + T cells increased, whereas CD4 + CD8 + T cells decreased in lupus-prone mice. Once B cells were reduced, the change was reversed. Furthermore, we found that B cells blocked thymic immature single positive (ISP) CD4 - CD8 + CD3 lo/- RORγt - T cells progression into CD4 + CD8 + T cells. Interestingly, we found a novel population of thymic immature T cells (CD4 - CD8 + CD3 lo RORγt + ) that were induced into mature CD4 - CD8 + CD3 + RORγt + T cells by B cells in lupus-prone mice. Importantly, we found that IgG, produced by thymic B cells, played a critical role in the differentiation of thymic CD8 + ISP and mature RORγt + CD8 + T cells in lupus-prone mice. In conclusion, B cells blocked the differentiation from thymic CD8 + ISP and induced the differentiation of a novel immature CD4 - CD8 + CD3 lo RORγt + T cells into mature RORγt + CD8 + T cells by secreting IgG antibody in lupus-prone mice.

A mathematical model of aging-related and cortisol induced hippocampal dysfunction

PubMed Central

McAuley, Mark T; Kenny, Rose Anne; Kirkwood, Thomas BL; Wilkinson, Darren J; Jones, Janette JL; Miller, Veronica M

2009-01-01

Background The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated. Results The in silicoSBML model reflected the in vivoaging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA), increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation. Conclusion Both acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitroand in vivostudies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people. PMID:19320982

Calculation of brain atrophy using computed tomography and a new atrophy measurement tool

NASA Astrophysics Data System (ADS)

Bin Zahid, Abdullah; Mikheev, Artem; Yang, Andrew Il; Samadani, Uzma; Rusinek, Henry

2015-03-01

Purpose: To determine if brain atrophy can be calculated by performing volumetric analysis on conventional computed tomography (CT) scans in spite of relatively low contrast for this modality. Materials & Method: CTs for 73 patients from the local Veteran Affairs database were selected. Exclusion criteria: AD, NPH, tumor, and alcohol abuse. Protocol: conventional clinical acquisition (Toshiba; helical, 120 kVp, X-ray tube current 300mA, slice thickness 3-5mm). Locally developed, automatic algorithm was used to segment intracranial cavity (ICC) using (a) white matter seed (b) constrained growth, limited by inner skull layer and (c) topological connectivity. ICC was further segmented into CSF and brain parenchyma using a threshold of 16 Hu. Results: Age distribution: 25-95yrs; (Mean 67+/-17.5yrs.). Significant correlation was found between age and CSF/ICC(r=0.695, p<0.01 2-tailed). A quadratic model (y=0.06-0.001x+2.56x10-5x2 ; where y=CSF/ICC and x=age) was a better fit to data (r=0.716, p < 0.01). This is in agreement with MRI literature. For example, Smith et al. found annual CSF/ICC increase in 58 - 94.5 y.o. individuals to be 0.2%/year, whereas our data, restricted to the same age group yield 0.3%/year(0.2-0.4%/yrs. 95%C.I.). Slightly increased atrophy among elderly VA patients is attributable to the presence of other comorbidities. Conclusion: Brain atrophy can be reliably calculated using automated software and conventional CT. Compared to MRI, CT is more widely available, cheaper, and less affected by head motion due to ~100 times shorter scan time. Work is in progress to improve the precision of the measurements, possibly leading to assessment of longitudinal changes within the patient.

Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease

PubMed Central

Swerdlow, Russell H.; Vidoni, Eric D.; Burns, Jeffrey M.

2011-01-01

Objective: Beyond age, having a family history is the most significant risk factor for Alzheimer disease (AD). This longitudinal brain imaging study examines whether there are differential patterns of regional gray matter atrophy in cognitively healthy elderly subjects with (FH+) and without (FH−) a family history of late-onset AD. Methods: As part of the KU Brain Aging Project, cognitively intact individuals with a maternal history (FHm, n = 11), paternal history (FHp, n = 10), or no parental history of AD (FH−, n = 32) similar in age, gender, education, and Mini-Mental State Examination (MMSE) score received MRI at baseline and 2-year follow-up. A custom voxel-based morphometry processing stream was used to examine regional differences in atrophy between FH groups, controlling for age, gender, and APOE ϵ4 (APOE4) status. We also analyzed APOE4-related atrophy. Results: Cognitively normal FH+ individuals had significantly increased whole-brain gray matter atrophy and CSF expansion compared to FH−. When FH+ groups were split, only FHm was associated with longitudinal measures of brain change. Moreover, our voxel-based analysis revealed that FHm subjects had significantly greater atrophy in the precuneus and parahippocampus/hippocampus regions compared to FH− and FHp subjects, independent of APOE4 status, gender, and age. Individuals with an ε4 allele had more regional atrophy in the frontal cortex compared to ε4 noncarriers. Conclusions: We conclude that FHm individuals without dementia have progressive gray matter volume reductions in select AD-vulnerable brain regions, specifically the precuneus and parahippocampal gyrus. These data complement and extend reports of regional cerebral metabolic differences and increases in amyloid-β burden in FHm subjects, which may be related to a higher risk for developing AD. PMID:21357834

Ablative dual-phase Erbium:YAG laser treatment of atrophy-related vaginal symptoms in post-menopausal breast cancer survivors omitting hormonal treatment.

PubMed

Mothes, A R; Runnebaum, M; Runnebaum, I B

2018-05-01

First evaluation of dual-phase vaginal Er:YAG laser to omit hormonal treatment for atrophy-related symptoms in post-menopausal breast cancer survivors following prolapse surgery. Patients with a history of breast cancer at the time of surgery for pelvic organ prolapse were offered non-hormonal vaginal Er:YAG laser treatment when complaining of atrophy-related genitourinary syndrome of menopause. A single 10-min course of dual-phase protocol of pulsed Er:YAG laser (2940 nm, fractional ablative and thermal mode, fluence according to tissue thickness). Follow-up included subjective satisfaction, vaginal pH, vaginal health index (VHI), and complications after 6 weeks. A total of 16 breast cancer survivors (age 71 years, SD 7) had been seeking treatment for pelvic floor symptoms related to vaginal atrophy at follow-up visits after prolapse surgery. All ablative vaginal Er:YAG laser outpatient procedures were successfully completed, all patients returned to daily activities without a need for analgetic medication. Evaluation was performed after 8.3 (SD 2.5) weeks. Pre-laser VHI scored 16 (SD 4.6) and post-laser VHI 20 (SD 3) with p = 0.01. Patients were satisfied in 94% (n = 15) regarding symptom relief. Breast cancer survivors with atrophy-related complaints after pelvic floor surgery may benefit from vaginal application of this innovative dual protocol of Er:YAG laser technology as a non-hormonal treatment approach.

Atrophy of Swallowing Muscles Is Associated With Severity of Dysphagia and Age in Patients With Acute Stroke.

PubMed

Sporns, Peter B; Muhle, Paul; Hanning, Uta; Suntrup-Krueger, Sonja; Schwindt, Wolfram; Eversmann, Julian; Warnecke, Tobias; Wirth, Rainer; Zimmer, Sebastian; Dziewas, Rainer

2017-07-01

Sarcopenia has been identified as an independent risk factor for dysphagia. Dysphagia is one of the most important and prognostically relevant complications of acute stroke. The role of muscle atrophy as a contributing factor for the occurrence of poststroke dysphagia is yet unclear. To assess whether there is a correlation between age and muscle volume and whether muscle volume is related to dysphagia in acute stroke patients. This retrospective, single-center study included 73 patients with acute ischemic or hemorrhagic stroke who underwent computed tomography angiography on admission and an objective dysphagia assessment by Fiberoptic Endoscopic Evaluation of Swallowing within 72 hours from admission. With the help of semiautomated muscle segmentation and 3-dimensional reconstruction volumetry of the digastric, temporal, and geniohyoid muscles was performed. For further analysis, participants were first divided into 4 groups according to their age (<61 years, n = 12; 61-75 years, n = 16; 76-85 years, n = 28; ≥86 years, n = 17), secondly into 3 different groups according to their dysphagia severity using the Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS) (FEDSS 1 and 2, n = 25; FEDSS 3 and 4, n = 32; FEDSS 5 and 6, n = 16). Correlation of muscle volumes with age and dysphagia severity. Muscle volumes of single muscles (except for geniohyoid and the right digastric muscles) as well as the sum muscle volume were significantly and inversely related to dysphagia severity. We found a significant decline of muscle volume with advancing age for most muscle groups and, in particular, for the total muscle volume. Apart from features being determined by the acute stroke itself (eg, site and size of stroke), also premorbid conditions, in particular age-related muscle atrophy, have an impact on the complex pathophysiology of swallowing disorders poststroke. Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine

The Association of Statin Use with Age-Related Macular Degeneration Progression The Age-Related Eye Disease Study 2 Report Number 9

PubMed Central

Al-Holou, Shaza N.; Tucker, William R.; Agrón, Elvira; Clemons, Traci E.; Cukras, Catherine; Ferris, Frederick L.; Chew, Emily Y.

2015-01-01

Objective/purpose To evaluate the association of statin use with progression of age-related macular degeneration (AMD). Design Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. Subjects Age-Related Eye Disease Study 2 participants, aged 50 to 85 years. Methods Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke, all known to be associated with statin use, were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses were also performed adjusting for the competing risk of death. Main Outcome Measures Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). Results Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratios [HR] of 1.08, 95% confidence intervals [CI] of 0.83–1.41, P=0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant with HR: 0.81, 95% CI: 0.55–1.20, P=0.29. Further subgroup analyses of persons with or without late AMD at baseline to the various components of late AMD (neovascular, central geographic atrophy, or any geographic atrophy) also showed no statistically significant association of statin use with progression to AMD. Conclusions Statin use was not statistically significantly associated with the

Role of ATF4 in skeletal muscle atrophy.

PubMed

Adams, Christopher M; Ebert, Scott M; Dyle, Michael C

2017-05-01

Here, we discuss recent work focused on the role of activating transcription factor 4 (ATF4) in skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression; however, the transcriptional regulatory proteins responsible for those changes are not yet well defined. Recent work indicates that some forms of muscle atrophy require ATF4, a stress-inducible bZIP transcription factor subunit that helps to mediate a broad range of stress responses in mammalian cells. ATF4 expression in skeletal muscle fibers is sufficient to induce muscle fiber atrophy and required for muscle atrophy during several stress conditions, including aging, fasting, and limb immobilization. By helping to activate specific genes in muscle fibers, ATF4 contributes to the expression of numerous mRNAs, including at least two mRNAs (Gadd45a and p21) that encode mediators of muscle fiber atrophy. Gadd45a promotes muscle fiber atrophy by activating the protein kinase MEKK4. p21 promotes atrophy by reducing expression of spermine oxidase, a metabolic enzyme that helps to maintain muscle fiber size under nonstressed conditions. In skeletal muscle fibers, ATF4 is critical component of a complex and incompletely understood molecular signaling network that causes muscle atrophy during aging, fasting, and immobilization.

Post-thymic maturation: young T cells assert their individuality.

PubMed

Fink, Pamela J; Hendricks, Deborah W

2011-07-22

T cell maturation was once thought to occur entirely within the thymus. Now, evidence is mounting that the youngest peripheral T cells in both mice and humans comprise a distinct population from their more mature, yet still naive, counterparts. These cells, termed recent thymic emigrants (RTEs), undergo a process of post-thymic maturation that can be monitored at the levels of cell phenotype and immune function. Understanding this final maturation step in the process of generating useful and safe T cells is of clinical relevance, given that RTEs are over-represented in neonates and in adults recovering from lymphopenia. Post-thymic maturation may function to ensure T cell fitness and self tolerance.

Longitudinal association between hippocampus atrophy and episodic-memory decline.

PubMed

Gorbach, Tetiana; Pudas, Sara; Lundquist, Anders; Orädd, Greger; Josefsson, Maria; Salami, Alireza; de Luna, Xavier; Nyberg, Lars

2017-03-01

There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Ectopic Thymic Cyst of the Subglottis: Considerations for Diagnosis and Management.

PubMed

Ahmad, Iram; Kirby, Patricia; Liming, Bryan

2018-03-01

To share the diagnostic and management challenges created by an extremely rare airway lesion-the subglottic ectopic thymic cyst. Case report and literature review. We review the presentation, management, and clinical course of an infant who presented with a subglottic mass that was histologically confirmed as a thymic cyst. A brief literature review supplements the case presentation Results: We present the third described case of an ectopic thymic cyst presenting as a subglottic mass. The differential diagnosis of subglottic masses in neonates consists primarily of subglottic hemangioma and mucous retention cysts. Otolaryngologists must be prepared for unexpected findings when dealing with critical airways. We compare the presentation and management of our patient with the 2 previously described cases. We propose an embryologic theory for the origin of these rare lesions. An ectopic thymic cyst is a rare and unexpected cause of neonatal stridor. Management of pediatric airway lesions must allow for unexpected findings at the time of diagnostic and therapeutic endoscopy. The appropriate management of subglottic thymic cysts is poorly defined, but close surveillance for recurrence is mandatory.

Newly developed vaginal atrophy symptoms II and vaginal pH: a better correlation in vaginal atrophy?

PubMed

Tuntiviriyapun, P; Panyakhamlerd, K; Triratanachat, S; Chatsuwan, T; Chaikittisilpa, S; Jaisamrarn, U; Taechakraichana, N

2015-04-01

The primary objective of this study was to evaluate the correlation among symptoms, signs, and the number of lactobacilli in postmenopausal vaginal atrophy. The secondary objective was to develop a new parameter to improve the correlation. A cross-sectional descriptive study. Naturally postmenopausal women aged 45-70 years with at least one clinical symptom of vaginal atrophy of moderate to severe intensity were included in this study. All of the objective parameters (vaginal atrophy score, vaginal pH, the number of lactobacilli, vaginal maturation index, and vaginal maturation value) were evaluated and correlated with vaginal atrophy symptoms. A new parameter of vaginal atrophy, vaginal atrophy symptoms II, was developed and consists of the two most bothersome symptoms (vaginal dryness and dyspareunia). Vaginal atrophy symptoms II was analyzed for correlation with the objective parameters. A total of 132 naturally postmenopausal women were recruited for analysis. Vaginal pH was the only objective parameter found to have a weak correlation with vaginal atrophy symptoms (r = 0.273, p = 0.002). The newly developed vaginal atrophy symptoms II parameter showed moderate correlation with vaginal pH (r = 0.356, p < 0.001) and a weak correlation with the vaginal atrophy score (r = 0.230, p < 0.001). History of sexual intercourse within 3 months was associated with a better correlation between vaginal atrophy symptoms and the objective parameters. Vaginal pH was significantly correlated with vaginal atrophy symptoms. The newly developed vaginal atrophy symptoms II was associated with a better correlation. The vaginal atrophy symptoms II and vaginal pH may be better tools for clinical evaluation and future study of the vaginal ecosystem.

Optimal surgical approach to thymic malignancies: New trends challenging old dogmas.

PubMed

Ruffini, Enrico; Filosso, Pier Luigi; Guerrera, Francesco; Lausi, Paolo; Lyberis, Paraskevas; Oliaro, Alberto

2018-04-01

Until recently, the surgical approach to thymic tumors has remained basically unchanged. The collaborative effort led by ITMIG with the collaboration of regional and society-based interest groups (ESTS, JART) produced an enthusiastic surge of interest in testing the new technological advances in thoracic surgery and many historical dogmas in thymic surgery have been questioned and challenged. The present review addresses the new trends in the optimal surgical management of thymic tumors based on the review of the current literature. 1. Minimally-invasive techniques (MIT) including video-assisted thoracic surgery (VATS) and robotic-assisted thoracic Surgery (RATS) are now to be considered the standard of care in early-stage thymic tumors. MIT are no inferior to open approaches in terms of postoperative complications, loco-regional recurrence rates and survival. MIT are associated with a shorter length of stay, reduced intraoperative blood loss and better cosmetic results. 2. The adoption of the ITMIG/IASLC TNM staging system for thymic tumors requires a paradigm shift among thoracic surgeons to include regional lymphadenectomy according to the IASLC/ITMIG nodal map in the surgical management of thymic tumors. 3. A limited thymectomy instead of total thymectomy along with the removal of the thymic tumor in nonmyasthenic Stage I-II tumors has been proposed by some authors, although the results are not uniform. Until more mature data is available, adherence to the current guidelines recommending total thymectomy in addition to thymomectomy is always indicated. 4. In locally-advanced Stage IVa patients with pleural involvement, major pleural resections, including pleurectomy/decortication or extrapleural pneumonectomy are indicated, provided a complete resection of the pleural deposits is anticipated, usually in a multidisciplinary setting, with excellent long-term results. The incorporation of these new concepts and techniques in the surgical armamentarium of the

Effect of age at onset on cortical thickness and cognition in posterior cortical atrophy

PubMed Central

Suárez-González, Aida; Lehmann, Manja; Shakespeare, Timothy J.; Yong, Keir X.X.; Paterson, Ross W.; Slattery, Catherine F.; Foulkes, Alexander J.M.; Rabinovici, Gil D.; Gil-Néciga, Eulogio; Roldán-Lora, Florinda; Schott, Jonathan M.; Fox, Nick C.; Crutch, Sebastian J.

2016-01-01

Age at onset (AAO) has been shown to influence the phenotype of Alzheimer’s disease (AD), but how it affects atypical presentations of AD remains unknown. Posterior cortical atrophy (PCA) is the most common form of atypical AD. In this study, we aimed to investigate the effect of AAO on cortical thickness and cognitive function in 98 PCA patients. We used Freesurfer (v5.3.0) to compare cortical thickness with AAO both as a continuous variable, and by dichotomizing the groups based on median age (58 years). In both the continuous and dichotomized analyses, we found a pattern suggestive of thinner cortex in precuneus and parietal areas in earlier-onset PCA, and lower cortical thickness in anterior cingulate and prefrontal cortex in later-onset PCA. These cortical thickness differences between PCA subgroups were consistent with earlier-onset PCA patients performing worse on cognitive tests involving parietal functions. Our results provide a suggestion that AAO may not only affect the clinico-anatomical characteristics in AD but may also affect atrophy patterns and cognition within atypical AD phenotypes. PMID:27318138

Brain tissues atrophy is not always the best structural biomarker of physiological aging: A multimodal cross-sectional study.

PubMed

Cherubini, Andrea; Caligiuri, Maria Eugenia; Péran, Patrice; Sabatini, Umberto; Cosentino, Carlo; Amato, Francesco

2015-01-01

This study presents a voxel-based multiple regression analysis of different magnetic resonance image modalities, including anatomical T1-weighted, T2* relaxometry, and diffusion tensor imaging. Quantitative parameters sensitive to complementary brain tissue alterations, including morphometric atrophy, mineralization, microstructural damage, and anisotropy loss, were compared in a linear physiological aging model in 140 healthy subjects (range 20-74 years). The performance of different predictors and the identification of the best biomarker of age-induced structural variation were compared without a priori anatomical knowledge. The best quantitative predictors in several brain regions were iron deposition and microstructural damage, rather than macroscopic tissue atrophy. Age variations were best resolved with a combination of markers, suggesting that multiple predictors better capture age-induced tissue alterations. These findings highlight the importance of a combined evaluation of multimodal biomarkers for the study of aging and point to a number of novel applications for the method described.

Association of Age Related Macular Degeneration and Age Related Hearing Impairment

PubMed Central

Ghasemi, Hassan; Pourakbari, Malihe Shahidi; Entezari, Morteza; Yarmohammadi, Mohammad Ebrahim

2016-01-01

Purpose: To evaluate the association between age-related macular degeneration (ARMD) and sensory neural hearing impairment (SHI). Methods: In this case-control study, hearing status of 46 consecutive patients with ARMD were compared with 46 age-matched cases without clinical ARMD as a control group. In all patients, retinal involvements were confirmed by clinical examination, fluorescein angiography (FA) and optical coherence tomography (OCT). All participants were examined with an otoscope and underwent audiological tests including pure tone audiometry (PTA), speech reception threshold (SRT), speech discrimination score (SDS), tympanometry, reflex tests and auditory brainstem response (ABR). Results: A significant (P = 0.009) association was present between ARMD, especially with exudative and choroidal neovascularization (CNV) components, and age-related hearing impairment primarily involving high frequencies. Patients had higher SRT and lower SDS against anticipated presbycusis than control subjects. Similar results were detected in exudative, CNV and scar patterns supporting an association between late ARMD with SRT and SDS abnormalities. ABR showed significantly prolonged wave I and IV latency times in ARMD (P = 0.034 and 0.022, respectively). Average latency periods for wave I in geographic atrophy (GA) and CNV, and that for wave IV in drusen patterns of ARMD were significantly higher than controls (P = 0.030, 0.007 and 0.050, respectively). Conclusion: The association between ARMD and age-related SHI may be attributed to common anatomical components such as melanin in these two sensory organs. PMID:27195086

Intrapericardial primary thymic carcinoma in a 73-year-old man.

PubMed

Calderon, Ana Maria; Merchan, Juan Andres; Rozo, Juan Carlos; Guerrero, Cesar Ivan; Treistman, Bernardo; Sulak, Laura E; Cheong, Benjamin Y C; Rodríguez, German; Mesa, Andrés

2008-01-01

Thymic carcinoma is a rare, highly aggressive type of tumor that typically occurs in the anterior mediastinum. We describe the case of a 73-year-old man who presented with weakness, cough, dyspnea, anorexia, and weight loss. An echocardiogram showed an intrapericardial mass that occupied the space around the lateral walls of the left ventricle and distally compressed the right ventricle. Magnetic resonance imaging and a biopsy confirmed the presence of intrapericardial primary thymic carcinoma. The patient underwent surgical excision of the tumor and died of right ventricular rupture during the procedure. This case highlights the importance of considering thymic carcinoma whenever an otherwise unexplained intrapericardial mass is encountered.

Potential effect of skull thickening on the associations between cognition and brain atrophy in ageing.

PubMed

Aribisala, Benjamin Segun; Royle, Natalie A; Valdés Hernández, Maria C; Murray, Catherine; Penke, Lars; Gow, Alan; Maniega, Susana Muñoz; Starr, John M; Bastin, Mark; Deary, Ian; Wardlaw, Joanna

2014-09-01

intracranial volume (ICV) is commonly used as a marker of premorbid brain size in neuroimaging studies as it is thought to remain fixed throughout adulthood. However, inner skull table thickening would encroach on ICV and could mask actual brain atrophy. we investigated the effect that thickening might have on the associations between brain atrophy and cognition. the sample comprised 57 non-demented older adults who underwent structural brain MRI at mean age 72.7 ± 0.7 years and were assessed on cognitive ability at mean age 11 and 73 years. Principal component analysis was used to derive factors of general cognitive ability (g), information processing speed and memory from the recorded cognitive ability data. The total brain tissue volume and ICV with (estimated original ICV) and without (current ICV) adjusting for the effects of inner table skull thickening were measured. General linear modelling was used to test for associations. all cognitive ability variables were significantly (P < 0.01) associated with percentage total brain volume in ICV measured without adjusting for skull thickening (g: η(2) = 0.177, speed: η(2) = 0.264 and memory: η(2) = 0.132). After accounting for skull thickening, only speed was significantly associated with percentage total brain volume in ICV (η(2) = 0.085, P = 0.034), not g or memory. not accounting for skull thickening when computing ICV can distort the association between brain atrophy and cognitive ability in old age. Larger samples are required to determine the true effect. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PubMed

Chakravarthy, Usha; Bailey, Clare C; Johnston, Robert L; McKibbin, Martin; Khan, Rehna S; Mahmood, Sajjad; Downey, Louise; Dhingra, Narendra; Brand, Christopher; Brittain, Christopher J; Willis, Jeffrey R; Rabhi, Sarah; Muthutantri, Anushini; Cantrell, Ronald A

2018-06-01

To understand levels of disease burden and progression in a real-world setting among patients from the United Kingdom with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Retrospective cohort analysis of a multicenter electronic medical record (EMR) database. Patients who were aged ≥50 years with bilateral GA and no history of choroidal neovascularization (CNV) and who attended 1 of 10 clinical sites using the EMR. A deidentified data set was constructed from the records held at the 10 sites. An algorithm was used to extract cases with a GA diagnosis, of which 1901 had bilateral GA and form the basis of this report. A sample of records randomly selected from each center was used to validate disease definitions. Progression to blindness (visual acuity [VA] <20 letters or Snellen 3/60 in the better-seeing eye), driving ineligibility (VA ≤70 letters or Snellen 6/12 in the better-seeing eye), progression to CNV, loss of 10 or more letters, and mean change in VA over time. At first record of GA, 7.1% had a VA in the better-seeing eye equal to or lower than the cutoff for blindness registration and 71.1% had a VA that would have rendered them ineligible to drive. Over time, 16% became legally blind (median time to outcome, 6.2 years) and 66.7% became ineligible to drive (median time to outcome, 1.6 years). In the worse-seeing eye, 40.1% lost ≥10 letters in 2.4 years. Among patients with baseline and 24-month VA measurements, mean VA decline was 6.1 letters in the worse-seeing eye (n = 413) and 12.4 letters in the better-seeing eye (n = 414). The rate of progression to CNV in either eye was 7.4% per patient-year. At initial diagnosis, based on VA in the better-seeing eye, a high proportion of patients with bilateral GA were ineligible to drive and approximately 7% were eligible for UK blindness registration. The subsequent reduction in VA that occurred in the better-seeing eye would render a further two-thirds ineligible to

Bioprocessing feasibility analysis. [thymic hormone bioassay and electrophoresis

NASA Technical Reports Server (NTRS)

1978-01-01

The biology and pathophysiology of the thymus gland is discussed and a clinical procedure for thymic hormone assay is described. The separation of null lymphocytes from mice spleens and the functional characteristics of the cells after storage and transportation were investigated to develop a clinical procedure for thymic hormone assay, and to determine whether a ground-based approach will provide the desired end-product in sufficient quantities, or whether the microgravity of space should be exploited for more economical preparation of the hormone.

Reduced age-related degeneration of the hippocampal subiculum in long-term meditators.

PubMed

Kurth, Florian; Cherbuin, Nicolas; Luders, Eileen

2015-06-30

Normal aging is known to result in a reduction of gray matter within the hippocampal complex, particularly in the subiculum. The present study was designed to address the question whether the practice of meditation can amend this age-related subicular atrophy. For this purpose, we established the correlations between subicular volume and chronological age within 50 long-term meditators and 50 control subjects. High-resolution magnetic resonance imaging (MRI) scans were automatically processed combining cytoarchitectonically defined probabilistic maps with advanced tissue segmentation and registration methods. Overall, we observed steeper negative regression slopes in controls. The analysis further revealed a significant group-by-age interaction for the left subiculum with a significant negative correlation between age and subicular volume in controls, but no significant correlation in meditators. Altogether, these findings seem to suggest a reduced age-related atrophy of the left subiculum in meditators compared to healthy controls. Possible explanations might be a relative increase of subicular tissue over time through long-term training as meditation is a process that incorporates regular and ongoing mental efforts. Alternatively, because meditation is an established form of reducing stress, our observation might reflect an overall preservation of subicular tissue through a reduced neuronal vulnerability to negative effects of stress. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Prevention of age-related macular degeneration

PubMed Central

Koo, Simon Chi Yan; Chan, Clement Wai Nang

2010-01-01

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world. Although effective treatment modalities such as anti-VEGF treatment have been developed for neovascular AMD, there is still no effective treatment for geographical atrophy, and therefore the most cost-effective management of AMD is to start with prevention. This review looks at current evidence on preventive measures targeted at AMD. Modalities reviewed include (1) nutritional supplements such as the Age-Related Eye Disease Study (AREDS) formula, lutein and zeaxanthin, omega-3 fatty acid, and berry extracts, (2) lifestyle modifications, including smoking and body-mass-index, and (3) filtering sunlight, i.e. sunglasses and blue-blocking intraocular lenses. In summary, the only proven effective preventive measures are stopping smoking and the AREDS formula. PMID:20862519

Prevention of age-related macular degeneration.

PubMed

Wong, Ian Yat Hin; Koo, Simon Chi Yan; Chan, Clement Wai Nang

2011-02-01

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world. Although effective treatment modalities such as anti-VEGF treatment have been developed for neovascular AMD, there is still no effective treatment for geographical atrophy, and therefore the most cost-effective management of AMD is to start with prevention. This review looks at current evidence on preventive measures targeted at AMD. Modalities reviewed include (1) nutritional supplements such as the Age-Related Eye Disease Study (AREDS) formula, lutein and zeaxanthin, omega-3 fatty acid, and berry extracts, (2) lifestyle modifications, including smoking and body-mass-index, and (3) filtering sunlight, i.e. sunglasses and blue-blocking intraocular lenses. In summary, the only proven effective preventive measures are stopping smoking and the AREDS formula.

Optical Coherence Tomography Reflective Drusen Substructures Predict Progression to Geographic Atrophy in Non-neovascular Age-related Macular Degeneration

PubMed Central

Veerappan, Malini; El-Hage Sleiman, Abdul-Karim M.; Tai, Vincent; Chiu, Stephanie J.; Winter, Katrina P.; Stinnett, Sandra S.; Hwang, Thomas S.; Hubbard, G. Baker; Michelson, Michelle; Gunther, Randall; Wong, Wai T.; Chew, Emily Y.; Toth, Cynthia A.

2016-01-01

Purpose Structural and compositional heterogeneity within drusen, composed of lipid, carbohydrates, and proteins, have been previously described. We sought to detect and define phenotypic patterns of drusen heterogeneity in the form of optical coherence tomography–reflective drusen substructures (ODS) and examine their associations with age-related macular degeneration (AMD)-related features and AMD progression. Design Retrospective analysis in a prospective study. Participants Patients with intermediate AMD (n = 349) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) ancillary spectral domain optical coherence tomography (SD OCT) study. Methods Baseline SD OCT scans of 1 eye per patient were analyzed for presence of ODS. Cross-sectional and longitudinal associations of ODS presence with AMD-related features visible on SD OCT and color photographs, including drusen volume, geographic atrophy (GA), and preatrophic features, were evaluated for the entire macular region. Similar associations were also made locally within a 0.5-mm diameter region around individual ODS and corresponding control region without ODS in the same eye. Main Outcome Measures Preatrophy SD OCT changes and GA, central GA, and choroidal neovascularization (CNV) from color photographs. Results Four phenotypic subtypes of ODS were defined: low reflective cores, high reflective cores, conical debris, and split drusen. Of the 349 participants, there were 307 eligible eyes and 74 (24%) had at least 1 ODS. The ODS at baseline were associated with (1) greater macular drusen volume at baseline (P < 0.001), (2) development of preatrophic changes at year 2 (P = 0.001–0.01), and (3) development of macular GA (P = 0.005) and preatrophic changes at year 3 (P = 0.002–0.008), but not development of CNV. The ODS at baseline in a local region were associated with (1) presence of preatrophy changes at baseline (P = 0.02-0.03) and (2) development of preatrophy changes at years 2 and 3 within

Bed Rest Muscular Atrophy

NASA Technical Reports Server (NTRS)

Greenleaf, John E.

2000-01-01

A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

The biology of recent thymic emigrants.

PubMed

Fink, Pamela J

2013-01-01

The generation of the TCRαβ lineage of T cells occurs in the thymus through a series of orchestrated developmental events that result in a carefully selected population of CD4 or CD8 lineage-committed TCR(+) thymocytes capable of recognizing foreign antigen in the context of self MHC. T cells first exit the thymus in a phenotypically and functionally immature state and require an approximately 3-week period of post-thymic maturation before transitioning into the mature T cell compartment. A greater understanding of recent thymic emigrant biology has come with the development of methods to exclusively identify and isolate this population for further characterization. I now review current knowledge about the phenotype and function of this key but understudied population of peripheral T cells.

Thymic cystic degeneration, pseudoepitheliomatous hyperplasia, and hemorrhage in a dog with brodifacoum toxicosis.

PubMed

Rickman, B H; Gurfield, N

2009-05-01

Thymic cysts with pseudoepitheliomatous hyperplasia are described in a 7-month-old female American Eskimo Dog that died of complications from brodifacoum poisoning. Grossly, there was hemothorax with marked cranial mediastinal hemorrhage. Histologically, thymic lobules were expanded and distorted by irregular cysts, lined by single to multiple layers of plump to slightly attenuated polygonal squamous epithelial cells supported by a basement membrane (pseudoepitheliomatous hyperplasia). The thymus had a paucity of lymphocytes and lacked corticomedullary differentiation. Extensive hemorrhage within the cysts and thymic parenchyma extended into the adjacent adipose tissue. To the authors' knowledge, this is the first report of cystic thymic degeneration with pseudoepitheliomatous hyperplasia in a nonhuman species.

Occupation Attributes Relate to Location of Atrophy in Frontotemporal Lobar Degeneration

ERIC Educational Resources Information Center

Spreng, R. N.; Rosen, H. J.; Strother, S.; Chow, T. W.; Diehl-Schmid, J.; Freedman, M.; Graff-Radford, N. R.; Hodges, J. R.; Lipton, A. M.; Mendez, M. F.; Morelli, S. A.; Black, S. E.; Miller, B. L.; Levine, Brian

2010-01-01

Frontotemporal lobar degeneration (FTLD) often presents with asymmetric atrophy. We assessed whether premorbid occupations in FTLD patients were associated with these hemispheric asymmetries. In a multi-center chart review of 588 patients, occupation information was related to location of tissue loss or dysfunction. Patients with atrophy…

The experiences of families living with the anticipatory loss of a school-age child with spinal muscular atrophy - the parents' perspectives.

PubMed

Yang, Bao-Huan; Mu, Pei-Fan; Wang, Wen-Sheng

2016-09-01

To probe into parents' anticipatory loss of school-age children with Type I or II spinal muscular atrophy. Spinal muscular atrophy is a rare disorder that causes death. Children die early due to either gradual atrophy or an infection of the lungs. Therefore, family members experience anticipatory loss, which causes grief before the actual loss. Family members feel physically and mentally exhausted, which results in a family crisis. Therefore, it is important to explore their experiences related to anticipatory loss to assist with the adjustment of the families to their circumstances. This study applied a phenomenology method and purposive sampling. The 19 parents who participated in this study were referred to us by two medical centers in Taiwan. Their average age was 32-49 years. Using in-depth interviews, this study explored parents' anticipatory loss. The interviews were recorded and transcribed. Meanings were extracted using Giorgi analysis, and precision was assessed according to Guba and Lincoln, which was treated as the evaluation standard. Four themes were identified from the parents' interviews. The themes included enduring the helplessness and pressure of care, suffering due to the child's rare and unknown condition, loss of hope and a reinforcement of the parent-child attachment, and avoiding the pressure of death and enriching the child's life. The research findings help nurses identify anticipatory loss among parents of school-age children with type I or II spinal muscular atrophy. They enhance health professionals' understanding of the panic that occurs in the society surrounding the families, family members' dynamic relationships, and the families' demands for care. In an attempt to providing intersubjective empathy and support with family having a child with type I and II SMA, nurses may recognize relevant family reactions and enhancing their hope and parent-child attachment. Encourage family members and child go beyond the pressure of death and

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems.

PubMed

Komatsu, Riyo; Okazaki, Tatsuma; Ebihara, Satoru; Kobayashi, Makoto; Tsukita, Yoko; Nihei, Mayumi; Sugiura, Hisatoshi; Niu, Kaijun; Ebihara, Takae; Ichinose, Masakazu

2018-05-22

Repetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase-3, followed by further degradation by the ubiquitin-proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms. We employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra-nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real-time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients. The aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase-3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin-proteasome system was detected in all the three muscles examined. The aspiration challenge

Effect of age at onset on cortical thickness and cognition in posterior cortical atrophy.

PubMed

Suárez-González, Aida; Lehmann, Manja; Shakespeare, Timothy J; Yong, Keir X X; Paterson, Ross W; Slattery, Catherine F; Foulkes, Alexander J M; Rabinovici, Gil D; Gil-Néciga, Eulogio; Roldán-Lora, Florinda; Schott, Jonathan M; Fox, Nick C; Crutch, Sebastian J

2016-08-01

Age at onset (AAO) has been shown to influence the phenotype of Alzheimer's disease (AD), but how it affects atypical presentations of AD remains unknown. Posterior cortical atrophy (PCA) is the most common form of atypical AD. In this study, we aimed to investigate the effect of AAO on cortical thickness and cognitive function in 98 PCA patients. We used Freesurfer (v5.3.0) to compare cortical thickness with AAO both as a continuous variable, and by dichotomizing the groups based on median age (58 years). In both the continuous and dichotomized analyses, we found a pattern suggestive of thinner cortex in precuneus and parietal areas in earlier-onset PCA, and lower cortical thickness in anterior cingulate and prefrontal cortex in later-onset PCA. These cortical thickness differences between PCA subgroups were consistent with earlier-onset PCA patients performing worse on cognitive tests involving parietal functions. Our results provide a suggestion that AAO may not only affect the clinico-anatomical characteristics in AD but may also affect atrophy patterns and cognition within atypical AD phenotypes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Outer retinal corrugations in age-related macular degeneration.

PubMed

Ooto, Sotaro; Vongkulsiri, Sritatath; Sato, Taku; Suzuki, Mihoko; Curcio, Christine A; Spaide, Richard F

2014-07-01

Optical coherence tomography (OCT) abnormalities of age-related macular degeneration (AMD) have not been fully characterized because of the complex morphology and a lack of correlative histologic studies. Expansion of our ability to interpret increasing attributes brings us closer to the goal of in vivo histologic analysis of the eye by OCT. To describe a new outer retinal finding of AMD using spectral-domain (SD) OCT and suggest histopathologic correlates. Twenty-five eyes of 16 patients with AMD with severe atrophy due to either choroidal neovascularization (CNV) or geographic atrophy (GA) and 53 donor eyes of 53 patients with late AMD were included. Imaging studies were conducted at a referral retinal practice and histopathology was done at a university research laboratory. Findings in the outer retina were evaluated in SD-OCT images in eyes with atrophy of the retinal pigment epithelium (RPE) and compared with histopathologic findings in eyes with GA or CNV that also showed loss of the RPE. Spectral-domain OCT and histologic characteristics of the outer retina. The mean (SD) age of the 16 patients was 82.7 (7.9) years. Twenty eyes had CNV and 5 eyes had GA. The mean best-corrected visual acuity was 0.800 logMAR (interquartile range, 0.350-1.000 logMAR), a Snellen equivalent of 20/126. A curvilinear hyperreflective density was identified above the Bruch membrane line within the atrophic area in the SD-OCT images. At the internal border, the material was contiguous with the outer portion of the RPE band. Below the material was a relatively hyporeflective space. The material was thrown into folds in cases with atrophy following CNV or was seen as a sheet with numerous bumps in eyes with GA. Review of histopathologic findings of eyes with advanced GA and CNV revealed a rippled layer of basal laminar deposits in an area of RPE atrophy that was located in the same level as the curvilinear line seen in the OCT images. We have described a new entity, termed outer

Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells

PubMed Central

Sojka, Dorothy K; Plougastel-Douglas, Beatrice; Yang, Liping; Pak-Wittel, Melissa A; Artyomov, Maxim N; Ivanova, Yulia; Zhong, Chao; Chase, Julie M; Rothman, Paul B; Yu, Jenny; Riley, Joan K; Zhu, Jinfang; Tian, Zhigang; Yokoyama, Wayne M

2014-01-01

Natural killer (NK) cells belong to the innate immune system; they can control virus infections and developing tumors by cytotoxicity and producing inflammatory cytokines. Most studies of mouse NK cells, however, have focused on conventional NK (cNK) cells in the spleen. Recently, we described two populations of liver NK cells, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, their lineage relationship was unclear; trNK cells could be developing cNK cells, related to thymic NK cells, or a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis and transcription factor-deficient mice to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells. Taken together with analysis of trNK cells in other tissues, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells. DOI: http://dx.doi.org/10.7554/eLife.01659.001 PMID:24714492

Increase of Myoglobin in Rat Gastrocnemius Muscles with Immobilization-induced Atrophy

PubMed Central

Lee, Jeong-Uk; Kim, Ju-Hyun; Kim, Mee-Young; Lee, Lim-Kyu; Yang, Seung-Min; Jeon, Hye-Joo; Lee, Won-Deok; Noh, Ji-Woong; Lee, Tae-Hyun; Kwak, Taek-Yong; Kim, Bokyung; Kim, Junghwan

2014-01-01

[Purpose] Atrophy is a common phenomenon caused by prolonged muscle disuse associated with bed-rest, aging, and immobilization. However, changes in the expression of atrophy-related myoglobin are still poorly understood. In the present study, we examined whether or not myoglobin expression is altered in the gastrocnemius muscles of rats after seven days of cast immobilization. [Methods] We conducted a protein expression and high-resolution differential proteomic analysis using, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry, and western blotting. [Results] The density and expression of myoglobin increased significantly more in atrophic gastrocnemius muscle strips than they did in the control group. [Conclusion] The results suggest that cast immobilization-induced atrophy may be related to changes in the expression of myoglobin in rat gastrocnemius muscles. PMID:24409033

[Sulphurous vaginal douching and vulvovaginal atrophy].

PubMed

Costantino, M; Conti, V; Marongiu, M B; Napolano, G; Filippelli, A

2017-01-01

During climacteric the reduction or interruption of estrogenic stimulus determines a gradual atrophy of the tissues of the urogenital tract.Vulvovaginal atrophy can be cause of dryness, itch, burning, and dyspareunia. Vulvovaginal atrophy is associated also with depression. Hence the importance of an appropriate treatment of the vulvovaginal atrophy. Between therapeutic options we can add, particularly for women who suffer only from vaginal symptoms, the spa therapy that uses mineral waters with benefic effects on vaginal tissue wellness and health. On the basis of considerations described above and on the insufficient literature data, the objective of our single-arm pilot study has been to evaluate, in women suffering from vulvovaginal atrophy, the effects and safety of a vaginal douching cycle with sulphurous mineral water and impact on depression disorder frequently observed. The study was conducted on 24 women affected by vulvovaginal atrophy; mean age:57±11 years; age range:42-81 years. The subjects were treated, for 2 weeks, with sulphurous vaginal douching from Terme of Telese S.p.A. (Benevento-Italy). At the beginning and at the end of the SPA treatment the following symptoms were evaluated: dryness, burning, itch, dyspareunia and leucorrhoea (using VAS scale); the impact on psychological distress (using S.D.S. Zung-test). At the end of the spa treatment, the mean values±SD, compared to baseline, have showed a significant (p<0.05) reduction in leucorrhoea (-88%), in vulvar itch (-79%), in vaginal burning (-71%), in vaginal dryness (-65%) with an improvement of psichological distress as demonstrated by S.D.S. Zung-test. The data of this single-arm pilot clinical trial show that the sulphurous vaginal douching cycle can be considered very useful in women suffering from vulvovaginal atrophy with improving of the quality of life and social relationship.

FK506 attenuates thymic output in patients with myasthenia gravis

PubMed Central

Kuroda, Yukiko; Ueno, Shu-ichi; Matsui, Naoko; Kaji, Ryuji

2013-01-01

Introduction Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4+ T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG. Material and methods We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants. Results T-cell receptor excision circle was not significantly different from those in age-matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4–CD8+ cells (p < 0.05), but total cell counts were not significantly changed. Conclusions These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also naïve T-cells. PMID:24482655

Purified enzymes improve isolation and characterization of the adult thymic epithelium.

