Age-related changes in neural functional connectivity and its behavioral relevance

<p>Abstract</p> <p>Background</p> <p>Resting-state recordings are characterized by widely distributed networks of coherent brain activations. Disturbances of the default network - a set of regions that are deactivated by cognitive tasks and activated during passive states - have been detected in age-related disorders such as Alzheimer's or Parkinson's disease but alterations in the course of healthy aging still need to be explored.</p> <p>Results</p> <p>Using magnetoencephalography (MEG), the present study investigated how age-related functional resting-state brain connectivity links to cognitive performance in healthy aging in fifty-three participants ranging in age from 18 to 89 years. A beamforming technique was used to reconstruct the brain activity in source space and the interregional coupling was investigated using partial directed coherence (PDC). We found significant age-related alterations of functional resting-state connectivity. These are mainly characterized by reduced information input into the posterior cingulum/precuneus region together with an enhanced information flow to the medial temporal lobe. Furthermore, higher inflow in the medial temporal lobe subsystem was associated with weaker cognitive performance whereas stronger inflow in the posterior cluster was related to better cognitive performance.</p> <p>Conclusion</p> <p>This is the first study to show age-related alterations in subsystems of the resting state network that are furthermore associated with cognitive performance.</p

Neuropsychological Sequelae of Carotid Angioplasty with Stent Placement: Correlation with Ischemic Lesions in Diffusion Weighted Imaging

BACKGROUND AND PURPOSE: Few studies investigated the neuropsychological outcome after carotid angioplasty with stent placement (CAS), yielding partially inconsistent results. The present investigation evaluated the effect of CAS in patients with high-grade stenosis and assessed the predictive value of ischemic lesion number for postinterventional cognitive deterioration. METHODS: 22 patients were tested neuropsychologically before and six weeks after CAS. Cerebral ischemic changes were assessed with diffusion weighted imaging (DWI) prior to and after angioplasty. RESULTS: Pre- to postinterventional cognitive performance improved significantly in terms of verbal memory (t = -2.30; p<0.05), whereas significant deterioration was noted regarding verbal memory span (t = 2.31; p<0.05). 8 (36%) persons conformed to the criteria of cognitive improvement. 6 patients (27%) were postinterventionally classified as having deficits. Analysis yielded no statistically significant correlations between lesion quantity and cognitive change. CONCLUSION: Both improvement and deterioration of cognitive functioning was observed in our collective of patients, leaving the neuropsychological outcome after percutaneous transluminal angioplasty unpredictable in individual cases. The presence of acute ischemic lesions on DWI was found to be not tightly associated with cognitive dysfunction after CAS

Scientific assessment of the use of sugars as cigarette tobacco ingredients: A review of published and other publicly available studies

Sugars, such as sucrose or invert sugar, have been used as tobacco ingredients in American-blend cigarettes to replenish the sugars lost during curing of the Burley component of the blended tobacco in order to maintain a balanced flavor. Chemical-analytical studies of the mainstream smoke of research cigarettes with various sugar application levels revealed that most of the smoke constituents determined did not show any sugar-related changes in yields (per mg nicotine), while ten constituents were found to either increase (formaldehyde, acrolein, 2-butanone, isoprene, benzene, toluene, benzo[k]fluoranthene) or decrease (4-aminobiphenyl, N-nitrosodimethylamine, N-nitrosonornicotine) in a statistically significant manner with increasing sugar application levels. Such constituent yields were modeled into constituent uptake distributions using simulations of nicotine uptake distributions generated on the basis of published nicotine biomonitoring data, which were multiplied by the constituent/nicotine ratios determined in the current analysis. These simulations revealed extensive overlaps for the constituent uptake distributions with and without sugar application. Moreover, the differences in smoke composition did not lead to relevant changes in the activity in in vitro or in vivo assays. The potential impact of using sugars as tobacco ingredients was further assessed in an indirect manner by comparing published data from markets with predominantly American-blend or Virginia-type (no added sugars) cigarettes. No relevant difference was found between these markets for smoking prevalence, intensity, some markers of dependence, nicotine uptake, or mortality from smoking-related lung cancer and chronic obstructive pulmonary disease. In conclusion, thorough examination of the data available suggests that the use of sugars as ingredients in cigarette tobacco does not increase the inherent risk and harm of cigarette smoking

The cross-sectional GRAS sample: A comprehensive phenotypical data collection of schizophrenic patients

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia.</p> <p>Methods</p> <p>For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected.</p> <p>Results</p> <p>The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail.</p> <p>Conclusions</p> <p>The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.</p

Mechanistic studies of Gemcitabine-loaded nanoplatforms in resistant pancreatic cancer cells

Background: Pancreatic cancer remains the deadliest of all cancers, with a mortality rate of 91%. Gemcitabine is considered the gold chemotherapeutic standard, but only marginally improves life-span due to its chemical instability and low cell penetrance. A new paradigm to improve Gemcitabine&#8217;s therapeutic index is to administer it in nanoparticles, which favour its delivery to cells when under 500 nm in diameter. Although promising, this approach still suffers from major limitations, as the choice of nanovector used as well as its effects on Gemcitabine intracellular trafficking inside pancreatic cancer cells remain unknown. A proper elucidation of these mechanisms would allow for the elaboration of better strategies to engineer more potent Gemcitabine nanotherapeutics against pancreatic cancer. Methods: Gemcitabine was encapsulated in two types of commonly used nanovectors, namely poly(lactic-co-glycolic acid) (PLGA) and cholesterol-based liposomes, and their physico-chemical parameters assessed in vitro. Their mechanisms of action in human pancreatic cells were compared with those of the free drug, and with each others, using cytotoxity, apoptosis and ultrastructural analyses. Results: Physico-chemical analyses of both drugs showed high loading efficiencies and sizes of less than 200 nm, as assessed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), with a drug release profile of at least one week. These profiles translated to significant cytotoxicity and apoptosis, as well as distinct intracellular trafficking mechanisms, which were most pronounced in the case of PLGem showing significant mitochondrial, cytosolic and endoplasmic reticulum stresses. Conclusions: Our study demonstrates how the choice of nanovector affects the mechanisms of drug action and is a crucial determinant of Gemcitabine intracellular trafficking and potency in pancreatic cancer settings.Canadian Institutes of Health Research (Fellowship)Breast Cancer Research Program (U.S.) (BCRP Era of Hope Scholar Award)Mary Kay Foundation (Mary Kay Ash Charitable Foundation Grant)Charles A. King Trust (Postdoctoral Research Fellowship Program