Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease

Introduction

The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers.

Correlation between heavy metal exposure and GSTM1 polymorphism in Iranian multiple sclerosis patients

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory disease of the central nervous system. Various exposures to heavy metals can lead to toxicity and oxidative stress. While glutathione-S-transferases are known as oxidative stress-related genes and involved in metal biotransformation. The aim of the present study is to investigate the correlation of GSTM1 polymorphism in MS patients and the possible association with blood concentration of arsenic (As) and cadmium (Cd) as major heavy metal pollutants. This study included 69 relapsing–remitting multiple sclerosis patients and 74 age/gender-matched healthy subjects. The genetic profile was analyzed by PCR, and heavy metal concentrations were measured by electrothermal atomic absorption spectrometry. Our results demonstrated that patients with the GSTM1 null genotype had considerably lower age of onset. However, the frequency of the GSTM1 null genotype was not significantly different between MS and control groups. In addition, the blood As and Cd concentrations were considerably higher in MS patients in comparison with healthy individuals. Also, it revealed that the GSTM1 null genotype associated with high Cd level in MS patients. There was also a trend toward an increase in As level in MS patients. These data may point to susceptibility to cadmium toxicity especially in RR–MS patients with smoking habit. Furthermore, the M1 null genotype will help in a prognosis of MS considering the age of onset. It confirms that the long-term prognosis in MS and patient’s disability are influenced by their ability to remove the toxic products and perhaps to decrease oxidative stress.     

Differential timing of neurogenesis underlies dorsal-ventral topographic projection of olfactory sensory neurons

Background

The mammalian primary olfactory system has a spatially-ordered projection in which olfactory sensory neurons (OSNs) located in the dorsomedial (DM) and ventrolateral (VL) region of the olfactory epithelium (OE) send their axons to the dorsal and ventral region of the olfactory bulb (OB), respectively. We previously found that OSN axonal projections occur sequentially, from the DM to the VL region of the OE. The differential timing of axonal projections is important for olfactory map formation because early-arriving OSN axons secrete guidance cues at the OB to help navigate late-arriving OSN axons. We hypothesized that the differential timing of axonal projections is regulated by the timing of OSN neurogenesis. To test this idea, we investigated spatiotemporal patterns of OSN neurogenesis during olfactory development.

Methods and results

To determine the time of OSN origin, we used two thymidine analogs, BrdU and EdU, which can be incorporated into cells in the S-phase of the cell-cycle. We injected these two analogs at different developmental time points and analyzed distribution patterns of labeled OSNs. We found that OSNs with different dates of origin were differentially distributed in the OE. The majority of OSNs generated at the early stage of development were located in the DM region of the OE, whereas OSNs generated at the later stage of development were preferentially located in the VL region of the OE.

Conclusions

These results indicate that the number of OSNs is sequentially increased from the DM to the VL axis of the OE. Moreover, the temporal sequence of OSN proliferation correlates with that of axonal extension and emergence of glomerular structures in the OB. Thus, we propose that the timing of OSN neurogenesis regulates that of OSN axonal projection and thereby helps preserve the topographic order of the olfactory glomerular map along the dorsal–ventral axis of the OB.

     

Right ventricular dyssynchrony in pulmonary hypertension: Phase analysis using FDG-PET imaging

Background

Right ventricular (RV) performance in patients of pulmonary hypertension (PH) requires optimal assessment. The objective of this study is to develop phase analysis using ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging as a feasible tool for evaluation of RV dyssynchrony in PH.