PubMed

Seach, Natalie; Wong, Kahlia; Hammett, Maree; Boyd, Richard L; Chidgey, Ann P

2012-11-30

The reproducible isolation and accurate characterization of thymic epithelial cell (TEC) subsets is of critical importance to the ongoing study of thymopoiesis and its functional decline with age. The study of adult TEC, however, is significantly hampered due to the severely low stromal to hematopoietic cell ratio. Non-biased digestion and enrichment protocols are thus essential to ensure optimal cell yield and accurate representation of stromal subsets, as close as possible to their in vivo representation. Current digestion protocols predominantly involve diverse, relatively impure enzymatic variants of crude collagenase and collagenase/dispase (col/disp) preparations, which have variable efficacy and are often suboptimal in their ability to mediate complete digestion of thymus tissue. To address these issues we compared traditional col/disp preparations with the latest panel of Liberase products that contain a blend of highly purified collagenase and neutral protease enzymes. Liberase enzymes revealed a more rapid, complete dissociation of thymus tissue; minimizing loss of viability and increasing recovery of thymic stromal cell (TSC) elements. In particular, the recovery and viability of TEC, notably the rare cortical subsets, were significantly enhanced with Liberase products containing medium to high levels of thermolysin. The improved stromal dissociation led to numerically increased TEC yield and total TEC RNA isolated from pooled digests of adult thymus. Furthermore, the increased recovery of TEC enhanced resolution and quantification of TEC subsets in both adult and aged mice, facilitating flow cytometric analysis on a per thymus basis. We further refined the adult TEC phenotype by correlating surface expression of known TEC markers, with expression of intracellular epithelial lineage markers, Keratin 5 and Keratin 8. The data reveal more extensive expression of K8 than previously recognized and indicates considerable heterogeneity still exists within

Brain MRI atrophy quantification in MS

PubMed Central

Rocca, Maria A.; Battaglini, Marco; Benedict, Ralph H.B.; De Stefano, Nicola; Geurts, Jeroen J.G.; Henry, Roland G.; Horsfield, Mark A.; Jenkinson, Mark; Pagani, Elisabetta

2017-01-01

Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years. PMID:27986875

Geographic atrophy phenotype identification by cluster analysis.

PubMed

Monés, Jordi; Biarnés, Marc

2018-03-01

To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm 2 /year, respectively, p=0.0005). Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Macular Atrophy Development and Subretinal Drusenoid Deposits in Anti-Vascular Endothelial Growth Factor Treated Age-Related Macular Degeneration.

PubMed

Zarubina, Anna V; Gal-Or, Orly; Huisingh, Carrie E; Owsley, Cynthia; Freund, K Bailey

2017-12-01

To explore the association between presence of subretinal drusenoid deposits (SDD) at baseline in eyes with neovascular age-related macular degeneration (nAMD) with the development of macular atrophy (MA) during anti-vascular endothelial growth factor (VEGF) therapy. There were 74 eyes without pre-existing MA receiving anti-VEGF therapy for nAMD for 2 years or longer analyzed. At least two image modalities that included spectral-domain optical coherence tomography, near-infrared reflectance, fluorescein angiography, and color fundus photos were used to assess for SDD presence, phenotype (dot and ribbon), and location, neovascularization type, and MA. Logistic regression models using generalized estimating equations assessed the association between SDD and the development of MA adjusting for age, neovascularization type, and choroidal thickness. SDD were present in 46 eyes (63%) at baseline. MA developed in 38 eyes (51%) during the mean of 4.7 ± 1.2 years of follow-up. Compared with eyes without SDD, those with SDD at baseline were 3.0 times (95% confidence interval [CI] 1.1-8.5, P = 0.0343) more likely to develop MA. Eyes with SDD present in the inferior macula and inferior extramacular fields at baseline were 3.0 times and 6.5 times more likely to develop MA at follow-up than eyes without SDD in these locations (95% CI 1.0-8.9, P = 0.0461 and 95% CI 1.3-32.4, P = 0.0218, respectively). MA development was not associated with a specific SDD phenotype. MA frequently developed in eyes during anti-VEGF treatment. SDD were independently associated with MA development. The extension of SDD into the inferior fundus, particularly in the inferior extramacular field, conferred higher odds of subsequent MA development.

Macular Atrophy Development and Subretinal Drusenoid Deposits in Anti-Vascular Endothelial Growth Factor Treated Age-Related Macular Degeneration

PubMed Central

Zarubina, Anna V.; Gal-Or, Orly; Huisingh, Carrie E.; Owsley, Cynthia

2017-01-01

Purpose To explore the association between presence of subretinal drusenoid deposits (SDD) at baseline in eyes with neovascular age-related macular degeneration (nAMD) with the development of macular atrophy (MA) during anti-vascular endothelial growth factor (VEGF) therapy. Methods There were 74 eyes without pre-existing MA receiving anti-VEGF therapy for nAMD for 2 years or longer analyzed. At least two image modalities that included spectral-domain optical coherence tomography, near-infrared reflectance, fluorescein angiography, and color fundus photos were used to assess for SDD presence, phenotype (dot and ribbon), and location, neovascularization type, and MA. Logistic regression models using generalized estimating equations assessed the association between SDD and the development of MA adjusting for age, neovascularization type, and choroidal thickness. Results SDD were present in 46 eyes (63%) at baseline. MA developed in 38 eyes (51%) during the mean of 4.7 ± 1.2 years of follow-up. Compared with eyes without SDD, those with SDD at baseline were 3.0 times (95% confidence interval [CI] 1.1–8.5, P = 0.0343) more likely to develop MA. Eyes with SDD present in the inferior macula and inferior extramacular fields at baseline were 3.0 times and 6.5 times more likely to develop MA at follow-up than eyes without SDD in these locations (95% CI 1.0–8.9, P = 0.0461 and 95% CI 1.3–32.4, P = 0.0218, respectively). MA development was not associated with a specific SDD phenotype. Conclusions MA frequently developed in eyes during anti-VEGF treatment. SDD were independently associated with MA development. The extension of SDD into the inferior fundus, particularly in the inferior extramacular field, conferred higher odds of subsequent MA development. PMID:29196768

Spinal Muscular Atrophy (SMA)

MedlinePlus

... kids of the same age or have trouble lifting things. Kids with SMA can develop scoliosis (a ... Nervous System Your Muscles Wheelchairs Scoliosis Steven's Story: Power Player Kyphosis Muscular Dystrophy Spinal Muscular Atrophy: Steven's ...

The effect of non-neovascular age-related macular degeneration on face recognition performance.

PubMed

Taylor, Deanna J; Smith, Nicholas D; Binns, Alison M; Crabb, David P

2018-04-01

There is a well-established research base surrounding face recognition in patients with age-related macular degeneration (AMD). However, much of this existing research does not differentiate between results obtained for 'wet' AMD and 'dry' AMD. Here, we test the hypothesis that face recognition performance is worse in patients with dry AMD compared with visually healthy peers. Patients (>60 years of age, logMAR binocular visual acuity 0.7 or better) with dry AMD of varying severity and visually healthy age-related peers (controls) completed a modified version of the Cambridge Face Memory Test (CFMT). Percentage of correctly identified faces was used as an outcome measure for performance for each participant. A 90% normative reference limit was generated from the distribution of CFMT scores recorded in the visually healthy controls. Scores for AMD participants were then specifically compared to this limit, and comparisons between average scores in the AMD severity groups were investigated. Thirty patients (median [interquartile range] age of 76 [70, 79] years) and 34 controls (median age of 70 [64, 75] years) were examined. Four, seventeen and nine patients were classified as having early, intermediate and late AMD (geographic atrophy) respectively. Five (17%) patients recorded a face recognition performance worse than the 90% limit (Fisher's exact test, p = 0.46) set by controls; four of these had geographic atrophy. Patients with geographic atrophy identified fewer faces on average (±SD) (61% ± 22%) than those with early and intermediate AMD (75 ± 11%) and controls (74% ± 11%). People with dry AMD may not suffer from problems with face recognition until the disease is in its later stages; those with late AMD (geographic atrophy) are likely to have difficulty recognising faces. The results from this study should influence the management and expectations of patients with dry AMD in both community practice and hospital clinics.

Characterization of Thymic Settling Progenitors in the Mouse Embryo Using In Vivo and In Vitro Assays

PubMed Central

Ramond, Cyrille; Bandeira, Antonio; Berthault, Claire; Pereira, Pablo; Cumano, Ana; Burlen-Defranoux, Odile

2015-01-01

Characterizing thymic settling progenitors is important to understand the pre-thymic stages of T cell development, essential to devise strategies for T cell replacement in lymphopenic patients. We studied thymic settling progenitors from murine embryonic day 13 and 18 thymi by two complementary in vitro and in vivo techniques, both based on the “hanging drop” method. This method allowed colonizing irradiated fetal thymic lobes with E13 and/or E18 thymic progenitors distinguished by CD45 allotypic markers and thus following their progeny. Colonization with mixed populations allows analyzing cell autonomous differences in biologic properties of the progenitors while colonization with either population removes possible competitive selective pressures. The colonized thymic lobes can also be grafted in immunodeficient male recipient mice allowing the analysis of the mature T cell progeny in vivo, such as population dynamics of the peripheral immune system and colonization of different tissues and organs. Fetal thymic organ cultures revealed that E13 progenitors developed rapidly into all mature CD3+ cells and gave rise to the canonical γδ T cell subset, known as dendritic epithelial T cells. In comparison, E18 progenitors have a delayed differentiation and were unable to generate dendritic epithelial T cells. The monitoring of peripheral blood of thymus-grafted CD3-/- mice further showed that E18 thymic settling progenitors generate, with time, larger numbers of mature T cells than their E13 counterparts, a feature that could not be appreciated in the short term fetal thymic organ cultures. PMID:26131754

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications.

PubMed

Janik, S; Schiefer, A I; Bekos, C; Hacker, P; Haider, T; Moser, J; Klepetko, W; Müllauer, L; Ankersmit, H J; Moser, B

2016-04-21

Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated.

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications

PubMed Central

Janik, S.; Schiefer, A. I.; Bekos, C.; Hacker, P.; Haider, T.; Moser, J.; Klepetko, W.; Müllauer, L.; Ankersmit, H. J.; Moser, B.

2016-01-01

Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated. PMID:27097982

Evolution of Geographic Atrophy in Participants Treated with Ranibizumab for Neovascular Age-related Macular Degeneration

PubMed Central

Thavikulwat, Alisa T.; Jacobs-El, Naima; Kim, Jane S.; Agrón, Elvira; Hasan, Jesia; Meyerle, Catherine B.; Valent, David; Cukras, Catherine A.; Wiley, Henry E.; Wong, Wai T.; Chew, Emily Y.

2016-01-01

Purpose To evaluate the risk factors, incidence, and rate of progression of geographic atrophy (GA) in eyes with neovascular age-related macular degeneration (nAMD) treated with ranibizumab. Design Post-hoc analysis of a prospective clinical study. Participants 69 participants with nAMD in at least one eye. Methods Participants were prospectively treated in the study eye with 0.5 mg intravitreal ranibizumab. Study eyes received 4 monthly injections followed by pro re nata injections until a fluid-free macula was achieved on optical coherence tomography. Risk factors assessed included baseline demographics, treatment, and ocular characteristics on imaging. Eyes were evaluated on fundus autofluorescence (FAF) for GA. The rate of GA area growth in study and fellow eyes was analyzed by linear regression of square-root transformed areas. Main Outcome Measures Development of new-onset GA and rate of GA area growth measured on ocular imaging, including FAF images of the study eyes. Results Sixty-nine participants (mean age 78.8±7.8 years) with an average of 40.0±13.6 months of follow-up were analyzed. Twenty-two of 69 study eyes (32%) were treatment naïve. During their first year of the study, participants received an average of 9.2±3.3 injections in the study eye. Of 63 study eyes with quality baseline images, 22 (35%) had pre-existing GA. Of the remaining 41 eyes, 7 (17%) developed new-onset GA during study follow-up. Those who developed new GA were older (all ≥79 years old) and had received fewer study injections on average (6.9 vs. 10.4 injections at 1 year) compared to those who did not develop new GA. Of the 12 treatment naïve study eyes without GA at baseline, 1 (8.3%) developed new GA during the study. In 21 study eyes with quantifiable GA area, eyes with GA present at baseline (16/21) enlarged by 0.34±0.26 mm/year, compared to 0.19±0.12 mm/year in eyes developing new-onset GA (5/21). Conclusions While 17% of study eyes without GA present at baseline

Evolution of Geographic Atrophy in Participants Treated with Ranibizumab for Neovascular Age-related Macular Degeneration.

PubMed

Thavikulwat, Alisa T; Jacobs-El, Naima; Kim, Jane S; Agrón, Elvira; Hasan, Jesia; Meyerle, Catherine B; Valent, David; Cukras, Catherine A; Wiley, Henry E; Wong, Wai T; Chew, Emily Y

2017-01-01

To evaluate the risk factors, incidence, and rate of progression of geographic atrophy (GA) in eyes with neovascular age-related macular degeneration (nAMD) treated with ranibizumab. Post-hoc analysis of a prospective clinical study. 69 participants with nAMD in at least one eye. Participants were prospectively treated in the study eye with 0.5 mg intravitreal ranibizumab. Study eyes received 4 monthly injections followed by pro re nata injections until a fluid-free macula was achieved on optical coherence tomography. Risk factors assessed included baseline demographics, treatment, and ocular characteristics on imaging. Eyes were evaluated on fundus autofluorescence (FAF) for GA. The rate of GA area growth in study and fellow eyes was analyzed by linear regression of square-root transformed areas. Development of new-onset GA and rate of GA area growth measured on ocular imaging, including FAF images of the study eyes. Sixty-nine participants (mean age 78.8±7.8 years) with an average of 40.0±13.6 months of follow-up were analyzed. Twenty-two of 69 study eyes (32%) were treatment naïve. During their first year of the study, participants received an average of 9.2±3.3 injections in the study eye. Of 63 study eyes with quality baseline images, 22 (35%) had pre-existing GA. Of the remaining 41 eyes, 7 (17%) developed new-onset GA during study follow-up. Those who developed new GA were older (all ≥79 years old) and had received fewer study injections on average (6.9 vs. 10.4 injections at 1 year) compared to those who did not develop new GA. Of the 12 treatment naïve study eyes without GA at baseline, 1 (8.3%) developed new GA during the study. In 21 study eyes with quantifiable GA area, eyes with GA present at baseline (16/21) enlarged by 0.34±0.26 mm/year, compared to 0.19±0.12 mm/year in eyes developing new-onset GA (5/21). While 17% of study eyes without GA present at baseline receiving ranibizumab developed new GA, the role of ranibizumab in the development

Childhood optic atrophy.

PubMed

Mudgil, A V; Repka, M X

2000-02-01

To determine the causes, and relative incidence of the common causes, of optic nerve atrophy in children under 10 years old and to compare prevalent aetiologies with those given in previous studies. The Wilmer Information System database was searched to identify all children, diagnosed between 1987 and 1997 with optic atrophy, who were under 10 years old at diagnosis. The medical records of these children were reviewed retrospectively A total of 272 children were identified, Complications from premature birth were the most frequent aetiology of optic atrophy (n = 44, 16%); 68% of these premature infants having a history of intraventricular haemorrhage. Tumour was the second most common aetiology (n = 40, 15%). The most frequent tumour was pilocytic astrocytoma (50%), followed by craniopharyngioma (17%). Hydrocephalus, unrelated to tumour, was the third most common aetiology (n = 26, 10%). In 114 cases (42%), the cause of optic atrophy became manifest in the perinatal period and/or could be attributed to adverse events in utero. A cause was not determined in 4% of cases. In the last decade, prematurity and hydrocephalus appear to have become important causes of optic atrophy in childhood. This trend is probably the result of improved survival of infants with extremely low birth weight.

Chronic shoulder pain referred from thymic carcinoma: a case report and review of literature

PubMed Central

Dee, Shu-Wei; Kao, Mu-Jung; Hong, Chang-Zern; Chou, Li-Wei; Lew, Henry L

2012-01-01

We report a case of thymic carcinoma presenting as unilateral shoulder pain for 13 months. Before an accurate diagnosis was made, the patient received conservative treatment, cervical discectomies, and myofascial trigger point injection, none of which relieved his pain. When thymic carcinoma was eventually diagnosed, he received total resection of the tumor and the shoulder pain subsided completely. Thymic carcinoma is a rare carcinoma, and our review of the literature did not show shoulder pain as its initial presentation except for one case report. The purpose of this report is to document our clinical experience so that other physiatrists can include thymic carcinoma in their differential diagnosis of shoulder pain. PMID:22969299

Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.

PubMed

Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M Shawkat; Nabeshima, Yo-ichi

2014-08-01

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.

Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

PubMed Central

Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M. Shawkat; Nabeshima, Yo-ichi

2014-01-01

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho-/- (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl-/- mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl-/- mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis. PMID:25080854

Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.

PubMed

Gensler, Gary; Clemons, Traci E; Domalpally, Amitha; Danis, Ronald P; Blodi, Barbara; Wells, Jack; Rauser, Michael; Hoskins, John; Hubbard, G Baker; Elman, Michael J; Fish, Gary E; Brucker, Alexander; Margherio, Alan; Chew, Emily Y

2018-05-01

To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA). Randomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers. Participants with GA. Participants eligible in one eye were randomly assigned to a monthly intravitreal injection of sirolimus (20 µL [440 µg]) or sham treatment while participants with two study eyes were assigned to a monthly intravitreal injection in a randomly-selected eye. Best-corrected visual acuities (BVCA), spectral domain optical coherence tomography (OCT), fundus color photography and fundus autofluorescence (FAF) images were obtained at baseline and every 6 months until visit month 24. Rate of progression of GA (mm 2 /year) measured on color fundus photograph from baseline to 24 months. Secondary outcome measures include change in BVCA, worsening of vision by ≥3 lines, and changes in area of GA measured on FAF and OCT. 52 participants (mean age 79 years) were enrolled with 27 study eyes assigned to sirolimus from May 2012 to March 2014. The baseline median area of GA was 4.73 DA (12.01 mm 2 ). The mean (standard deviation) growth rates of GA detected on color fundus photographs were 2.27 (2.17) mm 2 and 1.91 (2.27) mm 2 at month 12, and 4.94 (2.96) mm 2 and 5.72 (3.97) mm 2 at month 24, for the sirolimus and sham groups, respectively. There was no statistically significant difference in the GA growth rates between the two treatment groups (P=0.33). Median visual acuity changes and incidence of 15-letter loss from baseline were not different between the 2 treatment groups (p=0.19). The intervention was stopped early because of sterile endophthalmitis that occurred in 3 participants in the sirolimus group. Participants were followed for safety until the study was closed in May 2015 due to lack of efficacy

Development of a risk score for geographic atrophy in complications of the age-related macular degeneration prevention trial.

PubMed

Ying, Gui-Shuang; Maguire, Maureen G

2011-02-01

To develop a risk score for developing geographic atrophy (GA) involving easily obtainable information among patients with bilateral large drusen. Cohort study within a multicenter randomized clinical trial. We included 1052 participants with ≥ 10 large (>125 μm) drusen and visual acuity ≥ 20/40 in each eye. In the Complications of Age-related Macular Degeneration (AMD) Prevention Trial (CAPT), 1 eye of each participant was randomly assigned to laser treatment and the contralateral eye was assigned to observation to evaluate whether laser treatment of drusen could prevent vision loss. Gradings by a reading center were used to identify: CAPT end point GA (total area of GA [>250 μm] > 1 disc area), GA (>175 μm) involving the foveal center (CGA), and GA of any size and location (any GA). Established risk factors (age, smoking status, hypertension, Age-related Eye Disease Study simple severity scale score), both with and without a novel risk factor (night vision score), were used in assigning risk points. The risk scores were evaluated for the ability to discriminate and calibrate GA risk. Development of end point GA, CGA, and any GA. Among 942 CAPT participants who completed 5 years of follow-up and did not have any GA at baseline, 6.8% participants developed CAPT end point GA, 9.6% developed CGA, and 34.4% developed any GA. The 5-year incidence of end point GA in 1 or both eyes of a participant increased with the 15-point GA risk score, from 0.6% for <7 points to 15% for ≥ 12 points. The 5-factor risk score predicted development of GA moderately well with the area under the receiver operating characteristic curve (AUC) 0.76 (95% confidence interval [CI], 0.71-0.81) for end point GA; 0.76 (95% CI, 0.71-0.80) for CGA, and 0.68 (95% CI, 0.65-0.72) for any GA. Prediction from the risk score without the night vision score had lower AUCs (range, 0.67-0.72). If validated in other patients, the GA risk score will be useful for identifying high-risk patients for

Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy.

PubMed

Bartley, Jenna M; Pan, Sarah J; Keilich, Spencer R; Hopkins, Jacob W; Al-Naggar, Iman M; Kuchel, George A; Haynes, Laura

2016-04-01

Although the influenza virus only infects the respiratory system, myalgias are commonly experienced during infection. In addition to a greater risk of hospitalization and death, older adults are more likely to develop disability following influenza infection; however, this relationship is understudied. We hypothesized that upon challenge with influenza, aging would be associated with functional impairments, as well as upregulation of skeletal muscle inflammatory and atrophy genes. Infected young and aged mice demonstrated decreased mobility and altered gait kinetics. These declines were more prominent in hind limbs and in aged mice. Skeletal muscle expression of genes involved in inflammation, as well as muscle atrophy and proteolysis, increased during influenza infection with an elevated and prolonged peak in aged mice. Infection also decreased expression of positive regulators of muscle mass and myogenesis components to a greater degree in aged mice. Gene expression correlated to influenza-induced body mass loss, although evidence did not support direct muscle infection. Overall, influenza leads to mobility impairments with induction of inflammatory and muscle degradation genes and downregulation of positive regulators of muscle. These effects are augmented and prolonged with aging, providing a molecular link between influenza infection, decreased resilience and increased risk of disability in the elderly.

Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy

PubMed Central

Bartley, Jenna M.; Pan, Sarah J.; Keilich, Spencer R.; Hopkins, Jacob W.; Al-Naggar, Iman M.; Kuchel, George A.; Haynes, Laura

2016-01-01

Although the influenza virus only infects the respiratory system, myalgias are commonly experienced during infection. In addition to a greater risk of hospitalization and death, older adults are more likely to develop disability following influenza infection; however, this relationship is understudied. We hypothesized that upon challenge with influenza, aging would be associated with functional impairments, as well as upregulation of skeletal muscle inflammatory and atrophy genes. Infected young and aged mice demonstrated decreased mobility and altered gait kinetics. These declines were more prominent in hind limbs and in aged mice. Skeletal muscle expression of genes involved in inflammation, as well as muscle atrophy and proteolysis, increased during influenza infection with an elevated and prolonged peak in aged mice. Infection also decreased expression of positive regulators of muscle mass and myogenesis components to a greater degree in aged mice. Gene expression correlated to influenza-induced body mass loss, although evidence did not support direct muscle infection. Overall, influenza leads to mobility impairments with induction of inflammatory and muscle degradation genes and downregulation of positive regulators of muscle. These effects are augmented and prolonged with aging, providing a molecular link between influenza infection, decreased resilience and increased risk of disability in the elderly. PMID:26856410

Comparison of surgical approach and extent of resection for Masaoka-Koga Stage I and II thymic tumours in Europe, North America and Asia: an International Thymic Malignancy Interest Group retrospective database analysis.

PubMed

Fang, Wentao; Yao, Xiaopan; Antonicelli, Alberto; Gu, Zhitao; Detterbeck, Frank; Vallières, Eric; Aye, Ralph W; Farivar, Alexander S; Huang, James; Shang, Yue; Louie, Brian E

2017-07-01

Surgeons at different institutions worldwide choose different types of operations for thymic tumours. It is not known whether these differences affect the outcomes of the patients. A total of 1430 patients with Masaoka-Koga pathological Stage I-II thymic tumours without myasthenia gravis or pre-treatment were identified from the International Thymic Malignancy Interest Group retrospective database. Outcomes of patients from 3 major continents (Europe, North America and Asia) were compared. Patients from the 3 continents were comparable in gender and performance status. More European patients had more paraneoplastic syndromes; North American patients had the smallest tumour sizes and less adjuvant therapy; and Asian patients were younger and had more Stage I disease but higher grade tumours. Partial thymectomy was performed more often in Asian patients (31.7%) than in European (2.4%) and North American (5.4%; P  < 0.001) patients. The median approach (sternotomy/clamshell) was the major approach in Europe (75.3%) and North America (76.6%). In contrast, the median approach was applied significantly less frequently in Asia (45.6%, P  < 0.001); unilateral open (thoracotomy/hemi-clamshell, 23.3%) and minimally invasive approaches (video-assisted thoracoscopic surgery/robot, 31.1%) were used more often with similar rates of complete resection. The 10-year overall survival rate was 82% for Europe, 78% for North America and 90% for Asia ( P  = 0.005), respectively. The 10-year cumulative recurrence rates were similar among the geographic groups (European 0.08, North American 0.07, and Asian 0.06, P  = 0.61). Age was the only independent predictive factor for overall survival ( P  < 0.001, HR = 1.089, 95% CI 1.056-1.123) in multivariable analysis. Types B3 and thymic carcinoma ( P  = 0.003, HR = 3.932, 95% CI 1.615-9.576) were independent risk factors for increased recurrence. This study shows that the selection of the surgical approach and

Vaginal Atrophy

MedlinePlus

... an Endocrinologist Search Featured Resource Menopause Map™ View Vaginal Atrophy October 2017 Download PDFs English Editors Christine ... during this time, including vaginal dryness. What is vaginal atrophy? Vaginal atrophy (also referred to as vulvovaginal ...

Differential Disease Progression in Atrophic Age-Related Macular Degeneration and Late-Onset Stargardt Disease.

PubMed

Lindner, Moritz; Lambertus, Stanley; Mauschitz, Matthias M; Bax, Nathalie M; Kersten, Eveline; Lüning, Anna; Nadal, Jennifer; Schmitz-Valckenberg, Steffen; Schmid, Matthias; Holz, Frank G; Hoyng, Carel B; Fleckenstein, Monika

2017-02-01

To compare the disease course of retinal pigment epithelium (RPE) atrophy secondary to age-related macula degeneratio (AMD) and late-onset Stargardt disease (STGD1). Patients were examined longitudinally by fundus autofluorescence, near-infrared reflectance imaging, and best-corrected visual acuity (BCVA). Areas of RPE atrophy were quantified using semi-automated software, and the status of the fovea was evaluated based on autofluorescence and near-infrared reflectance images. Mixed-effects models were used to compare atrophy progression rates. BCVA loss and loss of foveal integrity were analyzed using Turnbull's estimator. A total of 151 patients (226 eyes) with RPE atrophy secondary to AMD and 38 patients (66 eyes) with RPE atrophy secondary to late-onset STGD1 were examined for a median time of 2.3 years (interquartile range, 2.7). Mean baseline age was 74.2 years (SD, 7.6) in AMD and 63.4 (SD, 9.9) in late-onset STGD1 (P = 1.1 × 10-7). Square root atrophy progression was significantly faster in AMD when compared with late-onset STGD1 (0.28 mm/year [SE, 0.01] vs. 0.23 [SE, 0.03]; P = 0.030). In late-onset STGD1, the median survival of the fovea was significantly longer when compared with eyes with AMD (8.60 vs. 3.35 years; P = 0.005) with a trend to a later BCVA loss of ≥3 lines (5.97 vs. 4.37 years; P = 0.382). These natural history data indicate differential disease progression in AMD versus late-onset STGD1. The results underline the relevance of refined phenotyping in elderly patients presenting with RPE atrophy in regard to prognosis and design of interventional trials.

Gray Matter Atrophy Is Primarily Related to Demyelination of Lesions in Multiple Sclerosis: A Diffusion Tensor Imaging MRI Study.

PubMed

Tóth, Eszter; Szabó, Nikoletta; Csete, Gergõ; Király, András; Faragó, Péter; Spisák, Tamás; Bencsik, Krisztina; Vécsei, László; Kincses, Zsigmond T

2017-01-01

Objective: Cortical pathology, periventricular demyelination, and lesion formation in multiple sclerosis (MS) are related (Hypothesis 1). Factors in the cerebrospinal fluid close to these compartments could possibly drive the parallel processes. Alternatively, the cortical atrophy could be caused by remote axonal transection (Hypothesis 2). Since MRI can differentiate between demyelination and axon loss, we used this imaging modality to investigate the correlation between the pattern of diffusion parameter changes in the periventricular- and deep white matter and the gray matter atrophy. Methods: High-resolution T1-weighted, FLAIR, and diffusion MRI images were acquired in 52 RRMS patients and 50 healthy, age-matched controls. We used EDSS to estimate the clinical disability. We used Tract Based Spatial Statistics to compare diffusion parameters (fractional anisotropy, mean, axial, and radial diffusivity) between groups. We evaluated global brain, white, and gray matter atrophy with SIENAX. Averaged, standard diffusion parameters were calculated in four compartment: periventricular lesioned and normal appearing white matter, non-periventricular lesioned and normal appearing white matter. PLS regression was used to identify which diffusion parameter and in which compartment best predicts the brain atrophy and clinical disability. Results: In our diffusion tensor imaging study compared to controls we found extensive alterations of fractional anisotropy, mean and radial diffusivity and smaller changes of axial diffusivity (maximal p > 0.0002) in patients that suggested demyelination in the lesioned and in the normal appearing white matter. We found significant reduction in total brain, total white, and gray matter (patients: 718.764 ± 14.968, 323.237 ± 7.246, 395.527 ± 8.050 cm 3 , controls: 791.772 ± 22.692, 355.350 ± 10.929, 436.422 ± 12.011 cm 3 ; mean ± SE), ( p < 0.015; p < 0.0001; p < 0.009; respectively) of patients compared to controls. The PLS analysis

A thymic neuroendocrine tumour in a young female: a rare cause of relapsing and remitting Cushing's syndrome.

PubMed

Trott, M J; Farah, G; Stokes, V J; Wang, L M; Grossman, A B

2016-01-01

We present a case of a young female patient with a rare cause of relapsing and remitting Cushing's syndrome due to ectopic ACTH secretion from a thymic neuroendocrine tumour. A 34-year-old female presented with a constellation of symptoms of Cushing's syndrome, including facial swelling, muscle weakness and cognitive impairment. We use the terms 'relapsing and remitting' in this case report, given the unpredictable time course of symptoms, which led to a delay of 2 years before the correct diagnosis of hypercortisolaemia. Diagnostic workup confirmed ectopic ACTH secretion, and a thymic mass was seen on mediastinal imaging. The patient subsequently underwent thymectomy with complete resolution of her symptoms. Several case series have documented the association of Cushing's syndrome with thymic neuroendocrine tumours (NETs), although to our knowledge there are a few published cases of patients with relapsing and remitting symptoms. This case is also notable for the absence of features of the MEN-1 syndrome, along with the female gender of our patient and her history of non-smoking. Ectopic corticotrophin (ACTH) secretion should always be considered in the diagnostic workup of young patients with Cushing's syndromeThere is a small but growing body of literature describing the correlation between ectopic ACTH secretion and thymic neuroendocrine tumours (NETs)The possibility of a MEN-1 syndrome should be considered in all patients with thymic NETs, and we note the observational association with male gender and cigarette smoking in this cohortAn exception to these associations is the finding of relatively high incidence of thymic NETs among female non-smoking MEN-1 patients in the Japanese compared with Western populationsThe relapsing and remitting course of our patient's symptoms is noteworthy, given the paucity of this finding among other published cases.

Subfoveal choroidal thickness predicts macular atrophy in age-related macular degeneration: results from the TREX-AMD trial.

PubMed

Fan, Wenying; Abdelfattah, Nizar Saleh; Uji, Akihito; Lei, Jianqin; Ip, Michael; Sadda, SriniVas R; Wykoff, Charles C

2018-03-01

Our purpose was to evaluate the relationship between subfoveal choroidal thickness (SCT) and development of macular atrophy (MA) in eyes with age-related macular degeneration (AMD). This was a prospective, multicenter study. Sixty participants (120 eyes) in the TREX-AMD trial (NCT01648292) with treatment-naïve neovascular AMD (NVAMD) in at least one eye were included. SCT was measured by certified reading center graders at baseline using spectral domain optical coherence tomography (SDOCT). The baseline SCT was correlated with the presence of MA at baseline and development of incident MA by month 18. Generalized estimating equations were used to account for information from both eyes. Baseline SCT in eyes with MA was statistically significantly less than in those without MA in both the dry AMD (DAMD) (P = 0.04) and NVAMD (P = 0.01) groups. Comparison of baseline SCT between MA developers and non-MA developers revealed a statistically significant difference (P = 0.03). Receiver operating characteristic curve (ROC) analysis showed the cut-off threshold of SCT for predicting the development of MA in cases without MA at baseline was 124 μm (AUC = 0.772; Sensitivity = 0.923; Specificity = 0.5). Among eyes without MA at baseline, those with baseline SCT ≤124 μm were 4.3 times more likely to develop MA (Odds ratio: 4.3, 95% confidence interval: 1.6-12, P = 0.005) than those with baseline SCT >124 μm. Eyes with AMD and MA had less SCT than those without MA. Eyes with less baseline SCT also appear to be at higher risk to develop MA within 18 months.

Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer's disease

PubMed Central

Lehmann, Manja; Koedam, Esther L.G.E.; Barnes, Josephine; Bartlett, Jonathan W.; Ryan, Natalie S.; Pijnenburg, Yolande A.L.; Barkhof, Frederik; Wattjes, Mike P.; Scheltens, Philip; Fox, Nick C.

2012-01-01

Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual rating scales are a convenient way of assessing atrophy in a clinical setting. In this study, 2 visual rating scales measuring MTA and PA were used to compare atrophy patterns in 62 pathologically-confirmed AD and 40 FTLD patients. Anatomical correspondence of MTA and PA was assessed using manually-delineated regions of the hippocampus and posterior cingulate gyrus, respectively. Both MTA and PA scales showed good inter- and intrarater reliabilities (kappa > 0.8). MTA scores showed a good correspondence with manual hippocampal volumes. Thirty percent of the AD patients showed PA in the absence of MTA. Adding the PA to the MTA scale improved discrimination of AD from FTLD, and early-onset AD from normal aging. These results underline the importance of considering PA in AD diagnosis, particularly in younger patients where medial temporal atrophy may be less conspicuous. PMID:21596458

Emixustat Hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Clinical Trial.

PubMed

Rosenfeld, Philip J; Dugel, Pravin U; Holz, Frank G; Heier, Jeffrey S; Pearlman, Joel A; Novack, Roger L; Csaky, Karl G; Koester, John M; Gregory, Jeffrey K; Kubota, Ryo

2018-04-28

To determine whether emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment. Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial. Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm 2 were enrolled. Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25. The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best-corrected visual acuity (NL-BCVA) was a secondary efficacy end point. Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm 2 /year; placebo: 1.69 mm 2 /year; P ≥ 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%). Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug's mechanism of action. Data gained from

Thymic hormone-containing cells. Characterization and localization of serum thymic factor in young mouse thymus studied by monoclonal antibodies

PubMed Central

1982-01-01

The characterization and distribution of cells containing the serum thymic factor (FTS) in the thymus of young mice was studied by immunofluorescence using monoclonal anti-FTS antibodies. FTS+ cells were distributed throughout the thymic parenchyma but were more frequent in the medullary region than in the cortex. FTS-containing cells presented a stellate or globular aspect, and some of them exhibited fluorescent cytoplasmic granules. The epithelial nature of FTS+ cells was confirmed by double-labeling experiments using an anti- keratin antiserum (as an epithelial cell marker). Nevertheless, only a minority of keratin-positive epithelial reticular cells contained FTS. All controls, including the incubation of sections from nonthymic tissues with the anti-FTS antibodies, were negative. Taken together, these results confirm the exclusive localization of FTS-containing cells within the mouse thymus. PMID:7047671

Macular Atrophy in Neovascular Age-Related Macular Degeneration with Monthly versus Treat-and-Extend Ranibizumab: Findings from the TREX-AMD Trial.

PubMed

Abdelfattah, Nizar S; Al-Sheikh, Mayss; Pitetta, Sean; Mousa, Ahmed; Sadda, SriniVas R; Wykoff, Charles C

2017-02-01

To compare the enlargement rate of macular atrophy (ERMA) in eyes treated with ranibizumab monthly or using a treat-and-extend (TREX) regimen for neovascular age-related macular degeneration (AMD) or fellow control eyes, as well as analyze risk factors for macular atrophy (MA) development and progression. Eighteen-month, multicenter, randomized, controlled clinical trial. Sixty patients with treatment-naïve neovascular AMD in 1 eye randomized 1:2 to monthly or TREX ranibizumab. Patients' study and fellow eyes were followed for 18 months using spectral-domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF) imaging. The MA was quantified on FAF images using Heidelberg Region Finder software (Heidelberg Engineering, Heidelberg, Germany), with suspected areas of atrophy confirmed by SD OCT and infrared reflectance imaging. For eyes without baseline MA yet developed MA by 18 months, intervening visits were assessed to determine the first visit at which MA appeared to define progression rates. Foveal choroidal thickness (FCT), subretinal hyperreflective material (SHRM), and pigment epithelial detachment (PED), were assessed at baseline to determine whether they influenced MA progression. Mean ERMA at 18 months. Relationship between visual acuity and MA, and the baseline risk factors for ERMA were also assessed. The final analysis cohort included 88 eyes in 3 groups: monthly (n = 19), TREX (n = 30), and control fellow eyes (n = 39). Mean ERMA over 18 months was 0.39±0.67 (monthly), 1.1±1.9 (TREX), and 0.49±1 mm 2 (control, P = 0.12). Mean ERMA per group among the 40.9% (n = 36) of baseline patients with MA was 0.9±1, 1.9±2.2, and 1±1.3 mm 2 , respectively (P = 0.31). The incidence rate of MA in the 3 groups was 40%, 0%, and 8.3%, respectively. Mann-Whitney U test revealed a statistically significant association between baseline FCT (127±46 vs. 155±55 μm, P = 0.01) and SHRM thickness (106±131 vs. 50±85 μm, P = 0.02) on MA. In

Reversing Age Related Changes of the Laryngeal Muscles by Chronic Electrostimulation of the Recurrent Laryngeal Nerve

PubMed Central

Karbiener, Michael; Jarvis, Jonathan C.; Perkins, Justin D.; Lanmüller, Hermann; Schmoll, Martin; Rode, Hanna S.; Gerstenberger, Claus; Gugatschka, Markus

2016-01-01

Age related atrophy of the laryngeal muscles -mainly the thyroarytenoid muscle (TAM)- leads to a glottal gap and consequently to a hoarse and dysphonic voice that significantly affects quality of life. The aim of our study was to reverse this atrophy by inducing muscular hypertrophy by unilateral functional electrical stimulation (FES) of the recurrent laryngeal nerve (RLN) in a large animal model using aged sheep (n = 5). Suitable stimulation parameters were determined by fatiguing experiments of the thyroarytenoid muscle in an acute trial. For the chronic trial an electrode was placed around the right RLN and stimulation was delivered once daily for 29 days. We chose a very conservative stimulation pattern, total stimulation time was two minutes per day, or 0.14% of total time. Overall, the mean muscle fiber diameter of the stimulated right TAM was significantly larger than the non-stimulated left TAM (30μm±1.1μm vs. 28μm±1.1 μm, p<0.001). There was no significant shift in fiber type distribution as judged by immunohistochemistry. The changes of fiber diameter could not be observed in the posterior cricoarytenoid muscle (PCAM). FES is a possible new treatment option for reversing the effects of age related laryngeal muscle atrophy. PMID:27893858

Reversing Age Related Changes of the Laryngeal Muscles by Chronic Electrostimulation of the Recurrent Laryngeal Nerve.

PubMed

Karbiener, Michael; Jarvis, Jonathan C; Perkins, Justin D; Lanmüller, Hermann; Schmoll, Martin; Rode, Hanna S; Gerstenberger, Claus; Gugatschka, Markus

2016-01-01

Age related atrophy of the laryngeal muscles -mainly the thyroarytenoid muscle (TAM)- leads to a glottal gap and consequently to a hoarse and dysphonic voice that significantly affects quality of life. The aim of our study was to reverse this atrophy by inducing muscular hypertrophy by unilateral functional electrical stimulation (FES) of the recurrent laryngeal nerve (RLN) in a large animal model using aged sheep (n = 5). Suitable stimulation parameters were determined by fatiguing experiments of the thyroarytenoid muscle in an acute trial. For the chronic trial an electrode was placed around the right RLN and stimulation was delivered once daily for 29 days. We chose a very conservative stimulation pattern, total stimulation time was two minutes per day, or 0.14% of total time. Overall, the mean muscle fiber diameter of the stimulated right TAM was significantly larger than the non-stimulated left TAM (30μm±1.1μm vs. 28μm±1.1 μm, p<0.001). There was no significant shift in fiber type distribution as judged by immunohistochemistry. The changes of fiber diameter could not be observed in the posterior cricoarytenoid muscle (PCAM). FES is a possible new treatment option for reversing the effects of age related laryngeal muscle atrophy.

Prefrontal involvement related to cognitive impairment in progressive muscular atrophy.

PubMed

Raaphorst, Joost; van Tol, Marie-José; Groot, Paul F C; Altena, Ellemarije; van der Werf, Ysbrand D; Majoie, Charles B; van der Kooi, Anneke J; van den Berg, Leonard H; Schmand, Ben; de Visser, Marianne; Veltman, Dick J

2014-08-26

To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p<0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALSrelated to an important clinical measure of executive dysfunction in patients with motor neuron disease with and without upper motor neuron signs. © 2014 American Academy of Neurology.

Tensiomygraphic Measurement of Atrophy Related Processes During Bed Rest and Recovery

NASA Astrophysics Data System (ADS)

Simunic, B. ostjan; Degens, Hans; Rittweger, Jorn; Narici, Marcco; Pisot, Venceslav; Mekjavic, Igor B.; Pisot, Rado

2013-02-01

Tensiomyographic (TMG) parameters were recently proposed for a non-invasive estimation of MHC distribution in human vastus lateralis muscle. However, TMG potential is even higher, offers additional insight into the skeletal muscle physiology, especially in the field of atrophy and hypertrophy. The purpose of this study is in developing time dynamics of TMG-measured contraction time (Tc) and maximal response amplitude (Dm), together with muscle belly thickness, measure thoroughly during 35-day bed rest and followed in 30-day recovery (N = 10 males; age 24.3 ± 2.6 years). Measurements were performed in two postural muscles (vastus medialis and lateralis) and one non-postural muscle (biceps femoris). During bed rest period we found different dynamics of muscle thickness decrease and Dm increase. Tc was unchanged in postural muscles, but in non-postural muscle increased significantly and stayed as such even at the end of recovery. We could conclude that TMG related parameters are more sensitive in measuring muscle atrophic and hypertrophic processes than biomedical imaging technique. However, a mechanism that regulates Dm still needs to be identified.

Palladium and Platinum Nanoparticles Attenuate Aging-Like Skin Atrophy via Antioxidant Activity in Mice

PubMed Central

Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

2014-01-01

Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1 −/− mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1 −/− mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage. PMID:25333617

Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice.

PubMed

Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

2014-01-01

Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage.

Cytomorphology and sonographic features of ectopic thymic tissue diagnosed in paediatric FNA biopsies.

PubMed

Escobar, F A; Pantanowitz, L; Picarsic, J L; Craig, F E; Simons, J P; Viswanathan, P A; Yilmaz, S; Monaco, S E

2018-03-26

Ectopic thymic tissue can arise as an asymptomatic neck mass, which may be detected on imaging studies. The aim of this study was to determine the incidence of ectopic thymic tissue in paediatric FNAs and to the correlate clinical, radiological and cytomorphological findings. FNAs in children with neck and mediastinal lesions performed between January 2012 and July 2016 were reviewed for cases of ectopic thymus. These were then evaluated and correlated with the cytology findings. Of 739 FNAs, 13 (1.8%) cases from 11 patients showed ectopic thymic tissue. The targeted lesions were in the thyroid (n = 7), submandibular region (n = 1), superior mediastinum (n = 1) and paratracheal region (n = 1). The most common indication was for microcalcifications concerning for papillary thyroid carcinoma on ultrasound (n = 6). Imaging findings included fusiform lesions with linear and punctuate bright echoes. The cytology evaluation showed small lymphocytes with discohesive epithelioid cells in most cases, and proteinaceous fluid in the cystic case. There were rare macrophages and Hassall's corpuscles. Flow cytometry and/or immunostains were performed in all cases, supporting thymic origin. Ectopic thymic tissue is rarely present as a neck mass or thyroid nodule on FNA biopsy. The ultrasound imaging findings reveal a well-defined fusiform lesion with punctate bright echoes that could be misinterpreted as papillary thyroid carcinoma. The aspirates show a small lymphoid population, immunophenotypically compatible with thymic T-cells, in addition to scattered epithelial cells. Therefore, knowledge of the typical ultrasonographic and cytopathological features can help make a definitive diagnosis and avoid more invasive procedures in paediatric patients. © 2018 John Wiley & Sons Ltd.

Frequent silencing of RASSF1A by DNA methylation in thymic neuroendocrine tumours.

PubMed

Kajiura, Koichiro; Takizawa, Hiromitsu; Morimoto, Yuki; Masuda, Kiyoshi; Tsuboi, Mitsuhiro; Kishibuchi, Reina; Wusiman, Nuliamina; Sawada, Toru; Kawakita, Naoya; Toba, Hiroaki; Yoshida, Mitsuteru; Kawakami, Yukikiyo; Naruto, Takuya; Imoto, Issei; Tangoku, Akira; Kondo, Kazuya

2017-09-01

Aberrant methylation of promoter CpG islands (CGIs) of tumour suppressor genes is a common epigenetic mechanism underlying cancer pathogenesis. The methylation patterns of thymic tumours have not been studied in detail since such tumours are rare. Herein, we sought to identify genes that could serve as epigenetic targets for thymic neuroendocrine tumour (NET) therapy. Genome-wide screening for aberrantly methylated CGIs was performed in three NET samples, seven thymic carcinoma (TC) samples, and eight type-B3 thymoma samples. The methylation status of thymic epithelial tumours (TETs) samples was validated by pyrosequencing in a larger cohort. The expression status was analysed by quantitative polymerase chain reaction (PCR) and immunohistochemistry. We identified a CGI on a novel gene, RASSF1A, which was strongly hypermethylated in NET, but not in thymic carcinoma or B3 thymoma. RASSF1A was identified as a candidate gene statistically and bibliographically, as it showed frequent CGI hypermethylation in NET by genome-wide screening. Pyrosequencing confirmed significant hypermethylation of a RASSF1A CGI in NET. Low-grade NET tissue was more strongly methylated than high-grade NET. Quantitative PCR and immunohistochemical staining revealed that RASSF1A mRNA and protein expression levels were negatively regulated by DNA methylation. RASSF1A is a tumour suppressor gene epigenetically dysregulated in NET. Aberrant methylation of RASSF1A has been reported in various tumours, but this is the first report of RASSF1A hypermethylation in TETs. RASSF1A may represent an epigenetic therapeutic target in thymic NET. Copyright © 2017 Elsevier B.V. All rights reserved.

Dietary modulation of thymic enzymes.

PubMed

Susana, Feliu María; Paula, Perris; Slobodianik, Nora

2014-01-01

Malnutrition is a complex syndrome caused by an inadequate intake of energy, protein, minerals and vitamins which affects the immune system. Nutritional imbalances, present in children with energy-protein malnutrition and infections, make defining the specific effects of each of them on the thymus difficult. For this reason, it is necessary to design an experimental model in animals that could define a single variable. As the thymus atrophy described in humans is similar to that observed in murines, a rat experimental model makes the extrapolation to man possible. Some authors suggest that the activity of Adenosine Deaminase (ADA) and Purine Nucleoside Phosphorylase (PNP)--involved in purine metabolism--have an influence on T lymphocyte development and the immune system, due to intracellular accumulation of toxic levels of deoxynucleotides. Studies in our group, performed in an experimental model on Wistar growing rats, have demonstrated that protein deficiency or imbalance in the profile of essential amino acids in the diet, produce loss of thymus weight, reduction in the number of thymocytes, a diminished proportion of T cells presenting the W3/13 antigenic determinant and DNA content with concomitant increase in cell size, and the proportion of immature T cells and activity of ADA and PNP, without modifying the activity of 5´Nucleotidase in the thymus. It is important to point out that there were neither differences in energy intake between experimental groups and their controls, nor clinical symptoms of deficiency of other nutrients. The increase in these thymic enzyme activities was an alternative mechanism to avoid the accumulation of high levels of deoxynucleotides, which would be toxic for T lymphocytes. On the other hand, the administration of a recovery diet, with a high amount of high quality protein, was able to reverse the mentioned effects. The quick reply of Adenosine Deaminase to nutritional disorders and the following nutritional recovery, points

Evaluation of the proposed International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) staging revisions in thymic well-differentiated neuroendocrine carcinoma patients.

PubMed

Zhao, Yang; Shi, Jianxin; Fan, Limin; Yang, Jun; Hu, Dingzhong; Zhao, Heng

2016-02-01

In 2014, the International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) launched a worldwide Tumor Node Metastasis (TNM) staging proposal for the next edition of thymic tumours. The objective of the current study was to evaluate the proposed new staging system specific to the thymic well-differentiated neuroendocrine carcinoma (TWDNC). From November 2003 to July 2014, 61 consecutive patients were enrolled in this study with pathologically confirmed TWDNC in Shanghai Chest Hospital. Clinical and pathological data were retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier and log-rank tests. Validity evaluation was addressed by Cox proportional hazards regression model, after adjusting for potential confounders and visually assessing the distinction of curves generated based on the staging system of Masaoka-Koga and the proposed TNM ones. Thymic carcinoids made up 4% of total thymic tumours in our institution. The 5-year overall survival (OS) rate and the disease-free survival (DFS) rate were 72 and 41%, respectively. Neither Masaoka-Koga staging system nor the proposed TNM system showed ordered appropriateness visually in survival curves and the prognostic demarcation between stages was poor on both OS and DFS. The IASLC/ITMIG suggested that the TNM and Masaoka-Koga staging systems fail to predict the clinical course of TWDNC patients. Collaborative effort is needed in the future staging validation as ITMIG recommended. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Emerging strategies to boost thymic function

PubMed Central

Holländer, Georg A.; Krenger, Werner; Blazar, Bruce R.

2011-01-01

The thymus constitutes the primary lymphoid organ for the generation of T cells. Its function is particularly susceptible to various negative influences ranging from age-related involution to atrophy as a consequence of malnutrition, infection or harmful iatrogenic influences such as chemotherapy and radiation. The loss of regular thymus function significantly increases the risk for infections and cancer because of a restricted capacity for immune surveillance. In recent years, thymus-stimulatory, -regenerative and -protective strategies have been developed to enhance and repair thymus function in the elderly and in individuals undergoing hematopoietic stem cell transplantation. These strategies include the use of sex steroid ablation, the administration of growth and differentiation factors, the inhibition of p53, and the transfer of T cell progenitors to alleviate the effects of thymus dysfunction and consequent T cell deficiency. PMID:20447867

Orphan disease: Cherubism, optic atrophy, and short stature.

PubMed

Jeevanandham, Balaji; Ramachandran, Rajoo; Dhanapal, Vignesh; Subramanian, Ilanchezhian; Sai, Venkata

2018-01-01

A 12-year-old female presented with complaints of progressive visual impairment in both her eyes. On clinical examination, she was short for her age and her ophthalmoscopic examination revealed bilateral optic atrophy. Computed tomography of the patient revealed multiple expansile lytic lesions of mandible suggesting cherubism. The optic atrophy was confirmed on magnetic resonance imaging, which additionally revealed bilateral retrocerebellar arachnoid cysts. This association of cherubism with optic atrophy and short stature was grouped as orphan disease by National Institutes of Health and only one case was reported in the literature so far.

Genetic Regulation of Development of Thymic Lymphomas Induced by N‐Propyl‐N‐nitrosourea in the Rat

PubMed Central

Fukami, Hiroko; Nishimura, Mayumi; Matsuyama, Mutsushi

1995-01-01

To clarify the linkage between Hbb and Tls‐1 (thymic lymphoma susceptible‐1) loci and to investigate other loci concerned in thymic lymphomagenesis, the BUF/Mna rat, which is highly sensitive to the lymphomagenic activity of N‐propyl‐N‐nitrosourea (PNU), the WKY/NCrj rat, reported to be resistant, and their cross offspring were subjected to genetic analysis. F1 hybrid and backcross generations were raised from the 2 strains, and 6 genetic markers including Hbb were analyzed in individuals of the backcross generation. However, no linkage between Hbb and Tls‐1 loci could be demonstrated since WKY rats also developed a high incidence of thymic lymphomas in response to PNU. Nevertheless, thymic lymphomas developed more rapidly and reached a larger size in the BUF rats. F1 rats expressed a rather rapid and large tumor growth phenotype, while the [(WKY × BUF) × WKY] backcross generation consisted of rats with either rapidly growing or slowly growing tumors. It was thus concluded that rapid development of thymic lymphomas is determined by a gene, provisionally designated Tls‐3. Analysis of the relationship between 6 genetic markers and development of thymic lymphoma in the backcross generation demonstrated that the Tls‐3 locus is loosely linked to the Gc locus, suggesting a possible location on rat chromosome 14. Tls‐3 may not be identical with Tls‐1 and other genes known to be relevant to thymic tumors, but its relationship with Tls‐2 remains obscure. PMID:7559080

IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity.

PubMed

Silva, Susana L; Albuquerque, Adriana S; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T; Victorino, Rui M M; Sousa, Ana E

2017-01-01

Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31 - subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31 + naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6 , a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31 - naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31 + naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.

Increased cFLIP expression in thymic epithelial tumors blocks autophagy via NF-κB signalling

PubMed Central

Belharazem, Djeda; Grass, Albert; Paul, Cornelia; Vitacolonna, Mario; Schalke, Berthold; Rieker, Ralf J.; Körner, Daniel; Jungebluth, Philipp; Simon-Keller, Katja; Hohenberger, Peter; Roessner, Eric M.; Wiebe, Karsten; Gräter, Thomas; Kyriss, Thomas; Ott, German; Geserick, Peter; Ströbel, Philipp; Marx, Alexander

2017-01-01

The anti-apoptotic cellular FLICE-like inhibitory protein cFLIP plays a pivotal role in normal tissues homoeostasis and the development of many tumors, but its role in normal thymus (NT), thymomas and thymic carcinomas (TC) is largely unknown. Expression, regulation and function of cFLIP were analyzed in biopsies of NT, thymomas, thymic squamous cell carcinomas (TSCC), thymic epithelial cells (TECs) derived thereof and in the TC line 1889c by qRT-PCR, western blot, shRNA techniques, and functional assays addressing survival, senescence and autophagy. More than 90% of thymomas and TSCCs showed increased cFLIP expression compared to NT. cFLIP expression declined with age in NTs but not in thymomas. During short term culture cFLIP expression levels declined significantly slower in neoplastic than non-neoplastic primary TECs. Down-regulation of cFLIP by shRNA or NF-κB inhibition accelerated senescence and induced autophagy and cell death in neoplastic TECs. The results suggest a role of cFLIP in the involution of normal thymus and the development of thymomas and TSCC. Since increased expression of cFLIP is a known tumor escape mechanism, it may serve as tissue-based biomarker in future clinical trials, including immune checkpoint inhibitor trials in the commonly PD-L1high thymomas and TCs. PMID:29163772

Increased cFLIP expression in thymic epithelial tumors blocks autophagy via NF-κB signalling.

PubMed

Belharazem, Djeda; Grass, Albert; Paul, Cornelia; Vitacolonna, Mario; Schalke, Berthold; Rieker, Ralf J; Körner, Daniel; Jungebluth, Philipp; Simon-Keller, Katja; Hohenberger, Peter; Roessner, Eric M; Wiebe, Karsten; Gräter, Thomas; Kyriss, Thomas; Ott, German; Geserick, Peter; Leverkus, Martin; Ströbel, Philipp; Marx, Alexander

2017-10-27

The anti-apoptotic cellular FLICE-like inhibitory protein cFLIP plays a pivotal role in normal tissues homoeostasis and the development of many tumors, but its role in normal thymus (NT), thymomas and thymic carcinomas (TC) is largely unknown. Expression, regulation and function of cFLIP were analyzed in biopsies of NT, thymomas, thymic squamous cell carcinomas (TSCC), thymic epithelial cells (TECs) derived thereof and in the TC line 1889c by qRT-PCR, western blot, shRNA techniques, and functional assays addressing survival, senescence and autophagy. More than 90% of thymomas and TSCCs showed increased cFLIP expression compared to NT. cFLIP expression declined with age in NTs but not in thymomas. During short term culture cFLIP expression levels declined significantly slower in neoplastic than non-neoplastic primary TECs. Down-regulation of cFLIP by shRNA or NF-κB inhibition accelerated senescence and induced autophagy and cell death in neoplastic TECs. The results suggest a role of cFLIP in the involution of normal thymus and the development of thymomas and TSCC. Since increased expression of cFLIP is a known tumor escape mechanism, it may serve as tissue-based biomarker in future clinical trials, including immune checkpoint inhibitor trials in the commonly PD-L1 high thymomas and TCs.

Association between thymic function and allogeneic hematopoietic stem cell transplantation outcome: results of a pediatric study.

PubMed

Saglio, Francesco; Cena, Silvia; Berger, Massimo; Quarello, Paola; Boccasavia, Viola; Ferrando, Federica; Pittana, Laura; Bruno, Benedetto; Fagioli, Franca

2015-06-01

Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Age effects on rat hindlimb muscle atrophy during suspension unloading

NASA Technical Reports Server (NTRS)

Steffen, Joseph M.; Fell, Ronald D.; Geoghegan, Thomas E.; Ringel, Lisa C.; Musacchia, X. J.

1990-01-01

The effects of hindlimb unloading on muscle mass and biochemical responses were examined and compared in adult (450-g) and juvenile (200-g) rats after 1, 7, or 14 days of whole-body suspension. Quantitatively and qualitatively the soleus, gastrocnemius, plantaris, and extensor digitorum longus (EDL) muscles of the hindlimb exhibited a differential sensitivity to suspension and weightlessness unloading in both adults and juveniles. The red slow-twitch soleus exhibited the most pronounced atrophy under both conditions, with juvenile responses being greater than adult. In contrast, the fast-twitch EDL hypertrophied during suspension and atrophied during weightlessness, with no significant difference between adults and juveniles. Determination of biochemical parameters (total protein, RNA, and DNA) indicates a less rapid rate of response in adult muscles.

Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge.

PubMed

Cash, David M; Frost, Chris; Iheme, Leonardo O; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B; Pennec, Xavier; Pierson, Ronald K; Gunter, Jeffrey L; Senjem, Matthew L; Jack, Clifford R; Guizard, Nicolas; Fonov, Vladimir S; Collins, D Louis; Modat, Marc; Cardoso, M Jorge; Leung, Kelvin K; Wang, Hongzhi; Das, Sandhitsu R; Yushkevich, Paul A; Malone, Ian B; Fox, Nick C; Schott, Jonathan M; Ourselin, Sebastien

2015-12-01

distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: -1.4% to -2.2% (AD) and -0.35% to -0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: -1.5% to -7.0% (AD) and -0.4% to -1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods. Copyright © 2015. Published by Elsevier Inc.

The Wnt signaling antagonist Kremen1 is required for development of thymic architecture.

PubMed

Osada, Masako; Ito, Emi; Fermin, Hector A; Vazquez-Cintron, Edwin; Venkatesh, Tadmiri; Friedel, Roland H; Pezzano, Mark

2006-01-01

Wnt signaling has been reported to regulate thymocyte proliferation and selection at several stages during T cell ontogeny, as well as the expression of FoxN1 in thymic epithelial cells (TECs). Kremen1 (Krm1) is a negative regulator of the canonical Wnt signaling pathway, and functions together with the secreted Wnt inhibitor Dickkopf (Dkk) by competing for the lipoprotein receptor-related protein (LRP)-6 co-receptor for Wnts. Here krm1 knockout mice were used to examine krm1 expression in the thymus and its function in thymocyte and TEC development. Krm1 expression was detected in both cortical and medullary TEC subsets, as well as in immature thymocyte subsets, beginning at the CD25+CD44+ (DN2) stage and continuing until the CD4+CD8+(DP) stage. Neonatal mice show elevated expression of krm1 in all TEC subsets. krm1(-/-) mice exhibit a severe defect in thymic cortical architecture, including large epithelial free regions. Much of the epithelial component remains at an immature Keratin 5+ (K5) Keratin 8(+)(K8) stage, with a loss of defined cortical and medullary regions. A TOPFlash assay revealed a 2-fold increase in canonical Wnt signaling in TEC lines derived from krm1(-/-) mice, when compared with krm1(+/+) derived TEC lines. Fluorescence activated cell sorting (FACS) analysis of dissociated thymus revealed a reduced frequency of both cortical (BP1(+)EpCAM(+)) and medullary (UEA-1(+) EpCAM(hi)) epithelial subsets, within the krm1(-/-) thymus. Surprisingly, no change in thymus size, total thymocyte number or the frequency of thymocyte subsets was detected in krm1(-/-) mice. However, our data suggest that a loss of Krm1 leads to a severe defect in thymic architecture. Taken together, this study revealed a new role for Krm1 in proper development of thymic epithelium.

Preventive effects of Chlorella on skeletal muscle atrophy in muscle-specific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice.

PubMed

Nakashima, Yuya; Ohsawa, Ikuroh; Nishimaki, Kiyomi; Kumamoto, Shoichiro; Maruyama, Isao; Suzuki, Yoshihiko; Ohta, Shigeo

2014-10-11

Oxidative stress is involved in age-related muscle atrophy, such as sarcopenia. Since Chlorella, a unicellular green alga, contains various antioxidant substances, we used a mouse model of enhanced oxidative stress to investigate whether Chlorella could prevent muscle atrophy. Aldehyde dehydrogenase 2 (ALDH2) is an anti-oxidative enzyme that detoxifies reactive aldehydes derived from lipid peroxides such as 4-hydroxy-2-nonenal (4-HNE). We therefore used transgenic mice expressing a dominant-negative form of ALDH2 (ALDH2*2 Tg mice) to selectively decrease ALDH2 activity in the muscles. To evaluate the effect of Chlorella, the mice were fed a Chlorella-supplemented diet (CSD) for 6 months. ALDH2*2 Tg mice exhibited small body size, muscle atrophy, decreased fat content, osteopenia, and kyphosis, accompanied by increased muscular 4-HNE levels. The CSD helped in recovery of body weight, enhanced oxidative stress, and increased levels of a muscle impairment marker, creatine phosphokinase (CPK) induced by ALDH2*2. Furthermore, histological and histochemical analyses revealed that the consumption of the CSD improved skeletal muscle atrophy and the activity of the mitochondrial cytochrome c oxidase. This study suggests that long-term consumption of Chlorella has the potential to prevent age-related muscle atrophy.

Risk Factors Associated with Age-Related Macular Degeneration

PubMed Central

2006-01-01

Objective: To investigate possible risk factors for age-related macular degeneration (AMD) in participants in the Age-Related Eye Disease Study (AREDS). Design: Case-control study. Participants: Of the 4757 persons enrolled in AREDS, 4519 persons aged 60 to 80 years were included in this study. The lesions associated with AMD ranged from absent in both eyes to advanced in one eye. Main Outcome Measures: Stereoscopic color fundus photographs of the macula were used to place participants into one of five groups, based on the frequency and severity of lesions associated with AMD. Participants with fewer than 15 small drusen served as the control group. Results: Staged model building techniques were used to compare each of the four case groups with the control group. Increased age was a consistent finding of all four of the case groups compared with the control group, and all the following associations were age adjusted. Persons with either intermediate drusen, extensive small drusen, or the pigment abnormalities associated with AMD (group 2) were more likely to be female, more likely to have a history of arthritis, and less likely to have a history of angina. Persons with one or more large drusen or extensive intermediate drusen (group 3) were more likely to use hydrochlorothiazide diuretics and more likely to have arthritis. Hypertension, hyperopia, presence of lens opacities, and white race were also found more frequently in this group as well as in persons with neovascular AMD (group 5). Only persons in group 5 were more likely to have an increased body mass index, whereas persons with geographic atrophy (group 4) as well as those in groups 3 and 5 were more likely to have completed fewer years in school or to be smokers. Those with geographic atrophy were also more likely to use thyroid hormones and antacids. Conclusions: Our findings for smoking and hypertension, which have been noted in previous studies, suggest that two important public health recommendations

Is There a Relationship Between Use of Anti-Vascular Endothelial Growth Factor Agents and Atrophic Changes in Age-Related Macular Degeneration Patients?

PubMed

Kaynak, Süleyman; Kaya, Mahmut; Kaya, Derya

2018-04-01

Choroidal neovascularization due to age-related macular degeneration (AMD) is currently treated successfully with anti-vascular endothelial growth factor (VEGF) intravitreal agents. Emerging evidence suggests that anti-VEGF treatment may potentially increase development of geographic atrophy. However, there is not yet direct proof of a causal relationship between geographic atrophy and use of anti-VEGF agents in neovaskuler AMD. The aim of this review is to discuss the evidence concerning the association between anti-VEGF therapy and progression of geographic atrophy.

Traffic-related air pollution impact on mouse brain accelerates myelin and neuritic aging changes with specificity for CA1 neurons

PubMed Central

Woodward, NC; Pakbin, P; Saffari, A; Shirmohammadi, F; Haghani, A; Sioutas, C; Cacciottolo, M; Morgan, TE; Finch, CE

2017-01-01

Traffic-related air pollution (TRAP) is associated with lower cognition and reduced white matter volume in older adults, specifically for particulate matter <2.5 μm diameter (PM2.5). Rodents exposed to TRAP have shown microglial activation and neuronal atrophy. We further investigated age differences of TRAP exposure, with focus on hippocampus for neuritic atrophy, white matter degeneration, and microglial activation. Young and middle-aged mice (3 and 18 month female C57BL/6J) were exposed to nanoscale-PM (nPM, <0.2 μm diameter). Young mice showed selective changes in the hippocampal CA1 region, with neurite atrophy (−25%), decreased MBP (−50%), and increased Iba1 (+50%), with dentate gyrus relatively unaffected. Exposure to nPM of young mice decreased GluA1 protein (−40%) and increased TNFa mRNA (10×). Older controls had age changes approximating nPM effects on young, with no response to nPM, suggesting an age ceiling effect. The CA1 selective vulnerability in young mice parallels CA1 vulnerability in Alzheimer’s disease. We propose that TRAP associated human cognitive and white matter changes involve hippocampal responses to nPM that begin at younger ages. PMID:28212893

Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults.

PubMed

Sexton, Claire E; Storsve, Andreas B; Walhovd, Kristine B; Johansen-Berg, Heidi; Fjell, Anders M

2014-09-09

To examine the relationship between sleep quality and cortical and hippocampal volume and atrophy within a community-based sample, explore the influence of age on results, and assess the possible confounding effects of physical activity levels, body mass index (BMI), and blood pressure. In 147 community-dwelling adults (92 female; age 53.9 ± 15.5 years), sleep quality was measured using the Pittsburgh Sleep Quality Index and correlated with cross-sectional measures of volume and longitudinal measures of atrophy derived from MRI scans separated by an average of 3.5 years. Exploratory post hoc analysis compared correlations between different age groups and included physical activity, BMI, and blood pressure as additional covariates. Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Results were largely driven by correlations within adults over the age of 60, and could not be explained by variation in physical activity, BMI, or blood pressure. Sleep quality was not associated with hippocampal volume or atrophy. We found that longitudinal measures of cortical atrophy were widely correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy, and future studies examining the effect of interventions that improve sleep quality on rates of atrophy may hold key insights into the direction of this relationship. © 2014 American Academy of Neurology.

Aging Is Not a Disease: Distinguishing Age-Related Macular Degeneration from Aging

PubMed Central

Ardeljan, Daniel; Chan, Chi-Chao

2013-01-01

Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD. PMID:23933169

Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences.

PubMed

Price, D; Tyler, L K; Neto Henriques, R; Campbell, K L; Williams, N; Treder, M S; Taylor, J R; Henson, R N A

2017-06-09

Slowing is a common feature of ageing, yet a direct relationship between neural slowing and brain atrophy is yet to be established in healthy humans. We combine magnetoencephalographic (MEG) measures of neural processing speed with magnetic resonance imaging (MRI) measures of white and grey matter in a large population-derived cohort to investigate the relationship between age-related structural differences and visual evoked field (VEF) and auditory evoked field (AEF) delay across two different tasks. Here we use a novel technique to show that VEFs exhibit a constant delay, whereas AEFs exhibit delay that accumulates over time. White-matter (WM) microstructure in the optic radiation partially mediates visual delay, suggesting increased transmission time, whereas grey matter (GM) in auditory cortex partially mediates auditory delay, suggesting less efficient local processing. Our results demonstrate that age has dissociable effects on neural processing speed, and that these effects relate to different types of brain atrophy.

Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences

PubMed Central

Price, D.; Tyler, L. K.; Neto Henriques, R.; Campbell, K. L.; Williams, N.; Treder, M.S.; Taylor, J. R.; Brayne, Carol; Bullmore, Edward T.; Calder, Andrew C.; Cusack, Rhodri; Dalgleish, Tim; Duncan, John; Matthews, Fiona E.; Marslen-Wilson, William D.; Rowe, James B.; Shafto, Meredith A.; Cheung, Teresa; Davis, Simon; Geerligs, Linda; Kievit, Rogier; McCarrey, Anna; Mustafa, Abdur; Samu, David; Tsvetanov, Kamen A.; van Belle, Janna; Bates, Lauren; Emery, Tina; Erzinglioglu, Sharon; Gadie, Andrew; Gerbase, Sofia; Georgieva, Stanimira; Hanley, Claire; Parkin, Beth; Troy, David; Auer, Tibor; Correia, Marta; Gao, Lu; Green, Emma; Allen, Jodie; Amery, Gillian; Amunts, Liana; Barcroft, Anne; Castle, Amanda; Dias, Cheryl; Dowrick, Jonathan; Fair, Melissa; Fisher, Hayley; Goulding, Anna; Grewal, Adarsh; Hale, Geoff; Hilton, Andrew; Johnson, Frances; Johnston, Patricia; Kavanagh-Williamson, Thea; Kwasniewska, Magdalena; McMinn, Alison; Norman, Kim; Penrose, Jessica; Roby, Fiona; Rowland, Diane; Sargeant, John; Squire, Maggie; Stevens, Beth; Stoddart, Aldabra; Stone, Cheryl; Thompson, Tracy; Yazlik, Ozlem; Barnes, Dan; Dixon, Marie; Hillman, Jaya; Mitchell, Joanne; Villis, Laura; Henson, R. N. A.

2017-01-01

Slowing is a common feature of ageing, yet a direct relationship between neural slowing and brain atrophy is yet to be established in healthy humans. We combine magnetoencephalographic (MEG) measures of neural processing speed with magnetic resonance imaging (MRI) measures of white and grey matter in a large population-derived cohort to investigate the relationship between age-related structural differences and visual evoked field (VEF) and auditory evoked field (AEF) delay across two different tasks. Here we use a novel technique to show that VEFs exhibit a constant delay, whereas AEFs exhibit delay that accumulates over time. White-matter (WM) microstructure in the optic radiation partially mediates visual delay, suggesting increased transmission time, whereas grey matter (GM) in auditory cortex partially mediates auditory delay, suggesting less efficient local processing. Our results demonstrate that age has dissociable effects on neural processing speed, and that these effects relate to different types of brain atrophy. PMID:28598417

Intelligence and cognitive function in children and adolescents with spinal muscular atrophy.

PubMed

von Gontard, A; Zerres, K; Backes, M; Laufersweiler-Plass, C; Wendland, C; Melchers, P; Lehmkuhl, G; Rudnik-Schöneborn, S

2002-02-01

Spinal muscular atrophy is a chronic disease characterised by loss of motor function. The aim of the study was to analyse cognitive functions in a large group of patients with spinal muscular atrophy. It was hypothesised that their intelligence is comparable to controls, but not above average as previously postulated. Ninety-six children and adolescents with spinal muscular atrophy I-III, aged 6.0-18.11 years, 45 non-affected siblings and 59 healthy, matched controls were examined with one- (CPM/SPM), as well as multi-dimensional intelligence tests (Kaufman-ABC; Wechsler tests). The mean IQ measured with the CPM/SPM tests was 109.6 for the spinal muscular atrophy group, 107.3 for the sibs and 104.1 for the healthy controls (no significant difference). In the older children and adolescents (SPM only) the mean IQ was significantly higher for the spinal muscular atrophy patients (109.6) than for the controls (95.4). The standard score in the 'mental processing composite' scale of the Kaufman-ABC was identical in the spinal muscular atrophy group and controls (103.8). The cognitive profile was relatively homogeneous. However, the older children and adolescents did have a significantly higher verbal IQ (113.8) than controls (104.6) in the Wechsler tests. There were no significant differences in any of the tests among different grades of severity (spinal muscular atrophy types I-III). It can be concluded that children and adolescents with spinal muscular atrophy have a general intelligence in the normal range. By adolescence, environmentally mediated aspects of intelligence are higher in patients with spinal muscular atrophy. It could be speculated that the development of cognitive skills and knowledge is a creative way to compensate the many restrictions due to their physical handicap.

Age-related effects of dexamethasone administration in adrenal zona reticularis.

PubMed

Almeida, Henrique; Matos, Liliana; Ferreira, Jorge; Neves, Delminda

2006-05-01

Suppression of adrenocorticotropic hormone results in reduced adrenal steroid output, adrenocortical cell atrophy, and apoptosis in young rats. To verify such effects during aging, dexamethasone was injected into rats for 3 days at five different ages; at day 4, adrenals and blood were collected for morphologic and corticosterone assay. Adrenal structure was similar at all ages, but in dexamethasone-injected animals there were ultrastructural features of apoptosis and a higher percentage of TUNEL and caspase-3-labeled nuclei and cytoplasm; their corticosterone decreased significantly. In both groups, there was age-related decrease in the percentage of apoptotic cells, significant only in dexamethasone-injected rats. The data suggest that aged adrenocortical cells are less susceptible to the lack of adrenocorticotropic hormone (ACTH), possibly as a result of their decreased functional ability.

Reinterpreting recent thymic emigrant function: defective or adaptive?

PubMed

Cunningham, Cody A; Helm, Eric Y; Fink, Pamela J

2018-04-01

Recent thymic emigrants (RTEs) are those peripheral T cells that have most recently completed thymic development and egress. Over the past decade, significant advances have been made in understanding the cell-extrinsic and cell-intrinsic requirements for RTE maturation to mature naïve (MN) T cells and in detailing the functional differences that characterize these two T cell populations. Much of this work has suggested that RTEs are hypo-functional versions of more mature T cells. However, recent evidence has indicated that rather than being defective T cells, RTEs are exquisitely adapted to their cellular niche. In this review, we argue that RTEs are not flawed mature T cells but are adapted to fill an underpopulated T cell compartment, while maintaining self tolerance and possessing the capacity to mount robust immune responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Calcified Neurocysticercosis Associates with Hippocampal Atrophy: A Population-Based Study

PubMed Central

Del Brutto, Oscar H.; Salgado, Perla; Lama, Julio; Del Brutto, Victor J.; Campos, Xavier; Zambrano, Mauricio; García, Héctor H.

2015-01-01

Calcified neurocysticercosis has been associated with hippocampal atrophy in patients with refractory epilepsy, but the relevance of this association in the population at large is unknown. We assessed calcified cysticerci and its association with hippocampal atrophy in elderly persons living in Atahualpa, an Ecuadorian village endemic for neurocysticercosis. All Atahualpa residents ≥ 60 years of age were invited to undergo computed tomography/magnetic resonance imaging for neurocysticercosis detection. Twenty-eight (11%) out of 248 enrolled persons had calcified cysticerci (case-patients) and were matched 1:1 by age, sex, and years of education to individuals without neurocysticercosis on computed tomography/magnetic resonance imaging (controls). Four case-patients and none of the controls had epilepsy (P = 0.134). Cognitive performance was similar across both groups. The Scheltens' medial temporal atrophy scale was used for hippocampal rating in case-patients and matched controls without neurocysticercosis. Mean score in the Scheltens' scale was higher in case-patients than in controls (P < 0.001). Atrophic hippocampi were noticed in 19 case-patients and five controls (P = 0.003). Atrophy was bilateral in 11 case-patients and unilateral in eight. All case-patients with unilateral hippocampal atrophy had at least one ipsilateral calcification. This study shows an association between calcified cysticerci and hippocampal atrophy and raises the possibility of an inflammation-mediated hippocampal damage as the responsible mechanism for these findings. PMID:25349375

Application values of 99mTc-methoxyisobutylisonitrile imaging for differentiating benign and malignant thymic masses.

PubMed

Lu, Chenghui; Wang, Xufu; Liu, Bin; Liu, Xinfeng; Wang, Guoming; Zhang, Qin

2017-08-01

The aim of the present study was to investigate the application value of 99m Tc-methoxyisobutylisonitrile (MIBI) imaging to differentiate between benign and malignant thymic masses. A total of 32 patients with space-occupying mediastinal masses were enrolled and early and delayed-phase images were collected following injection with the imaging agent. The tumor to background ratio (T/N) values at the different phases were also recorded. The sensitivity of the qualitative analysis to distinguish between benign and malignant thymic masses was 95.24%, with specificity as 90.91%. The T/N values in the early and delayed phases were not significantly different in the group with benign thymic masses, but demonstrated statistical significant differences in the groups with low- and intermediate-grade malignant thymic masses. The T/N values at the above early and delayed phase were significantly different between the benign and low-grade malignancy groups, as well as between low- and moderate-grade malignancy groups. Those between the benign and moderate-grade malignancy groups demonstrated no significant difference. 99m Tc-MIBI imaging was able to differentiate between benign and malignant thymic masses, and the simultaneous semi-quantitative analysis of the T/N values of the tumors may be able to initially determine the degree of malignancy of thymoma.

Thymic hyperplasia in a patient with Grave's disease.

PubMed

Hamzaoui, Amira A; Klii, Rim R; Salem, Randa R; Kochtali, Ines I; Golli, Mondher M; Mahjoub, Silvia S

2012-02-09

Hyperplastic changes of the thymus may be found in patients with Graves' disease. However, this rarely presents as an anterior mediastinal mass, particularly among adults. In this report, we describe a 46-year old woman with Graves' disease and thymic hyperplasia.

Network structure of brain atrophy in de novo Parkinson's disease

PubMed Central

Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

2015-01-01

We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. DOI: http://dx.doi.org/10.7554/eLife.08440.001 PMID:26344547

Focal temporal pole atrophy and network degeneration in semantic variant primary progressive aphasia

PubMed Central

Collins, Jessica A; Montal, Victor; Hochberg, Daisy; Quimby, Megan; Mandelli, Maria Luisa; Makris, Nikos; Seeley, William W; Gorno-Tempini, Maria Luisa; Dickerson, Bradford C

2017-01-01

Abstract A wealth of neuroimaging research has associated semantic variant primary progressive aphasia with distributed cortical atrophy that is most prominent in the left anterior temporal cortex; however, there is little consensus regarding which region within the anterior temporal cortex is most prominently damaged, which may indicate the putative origin of neurodegeneration. In this study, we localized the most prominent and consistent region of atrophy in semantic variant primary progressive aphasia using cortical thickness analysis in two independent patient samples (n = 16 and 28, respectively) relative to age-matched controls (n = 30). Across both samples the point of maximal atrophy was located in the same region of the left temporal pole. This same region was the point of maximal atrophy in 100% of individual patients in both semantic variant primary progressive aphasia samples. Using resting state functional connectivity in healthy young adults (n = 89), we showed that the seed region derived from the semantic variant primary progressive aphasia analysis was strongly connected with a large-scale network that closely resembled the distributed atrophy pattern in semantic variant primary progressive aphasia. In both patient samples, the magnitude of atrophy within a brain region was predicted by that region’s strength of functional connectivity to the temporopolar seed region in healthy adults. These findings suggest that cortical atrophy in semantic variant primary progressive aphasia may follow connectional pathways within a large-scale network that converges on the temporal pole. PMID:28040670

Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma.

PubMed

Moser, Bernhard; Schiefer, Ana Iris; Janik, Stefan; Marx, Alexander; Prosch, Helmut; Pohl, Wolfgang; Neudert, Barbara; Scharrer, Anke; Klepetko, Walter; Müllauer, Leonhard

2015-04-01

We report 2 cases of primary thymic adenocarcinoma with enteric differentiation. One carcinoma occurred in a 41-year-old man as a 7-cm-diameter cystic tumor and the other one in a 39-year-old woman as a 6-cm-diameter solid mass. Both tumors were located in the anterior mediastinum. Clinical staging did not reveal any extrathymic tumor. Histologically, the tumors were classified as adenocarcinoma, not otherwise specified, and a mucinous (colloid) carcinoma, respectively. Immunohistochemically, both tumors were positive for cytokeratin 20 (CK20), CDX2, and carcinoembryonic antigen, reflecting enteric differentiation. A review of the literature on 43 other cases of primary thymic adenocarcinomas suggested 11 further cases with enteric differentiation, as assessed by CK20 and/or CDX2 expression. We propose that thymic adenocarcinoma with enteric differentiation represents a novel subtype of thymic carcinoma. It is mostly of mucinous morphology and frequently associated with thymic cysts. The clinical outcome is variable. Recognition of primary thymic adenocarcinoma with enteric differentiation is helpful for the differentiation from metastatic disease, mainly from the gastrointestinal tract.

The association of aspirin use with age-related macular degeneration.

PubMed

Liew, Gerald; Mitchell, Paul; Wong, Tien Yin; Rochtchina, Elena; Wang, Jie Jin

2013-02-25

To determine whether regular aspirin use is associated with a higher risk for developing age-related macular degeneration (AMD) by using analyzed data from a 15-year prospective cohort. A prospective analysis was conducted of data from an Australian population-based cohort with 4 examinations during a 15-year period (1992-1994 to 2007-2009). Participants completed a detailed questionnaire at baseline assessing aspirin use, cardiovascular disease status, and AMD risk factors. Age-related macular degeneration was graded side-by-side from retinal photographs taken at each study visit to assess the incidence of neovascular (wet) AMD and geographic atrophy (dry AMD) according to the international AMD classification. Of 2389 baseline participants with follow-up data available, 257 individuals (10.8%) were regular aspirin users and 63 of the 2389 developed neovascular AMD. Persons who were regular aspirin users were more likely to have incident neovascular AMD: the 15-year cumulative incidence was 9.3% in users and 3.7% in nonusers. After adjustment for age, sex, smoking, history of cardiovascular disease, systolic blood pressure, and body mass index, persons who were regular aspirin users had a higher risk of developing neovascular AMD (odds ratio [OR], 2.46; 95% CI, 1.25-4.83). The association showed a dose-response effect (multivariate-adjusted P = .01 for trend). Aspirin use was not associated with the incidence of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59-1.65). Regular aspirin use is associated with increased risk of incident neovascular AMD, independent of a history of cardiovascular disease and smoking.

Thymic hyperplasia in a patient with Grave's disease

PubMed Central

2012-01-01

Hyperplastic changes of the thymus may be found in patients with Graves' disease. However, this rarely presents as an anterior mediastinal mass, particularly among adults. In this report, we describe a 46-year old woman with Graves' disease and thymic hyperplasia. PMID:22321290

Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge

PubMed Central

Cash, David M.; Frost, Chris; Iheme, Leonardo O.; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B.; Pennec, Xavier; Pierson, Ronald K.; Gunter, Jeffrey L.; Senjem, Matthew L.; Jack, Clifford R.; Guizard, Nicolas; Fonov, Vladimir S.; Collins, D. Louis; Modat, Marc; Cardoso, M. Jorge; Leung, Kelvin K.; Wang, Hongzhi; Das, Sandhitsu R.; Yushkevich, Paul A.; Malone, Ian B.; Fox, Nick C.; Schott, Jonathan M.; Ourselin, Sebastien

2015-01-01

distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24 months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: − 1.4% to − 2.2% (AD) and − 0.35% to − 0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: − 1.5% to − 7.0% (AD) and − 0.4% to − 1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12 month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods. PMID:26275383

FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension

PubMed Central

Eash, John; Olsen, Aaron; Breur, Gert; Gerrard, Dave; Hannon, Kevin

2007-01-01

Background Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs) and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined. Methods We examined the effects of ectopic expression of FGFR1 during disuse-mediated skeletal muscle atrophy, utilizing hindlimb suspension and DNA electroporation in mice. Results We found skeletal muscle FGF4 and FGFR1 mRNA expression to be modified by hind limb suspension,. In addition, we found FGFR1 protein localized in muscle fibers within atrophying mouse muscle which appeared to be resistant to atrophy. Electroporation and ectopic expression of FGFR1 significantly inhibited the decrease in muscle fiber area within skeletal muscles of mice undergoing suspension induced muscle atrophy. Ectopic FGFR1 expression in muscle also significantly stimulated protein synthesis in muscle fibers, and increased protein degradation in weight bearing muscle fibers. Conclusion These results support the theory that FGF signaling can play a role in regulation of postnatal skeletal muscle maintenance, and could offer potentially novel and efficient therapeutic options for attenuating muscle atrophy during aging, illness and spaceflight. PMID:17425786

Assessing Susceptibility to Age-Related Macular Degeneration With Genetic Markers and Environmental Factors

PubMed Central

Chen, Yuhong; Zeng, Jiexi; Zhao, Chao; Wang, Kevin; Trood, Elizabeth; Buehler, Jeanette; Weed, Matthew; Kasuga, Daniel; Bernstein, Paul S.; Hughes, Guy; Fu, Victoria; Chin, Jessica; Lee, Clara; Crocker, Maureen; Bedell, Matthew; Salasar, Francesca; Yang, Zhenglin; Goldbaum, Michael; Ferreyra, Henry; Freeman, William R.; Kozak, Igor; Zhang, Kang

2014-01-01

Objectives To evaluate the independent and joint effects of genetic factors and environmental variables on advanced forms of age-related macular degeneration (AMD), including geographic atrophy and choroidal neovascularization, and to develop a predictive model with genetic and environmental factors included. Methods Demographic information, including age at onset, smoking status, and body mass index, was collected for 1844 participants. Genotypes were evaluated for 8 variants in 5 genes related to AMD. Unconditional logistic regression analyses were performed to generate a risk predictive model. Results All genetic variants showed a strong association with AMD. Multivariate odds ratios were 3.52 (95% confidence interval, 2.08-5.94) for complement factor H, CFH rs1061170 CC, 4.21 (2.30-7.70) for CFH rs2274700 CC, 0.46 (0.27-0.80) for C2 rs9332739 CC/CG, 0.44 (0.30-0.66) for CFB rs641153 TT/CT, 10.99 (6.04-19.97) for HTRA1/LOC387715 rs10490924 TT, and 2.66 (1.43-4.96) for C3 rs2230199 GG. Smoking was independently associated with advanced AMD after controlling for age, sex, body mass index, and all genetic variants. Conclusion CFH confers more risk to the bilaterality of geographic atrophy, whereas HTRA1/LOC387715 contributes more to the bilaterality of choroidal neovascularization. C3 confers more risk for geographic atrophy than choroidal neovascularization. Risk models with combined genetic and environmental factors have notable discrimination power. Clinical Relevance Early detection and risk prediction of AMD could help to improve the prognosis of AMD and to reduce the outcome of blindness. Targeting high-risk individuals for surveillance and clinical interventions may help reduce disease burden. PMID:21402993

Treatment and prognosis of primary thymic carcinoma.

