Objective:
Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary ...psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models.
Methods:
Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models).
Results:
Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS.
Conclusions:
This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
Previous studies showed that exposure toVibrio vulnificus cytolysin (VVC) caused characteristic morphologic changes and dysfunction of vascular structures in lung. VVC showed cytotoxicity for ...mammalian cells in culture and acted as a vascular permeability factor. In this study, the underlying mechanisms of VVC-induced cytotoxicity was investigated on ECV304 cell, a human vascular endothelial cell line. When cells were exposed to 0.4 hemolytic units (HU) of VVC, consecutive apoptotic events were observed; the elevation of superoxide anion (O⨪2), the release of cytochrome c, the activation of caspase-3, the cleavage of poly(ADP-ribose) polymerase, and the DNA fragmentation. The pretreatment with 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), O⨪2 scavenger, completely abolished O⨪2 levels and downstream apoptotic events. Moreover, pretreatment with cyclosporin A (CsA), a mitochondrial permeability transition inhibitor, was capable of attenuating O⨪2-mediated cytochrome c release and caspase-3 activation, and consequent apoptosis. Apoptosis, as demonstrated by oligonucleosomal DNA fragmentation and fluorescence microscopy, was induced 24 h after VVC treatment, which was also prevented by caspase-3 inhibitor, Ac-DEVD-CHO. Caspase-1 inhibitor, Ac-YVAD-CHO, did not protect ECV 304 cells from apoptosis. These results suggest a scenario where VVC-induced apoptosis is triggered by the generation of O⨪2, release of cytochrome c from mitochondria, activation of caspase-3, degradation of poly(ADP-ribose) polymerase, and DNA fragmentation. The induction of apoptosis in endothelial cells by VVC may provide a pivotal mechanism for understanding the pathophysiology of septicemia.
YKP1358 is a novel serotonin (5‐HT2A) and dopamine (D2) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D2 receptor occupancy study with ...YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D2 receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose‐escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer 11Craclopride. The D2 receptor occupancy of striatum was measured pre‐dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D2 receptor occupancy by YKP1358 increased to 53–83% at 2 h, and then decreased afterwards, ranging from 40–64% at 5 h to 20–51% at 10 h. The YKP1358 dose‐plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D2 receptor occupancy that was well predicted by a sigmoid Emax model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D2 receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D2 receptor occupancy.
Clinical Pharmacology & Therapeutics (2007) 81, 252–258. doi:10.1038/sj.clpt.6100049
This study aimed to elucidate the relationship between climate and the phylogenetic and morphological divergence of spruces (Picea) worldwide. Climatic and georeferenced data were collected from a ...total of 3388 sites distributed within the global domain of spruce species. A phylogenetic tree and a morphological tree for the global spruces were reconstructed based on DNA sequences and morphological characteristics. Spatial evolutionary and ecological vicariance analysis (SEEVA) was used to detect the ecological divergence among spruces. A divergence index (D) with (0, 1) scaling was calculated for each climatic factor at each node for both trees. The annual mean values, extreme values and annual range of the climatic variables were among the major determinants for spruce divergence. The ecological divergence was significant (P < 0. 001) for 185 of the 279 comparisons at 31 nodes in the phylogenetic tree, as well as for 196 of the 288 comparisons at 32 nodes in the morphological tree. Temperature parameters and precipitation parameters tended to be the main driving factors for the primary divergences of spruce phylogeny and morphology, respectively. Generally, the maximum D of the climatic variables was smaller in the basal nodes than in the remaining nodes. Notably, the primary divergence of morphology and phylogeny among the investigated spruces tended to be driven by different selective pressures. Given the climate scenario of severe and widespread drought over land areas in the next 30–90 years, our findings shed light on the prediction of spruce distribution under future climate change.
The size effects on fracture behavior of Cu foil are investigated by a new optical technique, the digital speckle correlation method (DSCM). Displacement and strain fields around a crack tip are ...analyzed for different thicknesses of Cu foil. Then, the J integral and fracture toughness JC are evaluated directly from the strain fields around the crack tip. The fracture toughness JC is obtained as a function of foil thickness. The results indicate that JC indeed depends on foil thickness within a certain range of thickness (the thickness varies from 20 micron to 1 millimeter in this work).
