Aging in vitro and D-glucose uptake kinetics of diploid human fibroblasts

By use of a rapid technique, initial rates of D-glucose transport were obtained during the lifespan in vitro of a commercially available strain of human embryo lung fibroblasts (Flow 2000). The apparent Km of the D-glucose carrier did not change during senescence in vitro: = 1.8 mM (range 1.3-2.3) in phase II, = 1.8 mM (range 1.5-2.2) in phase III. Transport rates remained constant in stationary phase II cultures, which had completed between 30% and 80% of their replicative lifespan. A wide variation, however, was observed in terminally differentiated cells (phase III), which showed a two- to threefold increase in average cell size and protein content. In some senescent cultures, glucose transport calculated on a per cell basis was also two-to threefold increased, while it was strongly decreased (-75%) in others. When calculated per unit of cell water, protein, and surface area, respectively, transport rates in phase III cultures ranged from values established for stationary phase II cultures down to very low values. Detaching cells flushed off from senescent cultures did not show measurable rates of glucose transport into the inulin impermeable cell space. Present evidence argues against the idea that an impairment of D-glucose transport might precede loss of replicative potential in aging human fibroblasts. Instead our data indicate that the transport capacity of cell membrane finally decreases during postreplicative senescence in terminally differentiated cells

Novel strategies for assessing platelet reactivity

There are many approaches to assessing platelet reactivity and many uses for such measurements. Initially, measurements were based on the ability of platelets separated from other blood cells to aggregate together following activation with an appropriate ‘aggregating agent’. Later, measurements of platelet aggregation in blood itself were performed, and this led to a point-of-care approach to platelet function testing. Measurement of secretory activity through the appearance of the activation marker P-selectin on platelets now provides an alternative approach, which enables remote testing. Measurement of vasodilator-stimulated phosphoprotein phosphorylation is also moving toward application in situations remote from the testing laboratory. Here we provide an overview of the various approaches that are now available, assess their advantages and disadvantages, and describe some of the clinical situations in which they are being used

Direct Detection of Dark Matter in Supersymmetric Models

We evaluate neutralino-nucleon scattering rates in several well-motivated supersymmetric models, and compare against constraints on the neutralino relic density, BF( b\to s\gamma ) as well as the muon anomalous magnetic moment a_\mu . In the mSUGRA model, the indirect constraints favor the hyperbolic branch/focus point (HB/FP) region of parameter space, and in fact this region is just where neutralino-nucleon scattering rates are high enough to be detected in direct dark matter search experiments! In Yukawa unified SUSY SO(10) models with scalar mass non-universality, the relic density of neutralinos is almost always above experimental bounds, while the corresponding direct detection rates are below experimental levels. Conversely, in five dimensional SO(10) models where gauge symmetry breaking is the result of compactification of the extra dimension, and supersymmetry breaking is communicated via gaugino mediation, the relic density is quite low, while direct detection rates can be substantial.Comment: 25 page latex file including 18 EPS figures; revised version with references added and cross sections rescaled; figures changed. A copy of the paper with better resolution figures can be found at http://www.hep.fsu.edu/~belyaev/projects/directz1

CPT-11 and concomitant hyperfractionated accelerated radiotherapy induce efficient local control in rectal cancer patients: results from a phase II

Patients with rectal cancer are at high risk of disease recurrence despite neoadjuvant radiochemotherapy with 5-Fluorouracil (5FU), a regimen that is now widely applied. In order to develop a regimen with increased antitumour activity, we previously established the recommended dose of neoadjuvant CPT-11 (three times weekly 90 mg m−2) concomitant to hyperfractionated accelerated radiotherapy (HART) followed by surgery within 1 week. Thirty-three patients (20 men) with a locally advanced adenocarcinoma of the rectum were enrolled in this prospective phase II trial (1 cT2, 29 cT3, 3 cT4 and 21 cN+). Median age was 60 years (range 43–75 years). All patients received all three injections of CPT-11 and all but two patients completed radiotherapy as planned. Surgery with total mesorectal excision (TME) was performed within 1 week (range 2–15 days). The preoperative chemoradiotherapy was overall well tolerated, 24% of the patients experienced grade 3 diarrhoea that was easily manageable. At a median follow-up of 2 years no local recurrence occurred, however, nine patients developed distant metastases. The 2-year disease-free survival was 66% (95% confidence interval 0.48–0.83). Neoadjuvant CPT-11 and HART allow for excellent local control; however, distant relapse remains a concern in this patient population