PubMed

Yano, T; Hara, N; Ichinose, Y; Asoh, H; Yokoyama, H; Ohta, M

1993-04-01

From 1972 to 1990, we treated eight cases of thymic carcinoma (6 squamous cell and 2 small cell carcinomas). According to the classification by Masaoka et al., they consisted of one stage I, four stage III, one stage IVa, and two stage IVb. A complete resection of the primary tumour could be done in only three patients; the others had diagnostic biopsy and then radiation treatment. Four of five patients had a prolonged regression of the primary tumors after irradiation at 40-61.2 Gy. Six patients suffered from extrathoracic metastases. All patients received systemic chemotherapy with different regimens to counter either metastatic or locally recurrent lesions. Only two patients (with a regimen including cyclophosphamide, doxorubicin, and vincristine) obtained a partial response. The median survival of the eight patients was 70 months after surgical operation. The identification of an effective drug combination may thus improve the long-term prognosis of thymic carcinoma since radiotherapy is able to control primary lesions, even in the case of unresectable advanced disease.

Effect on IgE production of transplanted cultured thymic fragments.

PubMed Central

Nishikawa, M; Hong, R

1987-01-01

The effect of cultured thymic fragment (CTF) transplantation on the IgE response of nude mice was studied. Nude mice (BALB/c nu/nu) were immunized with a mixture of tetanus toxoid and aluminium gel intraperitoneally. Non-CTF transplanted nude mice could not regulate IgE production nor synthesize specific IgE antibody, and all died at 16 weeks of age. Nude mice that were transplanted with CTF from allogeneic low responder strains (C57BL/6, SJL), allogeneic high responder strain (ASW) and syngeneic high responder strain (BALB/c) could regulate IgE production, and these lived a normal life span. Additionally, the tetanus toxoid-specific IgE antibody response, which was estimated by PCA, paralleled that seen in the strain of the thymus donor, i.e. BALB/c and ASW thymus reconstitution produced the highest response, whereas SJL and C57BL/6 recipients' levels were significantly less (P less than 0.05). We postulate that the lesser responses were due to the determination of the phenotype response by the thymic microenvironment. The low responses were shown to be due to regulator T-cell imbalance. These data show that BALB/c T-cell precursors developing in non-BALB/c thymuses interact with BALB/c B cells to produce levels of IgE antibody that are more characteristic of the non-BALB/c differentiating microenvironment than of their own genetic background. PMID:3493208

Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover.

PubMed

Westera, Liset; van Hoeven, Vera; Drylewicz, Julia; Spierenburg, Gerrit; van Velzen, Jeroen F; de Boer, Rob J; Tesselaar, Kiki; Borghans, José A M

2015-04-01

In healthy humans, lymphocyte populations are maintained at a relatively constant size throughout life, reflecting a balance between lymphocyte production and loss. Given the profound immunological changes that occur during healthy aging, including a significant decline in T-cell production by the thymus, lymphocyte maintenance in the elderly is generally thought to require homeostatic alterations in lymphocyte dynamics. Surprisingly, using in vivo (2) H2 O labeling, we find similar dynamics of most lymphocyte subsets between young adult and elderly healthy individuals. As the contribution of thymic output to T-cell production is only minor from young adulthood onward, compensatory increases in peripheral T-cell division rates are not required to maintain the T-cell pool, despite a tenfold decline in thymic output. These fundamental insights will aid the interpretation of further research into aging and clinical conditions related to disturbed lymphocyte dynamics. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Frontal lobe atrophy is associated with small vessel disease in ischemic stroke patients.

PubMed

Chen, Yangkun; Chen, Xiangyan; Xiao, Weimin; Mok, Vincent C T; Wong, Ka Sing; Tang, Wai Kwong

2009-12-01

The pathogenesis of frontal lobe atrophy (FLA) in stroke patients is unclear. We aimed to ascertain whether subcortical ischemic changes were more associated with FLA than with parietal lobe atrophy (PLA) and temporal lobe atrophy (TLA). Brain magnetic resonance images (MRIs) from 471 Chinese ischemic stroke patients were analyzed. Lobar atrophy was defined by a widely used visual rating scale. All patients were divided into non-severe, mild-moderate, and severe atrophy of the frontal, parietal, and temporal lobe groups. The severity of white matter lesions (WMLs) was rated with the Fazekas' scale. Clinical and radiological features were compared among the groups. Subsequent logistic regressions were performed to determine the risk factors of atrophy and severe atrophy of the frontal, parietal and temporal lobes. The frequency of FLA in our cohort was 36.9% (174/471). Severe FLA occurred in 30 (6.4%) patients. Age, previous stroke, and periventricular hyperintensities (PVH) (odds ratio (OR)=1.640, p=0.039) were independent risk factors of FLA. Age and deep white matter hyperintensities (DWMH) (OR=3.634, p=0.002) were independent risk factors of severe FLA. PVH and DWMH were not independent risk factors of PLA and TLA. Frontal lobe atrophy in ischemic stroke patients may be associated with small vessel disease. The association between WMLs and FLA was predominant over atrophy of the parietal and temporal lobes, which suggests that the frontal lobe may be vulnerable to subcortical ischemic changes.

CD52, CD22, CD26, EG5 and IGF-1R expression in thymic malignancies.

PubMed

Remon, J; Abedallaa, N; Taranchon-Clermont, E; Bluthgen, V; Lindsay, C R; Besse, B; Thomas de Montpréville, V

2017-06-01

Thymic epithelial tumours are rare cancers for which new treatment options are required. Identification of putative predictive markers is important for developing clinical trials. We studied the expression of five putative predictive biomarkers, potentially actionable by approved experimental drugs. CD52, CD22, CD26, EG5, and IGF-1R expression were investigated by immunohistochemistry in formalin-fixed surgical samples of thymic epithelial tumour patients. All samples containing 10% positive epithelial tumour cells, independent of tumour cell intensity, were considered as positive. Correlation with histological subtype was performed. 106 surgical samples (89 thymomas, 12 thymic carcinoma, and 5 thymic neuroendocrine tumours) were evaluated. Overall, CD52, CD22, CD26, EG5 and IGF-1R expression was observed in 7%, 42%, 25%, 42% and 77% of samples, respectively. CD52 expression was more frequent in B2 and B3 thymoma. All TET subtypes stained for CD22, mainly AB thymoma (68%). CD26 expression also correlated with AB thymoma (68%), and A thymoma (50%) subtype, while IGFR1 was the most common marker expressed by thymic carcinoma samples (92%), followed by EG5 (60%). Only EG5 expression was significantly higher in thymic carcinomas than in thymomas (75% vs. 38%, p=0.026). Our data were consistent with a previous study of IGF-1R expression. Based on their expression, activity of agents targeting CD52, CD 22, CD26 and EG5 could be further explored in TET patients. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of hormones, cytokines and heat shock proteins during age-related muscle loss.

PubMed

Lee, Claire E; McArdle, Anne; Griffiths, Richard D

2007-10-01

Ageing is associated with a progressive decline of muscle mass, strength, and quality, a condition known as sarcopenia. Due to the progressive ageing of western populations, age-related sarcopenia is a major public health problem. Several possible mechanisms for age-related muscle atrophy have been described; however the precise contribution of each is unknown. Age-related muscle loss is thought to be a multi-factoral process composed of events such as physical activity, nutritional intake, oxidative stress, inflammatory insults and hormonal changes. There is a need for a greater understanding of the loss of muscle mass with age as this could have a dramatic impact on the elderly and critically ill if this research leads to maintenance or improvement in functional ability. This review aims to outline the process of skeletal muscle degeneration with ageing, normal and aberrant skeletal muscle regeneration, and to address recent research on the effects of gender and sex steroid hormones during the process of age-related muscle loss.

Spinal Muscular Atrophy FAQ

MedlinePlus

... in SMA. What is Spinal Muscular Atrophy with Respiratory Distress (SMARD)? SMARD and SMA are separate diseases ... muscle weakness and atrophy. Spinal Muscular Atrophy with Respiratory Distress (SMARD) is a rare neuromuscular disease that ...

Recent developments in the management of dry age-related macular degeneration

PubMed Central

Buschini, Elisa; Fea, Antonio M; Lavia, Carlo A; Nassisi, Marco; Pignata, Giulia; Zola, Marta; Grignolo, Federico M

2015-01-01

Dry age-related macular degeneration (AMD), also called geographic atrophy, is characterized by the atrophy of outer retinal layers and retinal pigment epithelium (RPE) cells. Dry AMD accounts for 80% of all intermediate and advanced forms of the disease. Although vision loss is mainly due to the neovascular form (75%), dry AMD remains a challenge for ophthalmologists because of the lack of effective therapies. Actual management consists of lifestyle modification, vitamin supplements, and supportive measures in the advanced stages. The Age-Related Eye Disease Study demonstrated a statistically significant protective effect of dietary supplementation of antioxidants (vitamin C, vitamin E, beta-carotene, zinc, and copper) on dry AMD progression rate. It was also stated that the consumption of omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, has protective effects. Other antioxidants, vitamins, and minerals (such as crocetin, curcumin, and vitamins B9, B12, and B6) are under evaluation, but the results are still uncertain. New strategies aim to 1) reduce or block drusen formation, 2) reduce or eliminate inflammation, 3) lower the accumulation of toxic by-products from the visual cycle, 4) reduce or eliminate retinal oxidative stress, 5) improve choroidal perfusion, 6) replace/repair or regenerate lost RPE cells and photoreceptors with stem cell therapy, and 7) develop a target gene therapy. PMID:25878491

Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale

PubMed Central

Bickart, Kevin C; Brickhouse, Michael; Negreira, Alyson; Sapolsky, Daisy

2015-01-01

Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others’ social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning. PMID:24133285

Alpha-synuclein levels in patients with multiple system atrophy: a meta-analysis.

PubMed

Yang, Fei; Li, Wan-Jun; Huang, Xu-Sheng

2018-05-01

This study evaluates the relationship between multiple system atrophy and α-synuclein levels in the cerebrospinal fluid, plasma and neural tissue. Literature search for relevant research articles was undertaken in electronic databases and study selection was based on a priori eligibility criteria. Random-effects meta-analyses of standardized mean differences in α-synuclein levels between multiple system atrophy patients and normal controls were conducted to obtain the overall and subgroup effect sizes. Meta-regression analyses were performed to evaluate the effect of age, gender and disease severity on standardized mean differences. Data were obtained from 11 studies involving 378 multiple system atrophy patients and 637 healthy controls (age: multiple system atrophy patients 64.14 [95% confidence interval 62.05, 66.23] years; controls 64.16 [60.06, 68.25] years; disease duration: 44.41 [26.44, 62.38] months). Cerebrospinal fluid α-synuclein levels were significantly lower in multiple system atrophy patients than in controls but in plasma and neural tissue, α-synuclein levels were significantly higher in multiple system atrophy patients (standardized mean difference: -0.99 [-1.65, -0.32]; p = 0.001). Percentage of male multiple system atrophy patients was significantly positively associated with the standardized mean differences of cerebrospinal fluid α-synuclein levels (p = 0.029) whereas the percentage of healthy males was not associated with the standardized mean differences of cerebrospinal fluid α-synuclein levels (p = 0.920). In multiple system atrophy patients, α-synuclein levels were significantly lower in the cerebrospinal fluid and were positively associated with the male gender.

Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors.

PubMed

Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

2016-01-01

Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Motion artifacts were significantly reduced for all structures by ECG gating ( p =0.0089 for the lungs and p <0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion ( p =0.03). ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures.

Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors

PubMed Central

Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

2016-01-01

Summary Background Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Material/Methods Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Results Motion artifacts were significantly reduced for all structures by ECG gating (p=0.0089 for the lungs and p<0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion (p=0.03). Conclusions ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures. PMID:27920842

Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules.

PubMed

Vanneste, Y; Thome, A N; Vandersmissen, E; Charlet, C; Franchimont, D; Martens, H; Lhiaubet, A M; Schimpff, R M; Rostène, W; Geenen, V

1997-06-01

This study shows the expression at the cell surface of human thymic epithelial cells (TEC) of a neurotensin (NT)-like immunoreactivity. NT radio-immunoassay (RIA) revealed that cultured human TEC contain +/-5 ng immunoreactive (ir) NT/10(6) cells, of which 5% is associated with plasma cell membranes. HPLC analysis of NT-ir present in human TEC showed a major peak of NT-ir corresponding to NT1-13. NT-ir was not detected in the supernatant of human TEC cultures. Using an affinity column prepared with a anti-MHC class I monoclonal antibody, NT-ir-related peptides were retained on the column and eluted together with MHC class I-related proteins. According to the elution time on HPLC of these peptides, they correspond to intact NT1-13, as well as to smaller fragments of NT1-13.

miR-182 attenuates atrophy-related gene expression by targeting FoxO3 in skeletal muscle

PubMed Central

Rahnert, Jill A.; Zheng, Bin; Woodworth-Hobbs, Myra E.; Franch, Harold A.; Russ Price, S.

2014-01-01

Skeletal muscle atrophy occurs in response to a variety of conditions including chronic kidney disease, diabetes, cancer, and elevated glucocorticoids. MicroRNAs (miR) may play a role in the wasting process. Activation of the forkhead box O3 (FoxO3) transcription factor causes skeletal muscle atrophy in patients, animals, and cultured cells by increasing the expression of components of the ubiquitin-proteasome and autophagy-lysosome proteolytic systems. To identify microRNAs that potentially modulate the atrophy process, an in silico target analysis was performed and miR-182 was predicted to target FoxO3 mRNA. Using a combination of immunoblot analysis, quantitative real-time RT-PCR, and FoxO3 3′-UTR luciferase reporter genes, miR-182 was confirmed to regulate FoxO3 expression in C2C12 myotubes. Transfection of miR-182 into muscle cells decreased FoxO3 mRNA 30% and FoxO3 protein 67% (P < 0.05) and also prevented a glucocorticoid-induced upregulation of multiple FoxO3 gene targets including MAFbx/atrogin-1, autophagy-related protein 12 (ATG12), cathepsin L, and microtubule-associated protein light chain 3 (LC3). Treatment of C2C12 myotubes with dexamethasone (Dex) (1 μM, 6 h) to induce muscle atrophy decreased miR-182 expression by 63% (P < 0.05). Similarly, miR-182 was decreased 44% (P < 0.05) in the gastrocnemius muscle of rats injected with streptozotocin to induce diabetes compared with controls. Finally, miR-182 was present in exosomes isolated from the media of C2C12 myotubes and Dex increased its abundance. These data identify miR-182 as an important regulator of FoxO3 expression that participates in the control of atrophy-inducing genes during catabolic diseases. PMID:24871856

A Comparative Analysis of the Murine Thymic Microenvironment in Normal, Autoimmune, and Immunodeficiency States

PubMed Central

Takeoka, Yuichi; Chen, Shao-Yuan; Boyd, Richard L.; Tsuneyama, Koichi; Taguchi, Nobuhisa; Morita, Shinji; Yago, Hisashi; Suehiro, Seishi; Ansari, Aftab A.; Shultz, Leonard D.

1997-01-01

It is widely accepted that the thymic microenvironment regulates normal thymopoiesis through a highly coordinated and complex series of cellular and cytokine interactions. A direct corollary of this is that abnormalities within the microenvironment could be of etiologic significance in T-cell-based diseases. Our laboratory has developed a large panel of monoclonal antibodies (mAbs) that react specifically with epithelial or nonepithelial markers in the thymus. We have taken advantage of these reagents to characterize the thymic microenvironment of several genetic strains of mice, including BALB/cJ, C57BL/6J, NZB/BlnJ, SM/J, NOD/Ltz, NOD/Ltz-scid/sz, C57BL/6J-Hcph me/Hcph me, and ALY/NscJcl-aly/aly mice, and littermate control animals. We report herein that control mice, including strains of several backgrounds, have a very consistent phenotypic profile with this panel of monoclonal antibodies, including reactivity with thymic epithelial cells in the cortex, the medulla and the corticomedullary junction, and the extracellular matrix. In contrast, the disease-prone strains studied have unique, abnormal staining of thymic cortex and medulla at both the structural and cellular levels. These phenotypic data suggest that abnormalities in interactions between developing thymocytes and stromal cells characterize disease-prone mice. PMID:9587708

Histologic patterns of thymic involvement in Langerhans cell proliferations: a clinicopathologic study and review of the literature.

PubMed

Picarsic, Jennifer; Egeler, R Maarten; Chikwava, Kudakwashe; Patterson, Kathleen; Jaffe, Ronald

2015-01-01

Thymic involvement by Langerhans cell histiocytosis (LCH) has been described mainly in isolated case reports. A description of the histopathologic patterns of LCH proliferations in the thymus, together with therapeutic implications, has not, to our knowledge, been previously addressed. The pathology consultation files at Children's Hospital of Pittsburgh of the University of Pennsylvania Medical Center were reviewed for cases of thymic involvement by LCH. Relevant cases in the literature were also reviewed, and the histopathology and clinical course of those cases were collected. Nine consultation cases of thymic involvement were reviewed, together with 23 cases in the literature, which provided adequate pathologic description and ancillary confirmation (n  =  32), revealing 4 distinct pathologic groups. Group 1 showed microscopic collection of hyperplastic LCH-like cells in incidental thymectomies of patients without LCH disease, requiring no further treatment (n  =  7; 22%). Group 2 showed solitary and/or cystic LCH of the thymus with gland disruption, and at least 3 cases resolved without systemic therapy (n  =  10; 31%). Group 3 showed more variable thymic involvement in multisystemic LCH disease, with either a medullary restricted pattern or more diffuse gland involvement, requiring adjuvant therapy and having a higher mortality rate (n  =  13; 41%). Group 4 showed a mixed histiocytic lesion with a concurrent LCH and juvenile xanthogranuloma-like proliferation (n  =  2; 6%). Thymic involvement in LCH is quite rare. Based on our cases and those in the literature, we propose 4 distinct pathologic groups of thymic involvement in Langerhans cell proliferations with relevance for diagnosis and treatment.

Amygdala atrophy affects emotion-related activity in face-responsive regions in frontotemporal degeneration.

PubMed

De Winter, François-Laurent; Van den Stock, Jan; de Gelder, Beatrice; Peeters, Ronald; Jastorff, Jan; Sunaert, Stefan; Vanduffel, Wim; Vandenberghe, Rik; Vandenbulcke, Mathieu

2016-09-01

In the healthy brain, modulatory influences from the amygdala commonly explain enhanced activation in face-responsive areas by emotional facial expressions relative to neutral expressions. In the behavioral variant frontotemporal dementia (bvFTD) facial emotion recognition is impaired and has been associated with atrophy of the amygdala. By combining structural and functional MRI in 19 patients with bvFTD and 20 controls we investigated the neural effects of emotion in face-responsive cortex and its relationship with amygdalar gray matter (GM) volume in neurodegeneration. Voxel-based morphometry revealed decreased GM volume in anterior medio-temporal regions including amygdala in patients compared to controls. During fMRI, we presented dynamic facial expressions (fear and chewing) and their spatiotemporally scrambled versions. We found enhanced activation for fearful compared to neutral faces in ventral temporal cortex and superior temporal sulcus in controls, but not in patients. In the bvFTD group left amygdalar GM volume correlated positively with emotion-related activity in left fusiform face area (FFA). This correlation was amygdala-specific and driven by GM in superficial and basolateral (BLA) subnuclei, consistent with reported amygdalar-cortical networks. The data suggests that anterior medio-temporal atrophy in bvFTD affects emotion processing in distant posterior areas. Copyright © 2016 Elsevier Ltd. All rights reserved.

Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice

PubMed Central

Jinadasa, Rasika; Balmus, Gabriel; Gerwitz, Lee; Roden, Jamie; Weiss, Robert; Duhamel, Gerald

2011-01-01

Established cell lines are a critical research tool that can reduce the use of laboratory animals in research. Certain strains of genetically modified mice, such as Atm-/- and p53-/- consistently develop thymic lymphoma early in life 1,2, and thus, can serve as a reliable source for derivation of murine T-cell lines. Here we present a detailed protocol for the development of established murine thymic lymphoma T-cell lines without the need to add interleukins as described in previous protocols 1,3. Tumors were harvested from mice aged three to six months, at the earliest indication of visible tumors based on the observation of hunched posture, labored breathing, poor grooming and wasting in a susceptible strain 1,4. We have successfully established several T-cell lines using this protocol and inbred strains ofAtm-/- [FVB/N-Atmtm1Led/J] 2 and p53-/- [129/S6-Trp53tm1Tyj/J] 5 mice. We further demonstrate that more than 90% of the established T-cell population expresses CD3, CD4 and CD8. Consistent with stably established cell lines, the T-cells generated by using the present protocol have been passaged for over a year. PMID:21490582

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease.

PubMed

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases

PubMed Central

Sato, Amy Y.; Richardson, Danielle; Cregor, Meloney; Davis, Hannah M.; Au, Ernie D.; McAndrews, Kevin; Zimmers, Teresa A.; Organ, Jason M.; Peacock, Munro; Plotkin, Lilian I.

2017-01-01

Glucocorticoid excess, either endogenous with diseases of the adrenal gland, stress, or aging or when administered for immunosuppression, induces bone and muscle loss, leading to osteopenia and sarcopenia. Muscle weakness increases the propensity for falling, which, combined with the lower bone mass, increases the fracture risk. The mechanisms underlying glucocorticoid-induced bone and muscle atrophy are not completely understood. We have demonstrated that the loss of bone and muscle mass, decreased bone formation, and reduced muscle strength, hallmarks of glucocorticoid excess, are accompanied by upregulation in both tissues in vivo of the atrophy-related genes atrogin1, MuRF1, and MUSA1. These are E3 ubiquitin ligases traditionally considered muscle-specific. Glucocorticoids also upregulated atrophy genes in cultured osteoblastic/osteocytic cells, in ex vivo bone organ cultures, and in muscle organ cultures and C2C12 myoblasts/myotubes. Furthermore, glucocorticoids markedly increased the expression of components of the Notch signaling pathway in muscle in vivo, ex vivo, and in vitro. In contrast, glucocorticoids did not increase Notch signaling in bone or bone cells. Moreover, the increased expression of atrophy-related genes in muscle, but not in bone, and the decreased myotube diameter induced by glucocorticoids were prevented by inhibiting Notch signaling. Thus, glucocorticoids activate different mechanisms in bone and muscle that upregulate atrophy-related genes. However, the role of these genes in the effects of glucocorticoids in bone is unknown. Nevertheless, these findings advance our knowledge of the mechanism of action of glucocorticoids in the musculoskeletal system and provide the basis for novel therapies to prevent glucocorticoid-induced atrophy of bone and muscle. PMID:28359087

Thymic Stromal Lymphopoietin: To Cut a Long Story Short.

PubMed

Tsilingiri, Katerina; Fornasa, Giulia; Rescigno, Maria

2017-03-01

Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.

Treatment results and prognostic indicators in thymic epithelial tumors: a clinicopathological analysis of 45 patients.

PubMed

Ansari, Mansour; Dehsara, Farzin; Mohammadianpanah, Mohammad; Mosalaei, Ahmad; Omidvari, Shapour; Ahmadloo, Niloofar

2014-07-01

Thymomas are rare epithelial tumors arising from thymus gland. This study aims at investigating the clinical presentation, prognostic factors and treatment outcome of forty five patients with thymoma and thymic carcinoma. Forty-five patients being histologically diagnosed with thymoma or thymic carcinoma that were treated and followed-up at a tertiary academic hospital during January 1987 and December 2008 were selected for the present study. Twelve patients were solely treated with surgery, 14 with surgery followed by adjuvant radiotherapy, 12 with sequential combined treatment of surgery, radiotherapy and/or chemotherapy and 7 with non-surgical approach including radiotherapy and/or chemotherapy.  Tumors were classified based on the new World Health Organization (WHO) histological classification. There were 18 women and 27 men with a median age of 43 years. Twelve patients (26.7%) had stage I, 7 (17.8%) had stage II, 23 (51%) had stage III and 2 (4.5%) had stage IV disease. Tumors types were categorized as type A (n=4), type AB (n=10), type B1 (n=9), type B2 (n=10), type B3 (n=5) and type C (n=7). In univariate analysis for overall survival, disease stage (P=0.001), tumor size (P=0.017) and the extent of surgical resection (P<0.001) were prognostic factors. Regarding the multivariate analysis, only the extent of the surgical resection (P<0.001) was the independent prognostic factor and non-surgical treatment had a negative influence on the survival. The 5-year and 10-year overall survival rates were 70.8% and 62.9%, respectively. Complete surgical resection is the most important prognostic factor in patients with thymic epithelial tumors.

Quercetin Reduces Tumor Necrosis Factor Alpha-Induced Muscle Atrophy by Upregulation of Heme Oxygenase-1.

PubMed

Kim, Yeji; Kim, Chu-Sook; Joe, Yeonsoo; Chung, Hun Taeg; Ha, Tae Youl; Yu, Rina

2018-06-01

The inflammatory cytokine tumor necrosis factor α (TNFα), upregulated in the obese condition, promotes protein degradation and is implicated in obesity-related skeletal muscle atrophy and age-related sarcopenia. Quercetin, a flavonoid, elicits antioxidative and anti-inflammatory activities. In this study, we investigated the effect of quercetin on TNFα-induced skeletal muscle atrophy as well as its potential mechanism of action. In this study, we observed that quercetin suppressed expression of TNFα-induced atrophic factors such as MAFbx/atrogin-1 and MuRF1 in myotubes, and it enhanced heme oxygenase-1 (HO-1) protein level accompanied by increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in myotubes. The HO-1 inhibitor ZnPP suppressed the inhibitory actions of quercetin on TNFα-induced atrophic responses and degradation of IκB-α in myotubes. Moreover, quercetin supplementation to high-fat diet-fed obese mice inhibited obesity-induced atrophic responses in skeletal muscle, accompanied by upregulation of HO-1 and inactivation of nuclear factor-kappa B (NF-κB), and the quercetin actions were attenuated in Nrf2-deficient mice. These findings suggest that quercetin protects against TNFα-induced muscle atrophy under obese conditions through Nrf2-mediated HO-1 induction accompanied by inactivation of NF-κB. Quercetin may be used as a dietary supplement to protect against obesity-induced skeletal muscle atrophy.

Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.

PubMed

Giaccone, Giuseppe; Kim, Chul; Thompson, Jillian; McGuire, Colleen; Kallakury, Bhaskar; Chahine, Joeffrey J; Manning, Maria; Mogg, Robin; Blumenschein, Wendy M; Tan, Ming T; Subramaniam, Deepa S; Liu, Stephen V; Kaplan, Ian M; McCutcheon, Justine N

2018-03-01

Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There

Thymic cytoarchitecture changes in mice exposed to vanadium.

PubMed

Ustarroz-Cano, Martha; Garcia-Pelaez, Isabel; Cervantes-Yepez, Silvana; Lopez-Valdez, Nelly; Fortoul, Teresa I

2017-12-01

The thymus is a vital immune system organ wherein selection of T-lymphocytes occurs in a process regulated by dendritic and epithelial thymic cells. Previously, we have reported that in a mouse model of vanadium inhalation, a decrease in CD11c dendritic cells was observed. In the present study, we report on a thymic cortex-medulla distribution distortion in these hosts due to apparent effects of the inhaled vanadium on cytokeratin-5 (K5 + ) epithelial cells in the same mouse model - after 1, 2, and 4 weeks of exposure - by immunohistochemistry. These cells - together with dendritic cells - eliminate autoreactive T-cell clones and regulate the production of regulatory T-cells in situ. Because both cell types are involved in the negative selection of autoreactive clones, a potential for an increase in development of autoimmune conditions could be a possible consequence among individuals who might be exposed often to vanadium in air pollution, including dwellers of highly polluted cities with elevated levels of particulate matter onto which vanadium is often adsorbed.

Correlation between Spectral Optical Coherence Tomography and Fundus Autofluorescence at the margins of Geographic Atrophy

PubMed Central

Brar, Manpreet; Kozak, Igor; Cheng, Lingyun; Bartsch, Dirk-Uwe G.; Yuson, Ritchie; Nigam, Nitin; Oster, Stephen F.; Mojana, Francesca; Freeman, William R.

2009-01-01

Purpose We studied the appearance of margins of Geographic atrophy in high- resolution optical coherence tomography (OCT) images and correlate those changes with fundus autofluorescence imaging. Design Retrospective observational case study. Methods Patients with geographic atrophy secondary to dry age related macular degeneration (ARMD) were assessed by means of Spectral Domain OCT (Spectralis HRA/OCT; Heidelberg Engineering, Heidelberg, Germany or OTI, Inc, Toronto, Canada) as well as Autofluoresence Imaging (HRA or Spectralis Heidelberg Engineering, Heidelberg, Germany): The outer retinal layer alterations were analyzed in the junctional zone between normal retina and atrophic retina, and correlated with corresponding fundus autofluorescence. Results 23 eyes of 16 patients aged between 62 years to 96 years were examined. There was a significant association between OCT findings and the fundus autofluorescence findings(r=0.67, p<0.0001). Severe alterations of the outer retinal layers at margins on Spectral OCT correspond significantly to increased autofluorescence; Smooth margins on OCT correspond significantly to normal fundus autofluorescence. (Kappa-0.7348, p<0.0001). Conclusion Spectral OCT provides in vivo insight into the pathogenesis of geographic atrophy and its progression. Visualization of reactive changes in the retinal pigment epithelial cells at the junctional zone and correlation with increased fundus autofluorescence; secondary to increased lipofuscin may together serve as determinants of progression of geographic atrophy. PMID:19541290

IMPROVING THE AGE-RELATED MACULAR DEGENERATION CONSTRUCT: A New Classification System.

PubMed

Spaide, Richard F

2018-05-01

Previous models of disease in age-related macular degeneration (AMD) were incomplete in that they did not encompass subretinal drusenoid deposits (pseudodrusen), subtypes of neovascularization, and polypoidal choroidal vasculopathy. In addition, Type 3 neovascularization starts in the retina and may not necessarily involve the choroid. As such, the term choroidal neovascularization is not appropriate for these eyes. The new aspects in the AMD construct are to include specific lipoprotein extracellular accumulations, namely drusen and subretinal drusenoid deposits, as early AMD. The deposition of specific types of deposit seems to be highly correlated with choroidal thickness and topographical location in the macula. Late AMD includes macular neovascularization or atrophy. The particular type of extracellular deposit is predictive of the future course of the patient. For example, eyes with subretinal drusenoid deposits have a propensity to develop outer retinal atrophy, complete outer retinal and retinal pigment epithelial atrophy, or Type 3 neovascularization as specific forms of late AMD. Given Type 3 neovascularization may never involve the choroid, the term macular neovascularization is suggested for the entire spectrum of neovascular disease in AMD. In contrast to older classification systems, the proposed system encompasses the relevant presentations of disease and more precisely predicts the future course of the patient. In doing so, the concept was developed that there may be genetic risk alleles, which are not necessarily the same alleles that influence disease expression.

A case of multiple system atrophy-parkinsonian type with stuttering- and palilalia-like dysfluencies and putaminal atrophy.

PubMed

Kikuchi, Yoshikazu; Umezaki, Toshiro; Uehara, Taira; Yamaguchi, Hiroo; Yamashita, Koji; Hiwatashi, Akio; Sawatsubashi, Motohiro; Adachi, Kazuo; Yamaguchi, Yumi; Murakami, Daisuke; Kira, Jun-Ichi; Nakagawa, Takashi

2017-11-14

Both developmental and acquired stuttering are related to the function of the basal ganglia-thalamocortical loop, which includes the putamen. Here, we present a case of stuttering- and palilalia-like dysfluencies that manifested as an early symptom of multiple system atrophy-parkinsonian type (MSA-P) and bilateral atrophy of the putamen. The patient was a 72-year-old man with no history of developmental stuttering who presented with a stutter for consultation with our otorhinolaryngology department. The patient was diagnosed with MSA-P based on parkinsonism, autonomic dysfunction, and bilateral putaminal atrophy revealed by T2-weighted magnetic resonance imaging. Treatment with levodopa improved both the motor functional deficits related to MSA-P and stuttering-like dysfluencies while reading; however, the palilalia-like dysfluencies were much less responsive to levodopa therapy. The patient died of aspiration pneumonia two years after his first consultation at our hospital. In conclusion, adult-onset stuttering- and palilalia-like dysfluencies warrant careful examination of the basal ganglia-thalamocortical loop, and especially the putamen, using neuroimaging techniques. Acquired stuttering may be related to deficits in dopaminergic function. Copyright © 2017 Elsevier Inc. All rights reserved.

DISCORDANCE BETWEEN BLUE-LIGHT AUTOFLUORESCENCE AND NEAR-INFRARED AUTOFLUORESCENCE IN AGE-RELATED MACULAR DEGENERATION.

PubMed

Heiferman, Michael J; Fawzi, Amani A

2016-12-01

To identify the origin and significance of discordance between blue-light autofluorescence (BL-AF; 488 nm) and near-infrared autofluorescence (NI-AF; 787 nm) in patients with age-related macular degeneration (AMD). A total of 86 eyes of 59 patients with a diagnosis of AMD were included in this cross-sectional study conducted between March 9, 2015 and May 1, 2015. A masked observer examined the BL-AF, NI-AF, and spectral-domain optical coherence tomography images. Areas with discordance of autofluorescence patterns between NI-AF and BL-AF images were correlated with structural findings at the corresponding location in optical coherence tomography scans. Seventy-nine eyes had discordance between BL-AF and NI-AF. The most common optical coherence tomography finding accounting for these discrepancies was pigment migration accounting for 35 lesions in 21 eyes. The most clinically relevant finding was geographic atrophy missed on BL-AF in 7 eyes. Our findings indicate that variations in the distribution of lipofuscin, melanin and melanolipofuscin account for the majority of discordance between BL-AF and NI-AF. Given our finding of missed geographic atrophy lesions on BL-AF in 24% of eyes with geographic atrophy (7/29 eyes), clinicians should consider multimodal imaging, including NI-AF and optical coherence tomography, especially in clinical trials of geographic atrophy.

Discordance between Blue-Light Autofluorescence and Near-Infrared Autofluorescence in Age-Related Macular Degeneration

PubMed Central

Heiferman, Michael J.; Fawzi, Amani A.

2016-01-01

Purpose To identify the origin and significance of discordance between blue-light autofluorescence (BL-AF; 488nm) and near-infrared autofluorescence (NI-AF; 787nm) in patients with age-related macular degeneration (AMD). Methods A total of 86 eyes of 59 patients with a diagnosis of AMD were included in this cross-sectional study conducted between March 9, 2015 and May 1, 2015. A masked observer examined the BL-AF, NI-AF, and spectral-domain optical coherence tomography (OCT) images. Areas with discordance of autofluorescence patterns between NI-AF and BL-AF images were correlated with structural findings at the corresponding location in OCT scans. Results 79 eyes had discordance between BL-AF and NI-AF. The most common OCT finding accounting for these discrepancies was pigment migration accounting for 35 lesions in 21 eyes. The most clinically relevant finding was geographic atrophy missed on BL-AF in seven eyes. Conclusions Our findings indicate that variations in the distribution of lipofuscin, melanin and melanolipofuscin account for the majority of discordance between BL-AF and NI-AF. Given our finding of missed geographic atrophy lesions on BL-AF in 24% of eyes with geographic atrophy (7/29 eyes), clinicians should consider multimodal imaging, including NI-AF and OCT, especially in clinical trials of geographic atrophy. PMID:28005672

Orchitis reveals an extragonadal primary mediastinal thymic seminoma: a coincidence or not?

PubMed

Tampakis, Athanasios; Tampaki, Ekaterini Christina; Damaskos, Christos; Feretis, Themistoklis; Thymara, Irene; Kontzoglou, Konstantinos; Tomos, Periklis; Kouraklis, Gregory

2017-04-13

Mediastinal thymic seminomas are rare male germ cell tumors with extragonadal origin that appear predominately with a cystic appearance. A 22-year-old male was referred to our department for further investigation of a mediastinal mass discovered incidentally during routine chest X-ray. The patient has denied any symptoms including dyspnea, chest pain, cough, fever, dysphagia, hemoptysis, weight loss, and weakness. His past medical history was remarkable for orchitis, for which he had undergone a bilateral testicular biopsy, without the latter however, indicating the presence of a germ cell tumor or a premalignant lesion. Contrast-enhanced chest computed tomography revealed a lobulated and well-marginated cystic lesion in the anterior mediastinum. Differential diagnosis included mostly a multilocular thymic cyst, a lymphoma, a seminoma, or a soft tissue tumor. Resection of the mass revealed a primary thymic seminoma. A surgical approach for the management of these tumors might be reasonable considering that an extensive sampling is mandatory to gain an appropriate biopsy preoperatively in order to securely confirm or refute the presence of a mediastinal extragonadal tumor. Orchitis might be a sign of a general disorder of the germ cells which might transform in time.

Volumetric magnetic resonance imaging evidence of bilateral hippocampal atrophy in mesial temporal lobe epilepsy.

PubMed

Quigg, M; Bertram, E H; Jackson, T; Laws, E

1997-05-01

We measured absolute volumes and volume differences of hippocampi in patients with mesial temporal lobe epilepsy (MTLE) using volumetric magnetic resonance imaging (MRI) to determine the extent of bilateral atrophy in MTLE and to relate hippocampal volumes (HV) to outcome of temporal lobectomy. HV and hippocampal differences (HD) were measured in 40 patients with MTLE determined by pathology of hippocampal sclerosis (HS) and compared with those of age-matched controls. Results were matched with surgical outcome. Hippocampi contralateral to lobectomy (right hippocampi 2.96 +/- 0.49 cm3, left 3.14 +/- 0.51 cm3) were significantly smaller than those of controls (right hippocampi 3.73 +/- 0.52 cm3, left 3.60 +/- 0.51 cm3) but were significantly larger than hippocampi ipsilateral to lobectomy (right hippocampi 2.63 +/- 0.61 cm3, 2.18 cm3) as compared across groups by analysis of variance (ANOVA: F = 27.2, p < 0.0001). The smaller hippocampus was ipsilateral to lobectomy in 39 of 40 cases. Seven of 40 MTLE patients (18%) had bilateral atrophy, defined by volumes of each hippocampi 2 SD lower than control means. Surgical outcome was independent of hippocampal asymmetry and bilateral atrophy measured by chi-square and Fisher's exact tests. We determined that most patients with MTLE have some degree of bilateral, asymmetric hippocampal pathology. However, asymmetry and bilateral atrophy have no clear relation to surgical outcome.

Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

PubMed

Lundell, H; Svolgaard, O; Dogonowski, A-M; Romme Christensen, J; Selleberg, F; Soelberg Sørensen, P; Blinkenberg, M; Siebner, H R; Garde, E

2017-10-01

To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume?

PubMed

Lemaitre, Herve; Goldman, Aaron L; Sambataro, Fabio; Verchinski, Beth A; Meyer-Lindenberg, Andreas; Weinberger, Daniel R; Mattay, Venkata S

2012-03-01

Normal aging is accompanied by global as well as regional structural changes. While these age-related changes in gray matter volume have been extensively studied, less has been done using newer morphological indexes, such as cortical thickness and surface area. To this end, we analyzed structural images of 216 healthy volunteers, ranging from 18 to 87 years of age, using a surface-based automated parcellation approach. Linear regressions of age revealed a concomitant global age-related reduction in cortical thickness, surface area and volume. Cortical thickness and volume collectively confirmed the vulnerability of the prefrontal cortex, whereas in other cortical regions, such as in the parietal cortex, thickness was the only measure sensitive to the pronounced age-related atrophy. No cortical regions showed more surface area reduction than the global average. The distinction between these morphological measures may provide valuable information to dissect age-related structural changes of the brain, with each of these indexes probably reflecting specific histological changes occurring during aging. Published by Elsevier Inc.

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging.

PubMed

Paltsev, Michael A; Polyakova, Victoria O; Kvetnoy, Igor M; Anderson, George; Kvetnaia, Tatiana V; Linkova, Natalia S; Paltseva, Ekaterina M; Rubino, Rosa; De Cosmo, Salvatore; De Cata, Angelo; Mazzoccoli, Gianluigi

2016-03-15

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin А); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing.

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging

PubMed Central

Paltsev, Michael A.; Polyakova, Victoria O.; Kvetnoy, Igor M.; Anderson, George; Kvetnaia, Tatiana V.; Linkova, Natalia S.; Paltseva, Ekaterina M.; Rubino, Rosa; De Cosmo, Salvatore; De Cata, Angelo; Mazzoccoli, Gianluigi

2016-01-01

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin A); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing. PMID:26943046

Association between histological alterations in the thymus and sudden infant death syndrome.

PubMed

Varga, Ivan; Bódi, Ildikó; Mešťanová, Veronika; Kováč, Martin; Klein, Martin

2018-04-01

Sudden infant death syndrome (SIDS) involves the death of an infant during the first year of life and it is among the leading causes of infant mortality worldwide. One hypothesis regarding the pathogenesis of SIDS is that it results from a combination of three independent factors: endogenous vulnerability, a critical time window during postnatal development, and exogenous stressors. This hypothesis is known as the "triple-risk model". In this study, we used an immunohistological approach to compare the cellular microenvironments of thymuses from 19 infants whose sudden death was classified as SIDS and a control group, which consisted of thymuses from age-matched children undergoing surgery for various congenital heart defects. We hypothesized that morphological signs of stress-related thymic involution would be present. Based on our observations, we found evidence that the proliferation and maturation of T-lymphocytes in the thymuses of infants with SIDS were suppressed. We observed enhanced macrophage activity, suggesting an increase in the apoptosis of lymphocytes and decrease in number of thymic dendritic cells and myoid cells. Significant apoptosis of thymic lymphocytes without cell regeneration typically leads to atrophy of the thymus. All cellular events we observed resemble the initial stage of stress-related thymic involution. These results support the "triple-risk model," suggesting that certain exogenous stressors might be involved in the pathogenesis of SIDS. This was probably not recognized during the autopsies of infants who died suddenly. Copyright © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Clinical application of SPECT-CT with 99mTc-Tektrotyd in bronchial and thymic neuroendocrine tumors (NETs).

