Cellular O-Glycome Reporter/Amplification to explore O-glycans of living cells

Protein O-glycosylation has key roles in many biological processes, but the repertoire of O-glycans synthesized by cells is difficult to determine. Here we describe an approach termed Cellular O-Glycome Reporter/Amplification (CORA), a sensitive method used to amplify and profile mucin-type O-glycans synthesized by living cells. Cells convert added peracetylated benzyl-α-N-acetylgalactosamine to a large variety of modified O-glycan derivatives that are secreted from cells, allowing for easy purification for analysis by HPLC and mass spectrometry (MS). Relative to conventional O-glycan analyses, CORA resulted in an ∼100-1,000-fold increase in sensitivity and identified a more complex repertoire of O-glycans in more than a dozen cell types from Homo sapiens and Mus musculus. Furthermore, when coupled with computational modeling, CORA can be used for predictions about the diversity of the human O-glycome and offers new opportunities to identify novel glycan biomarkers for human diseases

Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington's Disease

Altered dopamine receptor labelling has been demonstrated in presymptomatic and symptomatic Huntington's disease (HD) gene carriers, indicating that alterations in dopaminergic signalling are an early event in HD. We have previously described early alterations in synaptic transmission and plasticity in both the cortex and hippocampus of the R6/1 mouse model of Huntington's disease. Deficits in cortical synaptic plasticity were associated with altered dopaminergic signalling and could be reversed by D1- or D2-like dopamine receptor activation. In light of these findings we here investigated whether defects in dopamine signalling could also contribute to the marked alteration in hippocampal synaptic function. To this end we performed dopamine receptor labelling and pharmacology in the R6/1 hippocampus and report a marked, age-dependent elevation of hippocampal D1 and D2 receptor labelling in R6/1 hippocampal subfields. Yet, pharmacological inhibition or activation of D1- or D2-like receptors did not modify the aberrant synaptic plasticity observed in R6/1 mice. These findings demonstrate that global perturbations to dopamine receptor expression do occur in HD transgenic mice, similarly in HD gene carriers and patients. However, the direction of change and the lack of effect of dopaminergic pharmacological agents on synaptic function demonstrate that the perturbations are heterogeneous and region-specific, a finding that may explain the mixed results of dopamine therapy in HD

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study

<p>Abstract</p> <p>Background</p> <p>Chronic kidney disease (CKD) is associated with an increased risk of fracture. Decreased bone mass and disruption of microarchitecture occur early in the course of CKD and worsens with the progressive decline in renal function so that at the time of initiation of dialysis at least 50% of patients have had a fracture. Despite the excess fracture risk, and the associated increases in morbidity and mortality, little is known about the factors that are associated with an increase in fracture risk. Our study aims to identify prognostic factors for bone loss and fractures in patients with stages 3 to 5 CKD.</p> <p>Methods</p> <p>This prospective study aims to enroll two hundred and sixty men and women with stages 3 to 5 CKD. Subjects will be followed for 24 months and we will examine the ability of: 1) bone mineral density by dual x-ray absorptiometry at the spine, hip, and radius; 2) volumetric bone density by high resolution peripheral quantitated computed tomography at the radius and tibia; 3) serum markers of bone turnover; 4) bone formation rate by bone biopsy; and 5) muscle strength and balance to predict spine and non-spine fractures, identified by self-report and/or vertebral morphometry. All measurements will be obtained at baseline, at 12 and at 24 months with the exception of bone biopsy, which will be measured once at 12 months. Subjects will be contacted every 4 months to determine if there have been incident fractures or falls.</p> <p>Discussion</p> <p>This study is one of the first that aims to identify risk factors for fracture in early stage CKD patients. Ultimately, by identifying risk factors for fracture and targeting treatments in this group-before the initiation of renal replacement therapy - we will reduce the burden of disease due to fractures among patients with CKD.</p

A Genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org

Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3-CA1 synapses.

Glycogen synthase kinase-3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long-term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation. We report that only the mutation in GSK3α affects long-term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3α should be investigated as a drug target in cognitive disorders including Alzheimer's Disease

Improving Mouse Models for Dementia. Are All the Effects in Tau Mouse Models Due to Overexpression?

Mouse models of Alzheimer's disease have commonly used transgenic overexpression of genes involved in production of amyloid β (APP and/or PSEN1/2) or Tau (MAPT) with mutations that result in familial forms of dementia. We discuss possible improvements that may create full models while avoiding the problems of overexpression and report synaptic results in APPKI models. We stress use of inappropriate controls without overexpression of the normal human protein and the mismatch between the learning deficits reported in mice with plaques but no tangles and the human condition. We focus on Tau overexpression, including new data that support previous reports of the grossly nonlinear relationship between Tau overexpression and neurofibrillary tangle load, with a twofold increase in Tau protein, resulting in a 100-fold increase in tangle density. These data also support the hypothesis that a high concentration of soluble Tau, in overexpression models, plays an important direct role in neurodegeneration, rather than only via aggregation. Finally, we hypothesize that there is an optimal concentration range over which Tau can bind to microtubules and a threshold beyond which much of the overexpressed protein is unable to bind. The excess thus causes toxicity in ways not necessarily related to the process in human dementias

The prevalence of radiographic vertebral fractures in Mexican men

The prevalence of radiographically ascertained vertebral fractures in a random sample of 413 in Mexican men is 9.7% (95% CI 6.85–12.55). Increase of vertebral fracture rises with age from 2.0% in the youngest group (50–59 years) to 21.4% in the oldest group (80 years and over). This is the first population-based study of vertebral fractures in Mexican men using a standardized methodology reported in other studies. The presence of radiographic vertebral fractures increases with age. This same pattern was found in Mexican women with steady age increments, but the higher prevalence of fractures in women starts at age 70, whereas in men, the higher prevalence starts a decade later (80 years and over). The standardized prevalence per 1,000 men 50 years and over in the Mexican population for the year 2005 is 65.8 (95% CI 29.9–105.5), and it is 68.6 (95% CI 32.2–108.7) in the US population for the year 2000

Current and emerging treatment of osteoporosis

The goal of treating a patient with recent fragility fracture should not only be to treat the patient in the acute phase but also to prevent further fractures. Interventions to increase bone mass to preventing further fragility fractures can be classified as non-pharmacological and pharmacological. All European and international guidelines base the need for treatment, not on the diagnosis of osteoporosis (based on the T-score), but on the risk of fracture, which is strongly influenced by the presence of a fragility fracture, especially vertebral or femoral fractures. Before treatment, it is important to make a differential diagnosis between primary and secondary osteoporosis because anti-osteoporotic drug treatment would be useless if the primary illness causing osteoporosis is not treated too. Some studies show that anti-osteoporotic drugs are frequently interrupted within 1 month of their prescription; this happens not so much due to the occurrence of adverse events but mostly because patients have not been sufficiently informed about the importance of taking the drug and because are not receiving personalised treatment. All data confirm that, in older people, vitamin D deficiency is highly prevalent and calcium intake is often not adequate. So, osteoporosis guidelines recommend calcium and vitamin D for all patients in association with antiosteoporotic therapy. We have many drugs for the treatment of patients at high risk of fracture, but we should use drugs based on evidence of their efficacy and safety in older-age subgroups, provided by targeted studies or extrapolated data. In this chapter, we describe efficacy, route of administration, adverse events and recent technical remarks of current antiresorptive and anabolic osteoporosis therapies. Furthermore, we describe emerging therapies, such as Abaloparatide and Romosozumab