Dual Energy X-Ray Absorptiometry Body Composition Reference Values from NHANES

In 2008 the National Center for Health Statistics released a dual energy x-ray absorptiometry (DXA) whole body dataset from the NHANES population-based sample acquired with modern fan beam scanners in 15 counties across the United States from 1999 through 2004. The NHANES dataset was partitioned by gender and ethnicity and DXA whole body measures of %fat, fat mass/height2, lean mass/height2, appendicular lean mass/height2, %fat trunk/%fat legs ratio, trunk/limb fat mass ratio of fat, bone mineral content (BMC) and bone mineral density (BMD) were analyzed to provide reference values for subjects 8 to 85 years old. DXA reference values for adults were normalized to age; reference values for children included total and sub-total whole body results and were normalized to age, height, or lean mass. We developed an obesity classification scheme by using estabbody mass index (BMI) classification thresholds and prevalences in young adults to generate matching classification thresholds for Fat Mass Index (FMI; fat mass/height2). These reference values should be helpful in the evaluation of a variety of adult and childhood abnormalities involving fat, lean, and bone, for establishing entry criteria into clinical trials, and for other medical, research, and epidemiological uses

Adverse Events in a Cohort of HIV Infected Pregnant and Non-Pregnant Women Treated with Nevirapine versus Non-Nevirapine Antiretroviral Medication

BACKGROUND: Predictors of adverse events (AE) associated with nevirapine use are needed to better understand reports of severe rash or liver enzyme elevation (LEE) in HIV+ women. METHODOLOGY: AE rates following ART initiation were retrospectively assessed in a multi-site cohort of 612 women. Predictors of onset of rash or LEE were determined using univariate and multivariate analyses. PRINCIPAL FINDINGS: Of 612 subjects, 152 (24.8%) initiated NVP-based regimens with 86 (56.6%) pregnant; 460 (75.2%) initiated non-NVP regimens with 67 (14.6%) pregnant. LEE: No significant difference was found between regimens in the development of new grade ≥2 LEE (p  =  0.885). Multivariate logistic regression demonstrated an increased likelihood of LEE with HCV co-infection (OR 2.502, 95% CI: 1.04 to 6, p =  0.040); pregnancy, NVP-based regimen, and baseline CD4 >250 cells/mm(3) were not associated with this toxicity. RASH: NVP initiation was associated with rash after controlling for CD4 and pregnancy (OR 2.78; 95%CI: 1.14-6.76), as was baseline CD4 >250 cells/mm(3) when controlling for pregnancy and type of regimen (OR 2.68; 95% CI: 1.19-6.02 p  =  0.017). CONCLUSIONS: CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women. Pregnancy was not an independent risk factor for the development of AEs assessed. The findings from this study have significant implications for women of child-bearing age initiating NVP-based ART particularly in resource limited settings. This study sheds more confidence on the lack of LEE risk and the need to monitor rash with the use of this medication

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Is Aquatic Life Correlated with an Increased Hematocrit in Snakes?

Background: Physiological adaptations that allow air-breathing vertebrates to remain underwater for long periods mainly involve modifications of the respiratory system, essentially through increased oxygen reserves. Physiological constraints on dive duration tend to be less critical for ectotherms than for endotherms because the former have lower mass-specific metabolic rates. Moreover, comparative studies between marine and terrestrial ectotherms have yet to show overall distinct physiological differences specifically associated with oxygen reserves. Methodology/Principal Findings: We used phylogenetically informed statistical models to test if habitat affects hematocrit (an indicator of blood oxygen stores) in snakes, a lineage that varies widely in habitat use. Our results indicate that both phylogenetic position (clade) and especially habitat are significant predictors of hematocrit. Our analysis also confirms the peculiar respiratory physiology of the marine Acrochordus granulatus. Conclusion/Significance: Contrary to previous findings, marine snakes have significantly–albeit slightly–elevated hematocrit, which should facilitate increased aerobic dive times. Longer dives could have consequences for foraging, mate searching, and predation risks. Alternatively, but not exclusively, increased Hct in marine species might also help t

Mammary stem cells, self-renewal pathways, and carcinogenesis

The mammary gland epithelial components are thought to arise from stem cells that undergo both self-renewal and differentiation. Self-renewal has been shown to be regulated by the Hedgehog, Notch, and Wnt pathways and the transcription factor B lymphoma Mo-MLV insertion region 1 (Bmi-1). We review data about the existence of stem cells in the mammary gland and the pathways regulating the self-renewal of these cells. We present evidence that deregulation of the self-renewal in stem cells/progenitors might be a key event in mammary carcinogenesis. If 'tumor stem cells' are inherently resistant to current therapies, targeting stem cell self-renewal pathways might provide a novel approach for breast cancer treatment

Identification of Hepatic Niche Harboring Human Acute Lymphoblastic Leukemic Cells via the SDF-1/CXCR4 Axis

In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis

The gait and balance of patients with diabetes can be improved: a randomised controlled trial

Item does not contain fulltextAIMS/HYPOTHESIS: Gait characteristics and balance are altered in diabetic patients. Little is known about possible treatment strategies. This study evaluates the effect of a specific training programme on gait and balance of diabetic patients. METHODS: This was a randomised controlled trial (n=71) with an intervention (n=35) and control group (n=36). The intervention consisted of physiotherapeutic group training including gait and balance exercises with function-orientated strengthening (twice weekly over 12 weeks). Controls received no treatment. Individuals were allocated to the groups in a central office. Gait, balance, fear of falls, muscle strength and joint mobility were measured at baseline, after intervention and at 6-month follow-up. RESULTS: The trial is closed to recruitment and follow-up. After training, the intervention group increased habitual walking speed by 0.149 m/s (p<0.001) compared with the control group. Patients in the intervention group also significantly improved their balance (time to walk over a beam, balance index recorded on Biodex balance system), their performance-oriented mobility, their degree of concern about falling, their hip and ankle plantar flexor strength, and their hip flexion mobility compared with the control group. After 6 months, all these variables remained significant except for the Biodex sway index and ankle plantar flexor strength. Two patients developed pain in their Achilles tendon: the progression for two related exercises was slowed down. CONCLUSIONS/INTERPRETATION: Specific training can improve gait speed, balance, muscle strength and joint mobility in diabetic patients. Further studies are needed to explore the influence of these improvements on the number of reported falls, patients' physical activity levels and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637546 FUNDING: This work was supported by the Swiss National Foundation (SNF): PBSKP-123446/1/1 maart 201

Phenotypic and Functional Characterization of Human Mammary Stem/Progenitor Cells in Long Term Culture

Background: Cancer stem cells exhibit close resemblance to normal stem cells in phenotype as well as function. Hence, studying normal stem cell behavior is important in understanding cancer pathogenesis. It has recently been shown that human breast stem cells can be enriched in suspension cultures as mammospheres. However, little is known about the behavior of these cells in long-term cultures. Since extensive self-renewal potential is the hallmark of stem cells, we undertook a detailed phenotypic and functional characterization of human mammospheres over long-term passages. Methodology: Single cell suspensions derived from human breast `organoids' were seeded in ultra low attachment plates in serum free media. Resulting primary mammospheres after a week (termed T1 mammospheres) were subjected to passaging every 7th day leading to the generation of T2, T3, and T4 mammospheres. Principal Findings: We show that primary mammospheres contain a distinct side-population (SP) that displays a CD24(low)/CD44(low) phenotype, but fails to generate mammospheres. Instead, the mammosphere-initiating potential rests within the CD44(high)/CD24(low) cells, in keeping with the phenotype of breast cancer-initiating cells. In serial sphere formation assays we find that even though primary (T1) mammospheres show telomerase activity and fourth passage T4 spheres contain label-retaining cells, they fail to initiate new mammospheres beyond T5. With increasing passages, mammospheres showed an increase in smaller sized spheres, reduction in proliferation potential and sphere forming efficiency, and increased differentiation towards the myoepithelial lineage. Significantly, staining for senescence-associated beta-galactosidase activity revealed a dramatic increase in the number of senescent cells with passage, which might in part explain the inability to continuously generate mammospheres in culture. Conclusions: Thus, the self-renewal potential of human breast stem cells is exhausted within five in vitro passages of mammospheres, suggesting the need for further improvisation in culture conditions for their long-term maintenance

Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer

Abstract Introduction In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype. Methods The clinical, pathological and biological features of claudin-low tumors were compared to the other tumor subtypes using an updated human tumor database and multiple independent data sets. These main features of claudin-low tumors were also evaluated in a panel of breast cancer cell lines and genetically engineered mouse models. Results Claudin-low tumors are characterized by the low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes and cancer stem cell-like features. Clinically, the majority of claudin-low tumors are poor prognosis estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and epidermal growth factor receptor 2 (HER2)-negative (triple negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Interestingly, we show that a group of highly utilized breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell. Conclusions These results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines