A critical review of the epidemiological evidence of effects of air pollution on dementia, cognitive function and cognitive decline in adult population

Dementia is arguably the most pressing public health challenge of our age. Since dementia does not have a cure,identifying risk factors that can be controlled has become paramount to reduce the personal, societal and eco-nomic burden of dementia. The relationship between exposure to air pollution and effects on cognitive function,cognitive decline and dementia has stimulated increasing scientific interest in the past few years. This review ofthe literature critically examines the available epidemiological evidence of associations between exposure to am-bient air pollutants, cognitive performance, acceleration of cognitive decline, risk of developing dementia, neuro-imaging and neurological biomarker studies, following Bradford Hill guidelines for causality.The evidence reviewed has been consistent in reporting associations between chronic exposure to air pollutionand reduced global cognition, as well as impairment in specific cognitive domains including visuo-spatial abili-ties. Cognitive decline and dementia incidence have also been consistently associated with exposure to air pollu-tion. The neuro-imaging studies reviewed report associations between exposure to air pollution and whitematter volume reduction. Other reported effects include reduction in gray matter, larger ventricular volume,and smaller corpus callosum. Findings relating to ischemic (white matter hyperintensities/silent cerebralinfarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease have been heteroge-neous, as have observations on hippocampal volume and air pollution. The few studies available on neuro-inflammation tend to report associations with exposure to air pollution. everal effect modifiers have been suggested in the literature, but more replication studies are required. Tradi-tional confounding factors have been controlled or adjusted for in most of the reviewed studies. Additional con-founding factors have also been considered, but the inclusion of these has varied among the different studies.Despite all the efforts to adjust for confounding factors, residual confounding cannot be completely ruled out, es-pecially since the factors affecting cognition and dementia are not yet fully understood.The available evidence meets many of the Bradford Hill guidelines for causality. The reported associations be-tween a range of air pollutants and effects oncognitive function in older people,including the acceleration of cog-nitive decline and the induction of dementia, are likely to be causal in nature.However, the diversity of study designs, air pollutants and endpoints examined precludes the attribution of theseadverse effects to a single class of pollutant and makes meta-analysis inappropriate

Structure and Function of a Mycobacterial NHEJ DNA Repair Polymerase

Non homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks in prokaryotes requires Ku and a specific multidomain DNA ligase (LigD). We present crystal structures of the primase/polymerisation domain (PolDom) of Mycobacterium tuberculosis LigD, alone and complexed with nucleotides. The PolDom structure combines the general fold of the archaeo-eukaryotic primase (AEP) superfamily with additional loops and domains that together form a deep cleft on the surface, likely used for DNA binding. Enzymatic analysis indicates that the PolDom of LigD, even in the absence of accessory domains and Ku proteins, has the potential to recognise DNA end-joining intermediates. Strikingly, one of the main signals for the specific and efficient binding of PolDom to DNA is the presence of a 5'-phosphate group, located at the single/double-stranded junction at both gapped and 3'-protruding DNA molecules. Although structurally unrelated, Pol lambda and Pol mu, the two eukaryotic DNA polymerases involved in NHEJ, are endowed with a similar capacity to bind a 5'-phosphate group. Other properties that are beneficial for NHEJ, such as the ability to generate template distortions and realignments of the primer, displayed by Pol lambda and Pol mu, are shared by the PolDom of bacterial LigD. In addition, PolDom can perform non-mutagenic translesion synthesis on termini containing modified bases. Significantly, ribonucleotide insertion appears to be a recurrent theme associated with NHEJ, maximised in this case by the deployment of a dedicated primase, although its in vivo relevance is unknown

Molecular envelopes derived from protein powder diffraction Molecular envelopes derived from protein powder diffraction data

The preparation of single crystals suitable for X-ray analysis is frequently the most difficult step in structural studies of proteins.With the aid of two examples, it is shown that de novo solution of the crystallographic phase problem can be achieved at low resolution using microcrystalline powder samples via the single isomorphous replacement method. With synchrotron radiation and optimized instrumentation, high-quality powder patterns have been recorded, from which it was possible to generate phase information for structure factors up to 6 A resolution. pH- and radiation-induced anisotropic lattice changes were exploited to reduce the problem of overlapping reflections, which is a major challenge in protein powder diffraction. The resulting data were of sufficient quality to compute molecular envelopes of the protein molecule and to map out the solvent channels in the crystals. The results show that protein powder diffraction can yield low-resolution data that are potentially useful for the characterization of microcrystalline proteins as novel micro- and mesoporous materials as well as for structural studies of biologically important macromolecules

Siponimod vs placebo in active secondary progressive multiple sclerosis: a post hoc analysis from the phase 3 EXPAND study.

