Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported.
The present study examined the relationships between different types of social and cognitive activities and different types of episodic and semantic memory. A total of 794 adult men and women from five age cohorts (aged 65-85 at baseline), participating in the longitudinal Betula project on ageing, memory, and health, were included in the study. The participants were studied over 10 years (1995-2005) in three waves. Recognition and recall were used as episodic memory tasks, and knowledge and verbal fluency as semantic memory tasks. The results, after controlling for age, gender, education, and some diseases, including heart disease and hypertension, as covariates, showed unidirectional effects of social activity on episodic memory on all test occasions (? = .10). Also, episodic memory predicted change in cognitive activity for all test waves (? = .21-.22). Findings suggest that social activity can be seen as protective factor against memory decline. It also seems that episodic memory performance is a predictor of cognitive activity in old people. However, the opposite direction does not hold true.
This study compared serum metabolites of demented patients (Alzheimer's disease and vascular dementia) and controls, and explored serum metabolite profiles of nondemented individuals 5 years preceding the diagnosis.
Cross-sectional neuroimaging studies suggest that hippocampal and prefrontal cortex functions underlie individual differences in memory ability in older individuals, but it is unclear how individual differences in cognitive ability in youth contribute to cognitive and neuroimaging measures in older age. Here, we investigated the relative influences of midlife memory ability and age-related memory change on memory-related BOLD-signal variability at one time point, using a sample from a longitudinal population-based aging study (N = 203, aged 55-80 years). Hierarchical regression analyses showed that midlife memory ability, assessed 15-20 years earlier, explained at least as much variance as memory change in clusters in the left inferior prefrontal cortex and the bilateral hippocampus, during memory encoding. Furthermore, memory change estimates demonstrated higher sensitivity than current memory levels in identifying distinct frontal regions where activity was selectively related to age-related memory change, as opposed to midlife memory. These findings highlight challenges in interpreting individual differences in neurocognitive measures as age-related changes in the absence of longitudinal data and also demonstrate the improved sensitivity of longitudinal measures.
The objective of this study was to evaluate total antioxidant capacity (TAC), total phenolic content (TPH), and the identification of anthocyanidin and polyphenolic compounds in 13 colored potatoes collected from the Andean region of Bolivia, and understand how the chemical composition correlated with the botanical classification and molecular characterization of genes, ans (anthocyanidin synthase) and stan1 (Solanum tuberosum anthocyanidin synthase), associated with the synthesis of anthocyanidins. The results show the existence of a limited correlation between botanical classification, based on morphological identification and polyphenol composition. No association between genetic grouping of the ans and stan genes and botanical classification was found. However, it was possible to identify a correlation between the ans gene clades and the levels of anthocyanidins as well as of other polyphenols. Thus, this result confirms the concept that potato color can be used in the search for high polyphenol potato cultivars.
A subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS)-defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q).
There is a gap between prescribed asthma medication and diagnosed asthma in children and adolescents. However, few studies have explored this issue among adults, where asthma medication is also used for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to examine the relationship between prescribing of medications indicated for asthma and COPD and the recorded diagnosis for these conditions.
Age-related changes in the default-mode network (DMN) have been identified in prior cross-sectional functional magnetic resonance imaging studies. Here, we investigated longitudinal change in DMN activity and connectivity. Cognitively intact participants (aged 49-79 years at baseline) were scanned twice, with a 6-year interval, while performing an episodic memory task interleaved with a passive control condition. Longitudinal analyses showed that the DMN (control condition > memory task) could be reliably identified at both baseline and follow-up. Differences in the magnitude of task-induced deactivation in posterior DMN regions were observed between baseline and follow-up indicating reduced deactivation in these regions with increasing age. Although no overall longitudinal changes in within-network connectivity were found across the whole sample, individual differences in memory change correlated with change in connectivity. Thus, our results show stability of whole-brain DMN topology and functional connectivity over time in healthy older adults, whereas within-region DMN analyses show reduced deactivation between baseline and follow-up. The current findings provide novel insights into DMN functioning that may assist in identifying brain changes in patient populations, as well as characterizing factors that distinguish between normal and pathologic aging.
Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
To characterize ovarian morphology and perfusion by magnetic resonance imaging (MRI) in women with and without polycystic ovary syndrome (PCOS) and to investigate associations with antimüllerian hormone (AMH), free T, and glucose disposal rate (GDR).
The rs1344706 single nucleotide polymorphism within intron 2 of the ZNF804A gene is strongly associated with schizophrenia and bipolar disorder. This variant has also been associated in some studies with a range of cognitive and neuroimaging phenotypes, but several studies have reported no effect on the same phenotypes in other samples. Here, we genotyped 670 healthy adult Norwegian subjects and 1753 healthy adult Swedish subjects for rs1344706, and tested for associations with cognitive phenotypes including general intellectual abilities, memory functions and cognitive inhibition. We also tested whether rs1344706 is associated with white matter microstructural properties using diffusion tensor imaging (DTI) data from 250 to 340 of the Norwegian and Swedish subjects, respectively. Whole-brain voxel-wise statistical modeling of the effect of the ZNF804A variant on two DTI indices, fractional anisotropy (FA) and radial diffusivity (RD), was performed using tract-based spatial statistics (TBSS), and commonly reported effect sizes were calculated within several large-scale white matter pathways based on neuroanatomical atlases. No significant associations were found between rs1344706 and the cognitive traits or white matter microstructure. We conclude that the rs1344706 SNP has no significant effect on these phenotypes in our two reasonably powered samples.
