PET imaging using (18)Ffluorodeoxyglucose (FDG) and (11)CPittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid ...protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.
Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts.
Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42).
PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. (18)Ffluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.
C1 inhibitor deficiency: consensus document Gompels, M. M.; Lock, R. J.; Abinun, M. ...
Clinical and experimental immunology,
March 2005, Letnik:
139, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio‐oedema. In hereditary ...angio‐oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non‐functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification.
Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our ...biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that—even at large sample sizes—these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases.
Summary
Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. ...However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference ‘Diet and Cardiometabolic Health – Beyond Calories’, and this paper summarizes the presentations and follow‐up discussions. Regarding the health effects of dietary fat, sugar and non‐nutritive sweeteners, it is concluded that food‐specific saturated fatty acids and sugar‐sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential ‘beyond calories’ mechanisms may lead to new strategies for attenuating the obesity crisis.
To compare brain beta-amyloid (Abeta) burden measured with (11)CPittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias.
Thirty-three subjects with dementia (17 ...AD, 10 dementia with Lewy bodies DLB, 6 frontotemporal dementia FTD), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio.
Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis.
Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.
Light-Curing Units Price, R.B.; Ferracane, J.L.; Shortall, A.C.
Journal of Dental Research,
09/2015, Letnik:
94, Številka:
9
Book Review, Journal Article
Recenzirano
For improved interstudy reproducibility, reduced risk of premature failures, and ultimately better patient care, researchers and dentists need to know how to accurately characterize the ...electromagnetic radiation (light) they are delivering to the resins they are using. The output from a light-curing unit (LCU) is commonly characterized by its irradiance. If this value is measured at the light tip, it describes the radiant exitance from the surface of the light tip, and not the irradiance received by the specimen. The value quoted also reflects only an averaged value over the total measurement area and does not represent the irradiance that the resin specimen is receiving locally or at a different moment in time. Recent evidence has reported that the spectral emission and radiant exitance beam profiles from LCUs can be highly inhomogeneous. This can cause nonuniform temperature changes and uneven photopolymerization within the resin restoration. The spectral radiant power can be very different between different brands of LCUs, and the use of irradiance values derived from dental radiometers to describe the output from an LCU for research purposes is discouraged. Manufacturers should provide more information about the light output from the LCU and the absorption spectrum of their resin-based composite (RBC). Ideally, future assessments and research publications should include the following information about the curing light: 1) radiant power output throughout the exposure cycle and the spectral radiant power as a function of wavelength, 2) analysis of the light beam profile and spectral emission across the light beam, and 3) measurement and reporting of the light the RBC specimen received as well as the output measured at the light tip.
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental ...models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti‐CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti‐human CD154 domain antibody (dAb, BMS‐986004). The anti‐CD154 dAb effectively blocked CD40‐CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti‐CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti‐CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti‐CD154 dAb treatment increased the frequency of CD4+CD25+Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti‐CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti‐CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
An Fc‐silent anti‐CD154 domain antibody safely and effectively promotes long‐term kidney transplant survival in nonhuman primates without the risk of thromboembolism when combined with a clinically relevant conventional immunosuppression regimen. See the editorial from Thomson and Ezzelarab on page 1156.
Hydrothermal vent fields found at mid-ocean ridges emit hydrothermal fluids that disperse as neutrally buoyant plumes. From these fluids seafloor massive sulfides (SMS) deposits are formed, which are ...being explored as possible new mining sites for (trace) metals and rare earth elements (REEs). It has been suggested that during mining activities large amounts of suspended matter will appear in the water column due to excavation processes and discharge of mining waste from the surface vessel. Understanding how hydrothermal plumes can be characterised by means of geochemistry and microbiology as they spread away from their source and how they affect their surrounding environment may help in characterising the behaviour of the dilute distal part of chemically enriched mining plumes.
The ability to distinguish between different migratory behaviours (e.g., anadromy and potamodromy) in fish can provide important insights into the ecology, evolution, and conservation of many aquatic ...species. We present a simple stable carbon isotope (δ13C) approach for distinguishing between sockeye (anadromous ocean migrants) and kokanee (potamodromous freshwater residents), two migratory ecotypes of Oncorhynchus nerka (Salmonidae) that is applicable throughout most of their range across coastal regions of the North Pacific Ocean. Analyses of kokanee (n = 239) and sockeye (n = 417) from 87 sites spanning the North Pacific (Russia to California) show that anadromous and potamodromous ecotypes are broadly distinguishable on the basis of the δ13C values of their scale and bone collagen. We present three case studies demonstrating how this approach can address questions in archaeology, archival, and conservation research. Relative to conventional methods for determining migratory status, which typically apply chemical analyses to otoliths or involve genetic analyses of tissues, the δ13C approach outlined here has the benefit of being non-lethal (when applied to scales), cost-effective, widely available commercially, and should be much more broadly accessible for addressing archaeological questions since the recovery of otoliths at archaeological sites is rare.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine factors associated with baseline neurocognitive performance in HIV-infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy.
...Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores <-2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression.
The 292 participants had a median CD4 cell count of 536 cells/mm(3), 88% had an HIV viral load < or =400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was -0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not.
In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation.
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