BACKGROUND Siponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS. METHODS Post hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND. ENDPOINTS 3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits. RESULTS Data from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p < 0.01); there was no significant effect on T25FW. Siponimod increased likelihood of 6-month confirmed SDMT improvement vs placebo (by 62%; p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm3; p < 0.0001), and fewer T1 Gd + and N/E T2 lesions than placebo (85% and 80% reductions, respectively; p < 0.0001). CONCLUSIONS In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo. TRIAL REGISTRATION ClinicalTrials.gov number: NCT01665144

Second primary cancers in patients with skin cancer: a population-based study in Northern Ireland

Among all 14 500 incident cases of basal cell carcinoma (BCC), 6405 squamous cell carcinomas (SCC) and 1839 melanomas reported to the Northern Ireland Cancer Registry between 1993 and 2002, compared with the general population, risk of new primaries after BCC or SCC was increased by 9 and 57%, respectively. The subsequent risk of cancer, overall, was more than double after melanoma

Ribosomal oxygenases are structurally conserved from prokaryotes to humans

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases

EXIT-chart aided hybrid multiuser detector design for frequency-domain-spread chip-interleaved MC-CDMA

With the advent of EXtrinsic Information Transfer (EXIT) charts, we are capable of analyzing, predicting and visually comparing the convergence behaviours of different turbo Multi-User Detectector (MUD)s. The different MUDs have diverse EXIT characteristics and hence their superposition allows us to create a combined EXIT curve, which closely matches that of the channel decoder. Hence a near-capacity operation is facilitated by combining the benifits of different MUDs and therefore to create a superior MUD. Thus in this contribution, we propose a novel hybrid MUD combining scheme, which combines the advantages of a high performance and low complexity in form of an advanced hybrid MUD solution. The transmitted bits are unknown at the receiver, hence it is not feasible to directly evaluate the mutual information gain of the iterative MUD in consecutive iterations, hence we propose a realistic algorithm for estimating this mutual information gain, which is then used for activating the most appropriate constituent MUD as and when it is necessary. The constituent MUDs are the Matched Filter (MF) based Soft Interference Cancellation (SoIC) and the optimum Bayesian MUDs, which are invoked in the scenario of Frequency-Domain-Spread Chip-Interleaved (FDSCI) Multiple Carrier Code Division Multiple Access (MC-CDMA). The resultant hybrid MUD is capable of outperforming both the MF-SoIC and Bayesian turbo MUDs in the terms of the attainable complexity and Bit-Error-Rate (BER) performance

Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings.

OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy. METHODS: In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed. RESULTS: Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, -0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter. CONCLUSIONS: Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years

Measurement of the ttbar production cross section using dilepton events in ppbar collisions

We present a measurement of the ttbar production cross section sigma(ttbar) in ppbar collisions at sqrt{s} = 1.96 TeV using 5.4 fb-1 of integrated luminosity collected with the D0 detector. We consider final states with at least two jets and two leptons (ee, emu, mumu), and events with one jet for the the emu final state as well. The measured cross section is sigma(ttbar)= 7.36 +0.90-0.79 (stat + syst) pb. This result combined with the cross section measurement in the lepton + jets final state yields sigma(ttbar)=7.56 +0.63-0.56 (stat + syst) pb, which agrees with the standard model expectation. The relative precision of 8% of this measurement is comparable to the latest theoretical calculations.Comment: 9 pages, published in Phys. Lett.

Race/Ethnicity and gender differences in health intentions and behaviors regarding exercise and diet for adults with type 2 diabetes: A cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Self-management is the cornerstone of diabetes control and prevention of complications; however, it is undetermined whether differences in intention to adopt healthy lifestyles and actual healthy behavior exist across race/ethnic groups. This study evaluated the differences across racial-ethnic groups in self-reported medical advice received and health intentions and behaviors among adults with type 2 diabetes mellitus.</p> <p>Methods</p> <p>A cross-sectional analysis of the 2007 SHIELD US survey ascertained self-reported health intentions and behaviors for regular exercise, diet, and weight management among Non-Hispanic Caucasian (n = 2526), Non-Hispanic African-American (n = 706), and Hispanic (n = 179) respondents with type 2 diabetes.</p> <p>Results</p> <p>A similar proportion of respondents from each race-gender group (43%-56%) reported receiving healthcare advice to increase their exercise (P = 0.32). Significantly more minorities reported an intention to follow the exercise recommendation compared with Non-Hispanic Caucasians (P = 0.03). More Non-Hispanic African-American (29%) and Hispanic (27%) men reported exercising regularly compared with other race-gender groups (P = 0.02). Significantly more Non-Hispanic Caucasian women (74%) and Hispanic women (79%) reported trying to lose weight compared with other groups (P < 0.0001).</p> <p>Conclusions</p> <p>Differences in health intentions and healthy behaviors were noted across race-gender groups. More Non-Hispanic African-American men reported an intention to follow advice on exercising and self-report of exercising regularly was also higher compared with other race-gender groups. More Hispanic men reported high physical activity levels than other groups. Despite an increased willingness to follow healthcare recommendations for diet, >50% of respondents were obese among all race-gender groups.</p