Combined vertebral fracture assessment and bone mineral density measurement: a new standard in the diagnosis of osteoporosis in academic populations

Vertebral Fracture Analysis enables the detection of vertebral fractures in the same session as bone mineral density testing. Using this method in 2,424 patients, we found unknown vertebral fractures in approximately one out of each six patients with significant impact on management. The presence of osteoporotic vertebral fractures (VF) is an important risk factor for all future fractures independent of BMD. Yet, determination of the VF status has not become standard practice. Vertebral Fracture Assessment (VFA) is a new feature available on modern densitometers. In this study we aimed to determine the prevalence of VF using VFA in all patients referred for BMD testing in a university medical center and to evaluate its added clinical value. Prospective diagnostic evaluation study in 2,500 consecutive patients referred for BMD. Patients underwent VFA in supine position after BMD testing. Questionnaires were used to assess perceived added value of VFA. In 2,424 patients (1,573 women), results were evaluable. In 541 patients (22%), VFA detected a prevalent VF that was unknown in 69%. In women, the prevalence was 20% versus 27% found in men (p <0.0001). The prevalence of VF was 14% in patients with normal BMD (97/678), increased to 21% (229/1,100) in osteopenia and to 26% in those with osteoporosis (215/646) by WHO criteria. After excluding mild fractures VF prevalence was 13% (322/2,424). In 468 of 942 questionnaires (50% response rate), 27% of the referring physicians reported VFA results to impact on patient management. VFA is a patient friendly new tool with a high diagnostic yield, as it detected unknown VF in one out of each six patients, with significant impact on management. We believe these findings justify considering VFA in all new patients referred for osteoporosis assessment in similar populations

Lymphocyte subsets in human immunodeficiency virus-unexposed Brazilian individuals from birth to adulthood

Ethnic origin, genetics, gender and environmental factors have been shown to influence some immunologic indices, so that development of reference values for populations of different backgrounds may be necessary. We have determined the distribution of lymphocyte subsets in healthy Brazilian individuals from birth to adulthood. Lymphocyte subsets were determined using four-colour cytometry in a cross-sectional study of 463 human immunodeficiency virus-unexposed children and adults from birth through 49 years of age. Lymphocyte subsets varied according to age, as previously observed in other studies. However, total CD4+ T cell numbers were lower than what was described in the Pediatric AIDS Clinical Trials Group P1009 (PACTG P1009), which assessed an American population of predominantly African and Hispanic backgrounds until the 12-18 year age range, when values were comparable. Naïve percentages and absolute values of CD8+ T cells, as assessed by CD45RA expression, were also lower than the PACTG P1009 data for all analysed age ranges. CD38 expression on both CD4+ and CD8+ T cells was lower than the PACTG P1009 values, with a widening gap between the two studies at older age ranges. Different patterns of cell differentiation seem to occur in different settings and may have characteristic expression within each population.Universidade Federal de São Paulo (UNIFESP) Departamento de MedicinaCentro Assistencial Cruz de MaltaUniversidade Federal de São Paulo (UNIFESP) Departamento de PediatriaUNIFESP, Depto. de MedicinaUNIFESP, Depto. de PediatriaSciEL

The HIV-1 Transactivator Factor (Tat) Induces Enterocyte Apoptosis through a Redox-Mediated Mechanism

The intestinal mucosa is an important target of human immunodeficiency virus (HIV) infection. HIV virus induces CD4+ T cell loss and epithelial damage which results in increased intestinal permeability. The mechanisms involved in nutrient malabsorption and alterations of intestinal mucosal architecture are unknown. We previously demonstrated that HIV-1 transactivator factor (Tat) induces an enterotoxic effect on intestinal epithelial cells that could be responsible for HIV-associated diarrhea. Since oxidative stress is implicated in the pathogenesis and morbidity of HIV infection, we evaluated whether Tat induces apoptosis of human enterocytes through oxidative stress, and whether the antioxidant N-acetylcysteine (NAC) could prevent it. Caco-2 and HT29 cells or human intestinal mucosa specimens were exposed to Tat alone or combined with NAC. In an in-vitro cell model, Tat increased the generation of reactive oxygen species and decreased antioxidant defenses as judged by a reduction in catalase activity and a reduced (GSH)/oxidized (GSSG) glutathione ratio. Tat also induced cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8-hydroxy-2′-deoxyguanosine. GSH/GSSG imbalance and apoptosis occurred in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pre-treatment with NAC prevented Tat-induced apoptosis and restored the glutathione balance in both the in-vitro and the ex-vivo model. These findings indicate that oxidative stress is one of the mechanism involved in HIV-intestinal disease

The Utility and Limitations of FRAX: A US Perspective

The FRAX calculator is a major achievement in terms of our understanding of measuring fracture risk. Along with being an easily accessible web-based tool, it is the only model based on extensive data on multiple cohorts. FRAX will help clinicians identify individuals who need osteoporosis treatments, while also screening out those who do not require osteoporosis treatments. However, FRAX is limited by a number of factors. Although it is web based, few physicians have the means to access it. It also assumes that body mass index and mortality are constant across different racial and ethnic groups. FRAX is further limited by the exclusion of variables known to be associated with fracture risk, lack of dose-response relationships for variables, increased subsequent fracture risk after initial fracture, restriction to only one bone mineral density site, racial and ethnic differences that may influence fracture risk, and availability of racial and ethnic fracture risk data to be used in the FRAX calculator. Finally, the values obtained from FRAX should not take the place of good clinical judgment

Progressive vertebral deformities despite unchanged bone mineral density in patients with sarcoidosis: a 4-year follow-up study

To evaluate the incidence of new and/or progressive vertebral deformities and changes in bone mineral density, we re-examined 66 patients with sarcoidosis after a follow-up period of four years. In 17 subjects (26%) new and/or progressive vertebral deformities were found, though BMD did not change significantly. INTRODUCTION: Previous studies from our group have shown that morphometric vertebral deformities suggestive of fractures can be found in 20% of patients with sarcoidosis, despite a normal bone mineral density (BMD). The aim of this study was to determine the incidence of new and/or progressive vertebral deformities and the evolution of BMD during the course of this disease. METHODS: BMD of the hip (DXA) and vertebral fracture assessment (VFA) with lateral single energy densitometry was performed at baseline and after 45 months in 66 patients with sarcoidosis. Potential predictors of new/ progressive vertebral deformities were assessed using logistic regression analysis. RESULTS: The BMD of the total group was unchanged after follow-up. The prevalence of vertebral deformities increased from 20 to 32% (p < 0.05); in 17 subjects (26%) new or progressive vertebral deformities were diagnosed. A lower T-score of the femoral neck [(OR = 2.5 (CI: 1.0-5.9), p < 0.05)] and mother with a hip fracture [(OR = 14.1 (CI: 1.4-142.6), p < 0.05)] were independent predictors of new/progressive deformities. CONCLUSIONS: In subjects with sarcoidosis the number of vertebral deformities increases in the course of this disease, despite unchanged BMD. The combination of low normal BMD and family history of fragility fractures confers an increased risk of the incidence of these deformities

Intracellular expression of Tat alters mitochondrial functions in T cells: a potential mechanism to understand mitochondrial damage during HIV-1 replication

HIV-1 replication results in mitochondrial damage that is enhanced during antiretroviral therapy (ART). The onset of HIV-1 replication is regulated by viral protein Tat, a 101-residue protein codified by two exons that elongates viral transcripts. Although the first exon of Tat (aa 1–72) forms itself an active protein, the presence of the second exon (aa 73–101) results in a more competent transcriptional protein with additional functions. Results: Mitochondrial overall functions were analyzed in Jurkat cells stably expressing full-length Tat (Tat101) or one-exon Tat (Tat72). Representative results were confirmed in PBLs transiently expressing Tat101 and in HIV-infected Jurkat cells. The intracellular expression of Tat101 induced the deregulation of metabolism and cytoskeletal proteins which remodeled the function and distribution of mitochondria. Tat101 reduced the transcription of the mtDNA, resulting in low ATP production. The total amount of mitochondria increased likely to counteract their functional impairment. These effects were enhanced when Tat second exon was expressed. Conclusions: Intracellular Tat altered mtDNA transcription, mitochondrial content and distribution in CD4+ T cells. The importance of Tat second exon in non-transcriptional functions was confirmed. Tat101 may be responsible for mitochondrial dysfunctions found in HIV-1 infected patients.We greatly appreciate the secretarial assistance of Mrs Olga Palao. This work was supported by FIPSE (360924/10), Spanish Ministry of Economy and Competitiveness (SAF2010-18388), Spanish Ministry of Health (EC11- 285), AIDS Network ISCIII-RETIC (RD12/0017/0015), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (FIS PI12/00506). The work of Sara Rodríguez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness (2013). The work of María Rosa López-Huertas is supported by a fellowship of the European Union Programme Health 2009 (CHAARM).S

Plasma biomarkers of depressive symptoms in older adults

The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (∼80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches