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Frederic Tort Olatz Ugarteburu Laura Texid Sabrina Gea‐Sorlí Judit García‐Villoria Xnia Ferrer‐Corts ngela Arias Leslie Matalonga Laura Gort Isidre Ferrer Mariona Guitart‐Mampel Glria Garrabou Frederick M Vaz Ana Pristoupilova María Isabel Esteban Rodríguez Sergi Beltran Francesc Cardellach Ronald JA Wanders Cristina Fillat María Teresa García‐Silva Antonia Ribes 《Human mutation》2019,40(10):1700-1712
3‐Methylglutaconic aciduria (3‐MGA‐uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole‐exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3‐MGA‐uria. A comprehensive analysis of the mitochondrial function was performed in fibroblasts of the patient to elucidate the molecular basis of the disease. TIMM50 protein was severely reduced in the patient fibroblasts, regardless of the normal mRNA levels, suggesting that the mutated residues might be important for TIMM50 protein stability. Severe morphological defects and ultrastructural abnormalities with aberrant mitochondrial cristae organization in muscle and fibroblasts were found. The levels of fully assembled OXPHOS complexes and supercomplexes were strongly reduced in fibroblasts from this patient. High‐resolution respirometry demonstrated a significant reduction of the maximum respiratory capacity. A TIMM50‐deficient HEK293T cell line that we generated using CRISPR/Cas9 mimicked the respiratory defect observed in the patient fibroblasts; notably, this defect was rescued by transfection with a plasmid encoding the TIMM50 wild‐type protein. In summary, we demonstrated that TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity. 相似文献
3.
LL Patton JA Phelan FJ Ramos-Gomez W Nittayananta CH Shiboski TL Mbuguye 《Oral diseases》2002,8(S2):98-109
OBJECTIVES: An International Workshop addressed the prevalence and classification of HIV/AIDS associated oral lesions.
DESIGN: Five questions provided the framework for discussion and literature review. What is the prevalence of oral lesions in children and adults? Should the accepted classification of HIV-related oral lesions be modified in the light of recent findings? Why is there a gender difference in the prevalence of oral lesions in developed and developing countries? Are there unusual lesions present in developing countries? Is there any association between modes of transmission and the prevalence of oral lesions?
RESULTS: Workshop discussion emphasized the urgent need for assistance in the development of expertise to obtain accurate global prevalence data for HIV-associated oral lesions. Oral candidiasis has been consistently reported as the most prevalent HIV-associated oral lesion in all ages. Penicilliosis marneffei, a newly described fungal infection, has emerged in South-east Asia. Oral hairy leukoplakia and Kaposi's sarcoma appear to be associated with male gender and male-to-male HIV transmission risk behaviours. These lesions occur only rarely in children.
CONCLUSIONS: Additional prevalence data are needed from developing countries prior to substantially altering the 1993 ECC/WHO Classification of oral lesions associated with adult HIV infection. The workshop confirmed current oral disease diagnostic criteria. 相似文献
DESIGN: Five questions provided the framework for discussion and literature review. What is the prevalence of oral lesions in children and adults? Should the accepted classification of HIV-related oral lesions be modified in the light of recent findings? Why is there a gender difference in the prevalence of oral lesions in developed and developing countries? Are there unusual lesions present in developing countries? Is there any association between modes of transmission and the prevalence of oral lesions?
RESULTS: Workshop discussion emphasized the urgent need for assistance in the development of expertise to obtain accurate global prevalence data for HIV-associated oral lesions. Oral candidiasis has been consistently reported as the most prevalent HIV-associated oral lesion in all ages. Penicilliosis marneffei, a newly described fungal infection, has emerged in South-east Asia. Oral hairy leukoplakia and Kaposi's sarcoma appear to be associated with male gender and male-to-male HIV transmission risk behaviours. These lesions occur only rarely in children.
CONCLUSIONS: Additional prevalence data are needed from developing countries prior to substantially altering the 1993 ECC/WHO Classification of oral lesions associated with adult HIV infection. The workshop confirmed current oral disease diagnostic criteria. 相似文献
4.
K. Siggeirsdottir T. Aspelund H. Johansson E. F. Gudmundsson B. Mogensen B. Y. Jonsson V. Gudnason E. McCloskey A. Oden G. Sigurdsson J. A. Kanis 《Osteoporosis international》2014,25(10):2445-2451
Summary
Based on an extensive cohort study over 25 years, the present study supports the assumption that major osteoporotic fractures can be reasonably predicted from hip fracture rates.Introduction
The construct for FRAX models depends on algorithms to adjust for double counting of fracture outcomes in some models and in others, to estimate the incidence of a major fracture from hip fracture rates. The aim of the present study was to test the validity of these algorithms in a large prospective cohort.Methods
The incidence of hip, clinical spine, distal forearm, and humerus fracture was determined in the prospective and ongoing population-based Reykjavik Study with follow up of 257,001 person-years. The incidence of a first major fracture was compared with the correction factors used in FRAX to adjust the incidence of several fracture outcomes for double counting. In addition, the incidence of a major osteoporotic fracture estimated from the Icelandic hip fracture rates was compared with the Malmo ratios used in FRAX.Results
The adjustments necessary to account for multiple fracture outcomes were similar to those previously derived from Sweden. Additionally, incidence of a first major osteoporotic fracture was similar to that derived for FRAX models.Conclusion
The findings of the present study support the algorithms used in FRAX to estimate the incidence of a first major fracture and the predictive value of hip fracture for other major fractures. 相似文献5.
S. L. Brennan W. D. Leslie L. M. Lix H. Johansson A. Oden E. McCloskey J. A. Kanis 《Osteoporosis international》2014,25(1):61-69
Summary
We investigated the fracture risk assessment tool (FRAX) Canada calibration and discrimination according to income quintile in 51,327 Canadian women, with and without a competing mortality framework. Our data show that, under a competing mortality framework, FRAX provides robust fracture prediction and calibration regardless of socioeconomic status (SES).Introduction
FRAX® predicts 10-year fracture risk. Social factors may independently affect fracture risk. We investigated FRAX calibration and discrimination according to SES.Methods
Women aged ≥50 years with baseline femoral neck bone mineral density (BMD) were identified from the Manitoba Bone Density Program, Canada (n?=?51,327), 1996–2011. Mean household income, extracted from 2006 census files, was categorized into quintiles. Ten-year fracture probabilities were calculated using FRAX Canada. Incident non-traumatic fractures were studied in relation to income quintile in adjusted Cox proportional hazards models. We compared observed versus predicted fractures with and without a competing mortality framework.Results
During mean 6.2?±?3.7 years of follow up, there were 6,392 deaths, 3,723 women with ≥1 major osteoporotic fracture (MOF), and 1,027 with hip fractures. Lower income was associated with higher risk for death, MOF, and hip fracture in adjusted models (all p?<?0.005). More women in income quintile 1 (lowest) versus quintile 5 experienced death (19 vs. 8 %), MOF (10 vs. 6 %), or hip fracture (3.0 vs. 1.3 %) (all p?≤?0.001). Adjustment for competing mortality mitigated the effect of SES on FRAX calibration, and good calibration was observed. FRAX provided good fracture discrimination for MOF and hip fracture within each income quintile (all p?<?0.001). Area under the curve was slightly lower for income quintiles 1 versus 5 for FRAX with BMD to predict MOF (0.68, 95 % CI 0.66–0.70 vs. 0.71, 95 % CI 0.69–0.74) and hip fracture (0.79, 95 % CI 0.76–0.81 vs. 0.87, 95 % CI 0.84–0.89).Conclusion
Increased fracture risk in individuals of lower income is offset by increased mortality. Under a competing mortality framework, FRAX provides robust fracture prediction and calibration regardless of SES. 相似文献6.