PubMed

Sergieva, Sonya; Robev, Bozhil; Dimcheva, Milena; Fakirova, Albena; Hristoskova, Radka

2016-01-01

Neuroendocrine tumors (NETs) of the thorax including bronchial and thymic tumors belong to foregut NETs. Limited loco-regional thoracic NETs can be resected with surgery, but in extensive metastatic disease the treatment is mainly palliative. A high incidence and density of somatostatin receptors (SSTR2, SSTR3, and SSTR5) are found in thoracic NETs. The purpose of this study was to evaluate the role of SPECT-CT somatostatin receptor scintigraphy (SRS) with 99mTc-Tektrotyd for imaging, staging and follow up of patients with bronchial and thymic neuroendocrine tumors. Forty-one patients with thoracic tumors with neuroendocrine differentiation were studied. Sixty-eight examinations including SPECT-CT studies of the neck and chest and/or abdomen and pelvis were carried out 2-4 hrs. post i.v. administration of aver-age 740 MBq activity dose of 99mTc-EDDA/HYNIC-TOC (Tektrotyd, Polatom). In all 41 investigated patients we obtained 81.25% (13/16), 88% (22/25) and 85.36% (35/41) of sensitivity, specificity and accuracy of this diagnostic approach, respectively. Somatostatin-receptor scintigraphy correctly identified all primary NETs located in the lungs and thymus. SPECT-CT studies with 99mTc-EDDA/HYNIC-TOC resulted in exact pre-surgical and pre-treatment N/M staging of bronchial and thymic NETs, except 2 cases with multiple hepatic metastases and 1 with massive suprarenal metastasis. It can be concluded that SPECT-CT with 99mTc-EDDA/HYNIC-TOC is a valuable tool for staging and follow-up of patients with thoracic NETs.

DICER1/Alu RNA dysmetabolism induces Caspase-8–mediated cell death in age-related macular degeneration

PubMed Central

Kim, Younghee; Tarallo, Valeria; Kerur, Nagaraj; Yasuma, Tetsuhiro; Gelfand, Bradley D.; Bastos-Carvalho, Ana; Hirano, Yoshio; Yasuma, Reo; Mizutani, Takeshi; Fowler, Benjamin J.; Li, Shengjian; Kaneko, Hiroki; Bogdanovich, Sasha; Ambati, Balamurali K.; Hinton, David R.; Hauswirth, William W.; Hakem, Razqallah; Wright, Charles; Ambati, Jayakrishna

2014-01-01

Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the disease. In this study, we implicate the involvement of Caspase-8 as a critical mediator of RPE degeneration. Here we show that DICER1 deficiency, Alu RNA accumulation, and IL-18 up-regulation lead to RPE cell death via activation of Caspase-8 through a Fas ligand-dependent mechanism. Coupled with our observation of increased Caspase-8 expression in the RPE of human eyes with geographic atrophy, our findings provide a rationale for targeting this apoptotic pathway in this disease. PMID:25349431

Treatment Results and Prognostic Indicators in Thymic Epithelial Tumors: A Clinicopathological Analysis of 45 Patients

PubMed Central

Ansari, Mansour; Dehsara, Farzin; Mohammadianpanah, Mohammad; Mosalaei, Ahmad; Omidvari, Shapour; Ahmadloo, Niloofar

2014-01-01

Background: Thymomas are rare epithelial tumors arising from thymus gland. This study aims at investigating the clinical presentation, prognostic factors and treatment outcome of forty five patients with thymoma and thymic carcinoma. Methods: Forty-five patients being histologically diagnosed with thymoma or thymic carcinoma that were treated and followed-up at a tertiary academic hospital during January 1987 and December 2008 were selected for the present study. Twelve patients were solely treated with surgery, 14 with surgery followed by adjuvant radiotherapy, 12 with sequential combined treatment of surgery, radiotherapy and/or chemotherapy and 7 with non-surgical approach including radiotherapy and/or chemotherapy.  Tumors were classified based on the new World Health Organization (WHO) histological classification. Results: There were 18 women and 27 men with a median age of 43 years. Twelve patients (26.7%) had stage I, 7 (17.8%) had stage II, 23 (51%) had stage III and 2 (4.5%) had stage IV disease. Tumors types were categorized as type A (n=4), type AB (n=10), type B1 (n=9), type B2 (n=10), type B3 (n=5) and type C (n=7). In univariate analysis for overall survival, disease stage (P=0.001), tumor size (P=0.017) and the extent of surgical resection (P<0.001) were prognostic factors. Regarding the multivariate analysis, only the extent of the surgical resection (P<0.001) was the independent prognostic factor and non-surgical treatment had a negative influence on the survival. The 5-year and 10-year overall survival rates were 70.8% and 62.9%, respectively. Conclusion: Complete surgical resection is the most important prognostic factor in patients with thymic epithelial tumors. PMID:25031486

Immunolocalization of thymosin alpha 1, thymopoietin and thymulin in mouse thymic epithelial cells at different stages of culture: a light and electron microscopic study.

PubMed Central

Fabien, N; Auger, C; Monier, J C

1988-01-01

The secretory evolution of the thymic hormones (thymulin, thymosin alpha 1 and thymopoietin) in cultured thymic reticuloepithelial cells (TREC) was studied by immunocytochemical techniques using monoclonal anti-thymulin or anti-thymosin alpha 1 and polyclonal anti-thymopoietin antibodies (Ab). The culture of TREC was performed with a medium where L-valine was replaced by D-valine, thus ensuring rapid and selective development of these cells. The number of thymulin, thymosin alpha 1 or thymopoietin-containing cells increased progressively from Day 6 to Day 12 of the culture. The localization of the three thymic hormones within the TREC also varied according to the age of the culture. By light microscopy the staining of the three hormones was localized in some cytoplasmic granules at the beginning of the culture and at Day 90, while at Day 12 it was throughout the cytoplasm. In electron microscopy these localizations corresponded respectively to vacuoles of different sizes and to cytosol. All these results show that the synthesis and excretion of thymulin, thymosin alpha 1 and thymopoietin evolve during the development of TREC in culture. Images Figure 1 Figure 2 PMID:3284819

Sleep duration and age-related changes in brain structure and cognitive performance.

PubMed

Lo, June C; Loh, Kep Kee; Zheng, Hui; Sim, Sam K Y; Chee, Michael W L

2014-07-01

To investigate the contribution of sleep duration and quality to age-related changes in brain structure and cognitive performance in relatively healthy older adults. Community-based longitudinal brain and cognitive aging study using a convenience sample. Participants were studied in a research laboratory. Relatively healthy adults aged 55 y and older at study commencement. N/A. Participants underwent magnetic resonance imaging and neuropsychological assessment every 2 y. Subjective assessments of sleep duration and quality and blood samples were obtained. Each hour of reduced sleep duration at baseline augmented the annual expansion rate of the ventricles by 0.59% (P = 0.007) and the annual decline rate in global cognitive performance by 0.67% (P = 0.050) in the subsequent 2 y after controlling for the effects of age, sex, education, and body mass index. In contrast, global sleep quality at baseline did not modulate either brain or cognitive aging. High-sensitivity C-reactive protein, a marker of systemic inflammation, showed no correlation with baseline sleep duration, brain structure, or cognitive performance. In healthy older adults, short sleep duration is associated with greater age-related brain atrophy and cognitive decline. These associations are not associated with elevated inflammatory responses among short sleepers. Lo JC, Loh KK, Zheng H, Sim SK, Chee MW. Sleep duration and age-related changes in brain structure and cognitive performance.

[Visual impairment in juvenile diabetes mellitus due to optic atrophy: Wolfram's syndrome].

PubMed

Immink, Annelies; Reeser, H Maarten; Brus, Frank

2010-01-01

Wolfram's syndrome is a rare neurodegenerative disorder, which usually first manifests itself around the age of 6 years. The diagnosis can be made based on the characteristics incorporated in the 'DIDMOAD' acronym: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. We present 2 boys, diagnosed with diabetes mellitus at the age of 5 and 4 years respectively. Both children developed optic atrophy over the years. These 2 cases illustrate that alongside diabetic retinopathy, possible syndromes, such as Wolfram's syndrome, should also be considered in children with diabetes mellitus and visual impairment.

Cholinergic epithelial cell with chemosensory traits in murine thymic medulla.

PubMed

Panneck, Alexandra Regina; Rafiq, Amir; Schütz, Burkhard; Soultanova, Aichurek; Deckmann, Klaus; Chubanov, Vladimir; Gudermann, Thomas; Weihe, Eberhard; Krasteva-Christ, Gabriela; Grau, Veronika; del Rey, Adriana; Kummer, Wolfgang

2014-12-01

Specialized epithelial cells with a tuft of apical microvilli ("brush cells") sense luminal content and initiate protective reflexes in response to potentially harmful substances. They utilize the canonical taste transduction cascade to detect "bitter" substances such as bacterial quorum-sensing molecules. In the respiratory tract, most of these cells are cholinergic and are approached by cholinoceptive sensory nerve fibers. Utilizing two different reporter mouse strains for the expression of choline acetyltransferase (ChAT), we observed intense labeling of a subset of thymic medullary cells. ChAT expression was confirmed by in situ hybridization. These cells showed expression of villin, a brush cell marker protein, and ultrastructurally exhibited lateral microvilli. They did not express neuroendocrine (chromogranin A, PGP9.5) or thymocyte (CD3) markers but rather thymic epithelial (CK8, CK18) markers and were immunoreactive for components of the taste transduction cascade such as Gα-gustducin, transient receptor potential melastatin-like subtype 5 channel (TRPM5), and phospholipase Cβ2. Reverse transcription and polymerase chain reaction confirmed the expression of Gα-gustducin, TRPM5, and phospholipase Cβ2. Thymic "cholinergic chemosensory cells" were often in direct contact with medullary epithelial cells expressing the nicotinic acetylcholine receptor subunit α3. These cells have recently been identified as terminally differentiated epithelial cells (Hassall's corpuscle-like structures in mice). Contacts with nerve fibers (identified by PGP9.5 and CGRP antibodies), however, were not observed. Our data identify, in the thymus, a previously unrecognized presumptive chemosensitive cell that probably utilizes acetylcholine for paracrine signaling. This cell might participate in intrathymic infection-sensing mechanisms.

Head circumference, atrophy, and cognition: implications for brain reserve in Alzheimer disease.

PubMed

Perneczky, R; Wagenpfeil, S; Lunetta, K L; Cupples, L A; Green, R C; Decarli, C; Farrer, L A; Kurz, A

2010-07-13

Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference. A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition. There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference. This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.

Health-related quality of life in children and adolescents with spinal muscular atrophy in the Czech Republic.

PubMed

Kocova, Helena; Dvorackova, Olga; Vondracek, Petr; Haberlova, Jana

2014-06-01

Spinal muscular atrophy is a rare hereditary neuromuscular disorder (with a prevalence of 1 per 30,000) that greatly debilitates patients and, in most cases, shortens their life expectancy. Although there is no causal therapy, improvements in symptomatic therapy have extended patients' life expectancy and increased their quality of life. Unfortunately, the advancements in care vary from country to country. To improve the care for children with spinal muscular atrophy in the Czech Republic, we created a survey to obtain the baseline information about their quality of life and compared the data with equivalent data from the United States. We used the Pediatric Quality of Life Inventory 3.0 Neuromuscular Measurement Model, which is a health-related quality of life questionnaire specific to children with neuromuscular disorders. The survey was conducted on 35 children with genetically proven spinal muscular atrophy and their parents. Compared with the US data, the Czech data generally show a lower quality of life, mainly in the family resources part. The greatest score was achieved in the section about communication. Altogether, the parents' scores are lower than those of the children. In the Czech Republic, patients with spinal muscular atrophy and, especially their parents, have a significantly lower quality of life compared with US patients, mostly because of economic factors and a lack of social support. Our results reveal areas toward which improvement should be directed. The need for family support through social care as well as civic, patient, or organizational support is accentuated. Copyright © 2014 Elsevier Inc. All rights reserved.

Thymic minimally invasive surgery: state of the art across the world: Central-South America

PubMed Central

2017-01-01

Literature suggests that, for thymectomy in myasthenia or resection of thymic tumors, minimally invasive surgery is equivalent to open surgery with regard to long-term outcomes. However, it could bring some benefits in the immediate results as complication rate or length-of-stay. There are doubts about the worldwide adoption of the method, though. In Latin America, the implementation of video-assisted thoracic surgery (VATS) started in the 1990s, but it progressed slowly. The main barriers were associated costs and training. Thymic surgery poses a bigger challenge due to its rarity, so just a few reports mention the use of the method in the region. Nonetheless, in recent years we observe a faster dissemination of the method both in number and in complexity of the procedures performed. Confirming this fact, half of the patients registered in the Brazilian Society of Thoracic Surgery database in the last 2 years as undergoing resection of thymic tumors, underwent a minimally invasive procedure. Although promising, robotic surgery is still in its early days in Latin America. PMID:29078684

Intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation; comparison with thymic lymphoepithelioma-like carcinoma and a possibility of development from a multipotential stem cell.

PubMed

Hirokawa, Mitsuyoshi; Miyauchi, Akira; Minato, Hiroshi; Yokoyama, Shigeo; Kuma, Seiji; Kojima, Masaru

2013-06-01

The purpose of our article is to describe the immunohistochemical findings of intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation (ITET/CASTLE) of the thyroid in detail, to clarify the difference between ITET/CASTLE and thymic lymphoepithelioma-like carcinoma (LELC), and to discuss the pathogenesis of ITET/CASTLE. We immunohistochemically examined five ITET/CASTLE and eight LELC cases. All of ITET/CASTLE cases were strongly positive for CD5, P63, high-molecular-weight cytokeratin and B-cell CLL/lymphoma-2. Carcinoembryonic antigen-positive carcinoma cells were found in four ITET/CASTLE cases. Neuroendocrine marker-positive carcinoma cells were scattered in all cases. Immunohistochemical findings in thymic LELC were essentially similar to those in ITET/CASTLE, but the sensitivity was different. There is a possibility that ITET/CASTLE and thymic LELC are not the quite same disease entity. We think that ITET/CASTLE is derived from ectopic thymus, but not related to solid cell nests. © 2012 APMIS Published by John Wiley & Sons Ltd.

Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy

PubMed Central

Bongers, Kale S.; Fox, Daniel K.; Kunkel, Steven D.; Stebounova, Larissa V.; Murry, Daryl J.; Pufall, Miles A.; Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.

2014-01-01

Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy. PMID:25406264

Quantitative Characteristics of Spectral-Domain Optical Coherence Tomography in Corresponding Areas of Increased Autofluorescence at the Margin of Geographic Atrophy in Patients With Age-Related Macular Degeneration.

PubMed

Hariri, Amir H; Nittala, Muneeswar G; Sadda, SriniVas R

2016-06-01

To evaluate the spectral-domain optical coherence tomography (SD-OCT) characteristics of the junctional zone corresponding to areas of increased autofluorescence (IAF) at the margin of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). SD-OCT and fundus autofluorescence (FAF) images from untreated eyes with GA available from archived studies at Doheny Image Reading Center were evaluated. Areas of definite decreased autofluorescence (DDAF) corresponding to GA, and areas of IAF at the margins of the GA were manually segmented. Eyes with evidence of IAF were selected. Following manual registration of FAF and OCT data, areas of IAF and normal fluorescence were correlated with OCT features at these locations. Thirty eyes were included. The mean retinal pigment epithelium (RPE) thickness in areas of IAF was 40.6 µm ± 7.69 µm, compared to 28.8 µm ± 7.09 µm in normal adjacent areas (P < .001). Regions of IAF at the junctional zone of GA lesions appear to correspond to thickening of the presumed RPE band on OCT. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:523-527.]. Copyright 2016, SLACK Incorporated.

Choroidal Round Hyporeflectivities in Geographic Atrophy.

PubMed

Corbelli, Eleonora; Sacconi, Riccardo; De Vitis, Luigi Antonio; Carnevali, Adriano; Rabiolo, Alessandro; Querques, Lea; Bandello, Francesco; Querques, Giuseppe

2016-01-01

In geographic atrophy (GA), choroidal vessels typically appear on structural optical coherence tomography (OCT) as hyperreflective round areas with highly reflective borders. We observed that some GA eyes show choroidal round hyporeflectivities with highly reflective borders beneath the atrophy, and futher investigated the charcteristcs by comparing structural OCT, indocyanine green angiography (ICGA) and OCT angiography (OCT-A). Round hyporeflectivities were individuated from a pool of patients with GA secondary to non-neovascular age-related macular degeneration consecutively presenting between October 2015 and March 2016 at the Medical Retina & Imaging Unit of the University Vita-Salute San Raffaele. Patients underwent a complete ophthalmologic examination including ICGA, structural OCT and OCT-A. The correspondence between choroidal round hyporeflectivities beneath GA on structural OCT and ICGA and OCT-A imaging were analyzed. Fifty eyes of 26 consecutive patients (17 females and 9 males; mean age 76.8±6.2 years) with GA were included. Twenty-nine round hyporeflectivities have been found by OCT in choroidal layers in 21 eyes of 21 patients (42.0%; estimated prevalence of 57.7%). All 29 round hyporeflectivities showed constantly a hyperreflective border and a backscattering on structural OCT, and appeared as hypofluorescent in late phase ICGA and as dark foci with non detectable flow in the choroidal segmentation of OCT-A. Interestingly, the GA area was greater in eyes with compared to eyes without round hyporeflectivities (9.30±5.74 and 5.57±4.48mm2, respectively; p = 0.01). Our results suggest that most round hyporeflectivities beneath GA may represent non-perfused or hypo-perfused choroidal vessels with non-detectable flow.

Research opportunities in muscle atrophy

NASA Technical Reports Server (NTRS)

Herbison, G. J. (Editor); Talbot, J. M. (Editor)

1984-01-01

Muscle atrophy in a weightless environment is studied. Topics of investigation include physiological factors of muscle atrophy in space flight, biochemistry, countermeasures, modelling of atrophied muscle tissue, and various methods of measurement of muscle strength and endurance. A review of the current literature and suggestions for future research are included.

T-cell receptor excision circles (TREC) in CD4+ and CD8+ T-cell subpopulations in atopic dermatitis and psoriasis show major differences in the emission of recent thymic emigrants.

PubMed

Just, Helle L; Deleuran, Mette; Vestergaard, Christian; Deleuran, Bent; Thestrup-Pedersen, Kristian

2008-01-01

We used T-cell receptor excision circles (TREC) to evaluate thymic function in adult patients with atopic dermatitis and psoriasis. We observed that men, but not women, with atopic dermatitis had a significantly faster decline in TREC content with increasing age compared with healthy men. In contrast, both men and women with psoriasis had significantly reduced TREC levels, which were, on average, only 30% of that of healthy persons. In atopic dermatitis the levels of TREC declined with increasing levels of IgE, disease intensity and extent of eczema. Furthermore, patients with atopic dermatitis showed signs of altered thymus function, as they had a significantly greater variation in TREC content measured over time than healthy controls, especially within the CD8+ T-cell subpopulation. Because both atopic dermatitis and psoriasis patients have an increased number of T-cells, this indicates that atopic dermatitis patients can have compensatory emissions of thymic emigrants, whereas psoriatic patients do not, thus supporting different thymic function in these two diseases.

Mesothelioma and thymic tumors: Treatment challenges in (outside) a network setting.

PubMed

Imbimbo, Martina; Maury, Jean-Michel; Garassino, Marina; Girard, Nicolas

2018-02-02

The management of patients with mesothelioma and thymic malignancy requires continuous multidisciplinary expertise at any step of the disease. A dramatic improvement in our knowledge has occurred in the last few years, through the development of databases, translational research programs, and clinical trials. Access to innovative strategies represents a major challenge, as there is a lack of funding for clinical research in rare cancers and their rarity precludes the design of robust clinical trials that could lead to specific approval of drugs. In this context, patient-centered initiatives, such as the establishment of dedicated networks, are warranted. International societies, such as IMIG (International Mesothelioma Interest Group) and ITMIG (International Thymic Malignancy Interest Group) provide infrastructure for global collaboration, and there are many advantages to having strong regional groups working on the same issues. There may be regional differences in risk factors, susceptibility, management and outcomes. The ability to address questions both regionally as well as globally is ideal to develop a full understanding of mesothelioma and thymic malignancies. In Europe, through the integration of national networks with EURACAN, the collaboration with academic societies and international groups, the development of networks in thoracic oncology provides multiplex integration of clinical care and research, ultimately ensuring equal access to high quality care to all patients, with the opportunity of conducting high level clinical and translational research projects. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

A Whole-Tumor Histogram Analysis of Apparent Diffusion Coefficient Maps for Differentiating Thymic Carcinoma from Lymphoma.

PubMed

Zhang, Wei; Zhou, Yue; Xu, Xiao-Quan; Kong, Ling-Yan; Xu, Hai; Yu, Tong-Fu; Shi, Hai-Bin; Feng, Qing

2018-01-01

To assess the performance of a whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating thymic carcinoma from lymphoma, and compare it with that of a commonly used hot-spot region-of-interest (ROI)-based ADC measurement. Diffusion weighted imaging data of 15 patients with thymic carcinoma and 13 patients with lymphoma were retrospectively collected and processed with a mono-exponential model. ADC measurements were performed by using a histogram-based and hot-spot-ROI-based approach. In the histogram-based approach, the following parameters were generated: mean ADC (ADC mean ), median ADC (ADC median ), 10th and 90th percentile of ADC (ADC 10 and ADC 90 ), kurtosis, and skewness. The difference in ADCs between thymic carcinoma and lymphoma was compared using a t test. Receiver operating characteristic analyses were conducted to determine and compare the differentiating performance of ADCs. Lymphoma demonstrated significantly lower ADC mean , ADC median , ADC 10 , ADC 90 , and hot-spot-ROI-based mean ADC than those found in thymic carcinoma (all p values < 0.05). There were no differences found in the kurtosis ( p = 0.412) and skewness ( p = 0.273). The ADC 10 demonstrated optimal differentiating performance (cut-off value, 0.403 × 10 -3 mm 2 /s; area under the receiver operating characteristic curve [AUC], 0.977; sensitivity, 92.3%; specificity, 93.3%), followed by the ADC mean , ADC median , ADC 90 , and hot-spot-ROI-based mean ADC. The AUC of ADC 10 was significantly higher than that of the hot spot ROI based ADC (0.977 vs. 0.797, p = 0.036). Compared with the commonly used hot spot ROI based ADC measurement, a histogram analysis of ADC maps can improve the differentiating performance between thymic carcinoma and lymphoma.

Reduced modulation of scanpaths in response to task demands in posterior cortical atrophy.

PubMed

Shakespeare, Timothy J; Pertzov, Yoni; Yong, Keir X X; Nicholas, Jennifer; Crutch, Sebastian J

2015-02-01

A difficulty in perceiving visual scenes is one of the most striking impairments experienced by patients with the clinico-radiological syndrome posterior cortical atrophy (PCA). However whilst a number of studies have investigated perception of relatively simple experimental stimuli in these individuals, little is known about multiple object and complex scene perception and the role of eye movements in posterior cortical atrophy. We embrace the distinction between high-level (top-down) and low-level (bottom-up) influences upon scanning eye movements when looking at scenes. This distinction was inspired by Yarbus (1967), who demonstrated how the location of our fixations is affected by task instructions and not only the stimulus' low level properties. We therefore examined how scanning patterns are influenced by task instructions and low-level visual properties in 7 patients with posterior cortical atrophy, 8 patients with typical Alzheimer's disease, and 19 healthy age-matched controls. Each participant viewed 10 scenes under four task conditions (encoding, recognition, search and description) whilst eye movements were recorded. The results reveal significant differences between groups in the impact of test instructions upon scanpaths. Across tasks without a search component, posterior cortical atrophy patients were significantly less consistent than typical Alzheimer's disease patients and controls in where they were looking. By contrast, when comparing search and non-search tasks, it was controls who exhibited lowest between-task similarity ratings, suggesting they were better able than posterior cortical atrophy or typical Alzheimer's disease patients to respond appropriately to high-level needs by looking at task-relevant regions of a scene. Posterior cortical atrophy patients had a significant tendency to fixate upon more low-level salient parts of the scenes than controls irrespective of the viewing task. The study provides a detailed characterisation of

Striatal and Hippocampal Atrophy in Idiopathic Parkinson's Disease Patients without Dementia: A Morphometric Analysis.

PubMed

Tanner, Jared J; McFarland, Nikolaus R; Price, Catherine C

2017-01-01

Analyses of subcortical gray structure volumes in non-demented idiopathic Parkinson's disease (PD) often, but not always, show volume loss of the putamen, caudate nucleus, nucleus accumbens, and hippocampus. There is building evidence that structure morphometry might be more sensitive to disease-related processes than volume. To assess morphometric differences of subcortical structures (putamen, caudate nucleus, thalamus, globus pallidus, nucleus accumbens, and amygdala) as well as the hippocampus in non-demented individuals with PD relative to age and education matched non-PD peers. Prospective recruitment of idiopathic no-dementia PD and non-PD peers as part of a federally funded investigation. T1-weighted isovoxel metrics acquired via 3-T Siemens Verio for all individuals [PD n  = 72 (left side onset n  = 27, right side onset n  = 45); non-PD n  = 48]. FIRST (FMRIB Software Library) applications provided volumetric and vertex analyses on group differences for structure size and morphometry. Group volume differences were observed only for putamen and hippocampi (PD < non-PD) with hippocampal volume significantly associating with disease duration. Group shape differences were observed for bilateral putamen, caudate nucleus, and hippocampus with greater striatal atrophy contralateral to side of motor symptom onset. Hippocampal shape differences disappeared when removing the effects of volume. The putamen was the primary structure to show both volume and shape differences in PD, indicating that the putamen is the predominant site of basal ganglia atrophy in early- to mid-stage PD. Side of PD symptom onset associates with contralateral striatal atrophy. Left-onset PD might experience more extensive striatal atrophy than right-onset PD. Hippocampus morphometric results suggest possible primary atrophy of CA3/4 and dentate gyrus.

Interleukin-1 stimulates zinc uptake by human thymic epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coto, J.A.; Hadden, J.W.

1991-03-15

Thymic epithelial cells (TEC) are known to secrete peptides which influence the differentiation and maturation of T-lymphocytes. These peptides include the thymic hormones thymulin, thymosin-{alpha}1, and thymopoietin. The biological activity of thymulin is dependent on the presence of zinc in an equimolar ratio. The authors have shown that both interleukin-1{alpha}(IL-1{alpha}) and interleukin-1{beta}(IL-1{beta}), which stimulate proliferation of TEC, stimulate the uptake of Zn-65 in-vitro independent of this proliferation. Mitomycin-C was used to inhibit the proliferation of TEC. Two other stimulators of proliferation of TEC, bovine pituitary extract (BPE) and epidermal growth factor (EGF), did not stimulate zinc uptake by the TECmore » independent of proliferation. They have also shown, utilizing in-situ hybridization, that IL-1 and zinc induce metallothionein(MT) mRNA expression in human thymic epithelial cells. The exact role of metallothionein is not clear, but it is thought to be involved in regulation of trace metal metabolism, especially in maintenance of zinc homeostasis. Their current hypothesis is that IL-1 stimulates uptake of zinc into the TEC, followed by its complexing with metallothionein. Zinc is then thought to be transferred from metallothionein to thymulin. Immunostaining, utilizing an antithymulin antibody and a fluoresceinated goat anti-rabbit second antibody, confirms the presence of thymulin in TEC and its dependence on zinc. Upon stimulation, thymulin is then secreted. Known stimulants for thymulin include progesterone, dexamethasone, estradiol, testosterone, and prolactin. None of these secretagogues increase zinc uptake, suggesting the priming of the zinc-thymulin complex is unrelated to the regulation of its secretion.« less

Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors

PubMed Central

Steele, Keith E.; Ni, Ai; Moreira, Andre L.; Rekhtman, Natasha; Robbins, Paul B.; Karakunnel, Joyson; Rimner, Andreas; Huang, James; Riely, Gregory J.; Hellmann, Matthew D.

2017-01-01

Introduction The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs. Methods Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry. Results PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p<0.01), and was associated with longer overall survival (p = 0.02). TIM-3 and GITR were expressed in all TETs, including 18/23 and 12/23 with at least moderate/high expression, respectively. Moderate/high CD137 expression correlated with CD8+ (p = 0.01) and moderate/high GITR expression co-associated with PD-1 (p = 0.043). Conclusions TETs are characterized by frequent PD-L1 expression and PD-L1 is associated with improved survival, suggesting PD-L1 signaling may be biologically important in TETs. Robust expression of markers of immune activation and immunotherapeutic target molecules in TETs emphasizes the potential for development of anti-PD-1/PD-L1 therapies. PMID:28771603

Pretransplant thymic function predicts acute rejection in antithymocyte globulin-treated renal transplant recipients.

PubMed

Bamoulid, Jamal; Courivaud, Cécile; Crepin, Thomas; Carron, Clémence; Gaiffe, Emilie; Roubiou, Caroline; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Ducloux, Didier

2016-05-01

Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Inflammation and Atrophy Precede Prostate Neoplasia in PhIP Induced Rat Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borowsky, A D; Dingley, K; Ubick, E

2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) has been implicated as a major mutagenic heterocyclic amine in the human diet and is carcinogenic in the rat prostate. In order to validate PhIP induced rat prostate neoplasia as a model of human prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow the progressive changes over time. We fed 67 male Fischer F344 5 week old rats with PhIP (400 PPM) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at age 25 weeks, 45 weeks, and 65 weeks. Animals treated with PhIPmore » showed significantly more inflammation (P=.002 (25wk), >.001(45wk), .016(65wk)) and atrophy (P=.003(25wk), >.001(45wk), .006 (65wk)) in their prostate glands relative to controls. Prostatic intraepithelial neoplasia (PIN) occurred only in PhIP treated rats. PIN lesions arose in areas of glandular atrophy, most often in the ventral prostate. Atypical cells in areas of atrophy show loss of glutathione S-transferase pi immunostaining preceding development of PIN. None of the animals in this study developed invasive carcinomas differing from previous reports. Overall, these findings suggest that the pathogenesis of prostatic neoplasia in the PhIP treated rat prostate proceeds from inflammation to post-inflammatory proliferative atrophy to PIN.« less

Disease-Induced Skeletal Muscle Atrophy and Fatigue

PubMed Central

Powers, Scott K.; Lynch, Gordon S.; Murphy, Kate T.; Reid, Michael B.; Zijdewind, Inge

2016-01-01

Numerous health problems including acute critical illness, cancer, diseases associated with chronic inflammation, and neurological disorders often result in skeletal muscle weakness and fatigue. Disease-related muscle atrophy and fatigue is an important clinical problem because acquired skeletal muscle weakness can increase the duration of hospitalization, result in exercise limitation, and contribute to a poor quality of life. Importantly, skeletal muscle atrophy is also associated with increased morbidity and mortality of patients. Therefore, improving our understanding of the mechanism(s) responsible for skeletal muscle weakness and fatigue in patients is a required first step to develop clinical protocols to prevent these skeletal muscle problems. This review will highlight the consequences and potential mechanisms responsible for skeletal muscle atrophy and fatigue in patients suffering from acute critical illness, cancer, chronic inflammatory diseases, and neurological disorders. PMID:27128663

Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients.

PubMed

Braverman, Eric R; Blum, Kenneth; Hussman, Karl L; Han, David; Dushaj, Kristina; Li, Mona; Marin, Gabriela; Badgaiyan, Rajendra D; Smayda, Richard; Gold, Mark S

2015-01-01

To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19-90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost

Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients

PubMed Central

Braverman, Eric R.; Blum, Kenneth; Hussman, Karl L.; Han, David; Dushaj, Kristina; Li, Mona; Marin, Gabriela; Badgaiyan, Rajendra D.; Smayda, Richard; Gold, Mark S.

2015-01-01

To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19–90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost

Fundus Autofluorescence in Age-related Macular Degeneration

PubMed Central

Ly, Angelica; Nivison-Smith, Lisa; Assaad, Nagi; Kalloniatis, Michael

2017-01-01

ABSTRACT Fundus autofluorescence (FAF) provides detailed insight into the health of the retinal pigment epithelium (RPE). This is highly valuable in age-related macular degeneration (AMD) as RPE damage is a hallmark of the disease. The purpose of this paper is to critically appraise current clinical descriptions regarding the appearance of AMD using FAF and to integrate these findings into a chair-side reference. A wide variety of FAF patterns have been described in AMD, which is consistent with the clinical heterogeneity of the disease. In particular, FAF imaging in early to intermediate AMD has the capacity to reveal RPE alterations in areas that appear normal on funduscopy, which aids in the stratification of cases and may have visually significant prognostic implications. It can assist in differential diagnoses and also represents a reliable, sensitive method for distinguishing reticular pseudodrusen. FAF is especially valuable in the detection, evaluation, and monitoring of geographic atrophy and has been used as an endpoint in clinical trials. In neovascular AMD, FAF reveals distinct patterns of classic choroidal neovascularization noninvasively and may be especially useful for determining which eyes are likely to benefit from therapeutic intervention. FAF represents a rapid, effective, noninvasive imaging method that has been underutilized, and incorporation into the routine assessment of AMD cases should be considered. However, the practicing clinician should also be aware of the limitations of the modality, such as in the detection of foveal involvement and in the distinction of phenotypes (hypo-autofluorescent drusen from small areas of geographic atrophy). PMID:27668639

Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance

PubMed Central

Lo, June C.; Loh, Kep Kee; Zheng, Hui; Sim, Sam K.Y.; Chee, Michael W.L.

2014-01-01

Study Objectives: To investigate the contribution of sleep duration and quality to age-related changes in brain structure and cognitive performance in relatively healthy older adults. Design: Community-based longitudinal brain and cognitive aging study using a convenience sample. Setting: Participants were studied in a research laboratory. Participants: Relatively healthy adults aged 55 y and older at study commencement. Interventions: N/A. Measurements and Results: Participants underwent magnetic resonance imaging and neuropsychological assessment every 2 y. Subjective assessments of sleep duration and quality and blood samples were obtained. Each hour of reduced sleep duration at baseline augmented the annual expansion rate of the ventricles by 0.59% (P = 0.007) and the annual decline rate in global cognitive performance by 0.67% (P = 0.050) in the subsequent 2 y after controlling for the effects of age, sex, education, and body mass index. In contrast, global sleep quality at baseline did not modulate either brain or cognitive aging. High-sensitivity C-reactive protein, a marker of systemic inflammation, showed no correlation with baseline sleep duration, brain structure, or cognitive performance. Conclusions: In healthy older adults, short sleep duration is associated with greater age-related brain atrophy and cognitive decline. These associations are not associated with elevated inflammatory responses among short sleepers. Citation: Lo JC, Loh KK, Zheng H, Sim SK, Chee MW. Sleep duration and age-related changes in brain structure and cognitive performance. SLEEP 2014;37(7):1171-1178. PMID:25061245

Visual recovery from optic atrophy following acute optic neuropathy in the fellow eye.

PubMed

Ornek, Kemal; Ornek, Nurgül

2012-06-01

The left eye of a 65-year-old male was blind due to optic atrophy and only seeing eye had also dry type age-related macular degeneration. An anterior ischemic optic neuropathy developed in the better seeing eye. Vision recovered in the blind eye in a short time after losing the better eye. Gaining some vision in a blind eye may be an adaptation of visual pathway in such patients.

Postradiation atrophy of mature bone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erguen, H.; Howland, W.J.

1980-01-01

The growing number of oncological patients subjected to radiotherapy require the diagnostic radiologist to be aware of expected bone changes following irradiation and the differentiation of this entity from metastasis. The primary event of radiation damage to bone is atrophy and true necrosis of bone is uncommon. The postradiation atrophic changes of bone are the result of combined cellular and vascular damage, the former being more important. The damage to the osteoblast resulting in decreased matrix production is apparently the primary histopathologic event. Radiation damaged bone is susceptible to superimposed complications of fracture, infection, necrosis, and sarcoma. The primary radiographicmore » evidence of atrophy, localized osteopenia, is late in appearing, mainly because of the relative insensitivity of radiographs in detecting demineralization. Contrary to former views, the mature bone is quite radiosensitive and reacts quickly to even small doses of radiation. In vivo midrodensitometric analysis and radionuclide bone and bone marrow scans can reveal early changes following irradiation. The differentiation of postirradiation atrophy and metastasis may be difficult. Biopsy should be the last resort because of the possibility of causing true necrosis in atrophic bone by trauma and infection.« less

Postradiation atrophy of mature bone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ergun, H.; Howland, W.J.

1980-01-01

The growing number of oncological patients subjected to radiotherapy require the diagnostic radiologist to be aware of expected bone changes following irradiation and the differentiation of this entity from metastasis. The primary event of radiation damage to bone is atrophy and true necrosis of bone is uncommon. The postradiation atrophic changes of bone are the result of combined cellular and vascular damage, the former being more important. The damage to the osteoblast resulting in decreased matrix production is apparently the primary histopathologic event. Radiation damaged bone is susceptible to superimposed complications of fracture, infection, necrosis, and sarcoma. The primary radiographicmore » evidence of atrophy, localized osteopenia, is late in appearing, mainly because of the relative insensitivity of radiographs in detecing demineralization. Contrary to former views, the mature bone is quite radiosensitive and reacts quickly to even small doses of radiation. In vivo midrodensitometric analysis and radionuclide bone and bone marrow scans can reveal early changes following irradiation. The differentiation of postirradiation atrophy and metastasis may be difficult. Biopsy should be the last resort because of the possibility of causing true necrosis in atrophic bone by trauma and infection.« less

Distinct aspects of frontal lobe structure mediate age-related differences in fluid intelligence and multitasking

PubMed Central

Kievit, Rogier A.; Davis, Simon W.; Mitchell, Daniel J.; Taylor, Jason R.; Duncan, John; Tyler, Lorraine K.; Brayne, Carol; Bullmore, Ed; Calder, Andrew; Cusack, Rhodri; Dalgleish, Tim; Matthews, Fiona; Marslen-Wilson, William; Rowe, James; Shafto, Meredith; Campbell, Karen; Cheung, Teresa; Geerligs, Linda; McCarrey, Anna; Tsvetanov, Kamen; Williams, Nitin; Bates, Lauren; Emery, Tina; Erzinçlioglu, Sharon; Gadie, Andrew; Gerbase, Sofia; Georgieva, Stanimira; Hanley, Claire; Parkin, Beth; Troy, David; Allen, Jodie; Amery, Gillian; Amunts, Liana; Barcroft, Anne; Castle, Amanda; Dias, Cheryl; Dowrick, Jonathan; Fair, Melissa; Fisher, Hayley; Goulding, Anna; Grewal, Adarsh; Hale, Geoff; Hilton, Andrew; Johnson, Frances; Johnston, Patricia; Kavanagh-Williamson, Thea; Kwasniewska, Magdalena; McMinn, Alison; Norman, Kim; Penrose, Jessica; Roby, Fiona; Rowland, Diane; Sargeant, John; Squire, Maggie; Stevens, Beth; Stoddart, Aldabra; Stone, Cheryl; Thompson, Tracy; Yazlik, Ozlem; Barnes, Dan; Dixon, Marie; Hillman, Jaya; Mitchell, Joanne; Villis, Laura; Henson, Richard N.A.

2014-01-01

Ageing is characterized by declines on a variety of cognitive measures. These declines are often attributed to a general, unitary underlying cause, such as a reduction in executive function owing to atrophy of the prefrontal cortex. However, age-related changes are likely multifactorial, and the relationship between neural changes and cognitive measures is not well-understood. Here we address this in a large (N=567), population-based sample drawn from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. We relate fluid intelligence and multitasking to multiple brain measures, including grey matter in various prefrontal regions and white matter integrity connecting those regions. We show that multitasking and fluid intelligence are separable cognitive abilities, with differential sensitivities to age, which are mediated by distinct neural subsystems that show different prediction in older versus younger individuals. These results suggest that prefrontal ageing is a manifold process demanding multifaceted models of neurocognitive ageing. PMID:25519467

Surgical outcome in thymic tumors with myasthenia gravis after plasmapheresis--a comparative study.

PubMed

Sarkar, Binay Krishna; Sengupta, Pratim; Sarkar, Uday Narayan

2008-12-01

Plasmapheresis has been used widely in the treatment of myasthenia gravis and also in symptomatic thymectomized patients with short-term clinical improvement. But the utility of preoperative plasmapheresis in the outcome has not been widely studied. The authors analyzed its impact in the surgical outcome of thymic tumors with myasthenia gravis. We studied a total of 19 patients, who were operated on in the period from January 2000 to July 2006 for thymic tumors with myasthenia gravis. Of these 19 patients, preoperative plasmapheresis was performed in 10 patients (group B) and the remaining nine patients (group A) had no preoperative plasmapheresis based on risk factors for requirement of postoperative ventilation. Outcome in the form of requirement of ventilation, symptomatic improvement, hospital stay and requirement of drugs were assessed at the end of one year and compared between the two groups. Six out of nine patients (67%) in group A required ventilatory support in the immediate postoperative period, whereas two out of ten patients (20%) in group B required it. Significant and sustained symptomatic improvement was noted in group B as compared with group A (P<0.01). Preoperative plasmapheresis in the patients of thymic tumors with myasthenia gravis is beneficial and can cause a significant difference in the postoperative outcome.

Anti-Apoptotic Signature in Thymic Squamous Cell Carcinomas - Functional Relevance of Anti-Apoptotic BIRC3 Expression in the Thymic Carcinoma Cell Line 1889c.

PubMed

Huang, Bei; Belharazem, Djeda; Li, Li; Kneitz, Susanne; Schnabel, Philipp A; Rieker, Ralf J; Körner, Daniel; Nix, Wilfred; Schalke, Berthold; Müller-Hermelink, Hans Konrad; Ott, German; Rosenwald, Andreas; Ströbel, Philipp; Marx, Alexander

2013-01-01

The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.

[Histological changes of gastric atrophy and intestinal metaplasia after Helicobacter pylori eradication].

