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The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.
The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.
The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.
Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.
Children of parents with mood and psychotic disorders are at elevated risk for a range of behavioral and emotional problems. However, as the usual reporter of psychopathology in children is the parent, reports of early problems in children of parents with mood and psychotic disorders may be biased by the parents' own experience of mental illness and their mental state.
Independent observers rated psychopathology using the Test Observation Form in 378 children and youth between the ages of 4 and 24 (mean = 11.01, s.d. = 4.40) who had a parent with major depressive disorder, bipolar disorder, schizophrenia, or no history of mood and psychotic disorders.
Observed attentional problems were elevated in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia (effect sizes ranging between 0.31 and 0.56). Oppositional behavior and language/thought problems showed variable degrees of elevation (effect sizes 0.17 to 0.57) across the three high-risk groups, with the greatest difficulties observed in offspring of parents with bipolar disorder. Observed anxiety was increased in offspring of parents with major depressive disorder and bipolar disorder (effect sizes 0.19 and 0.25 respectively) but not in offspring of parents with schizophrenia.
Our results suggest that externalizing problems and cognitive and language difficulties may represent a general manifestation of familial risk for mood and psychotic disorders, while anxiety may be a specific marker of liability for mood disorders. Observer assessment may improve early identification of risk and selection of youth who may benefit from targeted prevention.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a disease continuum with common genetic causes and molecular pathology. We recently identified mutations in the T-cell restricted intracellular antigen-1 (TIA1) protein as a cause of ALS +/− FTD. TIA1 is an RNA-binding protein containing a low complexity domain (LCD) that promotes the assembly of membrane-less organelles, such as stress granules (SG). Whole exome sequencing of two family members with fALS/FTD revealed a novel missense mutation in the TIA1 LCD (P362L). Subsequent screening identified five more TIA1 mutations in six additional ALS patients, but none in controls. All mutation carriers presented with weakness, behavioral abnormalities or language impairments and had a final diagnosis of ALS +/− FTD. Autopsy on five TIA1 mutation carriers showed widespread neurodegeneration with TDP-43 pathology. Round eosinophilic inclusions in lower motor neurons were a consistent feature. Cellular assays revealed abnormal SG dynamics in the presence of TIA1 mutations. In summary, missense mutations in the LCD of TIA1 are a newly recognized cause of ALS/FTD with TDP-43 pathology and strengthen the role of RNA metabolism in the pathogenesis in this disease.
Psychotic symptoms are common in children and adolescents and may be early manifestations of liability to severe mental illness (SMI), including schizophrenia. SMI and psychotic symptoms are associated with impairment in executive functions. However, previous studies have not differentiated between ‘cold’ and ‘hot’ executive functions. We hypothesized that the propensity for psychotic symptoms is specifically associated with impairment in ‘hot’ executive functions, such as decision-making in the context of uncertain rewards and losses.
In a cohort of 156 youth (mean age 12.5, range 7–24 years) enriched for familial risk of SMI, we measured cold and hot executive functions with the spatial working memory (SWM) task (total errors) and the Cambridge Gambling Task (decision-making), respectively. We assessed psychotic symptoms using the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia interview, Structured Interview for Prodromal Syndromes, Funny Feelings, and Schizophrenia Proneness Instrument – Child and Youth version.
In total 69 (44.23%) youth reported psychotic symptoms on one or more assessments. Cold executive functioning, indexed with SWM errors, was not significantly related to psychotic symptoms [odds ratio (OR) 1.36, 95% confidence interval (CI) 0.85–2.17, p = 0.204). Poor hot executive functioning, indexed as decision-making score, was associated with psychotic symptoms after adjustment for age, sex and familial clustering (OR 2.37, 95% CI 1.25–4.50, p = 0.008). The association between worse hot executive functions and psychotic symptoms remained significant in sensitivity analyses controlling for general cognitive ability and cold executive functions.
Impaired hot executive functions may be an indicator of risk and a target for pre-emptive early interventions in youth.
Bentonite is one of the more safety-critical components of the engineered barrier system in the disposal concepts developed for many types of radioactive waste. It is used due to its favourable properties (including plasticity, swelling capacity, colloid filtration, low hydraulic conductivity, high retardation of key radionuclides) and its stability in relevant geological environments. However, bentonite is unstable under alkaline conditions and this has driven interest in low-alkali cements (leachate pH of 10–11). To build a robust safety case, it is important to have supporting natural analogue data to confirm understanding of the likely long-term performance of bentonite. In Cyprus, the presence of natural bentonite in close proximity to natural alkaline groundwaters permits the zones of potential bentonite/alkaline water reaction to be studied as an analogy of the potential reaction zones in the repository. Here, the results indicate minimal volumetric reaction of bentonite, with production of a palygorskite secondary phase.
To determine the frequency of multiple pathology [Alzheimer Disease (AD) plus Vascular Dementia and/or Dementia with Lewy Bodies] in patients enrolled in clinical trials of AD therapy, and to compare the cognitive and functional assessments between patients with pure AD and AD with multiple pathology.
We conducted a retrospective analysis of patients with a clinical diagnosis of AD who were enrolled in AD therapy clinical trials and subsequently received an autopsy for confirmation of their diagnosis from 2000 to 2009. Performance on cognitive screening tests, namely Modified Mini Mental state (3MS) exam, Mini Mental state Exam (MMSE) and Functional Rating Scale (FRS) were compared between patients with pure AD and multiple pathology.
Autopsy reports were available for 16/47 (34%) of deceased patients. Of these 16 patients, 5 (31%) had pure AD pathology, 10 (63%) had AD with other pathology, and 1 (6%) had non-AD pathology. Compared to patients with pure AD, patients with AD mixed with other pathology had poorer baseline FRS in problem-solving (p<0.01) and community affairs (p<0.02).
While the strict enrollment criteria for clinical trials identified the presence of AD pathology in the majority of cases (15/16), multiple pathology was more common than pure AD in our series of autopsied patients. Premortem biomarkers that can distinguish between pure AD and AD with multiple pathology will be beneficial in future clinical trials and dementia patient management.
It was hypothesized that exposure of the fetus to adverse conditions in utero due to either maternal constraint or nutrition may result in developmental adaptations altering metabolism and postnatal growth of the offspring. Heavy (H) and light (L) Romney dams (G0) were allocated to ad libitum (A) or maintenance (M) nutritional regimens, from day 21–day 140 of pregnancy. Female twin-born offspring (G1) born to the dams in the four treatment groups will be referred to as HA-ewes, LA-ewes, HM-ewes and LM-ewes. At 16 months of age, offspring were catheterized and given intravenous insulin tolerance test (ITT), glucose tolerance test (GTT) and epinephrine tolerance test challenges to assess their glucose and fat metabolism in relation to their birth weight and postnatal growth. In HA-ewes, the regression coefficients of growth rates prior to puberty on insulin and glucose curves in response to GTT (InsAUCGTT) and ITT (GluAUCITT), respectively, were different from 0 (P < 0.05) and were different from the regression coefficients of HM-ewes. This may indicate that HA-ewes may have showed puberty-related insulin resistance at 16 months of age with increasing growth rates prior to puberty compared to HM- or LM-ewes. In HM-ewes, the regression coefficients of growth rates after puberty on InsAUCGTT and GluAUCITT were different from 0 (P < 0.05) and were different from those of HA-ewes. These results may indicate that offspring born to heavy dams fed maintenance during pregnancy and with greater postnatal growth rates after puberty could develop glucose intolerance and insulin resistance in later life.
Strains of Candida albicans can be differentiated by the morphological features of streak colonies developed on malt agar. A morphotyping system is proposed, where numerical codes are assigned primarily on the basis of the nature and extent of marginal fringing and the surface topography of the streak colony. The system allows ready differentiation to be made of morphotypcs, requires no specialized equipment or expertise and provides a simple and reproducible means for epidemiological studies of candida and candidosis.
Insulin plays an important role in regulating the partitioning of nutrients to the mammary gland, particularly in lactating ruminants fed concentrate-based diets. There is evidence that the nutritional status of the animals might also affect their response to insulin. This is largely untested in early lactating ruminants fed fresh forage. To investigate nutritional effects on insulin response, 12 lactating sheep, housed indoors, were allocated to one of two treatment groups (hyperinsulinaemic euglycaemic clamp (HEC) or control) in a randomised block design and fed perennial ryegrass (Lolium perenne)/white clover (Trifolium repens) pasture. Mammary amino acid (AA) net uptake from plasma and utilisation for milk protein synthesis was measured during the 4th day of the HEC using arterio–venous concentration differences, and 1-13C-leucine was used to estimate whole body and mammary gland leucine kinetics. There was no change in feed intake, milk protein output and mammary blood flow during the HEC (P > 0.1). The HEC decreased (P < 0.1) the arterial concentrations of all essential AA (EAA) except histidine. The mammary net uptake of some EAA (isoleucine, leucine, methionine and phenylalanine) was reduced by the HEC (P < 0.1). Leucine oxidation in the mammary gland was not altered during the HEC (P > 0.1) but mammary protein synthesis was reduced by the HEC (P < 0.05). These results show that sheep mammary gland can adapt to changing AA precursor supply to maintain milk protein production during early lactation, when fed fresh forage. How this occurs remains unclear, and this area deserves further study.
Non-diabetic individuals who are non-secretors of blood group antigens are prone to superficial infections by Candida albicans. In this study, 216 patients with diabetes mellitus who were denture wearers were examined for the presence or absence of denture stomatitis. There was an overall trend for non-secretors to be prone to denture stomatitis compared with secretors. Stepwise linear discriminant analysis was used to dissect the contribution of secretor status and other variables to the development of the disease. Secretor status was found to be a contributory factor among patients with non-insulin dependent diabetes but not among those with insulin-dependent diabetes. The possible reasons for this are discussed.
The mechanisms by which coatings develop on weathered grain surfaces, and their potential impact on rates of fluid-mineral interaction, have been investigated by examining feldspars from a 1.1 ky old soil in the Glen Feshie chronosequence, Scottish highlands. Using the focused ion beam technique, electron-transparent foils for characterization by transmission electron microscopy were cut from selected parts of grain surfaces. Some parts were bare whereas others had accumulations, a few micrometres thick, of weathering products, often mixed with mineral and microbial debris. Feldspar exposed at bare grain surfaces is crystalline throughout and so there is no evidence for the presence of the amorphous ‘leached layers’ that typically form in acid-dissolution experiments and have been described from some natural weathering contexts. The weathering products comprise sub-urn thick crystallites of an Fe-K aluminosilicate, probably smectite, that have grown within an amorphous and probably organic-rich matrix. There is also evidence for crystallization of clays having been mediated by fungal hyphae. Coatings formed within Glen Feshie soils after ∼1.1 ky are insufficiently continuous or impermeable to slow rates of fluid-feldspar reactions, but provide valuable insights into the complex weathering microenvironments on debris and microbe-covered mineral surfaces.
Endoscopic CO2 laser excision for T1a glottic cancer is a recognized treatment modality producing equivalent disease-free and voice results to external beam radiotherapy. On reviewing a series of 15 patients who had undergone endoscopic resection of a T1a glottic squamous cancer, it was noted that five patients had negative excisional pathology following the initial biopsy of an invasive squamous carcinoma. The histopathology of each patient’s resected specimen was reviewed by a second pathologist who confirmed the accuracy of the results in all cases. We conclude that a significant number of early squamous carcinomas of the glottis present with very small localized, minimally invasive disease and that a proportion may be treated by biopsy alone.