We investigated the individual and combined effects of enactment and testing on memory for action phrases to address whether both study techniques commonly promote item-specific processing. Participants (N = 112) were divided into four groups (n = 28). They either exclusively studied 36 action phrases (e.g., "lift the glass") or both studied and cued-recalled them in four trials. During study trials participants encoded the action phrases either by motorically performing them, or by reading them aloud, and they took final verb-cued recall tests over 18-min and 1-week retention intervals. A testing effect was demonstrated for action phrases, however, only when they were verbally encoded, and not when they were enacted. Similarly, enactive (relative to verbal) encoding reduced the rate of forgetting, but only when the action phrases were exclusively studied, and not when they were also tested. These less-than-additive effects of enactment and testing on the rate of forgetting, as well as on long-term retention, support the notion that both study techniques effectively promote item-specific processing that can only be marginally increased further by combining them.
We examined whether conversion to dementia can be predicted by self-reported olfactory impairment and/or by an inability to identify odors. Common forms of dementia involve an impaired sense of smell, and poor olfactory performance predicts cognitive decline among the elderly. We followed a sample of 1529 participants, who were within a normal range of overall cognitive function at baseline, over a 10-year period during which 159 were classified as having a dementia disorder. Dementia conversion was predicted from demographic variables, Mini-Mental State Examination score, and olfactory assessments. Self-reported olfactory impairment emerged as an independent predictor of dementia. After adjusting for effects of other predictors, individuals who rated their olfactory sensitivity as "worse than normal" were more likely to convert to dementia than those who reported normal olfactory sensitivity (odds ratio [OR] = 2.17; 95% confidence interval [CI] [1.40, 3.37]). Additionally, low scores on an odor identification test also predicted conversion to dementia (OR per 1 point increase = 0.89; 95% CI [0.81, 0.98]), but these two effects were additive. We suggest that assessing subjective olfactory complaints might supplement other assessments when evaluating the risk of conversion to dementia. Future studies should investigate which combination of olfactory assessments is most useful in predicting dementia conversion.
This study examines the association between marital and parental status and their individual and combined effect on risk of dementia diseases in a population-based longitudinal study while controlling for a range of potential confounders, including social networks and exposure to stressful negative life events.
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-? precursor protein (A?PP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.
Knowledge regarding unbound concentrations is of vital importance when exploring the PK and PD of a drug. The accurate and reproducible determination of plasma protein binding and unbound concentrations for a compound/drug is a serious challenge for the bioanalytical laboratory. When the drug is in equilibrium with the binding protein(s), this equilibrium will shift when physiological conditions are not met. Furthermore, the true unbound fraction/concentration is unknown, and there are numerous publications in the scientific literature reporting and discussing data that have been produced without sufficient control of the parameters influencing the equilibrium. In this Review, different parameters affecting the equilibrium and analysis are discussed, together with suggestions on how to control these parameters in order to produce as trustworthy results for unbound concentrations/fractions as possible.
The dorsolateral pFC (DLPFC) is a key region for working memory. It has been proposed that the DLPFC is dynamically recruited depending on task demands. By this view, high DLPFC recruitment for low-demanding tasks along with weak DLPFC upregulation at higher task demands reflects low efficiency. Here, the fMRI BOLD signal during working memory maintenance and manipulation was examined in relation to aging and catechol-O-methyltransferase (COMT) Val(158)Met status in a large representative sample (n = 287). The efficiency hypothesis predicts a weaker DLPFC response during manipulation, along with a stronger response during maintenance for older adults and COMT val carriers compared with younger adults and COMT met carriers. Consistent with the hypothesis, younger adults and met carriers showed maximal DLPFC BOLD response during manipulation, whereas older adults and val carriers displayed elevated DLPFC responses during the less demanding maintenance condition. The observed inverted relations support a link between dopamine and DLPFC efficiency.
leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging.
ABSTRACT Background: The impact of stressful life events as a risk factor of dementia diseases is inconclusive. We sought to determine whether stressful negative life events are associated with incidental dementia in a population-based study with long-term follow-up. We also tested the hypothesis that the occurrence of positive life events could mitigate or overcome the possible adverse effects of negative life events on dementia conversion. Methods: The study involved 2,462 dementia-free participants aged 55 years and older. Information on life events was ascertained at baseline from a comprehensive Life Event Inventory, which included 56 questions about specific life events. For each life event, the emotional impact (both positive and negative) and emotional adjustment were asked for. Results: During follow-up, 423 participants developed dementia; of these, 240 developed Alzheimers disease (AD). Cox regression analysis showed no association between the total number of negative life events and the incidence of dementia when adjusted solely for age and gender (hazard ratio = 0.97, 95% CI = 0.92-1.02), or with multiple adjustments for a range of covariates (hazard ratio = 0.96, 95% CI = 0.91-1.01). Similarly, neither emotional impact nor emotional adjustment to these life events was associated with incident dementia. A separate analysis of AD did not alter the results. Conclusions: The result of this population-based study finds no association between negative or positive life events and dementia. Accordingly, our results reject the hypothesis that stressful life events trigger the onset of dementia diseases.
Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ?4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ?4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF.
Complex species-specific, developmental- and tissue-dependent mechanisms regulate alternative splicing of tau, thereby diversifying tau protein synthesis. The functional role of alternative splicing of tau e.g. exon 10 has never been examined in vivo, although genetic studies suggest that it is important to neurodegenerative disease.
Impairment of the central serotonin system in Parkinsons disease (PD) has been shown postmortem and in vivo with positron emission tomography (PET). The aim of this PET study was to examine and compare the availability of the 5-hydroxytryptamine (5-HT)1B-receptor subtype in patients with PD and age-matched control subjects. Twelve control subjects and 12 PD patients were examined with PET using the 5-HT1B-radioligand [(11)C]AZ10419369. In PD patients, 5-HT1B-receptor availability in the right orbitofrontal cortex was lower than in control subjects. A statistically significant negative correlation between 5-HT1B-receptor availability and age was obtained for the right temporal cortex in control subjects and for the right midbrain and left parahippocampal gyrus in PD patients. The lower regional 5-HT1B-receptor availability is in line with previous studies showing a decrease of serotonin imaging markers in PD and corroborates a role of the serotonin system in the pathophysiology of PD. The demonstrated age effect on 5-HT1B receptors suggest a physiologic and PD-related decline of serotonin function, indicating the importance of controlling for age in clinical studies.
The Arctic mutation (p.E693G/p.E22G)fs within the ?-amyloid (A?) region of the ?-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimers disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.
Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder. Ovarian changes in PCOS women are well characterized by ultrasound. However, the ovarian pathophysiology is not fully understood. The aim of this study was to characterize the expression, in both the central ovarian stroma and in granulosa cells (GCs), of a number of genes, including several inflammation-related genes, which have been hypothesized to be involved in the pathophysiology of PCOS. Biopsies of the central ovarian stroma were obtained from PCOS women (Rotterdam criteria) and from normally ovulating women in follicular phase. GCs were retrieved from PCOS-women and non-PCOS women, undergoing in vitro maturation. The expressions of 57 genes were analyzed by quantitative-PCR using a low-density-gene array. The main outcome measures were over-expression or under-expression of the specific genes. The results showed that in the central stroma of PCOS ovaries, five inflammation-related genes (CCL2, IL1R1, IL8, NOS2, TIMP1), the leukocyte marker CD45, the inflammation-related transcription factor RUNX2 and the growth factor AREG were under-expressed. The growth factor DUSP12 and the coagulation factor TFPI2 were over-expressed. In the GC of PCOS, all of the differentially expressed genes were over-expressed; the inflammation-related IL1B, IL8, LIF, NOS2 and PTGS2, the coagulation-related F3 and THBS1, the growth factors BMP6 and DUSP12, the permeability-related AQ3 and the growth-arrest-related GADD45A. In conclusion, the results indicate major alterations in the local ovarian immune system of PCOS ovaries. This may have implications for the PCOS-related defects in the inflammation-like ovulatory process and for the susceptibility to acquire the inflammatory state of ovarian hyperstimulation syndrome.
Objectives.The aim of this study was to investigate whether leisure activity is associated with incident dementia in an older sample.Method.We examined a sample of 1,475 elderly (? 65 years) who were dementia free at baseline over a follow-up period of up to 15 years. In addition to analyses involving the total time period, separate analyses of three time periods were performed, 1-5, 6-10, and 11-15 years, following baseline measurement of leisure activity. RESULTS: After controlling for a variety of potential confounders, analyses of data for the total time period revealed that higher levels of "Total activity" and "Social activity," but not "Mental activity," were associated with decreased risk of dementia. However, analyses of the separate time periods showed that this association was only significant in the first time period, 1-5 years after baseline.Discussion.The results from this study provide little support for the hypothesis that frequent engagement in leisure activities among elderly serve to protect against dementia diseases across a longer time frame. The finding of a relationship for the first time period, 1-5 years after baseline, could indicate short-term protective effects but could also reflect reverse causality.
Some elderly appear to resist age-related decline in cognitive functions, but the neural correlates of successful cognitive aging are not well known. Here, older human participants from a longitudinal study were classified as successful or average relative to the mean attrition-corrected cognitive development across 15-20 years in a population-based sample (n = 1561). Fifty-one successful elderly and 51 age-matched average elderly (mean age: 68.8 years) underwent functional magnetic resonance imaging while performing an episodic memory face-name paired-associates task. Successful older participants had higher BOLD signal during encoding than average participants, notably in the bilateral PFC and the left hippocampus (HC). The HC activation of the average, but not the successful, older group was lower than that of a young reference group (n = 45, mean age: 35.3 years). HC activation was correlated with task performance, thus likely contributing to the superior memory performance of successful older participants. The frontal BOLD response pattern might reflect individual differences present from young age. Additional analyses confirmed that both the initial cognitive level and the slope of cognitive change across the longitudinal measurement period contributed to the observed group differences in BOLD signal. Further, the differences between the older groups could not be accounted for by differences in brain structure. The current results suggest that one mechanism behind successful cognitive aging might be preservation of HC function combined with a high frontal responsivity. These findings highlight sources for heterogeneity in cognitive aging and may hold useful information for cognitive intervention studies.
Transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid-? precursor protein (A?PP) develop amyloid-beta (A?) deposits in the brain that resemble Alzheimers disease neuropathology. Earlier studies of this model have documented morphologic features in selected parts of the cerebral cortex and hippocampus, but the spatial distribution within the brain and variance of A? deposits within a group of tg-ArcSwe mice is unknown. Using immunohistochemistry and brainwide microscopic analysis of 12-month-old tg-ArcSwe mice, we show that A?x-40 plaque deposits are consistently present in the cerebral cortex, hippocampus, and thalamus and variably present in other regions. Using quantitative image analysis, we demonstrated that the average A? burden in the cortex and hippocampus is similar across animals, with coefficients of variance of 22% and 25%, respectively. This indicates that interventional studies of tg-ArcSwe mice are feasible using region-of-interest comparisons and that interventional trials require larger group sizes than commonly used. We also present an online atlas providing access to images showing the detailed characteristics and spatial distribution patterns of A?x-40 labeling.
Alzheimers disease (AD) is a disease of major public health significance, whose pathogenesis is strongly linked to the presence of fibrillar aggregates of amyloid-beta (A?) in the aging human brain. We exploited the transgenic (Tg)-ArcSwe mouse model for human AD to explore whether oxidative stress and the capacity to repair oxidative DNA damage via base excision repair (BER) are related to A? pathology in AD. Tg-ArcSwe mice express variants of A?, accumulating senile plaques at 4-6 months of age, and develop AD-like neuropathology as adult animals. The relative mRNA levels of genes encoding BER enzymes, including 8-oxoguanine glycosylase (OGG1), AP endonuclease 1 (APE1), polymerase ? (Pol?) and poly(ADP-ribose) polymerase 1 (PARP1), were quantified in various brain regions of 6 weeks, 4 months and 12 months old mice. The results show that OGG1 transcriptional expression was higher, and APE1 expression lower, in 4 months old Tg-ArcSwe than in wildtype (wt) mice. Furthermore, Pol? transcriptional expression was significantly lower in transgenic 12 months old mice than in wt. Transcriptional profiling also showed that BER repair capacity vary during the lifespan in Tg-ArcSwe and wt mice. The BER expression pattern in Tg-ArcSwe mice thus reflects responses to oxidative stress in vulnerable brain structures.
The relationship between mastication and cognitive function remains unclear, but both animal and experimental human studies suggest a possible causal relationship. In the present study it was hypothesized that natural teeth are of importance for hippocampus-based cognitive processes, such as episodic long-term memory. A population-based sample of 273 participants (55-80 yr of age; 145 women) was investigated in a cross-sectional study. The participants underwent health assessment, completed a battery of cognitive tests, and took part in an extensive clinical oral examination. The number of natural teeth contributed uniquely and significantly to explaining variance (3-4%) in performance on measures of episodic memory and semantic memory over and above individual differences in age, years of education, gender, occupation, living conditions, and medical history. The number of natural teeth did not have an influence on the performance of measures of working memory, visuospatial ability, or processing speed. Within the limitations of the current study, a small, but significant, relationship between episodic memory and number of natural teeth is evident.
Several judgment and decision-making tasks are assumed to involve memory functions, but significant knowledge gaps on the memory processes underlying these tasks remain. In a study on 568 adults between 25 and 80 years of age, hypotheses were tested on the specific relationships between individual differences in working memory, episodic memory, and semantic memory, respectively, and 6 main components of decision-making competence. In line with the hypotheses, working memory was positively related with the more cognitively demanding tasks (Resistance to Framing, Applying Decision Rules, and Under/Overconfidence), whereas episodic memory was positively associated with a more experience-based judgment task (Recognizing Social Norms). Furthermore, semantic memory was positively related with 2 more knowledge-based decision-making tasks (Consistency in Risk Perception and Resistance to Sunk Costs). Finally, the age-related decline observed in some of the decision-making tasks was (partially or totally) mediated by the age-related decline in working memory or episodic memory. These findings are discussed in relation to the functional roles fulfilled by different memory processes in judgment and decision-making tasks.
The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid.
The longitudinal effects of perceived stress on measures of memory and two other cognitive functions (word fluency, visuospatial ability) in a middle-aged sample (40-60 years, M age = 47.1 years, SD = 6.1 years; n = 192) were examined. A group describing themselves as stressed in general at baseline, and at follow-up measurement 5 and 10 years later (n = 96) was compared with a matched (age, sex) low-stress group (n = 96). The results revealed more depressive symptoms over time in the high-stress group. With regard to memory, a dissociation between subjective and objective measures was observed. Specifically, participants in the high-stress group rated their memory as worse over time as compared with controls, and reported a higher frequency of occurrence of everyday memory failures, effects partly independent of depressive symptoms. However, the groups did not differ in terms of objective episodic memory performance, word fluency or block design performance, with stable levels of performance over time regardless of perceived stress. The lack of effects of stress on cognitive performance is discussed in the light of factors such as stress level, age of the participants, and other individual difference factors.