PubMed

Lee, Yonggu; Jeon, Yong Cheol; Koo, Tai Yeon; Cho, Hyun Seok; Byun, Tae Jun; Kim, Tae Yeob; Lee, Hang Lak; Eun, Chang Soo; Lee, Oh Young; Han, Dong Soo; Sohn, Joo Hyun; Yoon, Byung Chul

2007-11-01

Long-term Helicobater pylori infection results in atrophic gastritis and intestinal metaplasia, and increases the risk of gastric cancer. However, it is still controversial that eradication of H. pylori improves atrophy or metaplasia. Therefore, we investigated histological changes after the H. pylori eradication in patients with atrophy or metaplasia. One hundred seven patients who received successful eradication of H. pylori infection in Hanyang University, Guri Hospital from March 2001 to April 2006, were enrolled. Antral biopsy was taken before the eradication to confirm the H. pylori infection and grade of atrophy or metaplasia by updated Sydney System. After a certain period of time, antral biopsy was repeatedly taken to confirm the eradication and investigate histological changes of atrophy or metaplasia. Mean age of the patients was 55.3+/-11.3, and average follow-up period was 28.7+/-13.9 months. Endoscopic diagnosis included gastric ulcer, duodenal ulcer, non-ulcer antral gastritis. Atrophy was observed in 41 of 91 and their average score was 0.73+/-0.92. After the eradication of H. pylori, atrophy was improved (0.38+/-0.70, p=0.025). However, metaplasia which was observed in 49 of 107, did not significantly improve during the follow-up period. Newly developed atrophy (7 of 38) or metaplasia (18 of 49) was observed in patients who without atrophy or metaplasia initially. Their average scores were slightly lower than those of cases with pre-existing atrophy or metaplasia without statistical significance. After the eradication of H. pylori infection, atrophic gastritis may be improved, but change of intestinal metaplasia is milder and may take longer duration for improvement.

cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.

PubMed

Kerur, Nagaraj; Fukuda, Shinichi; Banerjee, Daipayan; Kim, Younghee; Fu, Dongxu; Apicella, Ivana; Varshney, Akhil; Yasuma, Reo; Fowler, Benjamin J; Baghdasaryan, Elmira; Marion, Kenneth M; Huang, Xiwen; Yasuma, Tetsuhiro; Hirano, Yoshio; Serbulea, Vlad; Ambati, Meenakshi; Ambati, Vidya L; Kajiwara, Yuji; Ambati, Kameshwari; Hirahara, Shuichiro; Bastos-Carvalho, Ana; Ogura, Yuichiro; Terasaki, Hiroko; Oshika, Tetsuro; Kim, Kyung Bo; Hinton, David R; Leitinger, Norbert; Cambier, John C; Buxbaum, Joseph D; Kenney, M Cristina; Jazwinski, S Michal; Nagai, Hiroshi; Hara, Isao; West, A Phillip; Fitzgerald, Katherine A; Sadda, SriniVas R; Gelfand, Bradley D; Ambati, Jayakrishna

2018-01-01

Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.

Histogram analysis of apparent diffusion coefficient maps for assessing thymic epithelial tumours: correlation with world health organization classification and clinical staging.

PubMed

Kong, Ling-Yan; Zhang, Wei; Zhou, Yue; Xu, Hai; Shi, Hai-Bin; Feng, Qing; Xu, Xiao-Quan; Yu, Tong-Fu

2018-04-01

To investigate the value of apparent diffusion coefficients (ADCs) histogram analysis for assessing World Health Organization (WHO) pathological classification and Masaoka clinical stages of thymic epithelial tumours. 37 patients with histologically confirmed thymic epithelial tumours were enrolled. ADC measurements were performed using hot-spot ROI (ADC HS-ROI ) and histogram-based approach. ADC histogram parameters included mean ADC (ADC mean ), median ADC (ADC median ), 10 and 90 percentile of ADC (ADC 10 and ADC 90 ), kurtosis and skewness. One-way ANOVA, independent-sample t-test, and receiver operating characteristic were used for statistical analyses. There were significant differences in ADC mean , ADC median , ADC 10 , ADC 90 and ADC HS-ROI among low-risk thymoma (type A, AB, B1; n = 14), high-risk thymoma (type B2, B3; n = 9) and thymic carcinoma (type C, n = 14) groups (all p-values <0.05), while no significant difference in skewness (p = 0.181) and kurtosis (p = 0.088). ADC 10 showed best differentiating ability (cut-off value, ≤0.689 × 10 -3 mm 2 s -1 ; AUC, 0.957; sensitivity, 95.65%; specificity, 92.86%) for discriminating low-risk thymoma from high-risk thymoma and thymic carcinoma. Advanced Masaoka stages (Stage III and IV; n = 24) tumours showed significant lower ADC parameters and higher kurtosis than early Masaoka stage (Stage I and II; n = 13) tumours (all p-values <0.05), while no significant difference on skewness (p = 0.063). ADC 10 showed best differentiating ability (cut-off value, ≤0.689 × 10 -3 mm 2 s -1 ; AUC, 0.913; sensitivity, 91.30%; specificity, 85.71%) for discriminating advanced and early Masaoka stage epithelial tumours. ADC histogram analysis may assist in assessing the WHO pathological classification and Masaoka clinical stages of thymic epithelial tumours. Advances in knowledge: 1. ADC histogram analysis could help to assess WHO pathological classification of thymic epithelial tumours. 2. ADC histogram analysis could

Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG).

PubMed

de Diego, Víctor; Martínez-Monseny, Antonio F; Muchart, Jordi; Cuadras, Daniel; Montero, Raquel; Artuch, Rafael; Pérez-Cerdá, Celia; Pérez, Belén; Pérez-Dueñas, Belén; Poretti, Andrea; Serrano, Mercedes

2017-09-01

We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.

FOUR-YEAR INCIDENCE AND PROGRESSION OF AGE-RELATED MACULAR DEGENERATION: THE LOS ANGELES LATINO EYE STUDY

PubMed Central

Varma, Rohit; Foong, Athena W.P.; Lai, Mei-Ying; Choudhury, Farzana; Klein, Ronald; Azen, Stanley P.

2011-01-01

Purpose To estimate 4-year incidence and progression of early and advanced age-related macular degeneration (AMD). Design Population-based cohort study. Methods A comprehensive ophthalmologic examination including stereoscopic fundus photography was performed on adult Latinos at baseline and follow-up. Photographs were graded using a modified Wisconsin Age-Related Maculopathy Grading System. For estimations of incidence and progression of AMD, the Age Related Eye Disease Study Scale was used. Main outcome measures are incidence and progression of early AMD (drusen type, drusen size, and retinal pigmentary abnormalities) and advanced AMD (exudative AMD and geographic atrophy). Results 4,658/6100 (76%) completed the follow-up examination. The 4-year incidence of early AMD was 7.5% (95%CI:6.6,8.4) and advanced AMD was 0.2% (95%CI:0.1,0.4). Progression of any AMD occurred in 9.3% (95%CI:8.4,10.3) of at-risk participants. Incidence and progression increased with age. Incidence of early AMD in the second eye (10.8%) was higher than incidence in the first eye (6.9%). Baseline presence of soft indistinct large drusen≥250μm in diameter was more likely to predict the 4-year incidence of pigmentary abnormalities, geographic atrophy, and exudative AMD than smaller or hard or soft distinct drusen. Conclusions Age-specific incidence and progression of AMD in Latinos are lower than in non-Hispanic whites. While incident early AMD is more often unilateral, the risk of its development in the second is higher than in the first eye. Older persons and those with soft indistinct large drusen had a higher risk of developing advanced AMD compared to those who were younger and did not have soft indistinct large drusen. PMID:20399926

Losartan Restores Skeletal Muscle Remodeling and Protects Against Disuse Atrophy in Sarcopenia

PubMed Central

Burks, Tyesha N.; Andres-Mateos, Eva; Marx, Ruth; Mejias, Rebeca; Van Erp, Christel; Simmers, Jessica L.; Walston, Jeremy D.; Ward, Christopher W.; Cohn, Ronald D.

2011-01-01

Sarcopenia, a critical loss of muscle mass and function because of the physiological process of aging, contributes to disability and mortality in older adults. It increases the incidence of pathologic fractures, causing prolonged periods of hospitalization and rehabilitation. The molecular mechanisms underlying sarcopenia are poorly understood, but recent evidence suggests that increased transforming growth factor–β (TGF-β) signaling contributes to impaired satellite cell function and muscle repair in aged skeletal muscle. We therefore evaluated whether antagonism of TGF-β signaling via losartan, an angiotensin II receptor antagonist commonly used to treat high blood pressure, had a beneficial impact on the muscle remodeling process of sarcopenic mice. We demonstrated that mice treated with losartan developed significantly less fibrosis and exhibited improved in vivo muscle function after cardiotoxin-induced injury. We found that losartan not only blunted the canonical TGF-β signaling cascade but also modulated the noncanonical TGF-β mitogen-activated protein kinase pathway. We next assessed whether losartan was able to combat disuse atrophy in aged mice that were subjected to hindlimb immobilization. We showed that immobilized mice treated with losartan were protected against loss of muscle mass. Unexpectedly, this protective mechanism was not mediated by TGF-β signaling but was due to an increased activation of the insulin-like growth factor 1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. Thus, blockade of the AT1 (angiotensin II type I) receptor improved muscle remodeling and protected against disuse atrophy by differentially regulating the TGF-β and IGF-1/Akt/mTOR signaling cascades, two pathways critical for skeletal muscle homeostasis. Thus, losartan, a Food and Drug Administration–approved drug, may prove to have clinical benefits to combat injury-related muscle remodeling and provide protection against disuse atrophy in humans with

Radioimmunoassays for the serum thymic factor (FTS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erickson, B.W.; Fok, K.F.; Incefy, G.S.

1987-01-06

This patent describes a radioimmunoassay of serum thymic factor (FTS) in a test sample, comprising: (a) contacting a first aliquot of the sample with anti-FTS antibody, with a known amount of FTS hormone standard and a known amount of radiolabeled FTS analogue; and (b) contacting a second aliquot of the sample with anti-FTS antibody and a known amount of radiolabeled FTS analogue; and (c) measuring the radioactivity of the antigen-antibody complex in each aliquot; and (d) calculating the amount of FTS in the test sample.

Risk assessment model for development of advanced age-related macular degeneration.

PubMed

Klein, Michael L; Francis, Peter J; Ferris, Frederick L; Hamon, Sara C; Clemons, Traci E

2011-12-01

To design a risk assessment model for development of advanced age-related macular degeneration (AMD) incorporating phenotypic, demographic, environmental, and genetic risk factors. We evaluated longitudinal data from 2846 participants in the Age-Related Eye Disease Study. At baseline, these individuals had all levels of AMD, ranging from none to unilateral advanced AMD (neovascular or geographic atrophy). Follow-up averaged 9.3 years. We performed a Cox proportional hazards analysis with demographic, environmental, phenotypic, and genetic covariates and constructed a risk assessment model for development of advanced AMD. Performance of the model was evaluated using the C statistic and the Brier score and externally validated in participants in the Complications of Age-Related Macular Degeneration Prevention Trial. The final model included the following independent variables: age, smoking history, family history of AMD (first-degree member), phenotype based on a modified Age-Related Eye Disease Study simple scale score, and genetic variants CFH Y402H and ARMS2 A69S. The model did well on performance measures, with very good discrimination (C statistic = 0.872) and excellent calibration and overall performance (Brier score at 5 years = 0.08). Successful external validation was performed, and a risk assessment tool was designed for use with or without the genetic component. We constructed a risk assessment model for development of advanced AMD. The model performed well on measures of discrimination, calibration, and overall performance and was successfully externally validated. This risk assessment tool is available for online use.

MiR-467a is Upregulated in Radiation-Induced Mouse Thymic Lymphomas and Regulates Apoptosis by Targeting Fas and Bax

PubMed Central

Gao, Fu; Chen, Song; Sun, Mingjuan; Mitchel, Ronald E.J.; Li, Bailong; Chu, Zhiyong; Cai, Jianming; Liu, Cong

2015-01-01

It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax

Thymic alterations in GM2 gangliosidoses model mice.

PubMed

Kanzaki, Seiichi; Yamaguchi, Akira; Yamaguchi, Kayoko; Kojima, Yoshitsugu; Suzuki, Kyoko; Koumitsu, Noriko; Nagashima, Yoji; Nagahama, Kiyotaka; Ehara, Michiko; Hirayasu, Yoshio; Ryo, Akihide; Aoki, Ichiro; Yamanaka, Shoji

2010-08-10

Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4(+)/CD8(+) T cells and a significantly increased number of CD4(+)/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRγ additionally disrupted Hexb(-/-) mice. These results suggest that the FcRγ chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13.

Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases.

PubMed

Kovacs, Gabor G; Robinson, John L; Xie, Sharon X; Lee, Edward B; Grossman, Murray; Wolk, David A; Irwin, David J; Weintraub, Dan; Kim, Christopher F; Schuck, Theresa; Yousef, Ahmed; Wagner, Stephanie T; Suh, Eunran; Van Deerlin, Vivianna M; Lee, Virginia M-Y; Trojanowski, John Q

2017-04-01

The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE ε4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

Anti-Apoptotic Signature in Thymic Squamous Cell Carcinomas – Functional Relevance of Anti-Apoptotic BIRC3 Expression in the Thymic Carcinoma Cell Line 1889c

PubMed Central

Huang, Bei; Belharazem, Djeda; Li, Li; Kneitz, Susanne; Schnabel, Philipp A.; Rieker, Ralf J.; Körner, Daniel; Nix, Wilfred; Schalke, Berthold; Müller-Hermelink, Hans Konrad; Ott, German; Rosenwald, Andreas; Ströbel, Philipp; Marx, Alexander

2013-01-01

The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC. PMID:24427739

Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein.

PubMed

Ramsey, Kimberley; Luckashenak, Nancy; Koretzky, Gary A; Clements, James L

2008-02-01

Intracellular signaling initiated by ligation of the TCR influences cell fate at multiple points during the lifespan of a T cell. This is especially evident during thymic selection, where the nature of TCR-dependent signaling helps to establish a MHC-restricted, self-tolerant T cell repertoire. The Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) adaptor protein is a required intermediate in multiple signaling pathways triggered by TCR engagement, several of which have been implicated in dictating the outcome of thymic selection (e.g., intracellular calcium flux and activation of ERK family MAPKs). To determine if thymocyte maturation and selection at later stages of development are sensitive to perturbations in SLP-76 levels, we analyzed these crucial events using several transgenic (Tg) lines of mice expressing altered levels of SLP-76 in the thymus. In Tg mice expressing low levels of SLP-76 in preselection thymocytes, the CD4:CD8 ratio in the thymus and spleen was skewed in a manner consistent with impaired selection and/or maturation of CD4+ thymocytes. Low SLP-76 expression also correlated with reduced CD5 expression on immature thymocytes, consistent with reduced TCR signaling potential. In contrast, reconstitution of SLP-76 at higher levels resulted in normal thymic CD5 expression and CD4:CD8 ratios in the thymus and periphery. It is curious that thymic deletion of TCR-Tg (HY) thymocytes was markedly impaired in both lines of Tg-reconstituted SLP-76-/- mice. Studies using chimeric mice indicate that the defect in deletion of HY+ thymocytes is intrinsic to the developing thymocyte, suggesting that maintenance of sufficient SLP-76 expression from the endogenous locus is a key element in the selection process.

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

PubMed Central

Sampaio, Hugo; Mowat, David; Roscioli, Tony

2017-01-01

Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis. PMID:28634552

Neuropsychiatric Symptoms in Posterior Cortical Atrophy and Alzheimer Disease

PubMed Central

Crutch, Sebastian J.; Franco-Macías, Emilio; Gil-Néciga, Eulogio

2016-01-01

Background: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by early progressive visual dysfunction in the context of relative preservation of memory and a pattern of atrophy mainly involving the posterior cortex. The aim of the present study is to characterize the neuropsychiatric profile of PCA. Methods: The Neuropsychiatric Inventory was used to assess 12 neuropsychiatric symptoms (NPS) in 28 patients with PCA and 34 patients with typical Alzheimer disease (AD) matched by age, disease duration, and illness severity. Results: The most commonly reported NPS in both groups were depression, anxiety, apathy, and irritability. However, aside from a trend toward lower rates of apathy in patients with PCA, there were no differences in the percentage of NPS presented in each group. All those patients presenting visual hallucinations in the PCA group also met diagnostic criteria for dementia with Lewy bodies (DLB). Auditory hallucinations were only present in patients meeting diagnosis criteria for DLB. Conclusion: Prevalence of the 12 NPS examined was similar between patients with PCA and AD. Hallucinations in PCA may be helpful in the differential diagnosis between PCA-AD and PCA-DLB. PMID:26404166

Tuberculosis, the Disrupted Immune-Endocrine Response and the Potential Thymic Repercussion As a Contributing Factor to Disease Physiopathology.

PubMed

D'Attilio, Luciano; Santucci, Natalia; Bongiovanni, Bettina; Bay, María L; Bottasso, Oscar

2018-01-01

Upon the pathogen encounter, the host seeks to ensure an adequate inflammatory reaction to combat infection but at the same time tries to prevent collateral damage, through several regulatory mechanisms, like an endocrine response involving the production of adrenal steroid hormones. Our studies show that active tuberculosis (TB) patients present an immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro-inflammatory cytokines, and decreased amounts of dehydroepiandrosterone. Studies in patients undergoing specific treatment revealed that cortisol levels remained increased even after several months of initiating therapy. In addition to the well-known metabolic and immunological effects, glucocorticoids are involved in thymic cortical depletion with immature thymocytes being quite sensitive to such an effect. The thymus is a central lymphoid organ supporting thymocyte T-cell development, i.e., lineage commitment, selection events and thymic emigration. While thymic TB is an infrequent manifestation of the disease, several pieces of experimental and clinical evidence point out that the thymus can be infected by mycobacteria. Beyond this, the thymic microenvironment during TB may be also altered because of the immune-hormonal alterations. The thymus may be then an additional target of organ involvement further contributing to a deficient control of infection and disease immunopathology.

Association of murine lupus and thymic full-length endogenous retroviral expression maps to a bone marrow stem cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krieg, A.M.; Gourley, M.F.; Steinberg, A.D.

1991-05-01

Recent studies of thymic gene expression in murine lupus have demonstrated 8.4-kb (full-length size) modified polytropic (Mpmv) endogenous retroviral RNA. In contrast, normal control mouse strains do not produce detectable amounts of such RNA in their thymuses. Prior studies have attributed a defect in experimental tolerance in murine lupus to a bone marrow stem cell rather than to the thymic epithelium; in contrast, infectious retroviral expression has been associated with the thymic epithelium, rather than with the bone marrow stem cell. The present study was designed to determine whether the abnormal Mpmv expression associated with murine lupus mapped to thymicmore » epithelium or to a marrow precursor. Lethally irradiated control and lupus-prone mice were reconstituted with T cell depleted bone marrow; one month later their thymuses were studied for endogenous retroviral RNA and protein expression. Recipients of bone marrow from nonautoimmune donors expressed neither 8.4-kb Mpmv RNA nor surface MCF gp70 in their thymuses. In contrast, recipients of bone marrow from autoimmune NZB or BXSB donors expressed thymic 8.4-kb Mpmv RNA and mink cell focus-forming gp70. These studies demonstrate that lupus-associated 8.4-kb Mpmv endogenous retroviral expression is determined by bone marrow stem cells.« less

Effects of muscle atrophy on motor control

NASA Technical Reports Server (NTRS)

Stuart, D. G.

1985-01-01

As a biological tissue, muscle adapts to the demands of usage. One traditional way of assessing the extent of this adaptation has been to examine the effects of an altered-activity protocol on the physiological properties of muscles. However, in order to accurately interpret the changes associated with an activity pattern, it is necessary to employ an appropriate control model. A substantial literature exists which reports altered-use effects by comparing experimental observations with those from animals raised in small laboratory cages. Some evidence suggests that small-cage-reared animals actually represent a model of reduced use. For example, laboratory animals subjected to limited physical activity have shown resistance to insulin-induced glucose uptake which can be altered by exercise training. This project concerned itself with the basic mechanisms underlying muscle atrophy. Specifically, the project addressed the issue of the appropriateness of rats raised in conventional-sized cages as experimental models to examine this phenomenon. The project hypothesis was that rats raised in small cages are inappropriate models for the study of muscle atrophy. The experimental protocol involved: 1) raising two populations of rats, one group in conventional (small)-sized cages and the other group in a much larger (133x) cage, from weanling age (21 days) through to young adulthood (125 days); 2) comparison of size- and force-related characteristics of selected test muscles in an acute terminal paradigm.

Age-related changes in the macula. A histopathological study of fifty Indian donor eyes.

PubMed

Biswas, Jyotirmay; Raman, Rajiv

2002-09-01

Age-related macular degeneration (ARMD) is clinically less common in India compared to the West. Therefore, clinicians are unfamiliar with histopathologic evidence of age-related macular changes in the Indian population. Fifty consecutive human donor eyes removed for corneal grafting were studied for gross, microscopic and histochemical features of age-related changes in the macula in the Indian population. A horizontal block was cut from the globe including the optic disc, and the macula. Six sections, 6 microns thick, were cut from three levels in the macula at a distance of 140 microns. These were stained with haemotoxylin-eosin, periodic acid-Schiff, Mallory, Masson trichrome, alcian blue and von Kossa stains. The presence of basal laminar deposits, drusen and thickening and calcification of Bruch's membrane in the macula were assessed at 400 x magnification using a modified version of Sark's classification. Twenty-four donor eyes (48%) had some form of age-related macular change. These included basal laminar deposits, hard drusen, soft drusen, extensive retinal pigment epithelium atrophy of the macula, and disciform degeneration of macula. A combination of changes was often seen. Age-related changes were more common in the seventh and eighth decade. Our study shows that histological changes characteristic of the early stages of age-related macular degeneration are fairly common in the Indian population. However, advanced macular changes are significantly rare.

Atrophy of the Parietal Lobe in Preclinical Dementia

ERIC Educational Resources Information Center

Jacobs, Heidi I. L.; Van Boxtel, Martin P. J.; Uylings, Harry B. M.; Gronenschild, Ed H. B. M.; Verhey, Frans R.; Jolles, Jelle

2011-01-01

Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults…

[Comparison of Preferential Hyperacuity Perimeter (PHP) test and Amsler grid test in the diagnosis of different stages of age-related macular degeneration].

PubMed

Kampmeier, J; Zorn, M M; Lang, G K; Botros, Y T; Lang, G E

2006-09-01

Age-related macular degeneration (ARMD) is the leading cause of blindness in people over 65 years of age. A rapid loss of vision occurs especially in cases with choroidal neovascularisation. Early detection of ARMD and timely treatment are mandatory. We have prospectively studied the results of two diagnostic self tests for the early detection of metamorphopsia and scotoma, the PHP test and the Amsler grid test, in different stages of ARMD. Patients with ARMD and best corrected visual acuity of 6/30 or better (Snellen charts) were examined with a standardised protocol, including supervised Amsler grid examination and PHP, a new device for metamorphopsia or scotoma measurement, based on the hyperacuity phenomenon in the central 14 degrees of the visual field. The stages of ARMD were independently graded in a masked fashion by stereoscopic ophthalmoscopy, stereoscopic fundus colour photographs, fluorescein angiography, and OCT. The patients were subdivided into 3 non-neovascular groups [early, late (RPE atrophy > 175 microm) and geographic atrophy], a neovascular group (classic and occult CNV) and an age-matched control group (healthy volunteers). 140 patients, with ages ranging from 50 to 90 years (median 68 years), were included in the study. Best corrected visual acuity ranged from 6/30 to 6/6 with a median of 6/12. 95 patients were diagnosed as non-neovascular ARMD. Thirty eyes had early ARMD (9 were tested positive by the PHP test and 9 by the Amsler grid test), and 50 late ARMD (positive: PHP test 23, Amsler grid test 26). The group with geographic atrophy consisted of 15 eyes (positive: PHP test 13, Amsler grid test 10). Forty-five patients presented with neovascular ARMD (positive: PHP test 38, Amsler grid test 36), 34 volunteers served as control group (positive: PHP test 1, Amsler grid test 5). The PHP and Amsler grid tests revealed comparable results detecting metamorphopsia and scotoma in early ARMD (30 vs. 30 %) and late ARMD (46 vs. 52 %). However, the

Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy

PubMed Central

Bialek, Peter; Morris, Carl; Parkington, Jascha; St. Andre, Michael; Owens, Jane; Yaworsky, Paul; Seeherman, Howard

2011-01-01

Skeletal muscle atrophy can be a consequence of many diseases, environmental insults, inactivity, age, and injury. Atrophy is characterized by active degradation, removal of contractile proteins, and a reduction in muscle fiber size. Animal models have been extensively used to identify pathways that lead to atrophic conditions. We used genome-wide expression profiling analyses and quantitative PCR to identify the molecular changes that occur in two clinically relevant mouse models of muscle atrophy: hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7, and 14 days after casting or injury. The total amount of muscle loss, as measured by wet weight and muscle fiber size, was equivalent between models on day 14, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tenotomy resulted in the regulation of significantly more mRNA transcripts then did casting. Analysis of the regulated genes and pathways suggest that the mechanisms of atrophy are distinct between these models. The degradation following casting was ubiquitin-proteasome mediated, while degradation following tenotomy was lysosomal and matrix-metalloproteinase mediated, suggesting a possible role for autophagy. These data suggest that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat atrophy resulting from different conditions. PMID:21791639

Domain atrophy creates rare cases of functional partial protein domains.

PubMed

Prakash, Ananth; Bateman, Alex

2015-04-30

Protein domains display a range of structural diversity, with numerous additions and deletions of secondary structural elements between related domains. We have observed a small number of cases of surprising large-scale deletions of core elements of structural domains. We propose a new concept called domain atrophy, where protein domains lose a significant number of core structural elements. Here, we implement a new pipeline to systematically identify new cases of domain atrophy across all known protein sequences. The output of this pipeline was carefully checked by hand, which filtered out partial domain instances that were unlikely to represent true domain atrophy due to misannotations or un-annotated sequence fragments. We identify 75 cases of domain atrophy, of which eight cases are found in a three-dimensional protein structure and 67 cases have been inferred based on mapping to a known homologous structure. Domains with structural variations include ancient folds such as the TIM-barrel and Rossmann folds. Most of these domains are observed to show structural loss that does not affect their functional sites. Our analysis has significantly increased the known cases of domain atrophy. We discuss specific instances of domain atrophy and see that there has often been a compensatory mechanism that helps to maintain the stability of the partial domain. Our study indicates that although domain atrophy is an extremely rare phenomenon, protein domains under certain circumstances can tolerate extreme mutations giving rise to partial, but functional, domains.

Renal Atrophy Secondary to Chemoradiotherapy of Abdominal Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Gary Y., E-mail: Gary.Yang@RoswellPark.or; May, Kilian Salerno; Iyer, Renuka V.

2010-10-01

Purpose: To identify factors predictive of renal atrophy after chemoradiotherapy of gastrointestinal malignancies. Methods and Materials: Patients who received chemotherapy and abdominal radiotherapy (RT) between 2002 and 2008 were identified for this study evaluating change in kidney size and function after RT. Imaging and biochemical data were obtained before and after RT in 6-month intervals. Kidney size was defined by craniocaudal measurement on CT images. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Receiver operating characteristic (ROC) curves were generated to predict risk for renal atrophy. Results: Of 130 patients, medianmore » age was 64 years, and 51.5% were male. Most primary disease sites were pancreas and periampullary tumors (77.7%). Median follow-up was 9.4 months. Creatinine clearance declined 20.89%, and size of the PK decreased 4.67% 1 year after completion of chemoradiation. Compensatory hypertrophy of the non-PK was not seen. Percentage volumes of the PK receiving {>=}10 Gy (V{sub 10}), 15 Gy (V{sub 15}), and 20 Gy (V{sub 20}) were significantly associated with renal atrophy 1 year after RT (p = 0.0030, 0.0029, and 0.0028, respectively). Areas under the ROC curves for V{sub 10}, V{sub 15}, and V{sub 20} to predict >5% decrease in PK size were 0.760, 0.760, and 0.762, respectively. Conclusions: Significant detriments in PK size and renal function were seen after abdominal RT. The V{sub 10}, V{sub 15}, and V{sub 20} were predictive of risk for PK atrophy 1 year after RT. Analyses suggest the association of lower-dose renal irradiation with subsequent development of renal atrophy.« less

The quasi-parallel lives of satellite cells and atrophying muscle

PubMed Central

Biressi, Stefano; Gopinath, Suchitra D.

2015-01-01

Skeletal muscle atrophy or wasting accompanies various chronic illnesses and the aging process, thereby reducing muscle function. One of the most important components contributing to effective muscle repair in postnatal organisms, the satellite cells (SCs), have recently become the focus of several studies examining factors participating in the atrophic process. We critically examine here the experimental evidence linking SC function with muscle loss in connection with various diseases as well as aging, and in the subsequent recovery process. Several recent reports have investigated the changes in SCs in terms of their differentiation and proliferative capacity in response to various atrophic stimuli. In this regard, we review the molecular changes within SCs that contribute to their dysfunctional status in atrophy, with the intention of shedding light on novel potential pharmacological targets to counteract the loss of muscle mass. PMID:26257645

99mTc-d,l-HMPAO and SPECT of the brain in normal aging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waldemar, G.; Hasselbalch, S.G.; Andersen, A.R.

1991-05-01

Single photon emission computed tomography (SPECT) with 99mTc-d,l-hexamethylpropyleneamine oxime (99mTc-d,l-HMPAO) was used to determine global and regional CBF in 53 healthy subjects aged 21-83 years. For the whole group, global CBF normalized to the cerebellum was 86.4% +/- 8.4 (SD). The contribution of age, sex, and atrophy to variations in global CBF was studied using stepwise multiple regression analysis. There was a significant negative correlation of global CBF with subjective ratings of cortical atrophy, but not with ratings of ventricular size, Evans ratio, sex, or age. In a subgroup of 33 subjects, in whom volumetric measurements of atrophy were performed,more » cortical atrophy was the only significant determinant for global CBF, accounting for 27% of its variance. Mean global CBF as measured with the 133Xe inhalation technique and SPECT was 54 +/- 9 ml/100 g/min and did not correlate significantly with age. There was a preferential decline of CBF in the frontal cortex with advancing age. The side-to-side asymmetry of several regions of interest increased with age. A method was described for estimation of subcortical CBF, which decreased with advancing cortical atrophy. The relative area of the subcortical low-flow region increased with age. These results are useful in distinguishing the effects of age and simple atrophy from disease effects, when the 99mTc-d,l-HMPAO method is used.« less

Regulation of theta-antigen expression by agents altering cyclic AMP level and by thymic factor.

PubMed

Bach, M A; Fournier, C; Bach, J F

1975-02-28

Thymic factor, cyclic AMP, and products increasing its cellular level, such as Prostaglandin E1, induce the appearance of the theta-antigen on T-cell precursors whether assessed by a rossette-inhibition assay or a cytotoxic assay after cell fractionation on BSA discontinuous gradiet. Synergism has been demonstrated between cyclic AMPT and TF for that effect. Conversely, decrease of theta expression has been obtained by altering cyclic AMP level in theta-positive cells either increasing it by dibutyryl cAMP treatment or decreasing it by indomethacin treatment. Finally, these data suggest the involvement of cyclic AMP in the regulation of theta expression under thymic hormone control.

Consideration of the method of image diagnosis with respect to frontal lobe atrophy

NASA Astrophysics Data System (ADS)

Sato, K.; Sugawara, K.; Narita, Y.; Namura, I.

1996-12-01

Proposes a segmentation method for a quantitative image diagnosis as a means of realizing an objective diagnosis of the frontal lobe atrophy. From the data obtained on the grade of membership, the fractal dimensions of the cerebral tissue [cerebral spinal fluid (CSF), gray matter, and white matter] and the contours are estimated. The mutual relationship between the degree of atrophy and the fractal dimension has been analyzed based on the estimated fractal dimensions. Using a sample of 42 male and female cases, ranging In age from 50's to 70's, it has been concluded that the frontal lobe atrophy can be quantified by regarding it as an expansion of CSF region on the magnetic resonance imaging (MRI) of the brain. Furthermore, when the process of frontal lobe atrophy is separated into early and advanced stages, the volumetric change of CSF and white matter in frontal lobe displays meaningful differences between the two stages, demonstrating that the fractal dimension of CSF rises with the progress of atrophy. Moreover, an interpolation method for three-dimensional (3-D) shape reconstruction of the region of diagnostic interest is proposed and 3-D shape visualization, with respect to the degree and form of atrophy, is performed on the basis of the estimated fractal dimension of the segmented cerebral tissue.

A zinc-dependent epitope on the molecule of thymulin, a thymic hormone.

PubMed Central

Dardenne, M; Savino, W; Berrih, S; Bach, J F

1985-01-01

Thymulin is a nonapeptide hormone produced by thymic epithelial cells. Its biological activity is strictly dependent on the presence of the metal zinc in the molecule. Antithymulin monoclonal antibodies have been produced against either the synthetic (AS1) or the natural intraepithelial (AE1) molecule. These monoclonal antibodies were screened for their abilities to inhibit the zinc-dependent biological activity of the hormone and were shown to bind to thymic epithelial cells. By using biological and immunofluorescence assays, the two antibodies were shown to recognize exclusively the zinc-coupled thymulin molecule. Other antithymulin antibodies screened by RIA or ELISA (using a zinc-deprived substrate) recognized a zinc-independent epitope on the thymulin molecule. These data indicate the existence of a zinc-specific conformation on the thymulin molecule. They are in agreement with NMR studies showing that the zinc-containing hormone has a unique structure. Images PMID:2413455

Automated image alignment and segmentation to follow progression of geographic atrophy in age-related macular degeneration.

PubMed

Ramsey, David J; Sunness, Janet S; Malviya, Poorva; Applegate, Carol; Hager, Gregory D; Handa, James T

2014-07-01

To develop a computer-based image segmentation method for standardizing the quantification of geographic atrophy (GA). The authors present an automated image segmentation method based on the fuzzy c-means clustering algorithm for the detection of GA lesions. The method is evaluated by comparing computerized segmentation against outlines of GA drawn by an expert grader for a longitudinal series of fundus autofluorescence images with paired 30° color fundus photographs for 10 patients. The automated segmentation method showed excellent agreement with an expert grader for fundus autofluorescence images, achieving a performance level of 94 ± 5% sensitivity and 98 ± 2% specificity on a per-pixel basis for the detection of GA area, but performed less well on color fundus photographs with a sensitivity of 47 ± 26% and specificity of 98 ± 2%. The segmentation algorithm identified 75 ± 16% of the GA border correctly in fundus autofluorescence images compared with just 42 ± 25% for color fundus photographs. The results of this study demonstrate a promising computerized segmentation method that may enhance the reproducibility of GA measurement and provide an objective strategy to assist an expert in the grading of images.

Description of the Age-Related Eye Disease Study 9-step severity scale applied to participants in the Complications of Age-related Macular Degeneration Prevention Trial.

PubMed

Ying, Gui-shuang; Maguire, Maureen G; Alexander, Judith; Martin, Revell W; Antoszyk, Andrew N

2009-09-01

To describe characteristics of the Age-Related Eye Disease Study (AREDS) 9-step severity scale applied to participants in the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Eligibility criteria for CAPT required 10 or more large (>or=125 microm) drusen in each eye. Readers graded baseline photographs from all participants and all follow-up photographs from 402 untreated eyes. Drusen and pigment characteristics were used to assign the AREDS scale score. Choroidal neovascularization was identified from fluorescein angiograms. Geographic atrophy involving the macular center was identified from color photographs. Among 1001 untreated eyes, 90% were at steps 5 to 7 at baseline. The 5-year incidence of advanced age-related macular degeneration (AMD) increased with each step from 8% (step 4) to 40% (steps 8 and 9 combined). These rates were similar to those reported in AREDS. Among 261 eyes with all 5 annual photograph gradings available and without progression to advanced AMD, 55% of eyes had scores that indicated improvement at least once. Before progression to advanced AMD, only 32% of 141 eyes either went through step 8 or 9 or had an increase of 2 or more steps from baseline. The AREDS 9-step severity scale was predictive of development of advanced AMD. The AREDS scale has deficiencies as a surrogate outcome for progression to advanced AMD.

Muscle atrophy

MedlinePlus

... muscle atrophy may include: Burns Long-term corticosteroid therapy Malnutrition Muscular dystrophy and other diseases of the muscle Osteoarthritis Rheumatoid arthritis Home Care An exercise program ...

Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy.

PubMed

Calabrese, Massimiliano; Gajofatto, Alberto; Gobbin, Francesca; Turri, Giulia; Richelli, Silvia; Matinella, Angela; Oliboni, Eugenio Simone; Benedetti, Maria Donata; Monaco, Salvatore

2015-04-01

Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs. © The Author(s), 2014.

The aging of elite male athletes: age-related changes in performance and skeletal muscle structure and function

PubMed Central

Faulkner, John A.; Davis, Carol S.; Mendias, Christopher L.; Brooks, Susan V.

2009-01-01

Objective The paper addresses the degree to which the attainment of the status as an elite athlete in different sports ameliorates the known age-related losses in skeletal muscle structure and function. Design The retrospective design, based on comparisons of published data on former elite and masters athletes and data on control subjects, assessed the degree to which the attainment of ‘elite and masters athlete status’ ameliorated the known age-related changes in skeletal muscle structure and function. Setting Institutional. Participants Elite male athletes. Interventions Participation in selected individual and team sports. Main Outcome Measurements Strength, power, VO2 max and performance. Results For elite athletes in all sports, as for the general population, age-related muscle atrophy begins at about 50 years of age. Despite the loss of muscle mass, elite athletes who maintain an active life style age gracefully with few health problems. Conversely, those who lapse into inactivity regress toward general population norms for fitness, weight control, and health problems. Elite athletes in the dual and team sports have careers that rarely extend into the thirties. Conclusions Life long physical activity does not appear to have any impact on the loss in fiber number. The loss of fibers can be buffered to some degree by hypertrophy of fibers that remain. Surprisingly, the performance of elite athletes in all sports appears to be impaired before the onset of the fiber loss. Even with major losses in physical capacity and muscle mass, the performance of elite and masters athletes is remarkable. PMID:19001883

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice.

PubMed

Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly; Gilbert, Debra; O'Sullivan, T Norene; Lu, Lucy; Wang, Sophie; Haines, Diana C; Van Dyke, Terry; Keller, Jonathan R

2017-01-01

Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size.

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

PubMed Central

El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

2016-01-01

Purpose The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Materials and Methods Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. Results CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores. Conclusions Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients. PMID:27089520

Age-Related Changes in Pharyngeal Lumen Size: A Retrospective MRI Analysis.

PubMed

Molfenter, Sonja M; Amin, M R; Branski, R C; Brumm, J D; Hagiwara, M; Roof, S A; Lazarus, C L

2015-06-01

Age-related loss of muscle bulk and strength (sarcopenia) is often cited as a potential mechanism underlying age-related changes in swallowing. Our goal was to explore this phenomenon in the pharynx, specifically, by measuring pharyngeal wall thickness and pharyngeal lumen area in a sample of young versus older women. MRI scans of the neck were retrospectively reviewed from 60 women equally stratified into three age groups (20s, 60s, 70+). Four de-identified slices were extracted per scan for randomized, blinded analysis: one mid-sagittal and three axial slices were selected at the anterior inferior border of C2 and C3, and at the pit of the vallecula. Pixel-based measures of pharyngeal wall thickness and pharyngeal lumen area were completed using ImageJ and then converted to metric units. Measures of pharyngeal wall thickness and pharyngeal lumen area were compared between age groups with one-way ANOVAs using Sidak adjustments for post-hoc pairwise comparisons. A significant main effect for age was observed across all variables whereby pharyngeal wall thickness decreased and pharyngeal lumen area increased with advancing age. Pairwise comparisons revealed significant differences between 20s versus 70+ for all variables and 20s versus 60s for all variables except those measured at C2. Effect sizes ranged from 0.54 to 1.34. Consistent with existing sacropenia literature, the pharyngeal muscles appear to atrophy with age and consequently, the size of the pharyngeal lumen increases.

Olivopontocerebellar atrophy

MedlinePlus

... degeneration; Multiple system atrophy cerebellar predominance; MSA-C Images Central nervous system and peripheral nervous system References Jankovic J, Lang AE. Diagnosis and assessment of Parkinson disease ...

Consensus statement for standard of care in spinal muscular atrophy.

PubMed

Wang, Ching H; Finkel, Richard S; Bertini, Enrico S; Schroth, Mary; Simonds, Anita; Wong, Brenda; Aloysius, Annie; Morrison, Leslie; Main, Marion; Crawford, Thomas O; Trela, Anthony

2007-08-01

Spinal muscular atrophy is a neurodegenerative disease that requires multidisciplinary medical care. Recent progress in the understanding of molecular pathogenesis of spinal muscular atrophy and advances in medical technology have not been matched by similar developments in the care for spinal muscular atrophy patients. Variations in medical practice coupled with differences in family resources and values have resulted in variable clinical outcomes that are likely to compromise valid measure of treatment effects during clinical trials. The International Standard of Care Committee for Spinal Muscular Atrophy was formed in 2005, with a goal of establishing practice guidelines for clinical care of these patients. The 12 core committee members worked with more than 60 spinal muscular atrophy experts in the field through conference calls, e-mail communications, a Delphi survey, and 2 in-person meetings to achieve consensus on 5 care areas: diagnostic/new interventions, pulmonary, gastrointestinal/nutrition, orthopedics/rehabilitation, and palliative care. Consensus was achieved on several topics related to common medical problems in spinal muscular atrophy, diagnostic strategies, recommendations for assessment and monitoring, and therapeutic interventions in each care area. A consensus statement was drafted to address the 5 care areas according to 3 functional levels of the patients: nonsitter, sitter, and walker. The committee also identified several medical practices lacking consensus and warranting further investigation. It is the authors' intention that this document be used as a guideline, not as a practice standard for their care. A practice standard for spinal muscular atrophy is urgently needed to help with the multidisciplinary care of these patients.

Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies.

PubMed

Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

2016-01-01

Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. PubMed, Cochrane's Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55-1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors.

Shining a light on posterior cortical atrophy.

PubMed

Crutch, Sebastian J; Schott, Jonathan M; Rabinovici, Gil D; Boeve, Bradley F; Cappa, Stefano F; Dickerson, Bradford C; Dubois, Bruno; Graff-Radford, Neill R; Krolak-Salmon, Pierre; Lehmann, Manja; Mendez, Mario F; Pijnenburg, Yolande; Ryan, Natalie S; Scheltens, Philip; Shakespeare, Tim; Tang-Wai, David F; van der Flier, Wiesje M; Bain, Lisa; Carrillo, Maria C; Fox, Nick C

2013-07-01

Posterior cortical atrophy (PCA) is a clinicoradiologic syndrome characterized by progressive decline in visual processing skills, relatively intact memory and language in the early stages, and atrophy of posterior brain regions. Misdiagnosis of PCA is common, owing not only to its relative rarity and unusual and variable presentation, but also because patients frequently first seek the opinion of an ophthalmologist, who may note normal eye examinations by their usual tests but may not appreciate cortical brain dysfunction. Seeking to raise awareness of the disease, stimulate research, and promote collaboration, a multidisciplinary group of PCA research clinicians formed an international working party, which had its first face-to-face meeting on July 13, 2012 in Vancouver, Canada, prior to the Alzheimer's Association International Conference. Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.

PubMed

Bond, Jonathan; Marchand, Tony; Touzart, Aurore; Cieslak, Agata; Trinquand, Amélie; Sutton, Laurent; Radford-Weiss, Isabelle; Lhermitte, Ludovic; Spicuglia, Salvatore; Dombret, Hervé; Macintyre, Elizabeth; Ifrah, Norbert; Hamel, Jean-François; Asnafi, Vahid

2016-06-01

Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently

Rates of decline in Alzheimer disease decrease with age.