C. Caroline Blackwell, Discipline of Immunology and Microbiology and Hunter Immunology Unit, University of Newcastle, Newcastle, Australia; Institute for Scientific Evaluation of Naturopathy, University of Cologne, Cologne, Germany,
Donald M. Weir, Department of Medical Microbiology, The Medical School, University of Edinburgh,
Abdulhamid M. Alkout, Department of Medical Microbiology, The Medical School, University of Edinburgh,
Omar R. Elahmer, Department of Medical Microbiology, The Medical School, University of Edinburgh,
Doris A. C. MacKenzie, Department of Medical Microbiology, The Medical School, University of Edinburgh,
Valerie S. James, Department of Medical Microbiology, The Medical School, University of Edinburgh,
J. Matthias Braun, Department of Medical Microbiology, The Medical School, University of Edinburgh; Institute for Scientific Evaluation of Naturopathy, University of Cologne, Cologne, Germany,
Osama M. Almadani, Department of Medical Microbiology, The Medical School University of Edinburgh; Forensic Medicine Unit, Edinburgh, Scotland, United Kingdom,
Anthony Busuttil, Forensic Medicine Unit, The Medical School University of Edinburgh, Edinburgh, Scotland, United Kingdom
The first observations on associations between blood groups and infectious diseases were made in the 1950s, but the underlying mechanisms were not elucidated for many years. This could have been due to limited explanations for the epidemiological findings or to conflicting reports of associations between different blood groups with the same disease. An example of the latter is the large numbers of papers on Helicobacter pylori and ABO or Lewis blood groups/secretor status during the past few years which have reported inconsistent or conflicting results. Because determination of blood groups is a relatively simple and inexpensive procedure, many investigators have used it for quick “simple” studies without consideration of possible confounding factors. For all studies on blood groups and infection, the following points (gained with the experience of hindsight) need to be considered in planning or assessment of surveys:
The disease or organism under investigation needs to be clearly defined. Severity of the symptoms should be also be considered, e.g., differentiation of cases of Escherichia coli O157 infection between patients with uncomplicated diarrhoeal disease and those that develop haemolytic uraemic syndrome (HUS) (Blackwell et al., 2002).
It should be made clear that the investigation examined an outbreak or defined epidemic due to a particular strain in contrast to sporadic cases which could be due to strains with different antigenic characteristics or virulence factors.
Different populations express different quantities of antigens such as H, Lewisa, or Lewisb.
Secondary copper deficiency in ruminant animals is induced by high dietary levels of molybdenum (Mo), iron (Fe) or sulphur (S). Within the rumen, sulphur reacts with Mo to form a series of thiomolybdate molecules (TM) which may chelate copper. This reduces copper absorption or if TM is absorbed, inhibits copper metallo-enzyme activities. Parental administration of TM has resulted in an increase in Cu to the brain and an increase in Mo to the pituitaries (Haywood et al., 1998). This redistribution may alter neurological, endocrine and reproductive function. However, there are no reports on effects of endogenously produced TM on brain or pituitary trace element accumulation. The objective of this study was to determine the effect of dietary Mo or Fe on copper status and mineral retention in the pituitary gland and ovary of growing lambs.
Investigations on microscopic and photovoltaic properties of polyfluorene blends are presented here. The length scale of lateral phase separation is manipulated by control of solvent evaporation conditions. Photoluminescence efficiency measurements show that charge transfer is more effective in blends phase separated on the nanometer scale. Vertically segregated structures are obtained by a combination of solution viscosity and spin coating conditions. The external quantum efficiency of photovoltaic devices fabricated with vertically segregated blend is found to be 4 times higher than that of devices made with laterally segregated blends.