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Helena Johansson John A Kanis Anders Odén Eugene McCloskey Roland D Chapurlat Claus Christiansen Steve R Cummings Adolfo Diez‐Perez John A Eisman Saeko Fujiwara Claus‐C Glüer David Goltzman Didier Hans Kay‐Tee Khaw Marc‐Antoine Krieg Heikki Kröger Andrea Z LaCroix Edith Lau William D Leslie Dan Mellström L Joseph Melton III Terence W O'Neill Julie A Pasco Jerilynn C Prior David M Reid Fernando Rivadeneira Tjerd van Staa Noriko Yoshimura M Carola Zillikens 《Journal of bone and mineral research》2014,29(1):223-233
Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person‐years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m2) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non‐obese women. Compared to a BMI of 25 kg/m2, the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m2 was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research. 相似文献
9.
Anders Odén John A Kanis Eugene V McCloskey Helena Johansson 《Journal of bone and mineral research》2014,29(10):2217-2223
Although the optimal requirement of vitamin D for skeletal health in the general community is controversial, vitamin D deficiency impairs bone mineralization and increases bone turnover via secondary hyperparathyroidism, thus accelerating bone loss and increasing fracture risk. Support for a role of vitamin D deficiency in the epidemiology of hip fracture is found in the seasonal variation of hip fracture incidence that is reported in several studies. If the association were causal, then the incidence and amplitude of the seasonal variation in hip fracture risk should vary by latitude. We addressed this hypothesis by examining the incidence of hip fracture in men and women aged 50 years or more from Sweden (latitudes 55 to 69°) between 1987 and 2009. In order to reduce double counting, only one fracture in a period of a year was counted per individual. Men contributed 104,888 fractures in 33,313,065 person years and women 264,362 fractures in 38,387,660 person years. The effects of season and latitude were examined by Poisson regression. As expected, hip fracture rates were higher in women than in men. After adjustment for age, season and population density, hip fracture incidence increased by 3.0% (95% CI: 2.7–3.2%) per degree increase in latitude for men and by 1.9% (95% CI: 1.8–2.1%) for women. There was a marked seasonal variation of hip fracture with the highest risk in February and lower by 37.5% in men and by 23.5% women during the summer. There were significant interactions of amplitude of the seasonal variation with latitude (p < 0.001 for both men and women), indicating that seasonal variation during the year was more pronounced in the north of Sweden than in the south. The associations found with latitude and season is consistent with a role of vitamin D in hip fracture causation. © 2014 American Society for Bone and Mineral Research. 相似文献
10.
Cortical Porosity Identifies Women With Osteopenia at Increased Risk for Forearm Fractures 下载免费PDF全文
Yohann Bala Roger Zebaze Ali Ghasem‐Zadeh Elizabeth J Atkinson Sandra Iuliano James M Peterson Shreyasee Amin Åshild Bjørnerem L Joseph Melton III Helena Johansson John A Kanis Sundeep Khosla Ego Seeman 《Journal of bone and mineral research》2014,29(6):1356-1362
Most fragility fractures arise among the many women with osteopenia, not the smaller number with osteoporosis at high risk for fracture. Thus, most women at risk for fracture assessed only by measuring areal bone mineral density (aBMD) will remain untreated. We measured cortical porosity and trabecular bone volume/total volume (BV/TV) of the ultradistal radius (UDR) using high‐resolution peripheral quantitative computed tomography, aBMD using densitometry, and 10‐year fracture probability using the country‐specific fracture risk assessment tool (FRAX) in 68 postmenopausal women with forearm fractures and 70 age‐matched community controls in Olmsted County, MN, USA. Women with forearm fractures had 0.4 standard deviations (SD) higher cortical porosity and 0.6 SD lower trabecular BV/TV. Compact‐appearing cortical porosity predicted fracture independent of aBMD; odds ratio (OR) = 1.92 (95% confidence interval [CI] 1.10–3.33). In women with osteoporosis at the UDR, cortical porosity did not distinguish those with fractures from those without because high porosity was present in 92% and 86% of each group, respectively. By contrast, in women with osteopenia at the UDR, high porosity of the compact‐appearing cortex conferred an OR for fracture of 4.00 (95% CI 1.15–13.90). In women with osteoporosis, porosity is captured by aBMD, so measuring UDR cortical porosity does not improve diagnostic sensitivity. However, in women with osteopenia, cortical porosity was associated with forearm fractures. © 2014 American Society for Bone and Mineral Research. 相似文献