PubMed

Holland, Dominic; Desikan, Rahul S; Dale, Anders M; McEvoy, Linda K

2012-01-01

Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ(1-42), tau, and phospho-tau(181p) (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.

Space travel directly induces skeletal muscle atrophy

NASA Technical Reports Server (NTRS)

Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

1999-01-01

Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

Carrier testing for spinal muscular atrophy

PubMed Central

Gitlin, Jonathan M.; Fischbeck, Kenneth; Crawford, Thomas O.; Cwik, Valerie; Fleischman, Alan; Gonye, Karla; Heine, Deborah; Hobby, Kenneth; Kaufmann, Petra; Keiles, Steven; MacKenzie, Alex; Musci, Thomas; Prior, Thomas; Lloyd-Puryear, Michele; Sugarman, Elaine A.; Terry, Sharon F.; Urv, Tiina; Wang, Ching; Watson, Michael; Yaron, Yuval; Frosst, Phyllis; Howell, R. Rodney

2014-01-01

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general. PMID:20808230

HTLV-1-infected thymic epithelial cells convey the virus to CD4+ T lymphocytes.

PubMed

Carvalho Barros, Luciana Rodrigues; Linhares-Lacerda, Leandra; Moreira-Ramos, Klaysa; Ribeiro-Alves, Marcelo; Machado Motta, Maria Cristina; Bou-Habib, Dumith Chequer; Savino, Wilson

2017-12-01

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4 + T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell-cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4 + T cell line and to CD4 + T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4 + T lymphocytes, which in turn will cause disease in the periphery. Copyright © 2017. Published by Elsevier GmbH.

Multidisciplinary Overview of Vaginal Atrophy and Associated Genitourinary Symptoms in Postmenopausal Women

PubMed Central

Goldstein, Irwin; Dicks, Brian; Kim, Noel N; Hartzell, Rose

2013-01-01

Introduction Vaginal atrophy, which may affect up to 45% of postmenopausal women, is often associated with one or more urinary symptoms, including urgency, increased frequency, nocturia, dysuria, incontinence, and recurrent urinary tract infection. Aims To provide an overview of the current literature regarding cellular and clinical aspects of vaginal atrophy and response to treatment with local vaginal estrogen therapy. Methods PubMed searches through February 2012 were conducted using the terms “vaginal atrophy,” “atrophic vaginitis,” and “vulvovaginal atrophy.” Expert opinion was based on review of the relevant scientific and medical literature. Main Outcome Measure Genitourinary symptoms and treatment of vaginal atrophy from peer-reviewed published literature. Results Typically, a diagnosis of vaginal atrophy is made based on patient-reported symptoms, including genitourinary symptoms, and an examination that reveals signs of the disorder; however, many women are hesitant to report vaginal-related symptoms, primarily because of embarrassment. Conclusions Physicians in various disciplines are encouraged to initiate open discussions about vulvovaginal health with postmenopausal women, including recommended treatment options. Goldstein I, Dicks B, Kim NN, and Hartzell R. Multidisciplinary overview of vaginal atrophy and associated genitourinary symptoms in postmenopausal women. Sex Med 2013;1:44–53. PMID:25356287

The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats

NASA Technical Reports Server (NTRS)

Chakravarthy, M. V.; Booth, F. W.; Spangenburg, E. E.

2001-01-01

Approximately 50% of humans older than 85 years have physical frailty due to weak skeletal muscles. This indicates a need for determining mechanisms to combat this problem. A critical cellular factor for postnatal muscle growth is a population of myogenic precursor cells called satellite cells. Given the complex process of sarcopenia, it has been postulated that, at some point in this process, a limited satellite cell proliferation potential could become rate-limiting to the regrowth of old muscles. It is conceivable that if satellite cell proliferative capacity can be maintained or enhanced with advanced age, sarcopenia could potentially be delayed or prevented. Therefore, the purposes of this paper are to describe whether IGF-I can prevent muscular atrophy induced by repeated cycles of hindlimb immobilization, increase the in vitro proliferation in satellite cells from these muscles and, if so, the molecular mechanisms by which IGF-I mediates this increased proliferation. Our results provide evidence that IGF-I can enhance aged muscle regrowth possibly through increased satellite cell proliferation. The results also suggest that IGF-I enhances satellite cell proliferation by decreasing the cell cycle inhibitor, p27Kip1, through the PI3'-K/Akt pathway. These data provide molecular evidence for IGF-I's rescue effect upon aging-associated skeletal muscle atrophy.

Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome

PubMed Central

Lorenzo, Laureanne P E; Shatynski, Kristen E; Clark, Sarah; Yarowsky, Paul J; Williams, Mark S

2013-01-01

In addition to archetypal cognitive defects, Down syndrome (DS) is characterized by altered lymphocyte development and function, including premature thymic involution and increased incidence of infections. However, the potential mechanisms for these changes have not been fully elucidated. The current study used the Ts65Dn mouse model of DS to assess deficiencies in T-cell development and possible molecular alterations. Ts65Dn mice exhibited premature thymic involution and a threefold to fourfold decrease in the number and proportion of immature, double-negative thymocyte progenitors. In addition, there were twofold fewer double-positive and CD4 single-positive thymocytes in Ts65Dn thymuses. Reflecting this deficient thymic function, there were fewer naive T cells in the spleen and polyclonal stimulation of peripheral T cells exhibited a marked reduction in proliferation, suggesting a senescent phenotype. In contrast, B-cell progenitors were unchanged in the bone marrow of Ts65Dn mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin-7Rα, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the Notch pathway were identified as possible mediators of decreased interleukin-7Rα expression in Ts65Dn mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling may alter lymphocyte development in Ts65Dn mice. PMID:23432468

MSA Mimic? Rare Occurrence of Anti-Hu Autonomic Failure and Thymoma in a Patient with Parkinsonism: Case Report and Literature Review

PubMed Central

Ricigliano, Vito A. G.; Fossati, Barbara; Saraceno, Lorenzo; Cavalli, Michele; Bazzigaluppi, Elena; Meola, Giovanni

2018-01-01

Thymoma is a tumor originating from thymic gland, frequently manifesting with paraneoplastic neurological disorders. Its association with paraneoplastic dysautonomia is relatively uncommon. Here, we describe the challenging case of a 71 year-old female who developed subacute autonomic failure with digestive pseudo-obstruction, dysphagia, urinary tract dysfunction and orthostatic hypotension complicating an underlying extrapyramidal syndrome that had started 3 months before hospital admission. Autonomic symptoms had 2-month course and acutely worsened just before and during hospitalization. Combination of severe dysautonomia and parkinsonism mimicked rapidly progressing multiple system atrophy. However, diagnostic exams showed thymic tumor with positive anti-Hu antibodies on both serum and cerebrospinal fluid. Complete response of dysautonomia to immunoglobulins followed by thymectomy confirmed the diagnosis of anti-Hu-related paraneoplastic neurological syndrome. With regards to extrapyramidal symptoms, despite previous descriptions of paraneoplastic parkinsonism caused by other antineuronal antibodies, in our case no relation between anti-Hu and parkinsonism could be identified. A literature review of published reports describing anti-Hu positivity in thymic neoplasms highlighted that a definite autonomic disease due to anti-Hu antibodies is extremely rare in patients with thymoma but without myasthenia gravis, with only one case published so far. PMID:29416500

Thymic pathologies in myasthenia gravis: a preoperative assessment of CAT scan and nuclear based imaging.

PubMed

Jordan, Berit; Kellner, Juliane; Jordan, Karin; Bähre, Manfred; Behrmann, Curd; Zierz, Stephan

2016-04-01

Precise diagnostic work up of a suspected thymic pathology in patients with myasthenia gravis (MG) is very important for potential surgical implications and further disease course. In this study the diagnostic value of combined preoperative radiological (CAT scan) and nuclear based imaging (octreotide and thallium scintigraphy) in patients with MG was evaluated. Twenty four patients were included. Histopathology revealed thymoma in nine patients, thymic carcinoma (TC) in one patient, lymphofollicular hyperplasia in seven patients, and involuted thymus in another seven patients. Diagnostic sensitivity for detecting thymoma/TC was 80 % in CAT scan as well as in somatostatin scintigraphy; the combination of both procedures reached 90 %. However, the diagnostic specifity to exclude thymoma in CAT scan was 100 % and in octreotide scintigraphy 85.7 %. Semiquantitative octreotide uptake significantly correlated with histological grading of thymoma/TC (r = 0.764) and histological proliferation rate Ki67 (r = 0.894). Thallium scintigraphy was positive only in one out of four thymoma cases. In this study, somatostatin scintigraphy has been shown to be a useful additional diagnostic technique in detecting thymic malignancies in patients with MG. These results might be especially helpful in patients with late onset MG as these patients are in general no candidates for thymectomy.

T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation.

PubMed

Vago, Luca; Oliveira, Giacomo; Bondanza, Attilio; Noviello, Maddalena; Soldati, Corrado; Ghio, Domenico; Brigida, Immacolata; Greco, Raffaella; Lupo Stanghellini, Maria Teresa; Peccatori, Jacopo; Fracchia, Sergio; Del Fiacco, Matteo; Traversari, Catia; Aiuti, Alessandro; Del Maschio, Alessandro; Bordignon, Claudio; Ciceri, Fabio; Bonini, Chiara

2012-08-30

The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell-depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+ -cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.

White matter hyperintensities and imaging patterns of brain ageing in the general population

PubMed Central

Erus, Guray; Toledo, Jon B.; Zhang, Tianhao; Bryan, Nick; Launer, Lenore J.; Rosseel, Yves; Janowitz, Deborah; Doshi, Jimit; Van der Auwera, Sandra; von Sarnowski, Bettina; Hegenscheid, Katrin; Hosten, Norbert; Homuth, Georg; Völzke, Henry; Schminke, Ulf; Hoffmann, Wolfgang; Grabe, Hans J.; Davatzikos, Christos

2016-01-01

Abstract White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer’s disease in a large populatison-based sample ( n = 2367) encompassing a wide age range (20–90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer’s disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly ( P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer’s disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant ( P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66

The effect of brain atrophy on outcome after a large cerebral infarction.

PubMed

Lee, Sang Hyung; Oh, Chang Wan; Han, Jung Ho; Kim, Chae-Yong; Kwon, O-Ki; Son, Young-Je; Bae, Hee-Joon; Han, Moon-Ku; Chung, Young Seob

2010-12-01

We retrospectively evaluated the effect of brain atrophy on the outcome of patients after a large cerebral infarct. Between June 2003 and Oct 2008, 134 of 2975 patients with stroke were diagnosed as having a large cerebral infarct. The mean age of the patients was 70 (21-95) y. The mean infarct volume was 223.6±95.2 cm(3) (46.0-491.0). The inter-caudate distance (ICD) was calculated as an indicator of brain atrophy by measuring the hemi-ICD of the intact side and then multiplying by two to account for brain swelling at the infarct site. The mean ICD was 18.0±4.8 mm (9.6-37.6). Forty-nine (36.6%) patients experienced a malignant clinical outcome (MCO) during management in the hospital. Thirty-one (23.1%) patients had a favourable functional outcome (FO) (modified Rankin scale (mRS) ≤3) and 49 (36.6%) had an acceptable functional outcome (AO) (mRS≤4) at 6 months after stroke onset. In the multivariate analysis, brain atrophy (ICD≥20 mm) had a significant and independent protective effect on MCO (p=0.003; OR=0.137; 95% CI 0.037 to 0.503). With respect to FO, the age and infarct volume reached statistical significance (p<0.001, OR=0.844, 95% CI 0.781 to 0.913; p=0.006, OR=0.987, 95% CI 0.977 to 0.996, respectively). Brain atrophy (ICD≥20 mm) was negatively associated only with AO (p=0.022; OR=0.164; 95% CI 0.035 to 0.767). Brain atrophy may have an association with clinical outcome after a large stroke by a trend of saving patients from an MCO but also by interfering with their functional recovery.

Age-related reduction of adaptive brain response during semantic integration is associated with gray matter reduction.

PubMed

Zhu, Zude; Yang, Fengjun; Li, Dongning; Zhou, Lianjun; Liu, Ying; Zhang, Ying; Chen, Xuezhi

2017-01-01

While aging is associated with increased knowledge, it is also associated with decreased semantic integration. To investigate brain activation changes during semantic integration, a sample of forty-eight 25-75 year-old adults read sentences with high cloze (HC) and low cloze (LC) probability while functional magnetic resonance imaging was conducted. Significant age-related reduction of cloze effect (LC vs. HC) was found in several regions, especially the left middle frontal gyrus (MFG) and right inferior frontal gyrus (IFG), which play an important role in semantic integration. Moreover, when accounting for global gray matter volume reduction, the age-cloze correlation in the left MFG and right IFG was absent. The results suggest that brain structural atrophy may disrupt brain response in aging brains, which then show less brain engagement in semantic integration.

Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: a meta-analysis.

PubMed

Rudnicka, Alicja R; Jarrar, Zakariya; Wormald, Richard; Cook, Derek G; Fletcher, Astrid; Owen, Christopher G

2012-03-01

To obtain prevalence estimates of age-related macular degeneration (AMD; late, geographic atrophy, neovascular) by age and gender amongst populations of European ancestry taking into account study design and time trends. Systematic review of population-based studies published by September 2010 with quantitative estimates of geographic atrophy (GA), neovascular (NV), and late AMD prevalence. Studies were identified by a literature search of MEDLINE (from 1950), EMBASE (from 1980), and Web of Science (from 1980) databases. Data from 25 published studies (57 173 subjects: 455 with GA, 464 with NVAMD, and 1571 with late AMD). Bayesian meta-regression of the log odds of AMD with age, gender, and year of study allowing for differences in study design characteristics, to estimate prevalences of AMD (late, GA, NVAMD) along with 95% credible intervals (CrI). Log odds and prevalence of AMD. There was considerable heterogeneity in prevalence rates between studies; for late AMD, 20% of the variability in prevalence rates was explained by differences in age and 50% by study characteristics. The prevalence of AMD increased exponentially with age (odds ratio [OR], 4.2 per decade; 95% CrI, 3.8-4.6), which did not differ by gender. There was some evidence to suggest higher risk of NVAMD in women compared with men (OR, 1.2; 95% CrI, 1.0-1.5). Compared with studies using fundus imaging and international classification systems, studies using fundus imaging with alternative classifications were more likely (OR, 2.7; 95% CrI, 1.1-2.8), and studies using alternative classifications without fundus imaging most likely to diagnose late AMD (OR, 2.9; 95% CrI, 1.3-7.8). There was no good evidence of trends in AMD prevalence over time. Estimated prevalence of late AMD is 1.4% (95% CrI, 1.0%-2.0%) at 70 years of age, rising to 5.6% (95% CrI, 3.9%-7.7%) at age 80 and 20% (95% CrI, 14%-27%) at age 90. Studies using recognized classifications systems with fundus photography reported the lowest

Atrophy of the Quadriceps Is Not Isolated to the Vastus Medialis Oblique in Individuals With Patellofemoral Pain.

PubMed

Giles, Lachlan S; Webster, Kate E; McClelland, Jodie A; Cook, Jill

2015-08-01

Cross-sectional. Objectives To determine if quadriceps atrophy was present in people with patellofemoral pain (PFP), and whether the vastus medialis oblique (VMO) was selectively involved. Despite the lack of research investigating individual quadriceps muscle size in individuals with PFP, it has been suggested that selective atrophy of the VMO relative to the vastus lateralis could be associated with PFP. The quadriceps muscle sizes of 35 participants with PFP (22 with unilateral and 13 with bilateral symptoms) and 35 asymptomatic control participants matched for age and sex were measured using real-time ultrasound. The thicknesses of the VMO, vastus lateralis, vastus medialis, rectus femoris, and vastus intermedius were measured. Paired-samples t tests were used to compare muscle thickness between limbs in those with unilateral PFP, and independent t tests were used to compare muscle thickness between groups with and without PFP. Results In those with unilateral PFP, the thickness of all portions of the quadriceps muscle was statistically smaller in the symptomatic compared to the asymptomatic limb: VMO (P = .038), vastus medialis (P<.001), vastus lateralis (P = .005), vastus intermedius (P = .013), and rectus femoris (P = .045). No difference was found in thickness of any of the portions of the quadriceps on the affected side of people with PFP compared to asymptomatic controls: VMO (P = .148), vastus medialis (P = .474), vastus lateralis (P = .122), vastus intermedius (P = .466), and rectus femoris (P = .508). Atrophy of all portions of the quadriceps muscles is present in the affected limb of people with unilateral PFP. There was no atrophy of the quadriceps in individuals with PFP compared to those without pathology. Selective atrophy of the VMO relative to the vastus lateralis was not identified in people with PFP.

Deficits in memory and visuospatial learning correlate with regional hippocampal atrophy in MS.

PubMed

Longoni, Giulia; Rocca, Maria A; Pagani, Elisabetta; Riccitelli, Gianna C; Colombo, Bruno; Rodegher, Mariaemma; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

2015-01-01

The hippocampus has a critical role in episodic memory and visuospatial learning and consolidation. We assessed the patterns of whole and regional hippocampal atrophy in a large group of multiple sclerosis (MS) patients, and their correlations with neuropsychological impairment. From 103 MS patients and 28 healthy controls (HC), brain dual-echo and high-resolution 3D T1-weighted images were acquired using a 3.0-Tesla scanner. All patients underwent a neuropsychological assessment of hippocampal-related cognitive functions, including Paired Associate Word Learning, Short Story, delayed recall of Rey-Osterrieth Complex Figure and Paced Auditory Serial Attention tests. The hippocampi were manually segmented and volumes derived. Regional atrophy distribution was assessed using a radial mapping analysis. Correlations between hippocampal atrophy and clinical, neuropsychological and MRI metrics were also evaluated. Hippocampal volume was reduced in MS patients vs HC (p < 0.001 for both right and hippocampus). In MS patients, radial atrophy affected CA1 subfield and subiculum of posterior hippocampus, bilaterally. The dentate hilus (DG:H) of the right hippocampal head was also affected. Regional hippocampal atrophy correlated with brain T2 and T1 lesion volumes, while no correlation was found with disability. Damage to the CA1 and subiculum was significantly correlated to the performances at hippocampal-targeted neuropsychological tests. These results show that hippocampal subregions have a different vulnerability to MS-related damage, with a relative sparing of the head of the left hippocampus. The assessment of regional hippocampal atrophy may help explain deficits of specific cognitive functions in MS patients, including memory and visuospatial abilities.

Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens.

PubMed

Matsuhisa, Takeshi; Tsukui, Taku

2012-05-01

During endoscopic examinations we collected fluid in the stomach that included reflux fluid from the duodenum, and assessed the effect of quantitatively determined bile acids on glandular atrophy and intestinal metaplasia using biopsy specimens. A total of 294 outpatients were enrolled in this study. Total bile acid concentration was measured by an enzyme immunoassay. Glandular atrophy and intestinal metaplasia scores were graded according to the Updated Sydney System. An effect of refluxed bile acids on atrophy and intestinal metaplasia was shown in the high-concentration reflux group in comparison with the control group. However, when the odds ratios (ORs) were calculated according to whether Helicobacter pylori (H. pylori) infection was present, no significant associations were shown between reflux bile acids and atrophy in either the H. pylori-positive cases or -negative cases. The same was true for intestinal metaplasia in the H. pylori-positive cases, whereas intestinal metaplasia was more pronounced in the high-concentration reflux group in the H. pylori-negative cases (OR 2.4, 95%CI 1.1-5.6). We could not clarify the effect of the reflux of bile acids into the stomach in the progression of atrophy. High-concentration bile acids had an effect on the progression of intestinal metaplasia in the H. pylori-negative cases.

Hippocampal atrophy and memory dysfunction associated with physical inactivity in community-dwelling elderly subjects: The Sefuri study.

PubMed

Hashimoto, Manabu; Araki, Yuko; Takashima, Yuki; Nogami, Kohjiro; Uchino, Akira; Yuzuriha, Takefumi; Yao, Hiroshi

2017-02-01

Physical inactivity is one of the modifiable risk factors for hippocampal atrophy and Alzheimer's disease. We investigated the relationship between physical activity, hippocampal atrophy, and memory using structural equation modeling (SEM). We examined 213 community-dwelling elderly subjects (99 men and 114 women with a mean age of 68.9 years) without dementia or clinically apparent depression. All participants underwent Mini-Mental State Examination (MMSE) and Rivermead Behavioral Memory Test (RBMT). Physical activities were assessed with a structured questionnaire. We evaluated the degree of hippocampal atrophy (z-score-referred to as ZAdvance hereafter), using a free software program-the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) based on statistical parametric mapping 8 plus Diffeomorphic Anatomical Registration Through an Exponentiated Lie algebra. Routine magnetic resonance imaging findings were as follows: silent brain infarction, n  = 24 (11.3%); deep white matter lesions, n  = 72 (33.8%); periventricular hyperintensities, n  = 35 (16.4%); and cerebral microbleeds, n  = 14 (6.6%). Path analysis based on SEM indicated that the direct paths from leisure-time activity to hippocampal atrophy (β = -.18, p  < .01) and from hippocampal atrophy to memory dysfunction (RBMT) (β = -.20, p  < .01) were significant. Direct paths from "hippocampus" gray matter volume to RBMT and MMSE were highly significant, while direct paths from "whole brain" gray matter volume to RBMT and MMSE were not significant. The presented SEM model fit the data reasonably well. Based on the present SEM analysis, we found that hippocampal atrophy was associated with age and leisure-time physical inactivity, and hippocampal atrophy appeared to cause memory dysfunction, although we are unable to infer a causal or temporal association between hippocampal atrophy and memory dysfunction from the present observational study.

Predictive models of long-term anatomic outcome in age-related macular degeneration treated with as-needed Ranibizumab.

PubMed

Gonzalez-Buendia, Lucia; Delgado-Tirado, Santiago; Sanabria, M Rosa; Fernandez, Itziar; Coco, Rosa M

2017-08-18

To analyze predictors and develop predictive models of anatomic outcome in neovascular age-related macular degeneration (AMD) treated with as-needed ranibizumab after 4 years of follow-up. A multicenter consecutive case series non-interventional study was performed. Clinical, funduscopic and OCT characteristics of 194 treatment-naïve patients with AMD treated with as-needed ranibizumab for at least 2 years and up to 4 years were analyzed at baseline, 3 months and each year until the end of the follow-up. Baseline demographic and angiographic characteristics were also evaluated. R Statistical Software was used for statistical analysis. Main outcome measure was final anatomic status. Factors associated with less probability of preserved macula were diagnosis in 2009, older age, worse vision, presence of atrophy/fibrosis, pigment epithelium detachment, and geographic atrophy/fibrotic scar/neovascular AMD in the fellow eye. Factors associated with higher probability of GA were presence of atrophy and greater number of injections, whereas male sex, worse vision, lesser change in central macular thickness and presence of fibrosis were associated with less probability of GA as final macular status. Predictive model of preserved macula vs. GA/fibrotic scar showed sensibility of 77.78% and specificity of 69.09%. Predictive model of GA vs. fibrotic scar showed sensibility of 68.89% and specificity of 72.22%. We identified predictors of final macular status, and developed two predictive models. Predictive models that we propose are based on easily harvested variables, and, if validated, could be a useful tool for individual patient management and clinical research studies.

Dry Age-Related Macular Degeneration Pharmacology

PubMed Central

Wright, Charles B.

2017-01-01

Age-related macular degeneration (AMD), the most common form of irreversible blindness in the industrially developed world, can present years before a patient begins to lose vision. For most of these patients, AMD never progresses past its early stages to the advanced forms that are principally responsible for the vast majority of vision loss. Advanced AMD can manifest as either an advanced avascular form known as geographic atrophy (GA) marked by regional retinal pigment epithelium (RPE) cell death or as an advanced form known as neovascular AMD marked by the intrusion of fragile new blood vessels into the normally avascular retina. Physicians have several therapeutic interventions available to combat neovascular AMD, but GA has no approved effective therapies as of yet. In this chapter, we will discuss the current strategies for limiting dry AMD in patients. We will also discuss previous attempts at pharmacological intervention that were tested in a clinical setting and consider reasons why these putative therapeutics did not perform successfully in large-scale trials. Despite the number of unsuccessful past trials, new pharmacological interventions may succeed. These future therapies may aid millions of AMD patients worldwide. PMID:27900609

Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis

PubMed Central

Shi, Jianjun; Fallahi, Mohammad; Luo, Jun-Li

2011-01-01

Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-αβ development is normal, as are NKT and TCRγδ cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele because insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are coexpressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out nonoverlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages. PMID:21768299

Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies

PubMed Central

Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

2016-01-01

Background Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. Methods PubMed, Cochrane’s Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Results Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55–1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Conclusion Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors. PMID:27524907

Regional gray matter atrophy in relapsing remitting multiple sclerosis: baseline analysis of multi-center data.

PubMed

Datta, Sushmita; Staewen, Terrell D; Cofield, Stacy S; Cutter, Gary R; Lublin, Fred D; Wolinsky, Jerry S; Narayana, Ponnada A

2015-03-01

Regional gray matter (GM) atrophy in multiple sclerosis (MS) at disease onset and its temporal variation can provide objective information regarding disease evolution. An automated pipeline for estimating atrophy of various GM structures was developed using tensor based morphometry (TBM) and implemented on a multi-center sub-cohort of 1008 relapsing remitting MS (RRMS) patients enrolled in a Phase 3 clinical trial. Four hundred age and gender matched healthy controls were used for comparison. Using the analysis of covariance, atrophy differences between MS patients and healthy controls were assessed on a voxel-by-voxel analysis. Regional GM atrophy was observed in a number of deep GM structures that included thalamus, caudate nucleus, putamen, and cortical GM regions. General linear regression analysis was performed to analyze the effects of age, gender, and scanner field strength, and imaging sequence on the regional atrophy. Correlations between regional GM volumes and expanded disability status scale (EDSS) scores, disease duration (DD), T2 lesion load (T2 LL), T1 lesion load (T1 LL), and normalized cerebrospinal fluid (nCSF) were analyzed using Pearson׳s correlation coefficient. Thalamic atrophy observed in MS patients compared to healthy controls remained consistent within subgroups based on gender and scanner field strength. Weak correlations between thalamic volume and EDSS (r=-0.133; p<0.001) and DD (r=-0.098; p=0.003) were observed. Of all the structures, thalamic volume moderately correlated with T2 LL (r=-0.492; P-value<0.001), T1 LL (r=-0.473; P-value<0.001) and nCSF (r=-0.367; P-value<0.001). Copyright © 2015 Elsevier B.V. All rights reserved.

Thymic emigration revisited

PubMed Central

McCaughtry, Tom M.; Wilken, Matthew S.; Hogquist, Kristin A.

2007-01-01

Conventional αβ T cell precursors undergo positive selection in the thymic cortex. When this is successful, they migrate to the medulla and are exposed to tissue-specific antigens (TSA) for purposes of central tolerance, and they undergo maturation to become functionally responsive T cells. It is commonly understood that thymocytes spend up to 2 wk in the medulla undergoing these final maturation steps before emigrating to peripheral lymphoid tissues. In addition, emigration is thought to occur via a stochastic mechanism whereby some progenitors leave early and others leave late—a so-called “lucky dip” process. However, recent research has revealed that medullary thymocytes are a heterogeneous mix of naive αβ T cell precursors, memory T cells, natural killer T cells, and regulatory T cells. Given this, we revisited the question of how long it takes naive αβ T cell precursors to emigrate. We combined the following three approaches to study this question: BrdU labeling, intrathymic injection of a cellular tag, and RAG2p-GFP reporter mice. We established that, on average, naive αβ T cell precursors emigrate only 4–5 d after becoming single-positive (SP) thymocytes. Furthermore, emigration occurs via a strict “conveyor belt” mechanism, where the oldest thymocytes leave first. PMID:17908937

Episodic Memory and Regional Atrophy in Frontotemporal Lobar Degeneration

PubMed Central

Söderlund, Hedvig; Black, Sandra E.; Miller, Bruce L.; Freedman, Morris; Levine, Brian

2008-01-01

It has been unclear to what extent memory is affected in frontotemporal lobar degeneration (FTLD). Since patients usually have atrophy in regions implicated in memory function, the frontal and/or temporal lobes, one would expect some memory impairment, and that the degree of atrophy in these regions would be inversely related to memory function. The purposes of this study were 1) to assess episodic memory function in FTLD, and more specifically patients' ability to episodically re-experience an event, and determine its source; 2) to examine whether memory performance is related to quantified regional brain atrophy. FTLD patients (n=18) and healthy comparison subjects (n=14) were assessed with cued recall, recognition, “remember/know” (self-reported re-experiencing) and source recall, at 30 min and 24 hr after encoding. Regional gray matter volumes were assessed with high resolution structural MRI concurrently to testing. Patients performed worse than comparison subjects on all memory measures. Gray matter volume in the left medial temporal lobe was positively correlated with recognition, re-experiencing, and source recall. Gray matter volume in the left posterior temporal lobe correlated significantly with recognition, at 30 min and 24 hr, and with source recall at 30 min. Estimated familiarity at 30 min was positively correlated with gray matter volume in the left inferior parietal lobe. In summary, episodic memory deficits in FTLD may be more common than previously thought, particularly in patients with left medial and posterior temporal atrophy. PMID:17888461

Robust Identification of Alzheimer's Disease subtypes based on cortical atrophy patterns.

PubMed

Park, Jong-Yun; Na, Han Kyu; Kim, Sungsoo; Kim, Hyunwook; Kim, Hee Jin; Seo, Sang Won; Na, Duk L; Han, Cheol E; Seong, Joon-Kyung

2017-03-09

Accumulating evidence suggests that Alzheimer's disease (AD) is heterogenous and can be classified into several subtypes. Here, we propose a robust subtyping method for AD based on cortical atrophy patterns and graph theory. We calculated similarities between subjects in their atrophy patterns throughout the whole brain, and clustered subjects with similar atrophy patterns using the Louvain method for modular organization extraction. We applied our method to AD patients recruited at Samsung Medical Center and externally validated our method by using the AD Neuroimaging Initiative (ADNI) dataset. Our method categorized very mild AD into three clinically distinct subtypes with high reproducibility (>90%); the parietal-predominant (P), medial temporal-predominant (MT), and diffuse (D) atrophy subtype. The P subtype showed the worst clinical presentation throughout the cognitive domains, while the MT and D subtypes exhibited relatively mild presentation. The MT subtype revealed more impaired language and executive function compared to the D subtype.

Clinical classification of age-related macular degeneration.

PubMed

Ferris, Frederick L; Wilkinson, C P; Bird, Alan; Chakravarthy, Usha; Chew, Emily; Csaky, Karl; Sadda, SriniVas R

2013-04-01

To develop a clinical classification system for age-related macular degeneration (AMD). Evidence-based investigation, using a modified Delphi process. Twenty-six AMD experts, 1 neuro-ophthalmologist, 2 committee chairmen, and 1 methodologist. Each committee member completed an online assessment of statements summarizing current AMD classification criteria, indicating agreement or disagreement with each statement on a 9-step scale. The group met, reviewed the survey results, discussed the important components of a clinical classification system, and defined new data analyses needed to refine a classification system. After the meeting, additional data analyses from large studies were provided to the committee to provide risk estimates related to the presence of various AMD lesions. Delphi review of the 9-item set of statements resulting from the meeting. Consensus was achieved in generating a basic clinical classification system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease. Persons with no visible drusen or pigmentary abnormalities should be considered to have no signs of AMD. Persons with small drusen (<63 μm), also termed drupelets, should be considered to have normal aging changes with no clinically relevant increased risk of late AMD developing. Persons with medium drusen (≥ 63-<125 μm), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD. Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a

Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials.

PubMed

Holz, Frank G; Sadda, Srinivas R; Busbee, Brandon; Chew, Emily Y; Mitchell, Paul; Tufail, Adnan; Brittain, Christopher; Ferrara, Daniela; Gray, Sarah; Honigberg, Lee; Martin, Jillian; Tong, Barbara; Ehrlich, Jason S; Bressler, Neil M

2018-06-01

Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm2 with diffuse or banded fundus autofluorescence patterns. Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I-profile genetic biomarker. A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were -0.02 mm2 (95% CI, -0.21 to 0.16 mm2; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm2 (95% CI, 0.00-0.31 mm2; P = .048) for lampalizumab every 4 weeks in Spectri

Optical coherence tomography angiography in the management of age-related macular degeneration.

PubMed

Schneider, Eric W; Fowler, Samuel C

2018-05-01

Optical coherence tomography angiography (OCT-A) provides rapid, flow-based imaging of the retinal and choroidal vasculature in a noninvasive manner. This review contrasts this novel technique with conventional angiography and discusses its current uses and limitations in the management of age-related macular degeneration (AMD). Initial work with OCT-A has focused on its ability to identify choriocapillaris flow alterations in dry AMD and to sensitively detect choroidal neovascular membranes (CNVs) in neovascular AMD. Reduced choriocapillaris flow beyond the borders of geographic atrophy seen on OCT-A suggests a primary vascular cause in geographic atrophy. Longitudinal OCT-A analysis of CNV morphology has demonstrated the transition from an immature to mature CNV phenotype following treatment. Current clinical applications of OCT-A include identification of asymptomatic CNV and monitoring for CNV development in the setting of an acquired vitelliform lesion. OCT-A remains a promising diagnostic tool but one still very much in evolution. Larger studies will be needed to more accurately describe its sensitivity and specificity for CNV detection and to better characterize longitudinal CNV morphologic changes. Anticipated hardware and software updates including swept-source light sources, automated montaging, and manual adjustment of interscan timing should enhance the capabilities of OCT-A in the management of AMD.

Dominant optic atrophy.

PubMed

Lenaers, Guy; Hamel, Christian; Delettre, Cécile; Amati-Bonneau, Patrizia; Procaccio, Vincent; Bonneau, Dominique; Reynier, Pascal; Milea, Dan

2012-07-09

DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs

Dominant optic atrophy

PubMed Central

2012-01-01

Definition of the disease Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of bilateral, mild

Thymic MIS: state of the art across the world (Russian Federation).

PubMed

Yablonskii, Piotr; Kudriashov, Grigorii; Pischik, Vadim; Sigal, Evgenii; Nuraliev, Sabriddin

2017-01-01

First VATS thymectomy was performed 25 years ago (Landreneau et al ., 1992). After that, minimally invasive approaches for surgical procedures have rapidly increased in the world. The aim of this paper was study of current problems and the status of surgery for thymus diseases in Russia. This is first global survey of all thoracic centers, which had experience in thymic surgery.

Thymic MIS: state of the art across the world (Russian Federation)

PubMed Central

Yablonskii, Piotr; Pischik, Vadim; Sigal, Evgenii; Nuraliev, Sabriddin

2017-01-01

First VATS thymectomy was performed 25 years ago (Landreneau et al., 1992). After that, minimally invasive approaches for surgical procedures have rapidly increased in the world. The aim of this paper was study of current problems and the status of surgery for thymus diseases in Russia. This is first global survey of all thoracic centers, which had experience in thymic surgery. PMID:29078679

Bilateral hippocampal atrophy in temporal lobe epilepsy: Effect of depressive symptoms and febrile seizures

PubMed Central

Finegersh, Andrey; Avedissian, Christina; Shamim, Sadat; Dustin, Irene; Thompson, Paul M.; Theodore, William H.

2011-01-01

Summary Purpose Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE). Methods We used radial atrophy mapping (RAM), a three-dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy. Key Findings Subjects with a history of febrile seizures (n = 15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI-II) score ≥14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI-II <14 (n = 29). Significance Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression. PMID:21269286

Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy.

PubMed

Iyer, Chitra C; McGovern, Vicki L; Wise, Dawnne O; Glass, David J; Burghes, Arthur H M

2014-05-01

Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx(-/-)-SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. Copyright © 2014 Elsevier B.V. All rights reserved.

Progressive contralateral hippocampal atrophy following surgery for medically refractory temporal lobe epilepsy.

PubMed

Elliott, Cameron A; Gross, Donald W; Wheatley, B Matt; Beaulieu, Christian; Sankar, Tejas

2016-09-01

Determine the extent and time course of volumetric changes in the contralateral hippocampus following surgery for medically refractory temporal lobe epilepsy (TLE). Serial T1-weighted MRI brain scans were obtained in 26 TLE patients pre- and post-temporal lobe epilepsy surgery as well as in 12 control subjects of similar age. Patients underwent either anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH). Blinded, manual hippocampal volumetry (head, body, and tail) was performed in two groups: 1) two scan group [ATL (n=6); SAH (n=10)], imaged pre-surgery and on average at 5.4 years post-surgery; and 2) longitudinal group [ATL (n=8); SAH (n=2)] imaged pre-surgery and on post-operative day 1, 2, 3, 6, 60, 120 and a delayed time point (average 2.4 years). In the two scan group, there was atrophy by 12% of the unresected contralateral hippocampus (p<0.001), with atrophy being most pronounced (27%) in the hippocampal body (p<0.001) with no significant differences seen for the hippocampal head or tail. In the longitudinal group, significant atrophy was also observed for the whole hippocampus and the body with atrophy seen as early as post-operative day #1 which progressed significantly over the first post-operative week (1.3%/day and 3.0%./day, respectively) before stabilizing over the long-term to a 13% reduction in total volume. There was no significant difference in atrophy compared by surgical approach (ATL vs. SAH; p=0.94) or side (p=0.31); however, atrophy was significantly more pronounced in patients with ongoing post-operative seizures (hippocampal body, p=0.019; whole hippocampus, p=0.048). There were no detectable post-operative neuropsychological deficits attributable to contralateral hippocampal atrophy. Significant contralateral hippocampal atrophy occurs following TLE surgery, which begins immediately and progresses over the first post-operative week. The observation that seizure free patients had significantly less atrophy of the

Hematological alterations and thymic function in newborns of HIV-infected mothers receiving antiretroviral drugs.

PubMed

Wongnoi, Rotjanee; Penvieng, Nawaporn; Singboottra, Panthong; Kingkeow, Doungnapa; Oberdorfer, Peninnah; Sirivatanapa, Pannee; Pornprasert, Sakorn

2013-06-08

To investigate the effects of antiretroviral (ARV) drugs on hematological parameters and thymic function in HIV-uninfected newborns of HIV-infected mothers. Cross sectional study. Chiang-Mai University Hospital, Chiang-Mai, Thailand. 49 HIV-uninfected and 26 HIV-infected pregnancies. Cord blood samples of newborns from HIV-uninfected and HIV-infected mothers were collected. Hematological parameters were measured using automatic blood cell count. T-cell receptor excision circles (TRECs) levels in cord blood mononuclear cells (CBMCs), CD4+ and CD8+ T-cells were quantified using real-time PCR.. Hemotological parameters and thymic function. Newborn of HIV-infected mother tended to have lower mean levels of hemoglobin than those of HIV-uninfected mother (137 ±22 vs 146 ±17 g/L, P = 0.05). Furthermore, mean of red blood cell (RBC) counts and hematocrit and median of TRECs in CD4+ T-cells in the newborns of the former were significantly lower than those of the latter [3.6 ±0.7 vs 4.8 ±0.6 x 1012 cells/L, P <0.001; 0.40 ±0.07 vs 0.46 ±0.05 L/L, P < 0.001 and 0.53 (IQR: 0.03-5.76) vs 13.20 (IQR: 2.77-27.51) x 10-3 pg/uL, P = 0.02, respectively]. ARV drugs altered hematological parameters and thymic function (TRECs CD4+ T-cells) in HIV-uninfected newborns of HIV-infected mothers.

Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy.

PubMed

Shakespeare, Timothy J; Kaski, Diego; Yong, Keir X X; Paterson, Ross W; Slattery, Catherine F; Ryan, Natalie S; Schott, Jonathan M; Crutch, Sebastian J

2015-07-01

whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer's disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer's disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy

PubMed Central

Kaski, Diego; Yong, Keir X. X.; Paterson, Ross W.; Slattery, Catherine F.; Ryan, Natalie S.; Schott, Jonathan M.; Crutch, Sebastian J.

2015-01-01

saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer’s disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer’s disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment. PMID:25895507

Use of various free flaps in progressive hemifacial atrophy.

PubMed

Baek, Rongmin; Heo, Chanyeong; Kim, Baek-kyu

2011-11-01

Romberg disease is an uncommon condition manifested by progressive hemifacial atrophy of the skin, soft tissue, and bone. Facial asymmetry with soft tissue deficiency in Romberg disease causes a significant disability affecting the social life and can bring about many psychological problems. The aim of surgical treatment is cosmetic amelioration of the defect. Several conventional reconstructive procedures have been used for correcting facial asymmetry. They include fat injections, dermal fat grafts, filler injections, cartilage and bone grafts, and pedicled and free flaps. We report our experiences with 11 patients involving 11 free flaps with a minimum 1-year follow-up. All patients were classified as having moderate to severe atrophy. The average age at disease onset was 4.5 years; the average duration of atrophy was 5.2 years. No patients were operated on with a quiescent interval of less than 1 year. The average age at operation was 20.1 years, ranging from 10 to 55 years. Reconstruction was performed using 4 groin dermofat free flaps, 4 latissimus dorsi muscle free flaps, and 3 other perforator flaps. To achieve the finest symmetrical and aesthetic results, several ancillary procedures were performed in 4 patients. These procedures included Le Fort I leveling osteotomy, sagittal split ramus osteotomy, reduction malarplasty and angle plasty, rib and calvarial bone graft, correction of alopecia, and additional fat graft. All patients were satisfied with the results. We believe that a free flap transfer is the requisite treatment modality for severe degree of facial asymmetry in Romberg disease.

Mechanisms of Botulinum Neurotoxin Induced Skeletal Muscle Atrophy

NASA Astrophysics Data System (ADS)

Hain, Brian A.

Our previous research suggests that the mechanism of botulinum neurotoxintype A (BoNT/A)-induced atrophy does not occur via a NF-kappaB/Foxo-dependent process. We thus hypothesized that the primary mechanism would be activation of either the proteosomal or calpain pathways. BoNT/A injection induced elevations in proteolytic activity markers of the ubiquitin-proteasome-system (UPS) and calpain systems after 3 days of a single dose. Inhibition of the proteasome significantly attenuated BoNT/Ainduced atrophy 3-days post BoNT/A injection. Calpastatin overexpression prevented BoNT/A-induced calpain activity at 3 days, and but did not result in a significant attenuation of atrophy. Concurrent attenuation of the UPS and calpain systems was sufficient to attenuate all of the atrophy associated with BoNT/A induced atrophy. In conclusion, it appears that the UPS and calpain system work in an additive fashion with neurotoxin-induced muscle atrophy. Inhibiting both of these pathways while administering BoNT/A attenuates all of the observed muscle atrophy.

Evaluation of age-related changes with cross-sectional CT imaging of teeth

NASA Astrophysics Data System (ADS)

Fukui, Tatsumasa; Kita, Kanade; Kamemoto, Hiromasa; Nishiyama, Wataru; Yoshida, Hiroyasu; Iida, Yukihiro; Katsumata, Akitoshi; Muramatsu, Chisako; Fujita, Hiroshi

2017-03-01

Tooth pulp atrophy occurs with increasing age. An age estimation procedure using dental cone beam computed tomography (CBCT) imaging was developed. Clinical dental CBCT images of 60 patients (aged from 20 to 80 years) were evaluated. The ratio of the cross-sectional area of the pulp cavity to the cross-sectional area of the tooth (pulp cavity ratio) was calculated. The pulp cavity ratio in the labio-lingual plane of the mandibular anterior teeth and the mesio-distal plane of the maxillary anterior teeth was strongly correlated with the patients' age. The pulp cavity ratio of anterior teeth may be a useful parameter for estimating age.