We report on the luminescence properties of Er doped GaN grown prepared by metalorganic molecular beam epitaxy (MOMBE) and solid-source molecular beam epitaxy (SSMBE) on Si substrates. Both types of samples emitted characteristic 1.54 µm PL resulting from the intra-4f Er3+ transition 4I13/2→4I15/2. Under below-gap excitation the samples exhibited very similar 1.54 µm PL intensities. On the contrary, under above-gap excitation GaN: Er (SSMBE) showed ∼80 times more intense 1.54 µm PL than GaN: Er (MOMBE). In addition, GaN: Er (SSMBE) also emitted intense green luminescence at 537 nm and 558 nm, which was not observed from GaN: Er (MOMBE). The average lifetime of the green PL was determined to be 10.8 µs at 15 K and 5.5 µs at room temperature. A preliminary lifetime analysis suggests that the decrease in lifetime is mainly due to the strong thermalization between the 2H11/2 and 4S3/2 excited states. Nonradiative decay processes are expected to only weakly affect the green luminescence.
The effect of selective vagotomy of the abomasum, pylorus, duodenum and liver on insulin release during the cephalic phase of digestion was investigated in wethers and lactating ewes. Electrical stimulation of the cervical vagus nerves was carried out to test the completeness of the vagotomies performed. In experiment 1, using wethers, the abomasal, pyloric and duodenal branches (ADV; n = 7) or the hepatic, abomasal, pyloric and duodenal branches (HADV; n = 10) of the ventral and/or dorsal vagus nerves were cut; a third group of wethers underwent sham-operation (SO; n = 8). In experiment 2, vagotomy (ADV; n = 5) or sham-operations (SO; n = 5) were carried out in lactating ewes. Jugular blood was drawn before and after presentation of food for glucose and insulin determination (experiments 1 and 2) or before, during and after the electrical stimulation of the peripheral ends of the cut cervical vagus nerves in randomly selected lactating ewes (experiment 3: ADV = 3, SO = 3) and wethers (experiment 4: ADV = 4, HADV = 4, SO = 4), for determination of insulin only. Presentation of food caused an immediate and significant (P < 0.05) rise in plasma insulin levels in SO animals compared with ADV or HADV wethers (experiment 1) or ADV ewes (experiment 2) without any significant change in blood glucose concentrations. In comparison with the SO group the baseline-corrected areas under the insulin response curve were significantly (P < 0.05) smaller for the respective vagotomized groups for periods 1-2, 2-4 and 4-6 min (experiment 1) and 1-2 and 2-4 min (experiment 2) after presentation of food. Total area under the response curve for 10 min was significantly (P < 0.05) lower (experiment 1) and tended (P < 0.10) to be lower (experiment 2) for the vagotomized groups compared with that of the control groups. Direct electrical stimulation of the cervical vagus nerves raised plasma insulin concentrations to significantly (P < 0.05) higher levels in the SO ewes but not in the ADV ewes (experiment 3). It was also evident that in experiment 1, HADV did not have any additive effect over that achieved by ADV alone. These results indicate that the vagal innervation of the gut mediates insulin release during the cephalic phase of feeding in sheep. It is concluded that insulin secretion from the pancreatic β-cells in response to either food-related reflex activation of the vagal nuclei in the hypothalamus or direct cervical vagus nerve stimulation is mediated through the vagal efferent fibres carried in the abomasal, pyloric and duodenal branches of the vagus nerves in sheep.
The III-V nitride semiconductors appear to be excellent host materials for optical device applications involving thin films doped with rare earth atoms. In particular, GaN epilayers doped with Er ions have shown a highly reduced thermal quenching of the Er luminescence intensity from cryogenic to elevated temperatures. The remarkable thermal stability of the light emission may be due to the large energy bandgap of the material, as well as to the optical inactivity of material defects in the GaN film. In this paper we present recent developments concerning the luminescence characteristics of Er-doped GaN thins films. We have used two methods for doping GaN films with Er ions, ion implantation and in-situ incorporation during gas source metal-organic molecular beam epitaxy (MOMBE). Bandedge (at ∼ 0.34 µm) and infrared (at ∼ 1.54 µm) photoluminescence (PL) spectra have been measured for both types of Er-doped GaN films. Considerably different emission spectra have been observed depending upon the incorporation method and the heat treatment procedure. In situ Er-doped GaN layers have been processed into hybrid light emitting devices and emission spectra at 1.54 µm have been measured.