The soluble proteins and protein aggregates in Belinda oats were characterized using asymmetric flow field-flow fractionation (AF4) coupled with online UV-vis spectroscopy and multiangle light-scattering detection (MALS). Fractions from the AF4 separation were collected and further characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The AF4 fractogram of the oat extracts revealed three peaks which were determined to be monomeric forms of soluble proteins, globulin aggregates, and ?-glucan, respectively. The early eluting monomeric proteins ranged in molar mass (MM) between 5 and 90 kg/mol and in hydrodynamic diameter (D h) from 1.6 to 13 nm. The MM at peak maximum of the globulin aggregate peak was found to be ?300 kg/mol and the D h was measured to be ?20 nm. SDS-PAGE of the collected fraction across this peak revealed two bands with MM of 37 and 27 kg/mol which correspond to the ? and ? subunits of globulin indicating the elution of globulin aggregates. A third peak at long retention time was determined to be ?-glucan through treatment of the oat extract with ?-glucanase and by injection of ?-glucan standards. The amount of soluble protein was measured to be 83.1?±?2.3 wt.%, and the amount of albumin proteins was measured to be 17.6?±?5.7 wt.% of the total protein in the oats. The results for Belinda oat extracts show that the AF4-MALS/UV platform is capable of characterizing the physicochemical properties such as MM and hydrodynamic size distribution of proteins and protein aggregates within a complicated food matrix environment and without the need to generate protein isolates.
Capillary microsampling (CMS) has recently been introduced as a response to the demands for more ethical use of laboratory animals according to the 3R principles. In CMS, an exact volume of the blood, plasma or other biofluid is collected in a capillary from which it is washed out, resulting in a diluted sample that can be handled using the existing equipment in the bioanalytical laboratory. CMS differs from traditional large volume sampling as the microsample is diluted before further handling and analysis, and reanalysis is performed using the diluted sample. This has some implications for the validation and this report is an attempt to clarify how to validate and use CMS methods in a regulatory environment. CMS also shows some distinct new opportunities: labile analytes can be immediately stabilized at sample collection and the addition of the internal standard to the whole sample can improve analytical performance. The experiences from 5 years use of CMS of plasma and blood for determination of drug exposure in animal studies are reviewed.
Cognitive complaints involving problems with concentration, memory, decision-making and thinking are relatively common in the work force. The sensitivity of both subjective and objective cognitive functioning to common psychiatric conditions, stress levels and to cognitive load makes it plausible that psychosocial working conditions play a role in cognitive complaints. Thus, this study aimed to test the associations between psychosocial work factors and cognitive complaints in nationally representative samples of the Swedish work force. Cross-sectional (n?=?9751) and prospective (n?=?3644; two time points two years apart) sequential multiple regression analyses were run, adjusting for general confounders, depressive- and sleeping problems. Additional prospective analyses were run adjusting for baseline cognitive complaints.
To develop a systems pharmacology model based on hormone physiology and pharmacokinetic-pharmacodynamic concepts describing the impact of thyroperoxidase (TPO) inhibition on thyroid hormone homeostasis in the dog and to predict drug-induced changes in thyroid hormones in humans.
Cognitive functioning is important for managing work and life in general. However, subjective cognitive complaints (SCC), involving perceived difficulties with concentration, memory, decision making, and clear thinking are common in the general and working population and can be coupled with both lowered well-being and work ability. However, the relation between SCC and cognitive functioning across the adult age-span, and in the work force, is not clear as few population-based studies have been conducted on non-elderly adults. Thus, the present study aimed to test the relation between SCC and executive cognitive functioning in a population-based sample of employees.
Typically, studies of cognitive advantages in bilinguals have been conducted previously by using executive and inhibitory tasks (e.g. Simon task) and applying cross-sectional designs. This study longitudinally investigated bilingual advantages on episodic memory recall, verbal letter and categorical fluency during the trajectory of life. Monolingual and bilingual participants (n=178) between 35-70 years at baseline were drawn from the Betula Prospective Cohort Study of aging, memory, and health. Results showed that bilinguals outperformed monolinguals at the first testing session and across time both in episodic memory recall and in letter fluency. No interaction with age was found indicating that the rate of change across ages was similar for bilinguals and monolinguals. As predicted and in line with studies applying cross-sectional designs, no advantages associated with bilingualism were found in the categorical fluency task. The results are discussed in the light of successful aging.
The dynamic nature of human working memory, the general-purpose system for processing continuous input, while keeping no longer externally available information active in the background, is well captured in immediate free recall of supraspan word-lists. Free recall tasks produce several benchmark memory phenomena, like the U-shaped serial position curve, reflecting enhanced memory for early and late list items. To account for empirical data, including primacy and recency as well as contiguity effects, we propose here a neurobiologically based neural network model that unifies short- and long-term forms of memory and challenges both the standard view of working memory as persistent activity and dual-store accounts of free recall. Rapidly expressed and volatile synaptic plasticity, modulated intrinsic excitability, and spike-frequency adaptation are suggested as key cellular mechanisms underlying working memory encoding, reactivation and recall. Recent findings on the synaptic and molecular mechanisms behind early LTP and on spiking activity during delayed-match-to-sample tasks support this view.