Trichoscopy of Steroid-Induced Atrophy.

PubMed

Pirmez, Rodrigo; Abraham, Leonardo S; Duque-Estrada, Bruna; Damasco, Patrícia; Farias, Débora Cadore; Kelly, Yanna; Doche, Isabella

2017-10-01

Intralesional corticosteroid (IL-CS) injections have been used to treat a variety of dermatological and nondermatological diseases. Although an important therapeutic tool in dermatology, a number of local side effects, including skin atrophy, have been reported following IL-CS injections. We recently noticed that a subset of patients with steroid-induced atrophy presented with ivory-colored areas under trichoscopy. We performed a retrospective analysis of trichoscopic images and medical records from patients presenting ivory-colored areas associated with atrophic scalp lesions. In this paper, we associate this feature with the presence of steroid deposits in the dermis and report additional trichoscopic features of steroid-induced atrophy on the scalp, such as prominent blood vessels and visualization of hair bulbs.

Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

PubMed Central

Baehr, Leslie M.; West, Daniel W. D.; Marshall, Andrea G.; Marcotte, George R.; Baar, Keith

2017-01-01

Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (−9 to −38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. NEW & NOTEWORTHY In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber

Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients.

PubMed

Bergsland, Niels; Zivadinov, Robert; Dwyer, Michael G; Weinstock-Guttman, Bianca; Benedict, Ralph Hb

2016-09-01

Deep gray matter (DGM) atrophy is common in multiple sclerosis (MS), but no studies have investigated surface-based structure changes over time with respect to healthy controls (HCs). Moreover, the relationship between cognition and the spatio-temporal evolution of DGM atrophy is poorly understood. To explore DGM structural differences between MS and HCs over time in relation to neuropsychological (NP) outcomes. The participants were 44 relapsing-remitting and 20 secondary progressive MS patients and 22 HCs. All were scanned using 3T magnetic resonance imaging (MRI) at baseline and 3-year follow-up. NP examination emphasized consensus standard tests of processing speed and memory. We performed both volumetric and shape analysis of DGM structures and assessed their relationships with cognition. Compared to HCs, MS patients presented with significantly smaller DGM volumes. For the thalamus and caudate, differences in shape were mostly localized along the lateral ventricles. NP outcomes were related to both volume and shape of the DGM structures. Over 3 years, decreased cognitive processing speed was related to localized atrophy on the anterior and superior surface of the left thalamus. These findings highlight the role of atrophy in the anterior nucleus of the thalamus and its relation to cognitive decline in MS. © The Author(s), 2015.

Gastric atrophy and oesophageal squamous cell carcinoma: possible interaction with dental health and oral hygiene habit

PubMed Central

Nasrollahzadeh, D; Malekzadeh, R; Aghcheli, K; Sotoudeh, M; Merat, S; Islami, F; Kamangar, F; Abnet, C C; Shakeri, R; Pourshams, A; Semnani, S; Boffetta, P; Dawsey, S M; Ye, W

2012-01-01

Background: Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results. Methods: We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). Results: After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 μg dl−1) was associated with a two-fold increased risk (OR=2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII <11.8 μg dl−1). Stratification by PGII decreased the misclassification errors due to cancer-induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR=4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: −1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR=8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI=4.34, 95% CI: −1.07, 9.76). Conclusion: Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk. PMID:22814581

How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes

NASA Astrophysics Data System (ADS)

Chen, Hanrong; Chakraborty, Arup K.; Kardar, Mehran

2018-03-01

T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies. Past theoretical work cast thymic selection as an extreme value problem and characterized the statistical enrichment or depletion of amino acids in the postselection TCR repertoire, showing how T cells are selected to be able to specifically recognize peptides derived from diverse pathogens yet have limited self-reactivity. Here, we investigate how the diversity of the postselection TCR repertoire is modified when TCRs make nonuniform contacts with peptide-MHC. Specifically, we were motivated by recent experiments showing that amino acids at certain positions of a TCR sequence have large effects on thymic selection outcomes, and crystal structure data that reveal a nonuniform contact profile between a TCR and its peptide-MHC ligand. Using a representative TCR contact profile as an illustration, we show via simulations that the statistical enrichment or depletion of amino acids now varies by position according to the contact profile, and, importantly, it depends on the implementation of nonuniform contacts during thymic selection. We explain these nontrivial results analytically. Our study has implications for understanding the selection forces that shape the functionality of the postselection TCR repertoire.

Diabetes mellitus and optic atrophy: study of the Wolfram syndrome

PubMed

Rivas-Gómez, Bernardette; Reza-Albarrán, Alfredo Adolfo

2017-01-01

Wolfram syndrome (WS), also known by the acronym DIDMOAD, is a rare and progresive hereditary disease of autosomal recessive inheritance which minimum ascertainment diagnostic criteria are the occurrence together of diabetes mellitus and optic atrophy before 15 years of age. To describe the clinical, biochemical and molecular profile of WS in a tertiary care hospital in Mexico. We reviewed patients records who fulfill the minimum ascertainment diagnostic criteria of WS presenting between January 1987 and May 2015 in a tertiary care hospital in Mexico. Five patients fulfill the inclusion criteria (three male and two female). Diabetes mellitus was the first manifestation of the syndrome in all of them, with a mean age at diagnosis of 5.8 ± 2.71 years, while the WS diagnosis was established at a mean age of 15.8 ± 8.37 years. All the patients had optic atrophy and two of them presented with the complete DIDMOAD spectrum. We found new associations with autoimmune hepatitis and testicular cancer. This study shows the variability of clinical presentation of WS, as well as two new associations. Copyright: © 2017 SecretarÍa de Salud

Dataset for reporting of thymic epithelial tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR).

PubMed

Nicholson, Andrew G; Detterbeck, Frank; Marx, Alexander; Roden, Anja C; Marchevsky, Alberto M; Mukai, Kiyoshi; Chen, Gang; Marino, Mirella; den Bakker, Michael A; Yang, Woo-Ick; Judge, Meagan; Hirschowitz, Lynn

2017-03-01

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organization formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists-Association Canadienne des Pathologists in association with the Canadian Partnership Against Cancer, and the European Society of Pathology. Its goal is to produce standardized, internationally agreed, evidence-based datasets for use throughout the world. This article describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of thymic epithelial tumours. The dataset includes 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are validated by a review of current evidence and supported by explanatory text. Seven required elements and 12 recommended elements were agreed by the international dataset authoring committee to represent the essential information for the reporting of thymic epithelial tumours. The use of an internationally agreed, structured pathology dataset for reporting thymic tumours provides all of the necessary information for optimal patient management, facilitates consistent and accurate data collection, and provides valuable data for research and international benchmarking. The dataset also provides a valuable resource for those countries and institutions that are not in a position to develop their own datasets. © 2016 John Wiley & Sons Ltd.

Genome-wide analysis of disease progression in age-related macular degeneration.

PubMed

Yan, Qi; Ding, Ying; Liu, Yi; Sun, Tao; Fritsche, Lars G; Clemons, Traci; Ratnapriya, Rinki; Klein, Michael L; Cook, Richard J; Liu, Yu; Fan, Ruzong; Wei, Lai; Abecasis, Gonçalo R; Swaroop, Anand; Chew, Emily Y; Weeks, Daniel E; Chen, Wei

2018-03-01

Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.

Chlorhexidine possesses unique cytotoxic actions in rat thymic lymphocytes: Its relation with electrochemical property of membranes.

PubMed

Nonami, Kayo; Saitoh, Shohei; Nishimura-Danjobara, Yumiko; Ishida, Shiro; Oyama, Yasuo

2016-12-01

Chlorhexidine (CHX) is an antibacterial agent used in various types of pharmaceutical products. Therefore, CHX is easily found around us. Owing to its positive charge, the electrochemical property of cell membranes was assumed to be a key point of cytotoxic action of CHX. Depolarization of membranes attenuated the cytotoxic action of CHX in rat thymic lymphocytes. CHX interfered with annexin V binding to membranes. Manipulations to induce exposure of phosphatidylserine on the outer membrane surface augmented the cytotoxic action of CHX, indicating that changes in the electrochemical property of membranes affected the cytotoxic action of CHX. Hence, CHX might kill cells physiologically undergoing apoptosis, resulting instead in necrotic cell death. However, the threshold CHX concentration in this in vitro study was slightly higher than blood CHX concentrations observed clinically. Therefore, these results may support the safety of CHX use although CHX possesses unique cytotoxic actions described in this study. Copyright © 2016 Elsevier B.V. All rights reserved.

Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group.

PubMed

Domalpally, Amitha; Clemons, Traci E; Danis, Ronald P; Sadda, SriniVas R; Cukras, Catherine A; Toth, Cynthia A; Friberg, Thomas R; Chew, Emily Y

2017-04-01

To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen). Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study. Participants from prospective studies. The 200° pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions. Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities. A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls. Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas

White matter hyperintensities and imaging patterns of brain ageing in the general population.

PubMed

Habes, Mohamad; Erus, Guray; Toledo, Jon B; Zhang, Tianhao; Bryan, Nick; Launer, Lenore J; Rosseel, Yves; Janowitz, Deborah; Doshi, Jimit; Van der Auwera, Sandra; von Sarnowski, Bettina; Hegenscheid, Katrin; Hosten, Norbert; Homuth, Georg; Völzke, Henry; Schminke, Ulf; Hoffmann, Wolfgang; Grabe, Hans J; Davatzikos, Christos

2016-04-01

White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE

Oxidative stress in dry age-related macular degeneration and exfoliation syndrome.

PubMed

Chiras, Dimitrios; Kitsos, George; Petersen, Michael B; Skalidakis, Iosif; Kroupis, Christos

2015-02-01

Oxidative stress refers to cellular or molecular damage caused by reactive oxygen species, which especially occurs in age-related conditions as a result of an imbalance between the production of reactive oxygen species and the antioxidant defense response. Dry age-related macular degeneration (AMD) and exfoliation syndrome (XFS) are two common and complex age-related conditions that can cause irreversible vision loss. Two subtypes of AMD, which is the leading cause of blindness in the Western world, exist: the most prevalent dry type and the most severe wet type. Early dry AMD is characterized by formation of drusen, which are sub-retinal deposits, in the macular area and may progress to geographic atrophy with more dramatic manifestation. XFS is a systemic disorder of the extracellular matrix characterized by the accumulation of elastic fibrils that leads, in most cases, to glaucoma development with progressive and irreversible vision loss. Due to the aging population, the prevalence of these already-widespread conditions is increasing and is resulting in significant economic and psychological costs for individuals and for society. The exact composition of the abnormal drusen and XFS material as well as the mechanisms responsible for their production and accumulation still remain elusive, and consequently treatment for both diseases is lacking. However, recent epidemiologic, genetic and molecular studies support a major role for oxidative stress in both dry AMD and XFS development. Understanding the early molecular events in their pathogenesis and the exact role of oxidative stress may provide novel opportunities for therapeutic intervention for the prevention of progression to advanced disease.

Education amplifies brain atrophy effect on cognitive decline: implications for cognitive reserve.

PubMed

Mungas, Dan; Gavett, Brandon; Fletcher, Evan; Farias, Sarah Tomaszewski; DeCarli, Charles; Reed, Bruce

2018-08-01

Level of education is often regarded as a proxy for cognitive reserve in older adults. This implies that brain degeneration has a smaller effect on cognitive decline in those with more education, but this has not been directly tested in previous research. We examined how education, quantitative magnetic resonance imaging-based measurement of brain degeneration, and their interaction affect cognitive decline in diverse older adults spanning the spectrum from normal cognition to dementia. Gray matter atrophy was strongly related to cognitive decline. While education was not related to cognitive decline, brain atrophy had a stronger effect on cognitive decline in those with more education. Importantly, high education was associated with slower decline in individuals with lesser atrophy but with faster decline in those with greater atrophy. This moderation effect was observed in Hispanics (who had high heterogeneity of education) but not in African-Americans or Caucasians. These results suggest that education is an indicator of cognitive reserve in individuals with low levels of brain degeneration, but the protective effect of higher education is rapidly depleted as brain degeneration progresses. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of highly active antiretroviral therapy on thymical reconstitution of CD4 T lymphocytes in vertically HIV-infected children.

PubMed

Correa, Rafael; Muñoz-Fernández, Angeles

2002-05-24

CD4 T-cell percentages, viral load and thymic function measured as T-cell receptor rearrangement excision circle (TREC) levels were determined every 2-3 months in six treated HIV-infected children for 4 years. All children experienced a marked increase in CD4 cell count after therapy, accompanied by a concomitantly marked increase in TREC levels. In children, the decrease in viral load caused by antiviral therapy leads to an increase in CD4 T cells, mainly because of a recovery in the thymic production of new T cells.

The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9.

PubMed

Al-Holou, Shaza N; Tucker, William R; Agrón, Elvira; Clemons, Traci E; Cukras, Catherine; Ferris, Frederick L; Chew, Emily Y

2015-12-01

To evaluate the association of statin use with progression of age-related macular degeneration (AMD). Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years. Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed. Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD. Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the

Mathematical Model of Naive T Cell Division and Survival IL-7 Thresholds.

PubMed

Reynolds, Joseph; Coles, Mark; Lythe, Grant; Molina-París, Carmen

2013-01-01

We develop a mathematical model of the peripheral naive T cell population to study the change in human naive T cell numbers from birth to adulthood, incorporating thymic output and the availability of interleukin-7 (IL-7). The model is formulated as three ordinary differential equations: two describe T cell numbers, in a resting state and progressing through the cell cycle. The third is introduced to describe changes in IL-7 availability. Thymic output is a decreasing function of time, representative of the thymic atrophy observed in aging humans. Each T cell is assumed to possess two interleukin-7 receptor (IL-7R) signaling thresholds: a survival threshold and a second, higher, proliferation threshold. If the IL-7R signaling strength is below its survival threshold, a cell may undergo apoptosis. When the signaling strength is above the survival threshold, but below the proliferation threshold, the cell survives but does not divide. Signaling strength above the proliferation threshold enables entry into cell cycle. Assuming that individual cell thresholds are log-normally distributed, we derive population-average rates for apoptosis and entry into cell cycle. We have analyzed the adiabatic change in homeostasis as thymic output decreases. With a parameter set representative of a healthy individual, the model predicts a unique equilibrium number of T cells. In a parameter range representative of persistent viral or bacterial infection, where naive T cell cycle progression is impaired, a decrease in thymic output may result in the collapse of the naive T cell repertoire.

HIGH-DOSE HIGH-FREQUENCY AFLIBERCEPT FOR RECALCITRANT NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PubMed

You, Qi Sheng; Gaber, Raouf; Meshi, Amit; Ramkumar, Hema L; Alam, Mostafa; Muftuoglu, Ilkay Kilic; Freeman, William R

2018-06-01

To determine the efficacy of monthly (0.1 mL/4 mg) aflibercept for refractory neovascular age-related macular degeneration (wet age-related macular degeneration). This was a retrospective interventional case series in which patients with wet age-related macular degeneration were treated with stepwise dose escalation. Nonvitrectomized patients resistant to monthly (Q4W) ranibizumab/bevacizumab were switched to 2 mg aflibercept every 8 weeks. With resistance, they were escalated to Q4W 2 mg aflibercept, then Q4W 4 mg (high dose high frequency, 4Q4W) aflibercept. Resistance was defined as ≥2 recurrences after being dry following ≥3 injections or persistent exudation on treatment of ≥5 injections. Thirty-three eyes of 28 patients were treated with 4Q4W aflibercept and followed for a mean of 16 months. A dry retina (no intraretinal or subretinal fluid) was achieved after initiating 4Q4W aflibercept treatment at a mean of 3.8 months. Central foveal thickness, maximum foveal thickness, intraretinal fluid, subretinal fluid, and retinal pigment detachment height decreased significantly at 1 month after initiating the 4Q4W aflibercept, and the morphologic therapeutic effect was sustained until the last visit. Forty-five percent of eyes had one or more lines of vision improvement. New geographic atrophy developed in 9% of eyes during follow-up. No ocular or systemic adverse events occurred after initiating 4Q4W aflibercept. Intravitreal high-dose high-frequency aflibercept is an effective treatment for patients with refractory wet age-related macular degeneration.

Optical Coherence Tomography Updates on Clinical and Technical Developments. Age-Related Macular Degeneration: Drusen and Geographic Atrophy

NASA Astrophysics Data System (ADS)

Fleckenstein, Monika; Schmitz-Valckenberg, Steffen; Holz, Frank G.

Age-related macular degeneration (AMD) is a complex disease with both genetic and environmental factors influencing its development. With the advent of high-resolution OCT imaging, the characterization of drusen in AMD has become possible. The in vivo morphologic characteristics imaged with SD-OCT may represent distinct subclasses of drusen variants, may relate closely to ultrastructural drusen elements identified in donor eyes, and may be useful imaging biomarkers for disease severity or risk of progression [Khanifar et al. Ophthalmology 115(11):1883-1890, 2008].

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease

PubMed Central

Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J.; Barrick, Thomas R.; Markus, Hugh S.

2016-01-01

Abstract Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson’s R = −0.69, P < 1 × 10 −7 ), and significant grey matter loss and whole brain atrophy occurs annually ( P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease.

PubMed

Lambert, Christian; Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J; Barrick, Thomas R; Markus, Hugh S

2016-04-01

Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 × 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity

Postradiation atrophy of mature bone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ergun, H.; Howland, W.J.

1980-01-01

The primary event of radiation damage to bone is atrophy and true necrosis of bone is uncommon. The postradiation atrophic changes of bone are the result of combined cellular and vascular damage, the former being more important. The damage to the osteoblast resulting in decreased matrix production is apparently the primary histopathologic event. Radiation damaged bone is susceptible to superimposed complications of fracture, infection, necrosis, and sarcoma. The primary radiographic evidence of atrophy, localized osteopenia, is late in appearing. Contrary to former views, the mature bone is quite radiosensitive and reacts quickly to even small doses of radiation. The differentiationmore » of postirradiation atrophy and metastasis may be difficult. Biopsy should be the last resort because of the possibility of causing true necrosis in atrophic bone by trauma and infection.« less

Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans.

PubMed

McGregor, Robin A; Poppitt, Sally D; Cameron-Smith, David

2014-09-01

Progressive age-related changes in skeletal muscle mass and composition, underpin decreases in muscle function, which can inturn lead to impaired mobility and quality of life in older adults. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in skeletal muscle and are associated with aging. Accumulating evidence suggests that miRNAs play an important role in the age-related changes in skeletal muscle mass, composition and function. At the cellular level, miRNAs have been demonstrated to regulate muscle cell proliferation and differentiation. Furthermore, miRNAs are involved in the transitioning of muscle stem cells from a quiescent, to either an activated or senescence state. Evidence from animal and human studies has shown miRNAs are modulated in muscle atrophy and hypertrophy. In addition, miRNAs have been implicated in changes in muscle fiber composition, fat infiltration and insulin resistance. Both exercise and dietary interventions can combat age-related changes in muscle mass, composition and function, which may be mediated by miRNA modulation in skeletal muscle. Circulating miRNA species derived from myogenic cell populations represent potential biomarkers of aging muscle and the molecular responses to exercise or diet interventions, but larger validation studies are required. In future therapeutic approaches targeting miRNAs, either through exercise, diet or drugs may be able to slow down or prevent the age-related changes in skeletal muscle mass, composition, function, hence help maintain mobility and quality of life in old age. Copyright © 2014 Elsevier B.V. All rights reserved.

Abnormal pain perception in patients with Multiple System Atrophy.

PubMed

Ory-Magne, F; Pellaprat, J; Harroch, E; Galitzsky, M; Rousseau, V; Pavy-Le Traon, A; Rascol, O; Gerdelat, A; Brefel-Courbon, C

2018-03-01

Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l-DOPA on pain thresholds. We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 °C ± 1.3 vs 45.7 °C ± 0.8; p = 0.0005 and 7.4 mA ± 3.8 vs 13.7 mA ± 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l-DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yasumizu, R.; Hiai, H.; Sugiura, K.

1988-09-15

The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/Jmore » mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis.« less

cGAS drives non-canonical inflammasome activation in age-related macular degeneration

PubMed Central

Kerur, Nagaraj; Fukuda, Shinichi; Banerjee, Daipayan; Kim, Younghee; Fu, Dongxu; Apicella, Ivana; Varshney, Akhil; Yasuma, Reo; Fowler, Benjamin J.; Baghdasaryan, Elmira; Marion, Kenneth M.; Huang, Xiwen; Yasuma, Tetsuhiro; Hirano, Yoshio; Serbulea, Vlad; Ambati, Meenakshi; Ambati, Vidya L.; Kajiwara, Yuji; Ambati, Kameshwari; Bastos-Carvalho, Ana; Ogura, Yuichiro; Terasaki, Hiroko; Oshika, Tetsuro; Kim, Kyung Bo; Hinton, David R.; Leitinger, Norbert; Cambier, John C.; Buxbaum, Joseph D.; Kenney, M. Cristina; Jazwinski, S. Michal; Nagai, Hiroshi; Hara, Isao; West, A. Phillip; Fitzgerald, Katherine A.; Sadda, SriniVas R.; Gelfand, Bradley D.; Ambati, Jayakrishna

2017-01-01

Geographic atrophy is a blinding form of age-related macular degeneration characterized by death of the retinal pigmented epithelium (RPE). In this disease, the RPE displays evidence of DICER1 deficiency, resultant accumulation of endogenous Alu retroelement RNA, and NLRP3 inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human cell culture and in mouse models is driven by a non-canonical inflammasome pathway that results in activation of caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β (IFN-β) production and gasdermin D-dependent interleukin-18 (IL-18) secretion. Reduction of DICER1 levelsor accumulation of Alu RNA triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, IFN-β, and cGAS levels are elevated in the RPE of human eyes with geographic atrophy. Collectively, these data highlight an unexpected role for cGAS in responding to mobile element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial damage-induced inflammasome activation, expand the immune sensing repertoire of cGAS and caspase-4 to non-infectious human disease, and identify new potential targets for treatment of a major cause of blindness. PMID:29176737

Superior cervical gangliectomy induces non-exudative age-related macular degeneration in mice.

PubMed

Dieguez, Hernán H; Romeo, Horacio E; González Fleitas, María F; Aranda, Marcos L; Milne, Georgia A; Rosenstein, Ruth E; Dorfman, Damián

2018-02-07

Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and

Cardiac and Carotid Markers Link With Accelerated Brain Atrophy: The AGES-Reykjavik Study (Age, Gene/Environment Susceptibility-Reykjavik).

PubMed

Sabayan, Behnam; van Buchem, Mark A; Sigurdsson, Sigurdur; Zhang, Qian; Meirelles, Osorio; Harris, Tamara B; Gudnason, Vilmundur; Arai, Andrew E; Launer, Lenore J

2016-11-01

Pathologies in the heart-brain axis might, independently or in combination, accelerate the process of brain parenchymal loss. We aimed to investigate the association of serum N-terminal brain natriuretic peptide (NT-proBNP), as a marker of cardiac dysfunction, and carotid intima media thickness (CIMT), as a marker of carotid atherosclerosis burden, with structural brain changes. In the longitudinal population-based AGES-Reykjavik study (Age, Gene/Environment Susceptibility-Reykjavik), we included 2430 subjects (mean age, 74.6 years; 41.4% men) with baseline data on NT-proBNP and CITM (assessed by ultrasound imaging). Participants underwent a high-resolution brain magnetic resonance imaging at baseline and 5 years later to assess total brain (TBV), gray matter, and white matter volumes. Each unit higher log-transformed NT-proBNP was associated with 3.6 mL (95% confidence interval [CI], -6.0 to -1.1) decline in TBV and 3.5 mL (95% CI, -5.7 to -1.3) decline in gray matter volume. Likewise, each millimeter higher CIMT was associated with 10.8 mL (95% CI, -17.3 to -4.2) decline in TBV and 8.6 mL (95% CI, -14.4 to -2.8) decline in gray matter volume. There was no association between NT-proBNP and CIMT and changes in white matter volume. Compared with participants with low NT-proBNP and CIMT, participants with both high NT-proBNP and CIMT had 3.8 mL (95% CI, -6.0 to -1.6) greater decline in their TBV and 4 mL (95% CI, -6.0 to -2.0) greater decline in GMW. These associations were independent of sociodemographic and cardiovascular factors. Older subjects with both cardiac dysfunction and carotid atherosclerosis are at an increased risk for brain parenchymal loss. Accumulated pathologies in the heart-brain axis might accelerate brain atrophy. © 2016 American Heart Association, Inc.

The Effects of Meditation on Grey Matter Atrophy and Neurodegeneration: A Systematic Review.

PubMed

Last, Nicole; Tufts, Emily; Auger, Leslie E

2017-01-01

The present systematic review is based on the premise that a variety of neurodegenerative diseases are accompanied by grey matter atrophy in the brain and meditation may impact this. Given that age is a major risk factor for many of these progressive and neurodegenerative diseases and that the percentage of the population over the age of 65 is quickly increasing, there is an obvious need for prompt treatment and prevention advances in research. As there is currently no cure for Alzheimer's disease and other neurodegenerative diseases, many are seeking non-pharmacological treatment options in attempts to offset the disease-related cognitive and functional declines. On the basis of a growing body of research suggesting that meditation is effective in increasing grey matter volume in healthy participants, this paper systematically reviewed the literature regarding the effects of meditation on restoring grey matter volume in healthy individuals and those affected by neurodegeneration. This review searched PubMed, CINAHL, and APA PsycNET to identify original studies that included MRI imaging to measure grey matter volume in meditators and post-mindfulness-based intervention participants compared to controls. Thirteen studies were considered eligible for review and involved a wide variety of meditation techniques and included participants with and without cognitive impairment. All studies reported significant increases in grey matter volume in the meditators/intervention group, albeit in assorted regions of the brain. Limited research exists on the mechanisms through which meditation affects disease-related neurodegeneration, but preliminary evidence suggests that it may offset grey matter atrophy.

The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla.

PubMed

Stephen, Tom Li; Tikhonova, Anastasia; Riberdy, Janice M; Laufer, Terri M

2009-11-01

Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.

Global brain atrophy is associated with physical performance and the risk of falls in older adults with cognitive impairment.

PubMed

Yamada, Minoru; Takechi, Hajime; Mori, Shuhei; Aoyama, Tomoki; Arai, Hidenori

2013-04-01

Falls are common in patients with cognitive disorder. The purpose of this study was to determine whether global brain atrophy is associated with cognitive function, physical performance and fall incidents in older adults with mild cognitive disorder. A total of 31 older adults with mild cognitive disorders (mean age 78.9 ± 7.3 years) were studied, and 10 of them had experienced falls and the others had not in the past 1 year. Cognitive function and physical performance were measured in these patients. Global brain atrophy was determined by the Voxel-Based Specific Regional Analysis System for Alzheimer's Disease software. Fallers showed significantly worse scores than the non-fallers in the Global Brain Atrophy Index, Clock Drawing Test (CDT), Verbal Fluency Test (animal), maximum walking time and Timed Up & Go (TUG) Test. The Global Brain Atrophy Index was correlated with the Verbal Fluency Test (animal; r = -0.522), the Verbal Fluency Test with letter (ka; r = -0.337), CDT (r = -0.547), TUG (r = 0.276) and Five Chair Stands Test (r = 0.303) by age-adjusted correlation analyses. Stepwise regression analysis showed that the Global Brain Atrophy Index (β = 1.265, 95% CI 1.022-1.567) was a significant and independent determinant of falls (R(2) = 0.356, P = 0.003). Global brain atrophy might be indicated as one of the risk factors for falls in older adults with mild cognitive disorders. © 2012 Japan Geriatrics Society.

COGNITIVELY NORMAL INDIVIDUALS WITH AD PARENTS MAY BE AT RISK FOR DEVELOPING AGING-RELATED CORTICAL THINNING PATTERNS CHARACTERISTIC OF AD

PubMed Central

Reiter, Katherine; Alpert, Kathryn I.; Cobia, Derin J.; Kwasny, Mary J.; Morris, John C.; Csernansky, John C.; Wang, Lei

2012-01-01

Children of Alzheimer's Disease (AD) patients are at heightened risk of developing AD due to genetic influences, including the apolipoprotein E4 (ApoE4) allele. In this study, we assessed the earliest cortical changes associated with AD in 71 cognitively healthy, adult children of AD patients (AD offspring) as compared with 69 with no family history of AD (non-AD offspring). Cortical thickness measures were obtained using FreeSurfer from 1.5T magnetic resonance (MR) scans. ApoE genotyping was obtained. Primary analyses examined family history and ApoeE4 effects on cortical thickness. Secondary analyses examined age effects within groups. All comparisons were adjusted using False Discovery Rate at a significance threshold of p < 0.05. There were no statistically significant differences between family history and ApoE4 groups. Within AD offspring, increasing age was related to reduced cortical thickness (atrophy) over large areas of the precuneus, superior frontal and superior temporal gyri, starting at around age 60. Further, these patterns existed within female and maternal AD offspring, but were absent in male and paternal AD offspring. Within non-AD offspring, negative correlations existed over small regions of the superior temporal, insula and lingual cortices. These results suggest that as AD offspring age, cortical atrophy is more prominent, particularly if the parent with AD is mother or if the AD offspring is female. PMID:22503937

The Petit Rat (pet/pet), a New Semilethal Mutant Dwarf Rat with Thymic and Testicular Anomalies

PubMed Central

Chiba, Junko; Suzuki, Katsushi; Suzuki, Hiroetsu

2008-01-01

The petit rat (pet/pet) is a recently discovered semilethal mutant dwarf. The neonatal pet/pet rats had a low body weight and small thymus and testis. During the first 3 d after birth, 50% of the male and 80% of the female pet/pet pups were lost or found dead. Surviving pet/pet rats showed marked retardation of postnatal growth, and their body weights were 41% (female rats) and 32% (male rats) of those of normal rats at the adult stage. The pet/pet rats exhibited proportional dwarfism, and their longitudinal bones were shorter than those of controls without skeletal malformations. Most organs of male pet/pet rats, especially the thymus, testis, adipose tissue surrounding the kidney, and accessory sex organs, weighed markedly less at 140 d of age than did those of their normal counterparts. The thymus of pet/pet rats was small with abnormal thymic follicles. Testes from pet/pet rats exhibited 2 patterns of abnormal histology. Spermatogenesis was present in testes that were only slightly anomalous, but the seminiferous tubules were reduced in diameter. In severely affected testes, most of the seminiferous tubules showed degeneration, and interstitial tissue was increased. Plasma growth hormone concentrations did not differ between pet/pet and normal male rats. The dwarf phenotype of pet/pet rats was inherited as an autosomal recessive trait. These results indicate that the pet/pet rat has a semilethal growth-hormone-independent dwarf phenotype that is accompanied by thymic and testicular anomalies and low birth weight. PMID:19149412

The petit rat (pet/pet), a new semilethal mutant dwarf rat with thymic and testicular anomalies.

PubMed

Chiba, Junko; Suzuki, Katsushi; Suzuki, Hiroetsu

2008-12-01

The petit rat (pet/pet) is a recently discovered semilethal mutant dwarf. The neonatal pet/pet rats had a low body weight and small thymus and testis. During the first 3 d after birth, 50% of the male and 80% of the female pet/pet pups were lost or found dead. Surviving pet/pet rats showed marked retardation of postnatal growth, and their body weights were 41% (female rats) and 32% (male rats) of those of normal rats at the adult stage. The pet/pet rats exhibited proportional dwarfism, and their longitudinal bones were shorter than those of controls without skeletal malformations. Most organs of male pet/pet rats, especially the thymus, testis, adipose tissue surrounding the kidney, and accessory sex organs, weighed markedly less at 140 d of age than did those of their normal counterparts. The thymus of pet/pet rats was small with abnormal thymic follicles. Testes from pet/pet rats exhibited 2 patterns of abnormal histology. Spermatogenesis was present in testes that were only slightly anomalous, but the seminiferous tubules were reduced in diameter. In severely affected testes, most of the seminiferous tubules showed degeneration, and interstitial tissue was increased. Plasma growth hormone concentrations did not differ between pet/pet and normal male rats. The dwarf phenotype of pet/pet rats was inherited as an autosomal recessive trait. These results indicate that the pet/pet rat has a semilethal growth-hormone-independent dwarf phenotype that is accompanied by thymic and testicular anomalies and low birth weight.

Robust Identification of Alzheimer’s Disease subtypes based on cortical atrophy patterns

NASA Astrophysics Data System (ADS)

Park, Jong-Yun; Na, Han Kyu; Kim, Sungsoo; Kim, Hyunwook; Kim, Hee Jin; Seo, Sang Won; Na, Duk L.; Han, Cheol E.; Seong, Joon-Kyung; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Shaw, Leslie M.; Liu, Enchi; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Jiminez, Gus; Harvey, Danielle; Bernstein, Matthew; Fox, Nick; Thompson, Paul; Schuff, Norbert; Decarli, Charles; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Landau, Susan; Cairns, Nigel J.; Householder, Erin; Taylor Reinwald, Lisa; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Crawford, Karen; Neu, Scott; Foroud, Tatiana M.; Potkin, Steven G.; Shen, Li; Kelley, Faber; Kim, Sungeun; Nho, Kwangsik; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Carter, Raina; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Heidebrink, Judith L.; Lord, Joanne L.; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Doody, Rachelle S.; Villanueva Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Grossman, Hillel; Mitsis, Effie; de Toledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; D'Agostino, Daniel, II; Kielb, Stephanie; Galvin, James E.; Pogorelec, Dana M.; Cerbone, Brittany; Michel, Christina A.; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; de Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Wong, Terence Z.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Lopez, Oscar L.; Oakley, Maryann; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc Adams Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz Arrastia, Ramon; King, Richard; Weiner, Myron; Martin Cook, Kristen; Devous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H. S.; Lu, Po H.; Bartzokis, George; Graff Radford, Neill R.; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Farlow, Martin R.; Marie Hake, Ann; Matthews, Brandy R.; Herring, Scott; Hunt, Cynthia; van Dyck, Christopher H.; Carson, Richard E.; Macavoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Robin Hsiung, Ging Yuek; Feldman, Howard; Mudge, Benita; Assaly, Michele; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Marsel Mesulam, Marek; Lipowski, Kristine; Kuo Wu, Chuang; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Scott Turner, Raymond; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan N.; Belden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Lynn Johnson, Patricia; Obisesan, Thomas O.; Wolday, Saba; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Hudson, Leon; Fletcher, Evan; Carmichael, Owen; Olichney, John; Kittur, Smita; Borrie, Michael; Lee, T. Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Santulli, Robert B.; Kitzmiller, Tamar J.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Finger, Elizabether; Pasternak, Stephen; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Schultz, Susan K.; Boles Ponto, Laura L.; Shim, Hyungsub; Smith, Karen Elizabeth; Relkin, Norman; Chaing, Gloria; Raudin, Lisa; Smith, Amanda; Fargher, Kristin; Raj, Balebail Ashok

2017-03-01

Accumulating evidence suggests that Alzheimer’s disease (AD) is heterogenous and can be classified into several subtypes. Here, we propose a robust subtyping method for AD based on cortical atrophy patterns and graph theory. We calculated similarities between subjects in their atrophy patterns throughout the whole brain, and clustered subjects with similar atrophy patterns using the Louvain method for modular organization extraction. We applied our method to AD patients recruited at Samsung Medical Center and externally validated our method by using the AD Neuroimaging Initiative (ADNI) dataset. Our method categorized very mild AD into three clinically distinct subtypes with high reproducibility (>90%) the parietal-predominant (P), medial temporal-predominant (MT), and diffuse (D) atrophy subtype. The P subtype showed the worst clinical presentation throughout the cognitive domains, while the MT and D subtypes exhibited relatively mild presentation. The MT subtype revealed more impaired language and executive function compared to the D subtype.

The thymus of the hairless rhino-j (hr/hr-j) mice

PubMed Central

SAN JOSE, I.; GARCÍA-SUÁREZ, O.; HANNESTAD, J.; CABO, R.; GAUNA, L.; REPRESA, J.; VEGA, J. A.

2001-01-01

The hairless (hr) gene is expressed in a large number of tissues, primarily the skin, and a mutation in the hr gene is responsible for the typical cutaneous phenotype of hairless mice. Mutant hr mouse strains show immune defects involving especially T cells and macrophages, as well as an age-related immunodeficiency and an accelerated atrophy of the thymus. These data suggest that the hr mutation causes a defect of this organ, although hr transcripts have not been detected in fetal or adult mice thymus. The present study analyses the thymus of young (3 mo) and adult (9 mo) homozygous hr-rh-j mice (a strain of hairless mice) by means of structural techniques and immunohistochemistry to selectively identify thymic epithelial cells, dendritic cells, and macrophages. There were structural alterations in the thymus of both young and adult rh-rh-j mice, which were more severe in older animals. These alterations consisted of relative cortical atrophy, enlargement of blood vessels, proliferation of perivascular connective tissue, and the appearance of cysts. hr-rh-j mice also showed a decrease in the number of epithelial and dendritic cells, and macrophages. Taken together, present results strongly suggest degeneration and accelerated age-dependent regression of the thymus in hr-rh-j mice, which could explain at least in part the immune defects reported in hairless mouse strains. PMID:11327202

MHC drives TCR repertoire shaping, but not maturation, in recent thymic emigrants.

PubMed

Houston, Evan G; Fink, Pamela J

2009-12-01

After developing in the thymus, recent thymic emigrants (RTEs) enter the lymphoid periphery and undergo a maturation process as they transition into the mature naive (MN) T cell compartment. This maturation presumably shapes RTEs into a pool of T cells best fit to function robustly in the periphery without causing autoimmunity; however, the mechanism and consequences of this maturation process remain unknown. Using a transgenic mouse system that specifically labels RTEs, we tested the influence of MHC molecules, key drivers of intrathymic T cell selection and naive peripheral T cell homeostasis, in shaping the RTE pool in the lymphoid periphery. We found that the TCRs expressed by RTEs are skewed to longer CDR3 regions compared with those of MN T cells, suggesting that MHC does streamline the TCR repertoire of T cells as they transition from the RTE to the MN T cell stage. This conclusion is borne out in studies in which the representation of individual TCRs was followed as a function of time since thymic egress. Surprisingly, we found that MHC is dispensable for the phenotypic and functional maturation of RTEs.

A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla.

PubMed

Hauri-Hohl, Mathias; Zuklys, Saulius; Holländer, Georg A; Ziegler, Steven F

2014-06-01

Medullary thymic epithelial cells (mTECs) are critical in establishing and maintaining the appropriate microenvironment for negative selection and maturation of immunocompetent T cells with a self-tolerant T cell antigen receptor repertoire. Cues that direct proliferation and maturation of mTECs are provided by members of the tumor necrosis factor (TNF) superfamily expressed on developing thymocytes. Here we demonstrate a negative role of the morphogen TGF-β in tempering these signals under physiological conditions, limiting both growth and function of the thymic medulla. Eliminating TGF-β signaling specifically in TECs or by pharmacological means increased the size of the mTEC compartment, enhanced negative selection and functional maturation of medullary thymocytes as well as the production of regulatory T cells, thus reducing the autoreactive potential of peripheral T cells.

The microbiota and microbiome in aging: potential implications in health and age-related diseases.

PubMed

Zapata, Heidi J; Quagliarello, Vincent J

2015-04-01

Advances in bacterial deoxyribonucleic acid sequencing allow for characterization of the human commensal bacterial community (microbiota) and its corresponding genome (microbiome). Surveys of healthy adults reveal that a signature composite of bacteria characterizes each unique body habitat (e.g., gut, skin, oral cavity, vagina). A myriad of clinical changes, including a basal proinflammatory state (inflamm-aging), that directly interface with the microbiota of older adults and enhance susceptibility to disease accompany aging. Studies in older adults demonstrate that the gut microbiota correlates with diet, location of residence (e.g., community dwelling, long-term care settings), and basal level of inflammation. Links exist between the microbiota and a variety of clinical problems plaguing older adults, including physical frailty, Clostridium difficile colitis, vulvovaginal atrophy, colorectal carcinoma, and atherosclerotic disease. Manipulation of the microbiota and microbiome of older adults holds promise as an innovative strategy to influence the development of comorbidities associated with aging. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

Glutamine metabolism in advanced age

PubMed Central

2016-01-01

Glutamine, reviewed extensively in the last century, is a key substrate for the splanchnic bed in the whole body and is a nutrient of particular interest in gastrointestinal research. A marked decrease in the plasma glutamine concentration has recently been observed in neonates and adults during acute illness and stress. Although some studies in newborns have shown parenteral and enteral supplementation with glutamine to be of benefit (by decreasing proteolysis and activating the immune system), clinical trials have not demonstrated prolonged advantages such as reductions in mortality or risk of infections in adults. In addition, glutamine is not able to combat the muscle wasting associated with disease or age-related sarcopenia. Oral glutamine supplementation initiated before advanced age in rats increases gut mass and improves the villus height of mucosa, thereby preventing the gut atrophy encountered in advanced age. Enterocytes from very old rats continuously metabolize glutamine into citrulline, which allowed, for the first time, the use of citrulline as a noninvasive marker of intestinal atrophy induced by advanced age. PMID:26936258

EVALUATION OF PATCHY ATROPHY SECONDARY TO HIGH MYOPIA BY SEMIAUTOMATED SOFTWARE FOR FUNDUS AUTOFLUORESCENCE ANALYSIS.

PubMed

Miere, Alexandra; Capuano, Vittorio; Serra, Rita; Jung, Camille; Souied, Eric; Querques, Giuseppe

2017-05-31

To evaluate the progression of patchy atrophy in high myopia using semiautomated software for fundus autofluorescence (FAF) analysis. The medical records and multimodal imaging of 21 consecutive highly myopic patients with macular chorioretinal patchy atrophy (PA) were retrospectively analyzed. All patients underwent repeated fundus autofluorescence and spectral domain optical coherence tomography over at least 12 months. Color fundus photography was also performed in a subset of patients. Total atrophy area was measured on FAF images using Region Finder semiautomated software embedded in Spectralis (Heidelberg Engineering, Heidelberg, Germany) at baseline and during follow-up visits. Region Finder was compared with manually measured PA on FAF images. Twenty-two eyes of 21 patients (14 women, 7 men; mean age 62.8 + 13.0 years, range 32-84 years) were included. Mean PA area using Region Finder was 2.77 ± 2.91 SD mm at baseline, 3.12 ± 2.68 mm at Month 6, 3.43 ± 2.68 mm at Month 12, and 3.73 ± 2.74 mm at Month 18 (overall P < 0.005); this accounts for PA progression rate of 0.821 mm/year. Atrophy progression was significantly greater among eyes with larger PA compared with smaller baseline PA at Months 6, 12, and 18. There was no statistically significant difference between semiautomated Region Finder PA area and manually measured PA area on FAF images. Fundus autofluorescence analysis by Region Finder semiautomated software provides accurate measurements of lesion area and allows us to quantify the progression of PA in high myopia. In our series, PA enlarged significantly over at least 12 months, and its progression seemed to be related to the lesion size at baseline.