Expression profile of genes regulated by activity of the Na-H exchanger NHE1

BACKGROUND: In mammalian cells changes in intracellular pH (pH(i)), which are predominantly controlled by activity of plasma membrane ion exchangers, regulate a diverse range of normal and pathological cellular processes. How changes in pH(i )affect distinct cellular processes has primarily been determined by evaluating protein activities and we know little about how pH(i )regulates gene expression. RESULTS: A global profile of genes regulated in mammalian fibroblasts by decreased pH(i )induced by impaired activity of the plasma membrane Na-H exchanger NHE1 was characterized by using cDNA microarrays. Analysis of selected genes by quantitative RT-PCR, TaqMan, and immunoblot analyses confirmed results obtained from cDNA arrays. Consistent with established roles of pH(i )and NHE1 activity in cell proliferation and oncogenic transformation, grouping regulated genes into functional categories and biological pathways indicated a predominant number of genes with altered expression were associated with growth factor signaling, oncogenesis, and cell cycle progression. CONCLUSION: A comprehensive analysis of genes selectively regulated by pH(i )provides insight on candidate targets that might mediate established effects of pH(i )on a number of normal and pathological cell functions

Management and Outcome of Cardiac and Endovascular Cystic Echinococcosis

Cardiac and vascular involvement are infrequent in classical cystic echinococcosis (CE), but when they occur they tend to present earlier and are associated with complications that may be life threatening. Cardiovascular CE usually requires complex surgery, so in low-income countries the outcome is frequently fatal. This case series describes the characteristics of cardiovascular CE in patients diagnosed and treated at a Tropical Medicine & Clinical Parasitology Center in Spain. A retrospective case series of 11 patients with cardiac and/or endovascular CE, followed-up over a period of 15 years (1995–2009) is reported. The main clinical manifestations included thoracic pain or dyspnea, although 2 patients were asymptomatic. The clinical picture and complications vary according to cyst location. Isolated cardiac CE may be cured after surgery, while endovascular extracardiac involvement is associated with severe chronic complications. CE should be included in the differential diagnosis of cardiovascular disease in patients from endemic areas. CE is a neglected disease and further studies are necessary in order to make more definite management recommendations for this rare and severe form of the disease. The authors propose a general approach based on cyst location: exclusively cardiac, endovascular or both

Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer's disease in veterans, using the Alzheimer's Disease Neuroimaging Initiative

Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid biomarkers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans

Mild cognitive impairment (MCI) and dementia in a sample of adults in the city of Bogotá

The low prevalence of dementia described in communities is likely due to the low sensitivity of screening tests and an absence of evaluation by specialists. Objective: To estimate the prevalence of mild cognitive impairment (MCI) and dementia in adults older than 50 years. Methods: A two-phase, cross-sectional study was conducted by specialists to evaluate cognition and associated demographic risk factors in 1,235 independent community-dwelling adults from Bogotá. In Phase I, screening was performed using the MMSE and MoCA tests. In Phase II, after application of a comprehensive neuropsychological battery with neurologic and psychiatric evaluations, a cognitive diagnosis was established by consensus. Results: The prevalence found for MCI was 34% and for dementia was 23%. MCI was associated with incomplete high school, OR=1.74 (95%CI=1.23-2.45), and with an age of 70-79 years, OR=1.93 (95%CI=1.47-2.53). A total of 73% of MCI cases were amnestic. Dementia was associated with incomplete primary education, OR=8.98 (95%CI=5.56-14.54), complete primary education, OR=6.23 (95%CI=3.70-10.47), and age older than eighty years, OR=3.49 (95%CI=2.23-5.44). Conclusion: The prevalence of dementia found was greater than the rates reported in previous studies. Low educational level was the main risk factor for cognitive impairment and should be considered in strategic planning for the local health system