The present study examined the influences of marital status on different episodic and semantic memory tasks. A total of 1882 adult men and women participated in a longitudinal project (Betula) on memory, health and aging. The participants were grouped into two age cohorts, 35-60 and 65-85, and studied over a period of 5 years. Episodic memory tasks concerned recognition and recall, whereas semantic memory tasks concerned knowledge and fluency. The results showed, after controlling for education, some diseases, chronological age and leisure activity as covariates, that there were significant differences between married and single individuals in episodic memory, but not in semantic memory. Married people showed significantly better memory performances than singles in both subsystems of episodic memory, that is, recall and recognition. Also, the rate of decline in episodic memory was significantly larger for singles and widowed than other groups over the 5-year time period in both age groups. The findings demonstrate that the positive relation found between marriage and health can be extended to the relation between marriage and cognitive performance. This effect might be explained by the role played by cognitive stimulation in memory and cognition.
Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD.
By integrating behavioral measures and imaging data, previous investigations have explored the relationship between biological markers of aging and cognitive functions. Evidence from functional and structural neuroimaging has revealed that hippocampal volume and activation patterns in the medial temporal lobe (MTL) may predict cognitive performance in old age. Most past demonstrations of age-related differences in brain structure-function were based on cross-sectional comparisons. Here, the relationship between 6-year intraindividual change in functional magnetic resonance imaging (fMRI) signal and change in memory performance over 2 decades was examined. Correlations between intraindividual change in fMRI signal during episodic encoding and change in memory performance measured outside of scanning were used as an estimate for relating brain-behavior changes. The results revealed a positive relationship between activation change in the hippocampus (HC) and change in memory performance, reflecting reduced hippocampal activation in participants with declining performance. Using a similar analytic approach as for the functional data, we found that individuals with declining performance had reduced HC volume compared with individuals with intact performance. These observations provide a strong link between cognitive change in older adults and MTL structure and function and thus provide insights into brain correlates of individual variability in aging trajectories.
Several studies have linked the KIBRA rs17070145 T polymorphism to superior episodic memory in healthy humans. One study investigated the effect of KIBRA on brain activation patterns (Papassotiropoulos et al., 2006) and observed increased hippocampal activation in noncarriers of the T allele during retrieval. Noncarriers were interpreted to need more hippocampal activation to reach the same performance level as T carriers. Using large behavioral (N = 2230) and fMRI (N = 83) samples, we replicated the KIBRA effect on episodic memory performance, but found increased hippocampal activation in T carriers during episodic retrieval. There was no evidence of compensatory brain activation in noncarriers within the hippocampal region. In the main fMRI sample, T carriers performed better than noncarriers during scanning but, importantly, the difference in hippocampus activation remained after post hoc matching according to performance, sex, and age (N = 64). These findings link enhanced memory performance in KIBRA T allele carriers to elevated hippocampal functioning, rather than to neural compensation in noncarriers.
The Arctic (p. E693G) mutation in the amyloid-? precursor protein (A?PP) facilitates amyloid-? (A?) protofibril formation and generates clinical symptoms of Alzheimers disease (AD). Here, molecular details of A? in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with A?42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal A? deposits stained differently with mid-domain, N- and C-terminal A? antibodies. A? fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. A?wild-type and A?arctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated A?. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of A?1-40. The absence of plaques with cores of fibrillary A? might be due to the scarcity of full-length A?, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.
Numb regulates endocytosis in many metazoans, but the mechanism by which it functions is not completely understood. Here we report that the Caenorhabditis elegans Numb ortholog, NUM-1A, a regulator of endocytic recycling, binds the C isoform of transbilayer amphipath transporter-1 (TAT-1), a P4 family adenosine triphosphatase and putative aminophospholipid translocase that is required for proper endocytic trafficking. We demonstrate that TAT-1 is differentially spliced during development and that TAT-1C-specific splicing occurs in the intestine where NUM-1A is known to function. NUM-1A and TAT-1C colocalize in vivo. We have mapped the binding site to an NXXF motif in TAT-1C. This motif is not required for TAT-1C function but is required for NUM-1As ability to inhibit recycling. We demonstrate that num-1A and tat-1 defects are both suppressed by the loss of the activity of PSSY-1, a phosphatidylserine (PS) synthase. PS is mislocalized in intestinal cells with defects in tat-1 or num-1A function. We propose that NUM-1A inhibits recycling by inhibiting TAT-1Cs ability to translocate PS across the membranes of recycling endosomes.
In this article, the authors examined predictors of self-reported everyday memory failures using the Prospective and Retrospective Questionnaire (PRMQ; Smith, Della Sala, Logie, & Maylor, 2000) in a population-based sample of older adults (age range = 60-90 years; N = 250). The results showed that a higher frequency of reported failures was associated with lower scores on the personality dimension of self-directedness as assessed by the Temperament and Character Inventory (TCI; Cloninger, Dragan, Svrakic, & Przybeck, 1993) and more depressive symptoms on the Center for Epidemiological Studies Depression Scale (CES-D; Radloff, 1977). However, PRMQ scores showed no relationships with objective memory ability, as reflected by a series of retrospective memory measures and a measure of prospective memory. Neither were the PRMQ scales associated with general cognitive functioning as assessed by the Mini-Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1977). Taken together, the results indicate that within the older population, self-reported memory as assessed by the PRMQ may reflect mood-state and personality factors rather than individual differences in memory and cognitive ability.
Anaemia in low-risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony-stimulating factor (G-CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L.
This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ? 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ? 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621.
The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls.
Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31).
Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n=287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest, WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
In this paper we investigate the size, structure and scaling relationships in glycogen isolated from five different animal sources. For this purpose a versatile fractionation technique, asymmetrical flow field-flow fractionation (AsFlFFF), coupled to multi-angle light scattering, is utilized. For determination of the average degree of branching (1)H NMR is utilized. The results give a detailed insight into the physico-chemical properties of glycogen over the whole size distribution. The results show that glycogen is a hyper branched macromolecule with wide size distributions, and in some samples two major populations are clearly observed which most likely correspond to ?- and ?-particles of glycogen. The results also illustrates that glycogen is a polysaccharide showing rather diverse conformational properties, over the size distribution, depending on its origin and the extraction procedure. The ratio between root-mean-square radius and hydrodynamic radius varies depending of both sample origin the molar mass of the macromolecules, reflecting differences in conformation and scaling within the size distribution. Thus, a priori assumptions regarding the r(rms)/r(h) are difficult to make and r(rms)/r(h) based on average properties give an incomplete description of the properties. Furthermore, the results display the strength of the apparent density (as obtained from AsFlFFF-MALS-RI) as a characterization parameter for scaling in disperse macromolecules.
Polyphenolic substances, such as flavonoids, attract considerable interest due to their ability to act as antioxidants. The vast majority of studies published deal with the nutritional, biochemical, or chemical structure aspects of these substances while few reports exist on the physico-chemical properties as well as solution behavior of the substances. In this article we report on the precipitation kinetics of naringenin, quercetin, and rutin in pure water as well as in micellar solutions of Tween 80. The methods used are dynamic and static light scattering in conjunction with cryo transmission electron microscopy. The results show that the substances precipitate rapidly in pure water. In the presence of Tween 80 micelles, however, the flavonoids can become solubilized in the micelles, which can result in solutions which are stable for days. The results suggest that the extent of solubilization is related to the chemical structure of the flavonoids. This study illustrates that precipitation kinetics and the distribution of polyphenolic substances in solutions and dispersions are factors of importance, which should be taken into account when designing investigations and interpreting results.
Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU).
The transcription factors CCAAT/enhancer binding proteins (C/EBP) ?, ? and ? have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor ?B (NF-?B). In general, C/EBP? is down-regulated, whereas both C/EBP? and ? are up-regulated in response to inflammatory stimuli. In Alzheimers disease (AD) one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-? (A?) deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by A? deposits with the aim of defining new therapeutic targets.
In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.
Nanoimprint lithography (NIL) is a nonconventional lithographic technique that promises low-cost, high-throughput patterning of structures with sub-10 nm resolution. Contamination of nanoimprint stamps is one of the key obstacles to industrialize the NIL technology. Here, we report two efficient approaches for removal of typical contamination of particles and residual resist from stamps: thermal and ultraviolet (UV) imprinting cleaning-both based on the self-cleaning effect of imprinting process. The contaminated stamps were imprinted onto polymer substrates and after demolding, they were treated with an organic solvent. The images of the stamp before and after the cleaning processes show that the two cleaning approaches can effectively remove contamination from stamps without destroying the stamp structures. The contact angles of the stamp before and after the cleaning processes indicate that the cleaning methods do not significantly degrade the anti-sticking layer. The cleaning processes reported in this work could also be used for substrate cleaning.
Increasing evidence suggests a role of the immune system in modulation of cognition, but details on affected memory systems are largely lacking. We therefore aimed to study the relation between selected cytokines and subsets of memory, and the impact of age in these relations. From a random population-based sample (the Betula Prospective Cohort Study), 298 women (age 45-90) were studied in terms of episodic recall and recognition, semantic fluency and knowledge, and prospective memory. Circulating cytokines of relevance for cognition and aging were measured with ELISA. Levels of interleukin (IL)-6 and sIL-2R were significantly and negatively associated with most cognitive variables, while the opposite was true for IL-1?. Age shared substantial variance with both cytokines and memory, and turned most correlations non-significant when controlled for together with education, BMI and presence of disease. Interactions between age and cytokines were further analyzed in multiple regressions. For IL-6, significant negative interactions with age were found for semantic fluency (p<0.05) and prospective memory (p<0.01), and for sIL-2R in predicting semantic knowledge (p<0.05), indicating an increased negative impact of these cytokines on memory with increasing age. In conclusion, the study indicates a relation between cytokines and memory that appears to be largely mediated by age, and supports the suggestion that cytokine dysregulation with higher age may interact with cognitive aging.
Klinefelter syndrome (47, XXY) is a sex chromosome aneuploidy associated with mild deficits in cognitive and language functions. Dysfunctions have also been reported in performance of tasks which examine executive functions. However, it is unclear whether the impaired performance is caused or accentuated by problems with semantic processing and information processing speed. In the present study we used an experimental task which is relatively insensitive to these confounding factors. We examined inhibitory executive functions in a group of XXY males compared with male (XY) and female (XX) controls, using a dichotic listening speech sound task with instructions to focus attention on either the right or the left ear stimulus. With this task, inhibitory executive functions can be assessed separately from language, processing speed, and attention orientation abilities. We found that XXY males showed a selective deficit in inhibitory executive functions compared to both control groups, whereas attentional orientation was not impaired. The present findings suggest that executive dysfunctions associated to Klinefelter syndrome can be selectively identified, and are particularly accentuated in the inhibitory sub-component. Such improved understanding of the nature of executive dysfunctions in XXY males may aid the development of specific neuropsychological rehabilitation strategies.