Methods and Results

Fifty-four PH patients with well-characterized hemodynamic parameters were enrolled. All subjects performed FDG-PET imaging for RV phase analysis and RV function evaluation. Two-dimensional echocardiography with speckle tracking analysis was conducted to obtain RV time to peak systolic strain (PSST) as a comparison. The median contraction delay difference between RV middle free wall and septum measured by PET phase analysis (RVPD_PET) was 20.12° (interquartile range, 4.99°-30.10°). The median difference of PSST between RV middle free wall and middle septal wall (RVPD_Echo) measured by echocardiography was 43.98° (interquartile range, 6.25°-72.00°). RVPD_PET was well correlated with RVPD_Echo (r = 0.685, P < .001). RV phase standard deviation (RVSD) and histogram bandwidth (RVBW) derived from PET phase histogram were significantly correlated with cardiac index, RV ejection fraction, 6-minute walking distance, and serum N-terminal pro B-type natriuretic peptide (NT-proBNP) (RVSD: r = ?0.532, P < .001; r = ?0.551, P < .001; r = ?0.544, P < .001; r = 0.404, P < .01; respectively, RVBW: r = ?0.492, P < .001; r = ?0.466, P < .001; r = ?0.544, P < .001; r = 0.349, P = .01, respectively), while there were no significant correlations between RVSD and RVBW with hemodynamic parameters (right atrial pressure, right ventricular systolic pressure, right ventricular end-diastolic pressure, mean pulmonary artery pressure, and total pulmonary resistance).

Conclusions

Contraction delays between RV free wall and septum in PH measured by phase analysis and speckle tracking echocardiography were well correlated. RV dyssynchrony measured by phase analysis of FDG-PET was significantly related to RV dysfunction. Phase analysis of FDG-PET is feasible to evaluate RV mechanical dyssynchrony in patients of PH.

     

Adipokine Chemerin Bridges Metabolic Dyslipidemia and Alveolar Bone Loss in Mice

Chemerin is an adipokine that regulates adipogenesis and metabolic functions of mature adipocytes mainly through the activation of chemokine‐like receptor 1 (CMKLR1). Elevated levels of chemerin have been found in individuals with obesity, type 2 diabetes, and osteoporosis. This adipokine was identified as an inflammatory and metabolic syndrome marker. Considering that the association between metabolic syndrome and bone health remains unclear, the present study aimed to clarify the role of chemerin in the pathophysiology of bone loss induced by dyslipidemia, particularly modulating osteoclastogenesis. In vitro analyses showed a downregulation of CMKLR1 at the early stage of differentiation and a gradual increase at late stages. Strikingly, chemerin did not modify osteoclast differentiation markers or osteoclast formation; however, it increased the actin‐ring formation and bone resorption activity in mature osteoclasts. The increased bone resorption activity induced by chemerin was effectively inhibited by CMKLR1 antagonist (CCX832). Chemerin boosting mature osteoclast activity involves ERK5 phosphorylation. Moreover, two models of dyslipidemia (high‐fat diet [HFD]‐treated C57/BL6 and db/db mice) exhibited significantly increased level of chemerin in the serum and gingival tissue. Morphometric analysis showed that HFD‐treated and db/db mice exhibited increased alveolar bone loss compared to respective control mice, which was associated with an up‐regulation of chemerin, CMKLR1 and cathepsin K mRNA expression in the gingival tissue. The treatment of db/db mice with CCX832 effectively inhibited bone loss. Antagonism of chemerin receptor also inhibited the expression of cathepsin K in the gingival tissue. Our results show that chemerin not only increases osteoclasts activity in vitro, but also that increased level of chemerin in dyslipidemic mice plays a critical role in bone homeostasis. © 2016 American Society for Bone and Mineral Research.     

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS)

Introduction

An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here.

Methods

Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity.

Results

Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids.

Conclusions

These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients’ satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients.

Funding

Molteni Farmaceutici, Italy.

     

Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development

Abstract

Rituximab (MabThera^®/Rituxan^®), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies. A subcutaneous (SC) formulation of rituximab has been developed, comprising the same monoclonal antibody as the originally marketed formulation [rituximab concentrate for solution for intravenous (IV) infusion], and has undergone a detailed, sequential clinical development program. This program demonstrated that, at fixed doses, rituximab SC achieves non-inferior serum trough concentrations in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia, with comparable efficacy and safety relative to the IV formulation. The added benefit of rituximab SC was demonstrated in dedicated studies showing that rituximab SC allows for simplified and shortened drug preparation and administration times resulting in a reduced treatment burden for patients as well as improved resource utilization (efficiency) at the treatment facility. The improved efficiency of delivering rituximab’s benefit to patients may broaden patient access to rituximab therapy in areas with low levels of healthcare resources, including IV-chair capacity constraints. This article is a companion paper to G. Salles, et al., which is also published in this issue.

Funding

F. Hoffmann-La Roche Ltd.