Virtual reality (VR) creates an exercise environment in which the intensity of practice and positive feedback can be systematically manipulated in various contexts. The purpose of this study was to ...investigate the training effects of a VR intervention on reaching behaviors in children with cerebral palsy (CP).
Four children with spastic CP were recruited.
A single-subject design (A-B with follow-up) was used. All children were evaluated with 3 baseline, 4 intervention, and 2 follow-up measures. A 4-week individualized VR training program (2 hours per week) with 2 VR systems was applied to all children. The outcome measures included 4 kinematic parameters (movement time, path length, peak velocity, and number of movement units) for mail-delivery activities in 3 directions (neutral, outward, and inward) and the Fine Motor Domain of the Peabody Developmental Motor Scales-Second Edition (PDMS-2). Visual inspection and the 2-standard-deviation-band method were used to compare the outcome measures.
Three children who had normal cognition showed improvements in some aspects of reaching kinematics, and 2 children's change scores on the PDMS-2 reached the minimal detectable change during the intervention. The improvements in kinematics were partially maintained during follow-up.
A 4-week individualized VR training program appeared to improve the quality of reaching in children with CP, especially in children with normal cognition and good cooperation. The training effects were retained in some children after the intervention.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The objective of this study was to determine the pathogenesis of experimental infection with a type 1 porcine reproductive and respiratory syndrome virus (PRRSV) by defining the sites of viral ...replication and apoptosis in male gonads from infected boars for a period of 21 days after intranasal inoculation. Microscopically, hypospermatogenesis and abundant germ cell depletion and death were observed in the testes. Such germ cell death occurs by apoptosis, as determined by a characteristic histological patterns and evidence of massive DNA fragment detected in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) reaction. PRRSV was detected in the testicular tissue of infected boars only. Viral nucleic acid was localized in spermatogonia, spermatocytes and spermatids but not in the vesicular and bulbourethral gland. In serial sections, PRRSV-positive cells did not co-localized with apoptotic cells. TUNEL-positive apoptotic cells were more numerous than PRRSV-positive cells in testicular sections. The present study demonstrated that type 1 PRRSV infects the spermatogonia and their progeny, and induces apoptosis in these germ cells.
Abstract
Background
There are a few studies about the relationship between inflammatory bowel disease (IBD) and atopic dermatitis (AD). It implicates that both diseases have common pathophysiologic ...mechanism and are able to affect each other. However, little information is available for the effect of AD on the clinical course of patients with IBD.
Methods
This is a retrospective, observational case-control study. Patients with concurrent IBD and AD were defined as case group and those with IBD only as control group. Diagnosis of AD was defined as chronic eczematoid dermatosis diagnosed by dermatologists. Age-, gender-, and IBD subtype-matched patients with a confirmed diagnosis of IBD were included as control group. The ratio of the case and control group was set as, 1:2. Trend in the duration from diagnosis of IBD to first use of biologics, first IBD-related operation and first IBD-related bowel resection were estimated with Cox regression analysis.
Results
The numbers of patients in the case and control group were, 31 and, 62, respectively. Compared with the control group, the case group showed an earlier disease onset (unit: years, 22.13 ±, 10.66 vs., 17.68 ±, 8.07, p = 0.043) and longer disease duration of IBD (unit: months, 98.37 ±, 69.24 vs., 150.77 ±, 83.45, p = 0.002). In addition, the proportion of biologics use (35% vs., 61%, p = 0.018) and the total numbers of biologics usages (0.48 ±, 0.76 vs., 1.06 ±, 1.12, p = 0.013) were higher in patients in the case group than those in the control group. In the Cox-regression analysis, there was a significant decrease of the duration for the biologics free survival in the case group compared with the control one after the adjustment with age, IBD subtype, onset age and disease duration (p < 0.001).
Conclusion
Patients having concurrent IBD and AD exhibited different characteristics compared with those having IBD only, particularly in terms of disease onset and severity. Furthermore, AD showed an significant effect on the time for the initiation of biologics. Further research is required to elucidate the common pathogenesis and the role of AD on the clinical course of IBD.
Objective To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians.Design Pooled ...analyses of 20 prospective cohorts in Asia, including data from 835 082 east Asians and 289 815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability.Setting General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh).Participants 1 124 897 men and women (mean age 53.4 years at baseline).Main outcome measures Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes.Results 49 184 cardiovascular deaths (40 791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and <15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12).Conclusions Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians.
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