The study reports on the development of a questionnaire for assessment of adult cognitive dysfunction (CDQ). Participants in a population-based sample (65±15 years, N=370) responded to a 90-item pilot version covering multiple aspects of memory/cognition. Based on exploratory principal components analyses and correlations with criterion measures of cognitive functioning (MMSE, Block Design, semantic/episodic memory), 20 items loading on 6 components were selected for the final version of the questionnaire. Cronbachs ? for the total score was 0.90. There was evidence of construct validity as judged by correlations between CDQ scores, objective cognitive measures, and a subjective memory measure (PRMQ). Discriminant validity was demonstrated by a low and non-significant correlation with depressive symptoms. Further evidence of construct validity was provided by correlations with age and educational attainment. In conclusion, the CDQ is promising as a self-rating screening tool for cognitive dysfunction, and will be the subject of further development and validation.
TERMINAL FLOWER2 (TFL2) is the plant homologue of metazoan HETEROCHROMATIN PROTEIN1 (HP1) protein family. It is known that, unlike most HP1 proteins, TFL2 does not primarily localize to heterochromatin; instead it functions in regulation of specific genes in euchromatic regions. We show that the tfl2 mutant has a lower rate of auxin biosynthesis, resulting in low levels of auxin. In line with this, tfl2 mutants have lower levels of expression of auxin response genes and retain an auxin response. The reduced rate of auxin biosynthesis in tfl2 is correlated to the down-regulation of specific genes in the tryptophan-dependent auxin biosynthesis pathway, a sub-set of the YUCCA genes. In vivo, TFL2 is targeted to a number of the YUCCA genes in an auxin-dependent fashion revealing a role of TFL2 in auxin regulation, probably as a component of protein complexes affecting transcriptional control.
Studies of familial Alzheimers disease suggest that misfolding and aggregation of amyloid-? (A?) peptides initiate the pathogenesis. The Arctic mutation of A? precursor protein (APP) results in AD, and Arctic A? is more prone to form A? protofibrils and extracellular deposits. Herein is demonstrated that the burden of diffuse A? deposits but not compact plaques is increased when tg-Swe mice are crossed with tg-ArcSwe mice synthesizing low levels of Arctic A?. The diffuse deposits in bitransgenic mice, which contain primarily wild-type A?42, accumulate in regions both with and without transgene expression. However, APP processing, when compared with tg-Swe, remains unchanged in young bitransgenic mice, whereas wild-type A?42 aggregation is accelerated and fibril architecture is altered in vitro and in vivo when a low level of Arctic A?42 is introduced. Thus, the increased number of diffuse deposits is likely due to physical interactions between Arctic A? and wild-type A?42. The selective increase of a single type of parenchymal A? deposit suggests that different pathways lead to formation of diffuse and compact plaques. These findings could have general implications for Alzheimers disease pathogenesis and particular relevance to patients heterozygous for the Arctic APP mutation. Moreover, it further illustrates how A? neuropathologic features can be manipulated in vivo by mechanisms similar to those originally conceptualized in prion research.
Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.
The identification of disease-causing mutations in Alzheimers disease has contributed greatly to the understanding of the pathogenesis of this disease. The amyloid-? (A?) peptide has come into focus and is believed to be central to the pathogenesis of Alzheimers disease. With only symptomatic treatment available, efforts to develop new therapeutics aimed at lowering the amount of A? peptides in the affected brain have intensified. In particular, immunotherapy against A? peptides has attracted considerable interest, as it offers the possibility to generate highly specific molecules targeting highly specific moieties. Due to intense research efforts and massive investments at universities and in the pharmaceutical industry, the outlook for patients and their relatives has never been brighter.
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism, oligo/amenorrhea, and polycystic ovaries. We aimed to determine whether low-frequency electro-acupuncture (EA) would decrease hyperandrogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention. We randomized 84 women with PCOS, aged 18-37 yr, to 16 wk of low-frequency EA, physical exercise, or no intervention. The primary outcome measure changes in the concentration of total testosterone (T) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat. Secondary outcome measures were changes in menstrual frequency; concentrations of androgens, estrogens, androgen precursors, and glucuronidated androgen metabolites; and acne and hirsutism. Outcomes were assessed at baseline, after 16 wk of intervention, and after a 16-wk follow-up. After 16 wk of intervention, circulating T decreased by -25%, androsterone glucuronide by -30%, and androstane-3?,17?-diol-3-glucuronide by -28% in the EA group (P = 0.038, 0.030, and 0.047, respectively vs. exercise); menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group (P = 0.018 vs. exercise). After the 16-wk follow-up, the acne score decreased by -32% in the EA group (P = 0.006 vs. exercise). Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention. Low-frequency EA and physical exercise improved hyperandrogenism and menstrual frequency more effectively than no intervention in women with PCOS. Low-frequency EA was superior to physical exercise and may be useful for treating hyperandrogenism and oligo/amenorrhea.
To allow for interdisciplinary research on the relations between socioeconomic conditions and health in the ageing population, a new anonymized longitudinal database - the Linnaeus Database - has been developed at the Centre for Population Studies at Umeå University. This paper presents the database and its research potential.
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