Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization

SummaryObjectiveTo investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage.DesignXbp1flox/flox.Col2a1-Cre mice (Xbp1CartΔEx2), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation.ResultsXbp1CartΔEx2 displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1CartΔEx2 growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1CartΔEx2 embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1CartΔEx2 growth plate. IRE1 hyperactivation occurred in Xbp1CartΔEx2 chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR.ConclusionOur work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease

Visualization of Active Glucocerebrosidase in Rodent Brain with High Spatial Resolution following In Situ Labeling with Fluorescent Activity Based Probes

Bio-organic SynthesisMedical Biochemistr

High prevalence of weight gain in childhood brain tumor survivors and its association with hypothalamic-pituitary dysfunction

PURPOSE Childhood brain tumor survivors (CBTS) are at risk for developing obesity, which negatively influences cardiometabolic health. The prevalence of obesity in CBTS may have been overestimated in previous cohorts because of inclusion of children with craniopharyngioma. On the contrary, the degree of weight gain may have been underestimated because of exclusion of CBTS who experienced weight gain, but were neither overweight nor obese. Weight gain may be an indicator of underlying hypothalamic-pituitary (HP) dysfunction. We aimed to study prevalence of and risk factors for significant weight gain, overweight, or obesity, and its association with HP dysfunction in a national cohort of noncraniopharyngioma and nonpituitary CBTS.METHODS Prevalence of and risk factors for significant weight gain (body mass index [BMI] change >= +2.0 standard deviation score [SDS]), overweight, or obesity at follow-up, and its association with HP dysfunction were studied in a nationwide cohort of CBTS, diagnosed in a 10-year period (2002-2012), excluding all craniopharyngioma and pituitary tumors.RESULTS Of 661 CBTS, with a median age at follow-up of 7.3 years, 33.1% had significant weight gain, overweight, or obesity. Of the CBTS between 4 and 20 years of age, 28.7% were overweight or obese, compared with 13.2% of the general population between 4 and 20 years of age. BMI SDS at diagnosis, diagnosis of low-grade glioma, diabetes insipidus, and central precocious puberty were associated with weight gain, overweight, or obesity. The prevalence of HP dysfunction was higher in overweight and obese CTBS compared with normal-weight CBTS.CONCLUSION Overweight, obesity, and significant weight gain are prevalent in CBTS. An increase in BMI during follow-up may be a reflection of HP dysfunction, necessitating more intense endocrine surveillance. (C) 2021 by American Society of Clinical OncologyDevelopment and application of statistical models for medical scientific researc

Risk factors and causes of ischemic stroke in 1322 young adults

Background:Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study).Methods:This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification.Results:The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%).Conclusions:Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.Neurological Motor Disorder

Trigger factors for stroke in young adults: a case-crossover study

Background and ObjectivesCauses of stroke in young adults differ from those in the elderly individuals, and in a larger percentage,no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in theyoung population, we investigated whether trigger factors, such as short-lasting exposure to toxins orinfection, may play a role.MethodsPatients aged 18–49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17participating centers in the Netherlands completed a questionnaire about exposure to 9 potentialtrigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used toassess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologicsubgroups of ischemic stroke.ResultsOne thousand one hundred forty-six patients completed the questionnaire (1,043 patients withan ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, anincreased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5–2.8) and vigorousphysical exercise (RR 2.6, 95% CI 2.2–3.0), within 2 hours after sexual activity (RR 2.4, 95% CI1.6–3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7–4.9), and within 24 hours afterfever or flu-like disease (RR 14.1, 95% CI 10.5–31.2; RR 13.9, 95% CI 8.9–21.9). Four triggerfactors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of car-dioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic strokecombined and stroke with multiple causes, and none that of stroke due to small vessel disease.DiscussionWe identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, andflu-like disease as potential trigger factors for stroke in the young population and found differencesin the type and number of trigger factors associated with different etiologic subgroups of ischemicstroke. These findings might help in better understanding the pathophysiologic mechanisms of(cryptogenic) stroke in the young population.Paroxysmal Cerebral Disorder

Structural network efficiency predicts cognitive decline in cerebral small vessel disease

Contains fulltext : 220281.pdf (publisher's version ) (Open Access)Cerebral small vessel disease (SVD) is a common disease in older adults and a major contributor to vascular cognitive impairment and dementia. White matter network damage is a potentially important mechanism by which SVD causes cognitive impairment. Earlier studies showed that a higher degree of white matter network damage, indicated by lower global efficiency (a graph-theory measure assessing efficiency of network information transfer), was associated with lower scores on cognitive performance independent of MRI markers for SVD. However, it is unknown whether this global efficiency index is the strongest predictor for cognitive impairment, as there is a wide range of network measures. Here, we investigate which network measure is the most informative in explaining baseline cognitive performance and decline over a period of 8.7 years in SVD. We used data from the Radboud University Nijmegen Diffusion tensor and MRI Cohort (RUN DMC), which included 436 participants without dementia (65.2 ± 8.8 years) but with evidence of SVD on neuroimaging. Binarized and weighted structural brain networks were reconstructed using diffusion tensor imaging and deterministic streamlining. Using graph-theory, we calculated 21 global network measures and performed linear regression analyses, elastic net analysis and linear mixed effect models to compare these measures. All analyses were adjusted for potential confounders (age, sex, educational level, depressive symptoms and conventional SVD MRI-markers (e.g. white matter hyperintensities (WMH), lacunes of presumed vascular origin and microbleeds). The elastic net analyses showed that, at baseline, global efficiency had the strongest association with cognitive index (CI), while characteristic path length showed the strongest association with psychomotor speed (PMS) and memory. Binary local efficiency showed the strongest association with attention & executive function (A&EF). In addition, linear mixed-effect models demonstrated that baseline global efficiency predicts decline in CI (X2(1) = 8.18, p = 0.004), PMS (X2(1) = 7.75, p = 0.005), memory (X2(1) = 27.28, p = 0.000) over time and that binary local efficiency predicts decline in A&EF (X2(1) = 8.66, p = 0.003) over time. Our results suggest that among all network measures, network efficiency measures, i.e. global efficiency and local efficiency, are the strongest predictors for cognitive functions at cross-sectional level and also predict faster cognitive decline in SVD, which is in line with earlier findings. These findings suggests that in our study sample network efficiency measures are the most suitable surrogate markers for cognitive performance in patients with cerebral SVD among all network measures and MRI markers, and play a key role in the genesis of cognitive decline in SVD.7 p

Physical Activity and Relaxation During and After Work are Independently Associated With Need for Recovery

BACKGROUND:To study the associations between during and after work hours physical activity and relaxation and need for recovery (NFR) in office workers at a financial service provider. METHODS:Self-reported baseline data of 412 employees (mean age 41.3 years; 39.6% women) were used. Linear regression analyses were performed to test associations of physical activity, relaxation, detachment and breaks at work with NFR. RESULTS: A lower NFR was significantly positively associated with standing, stair climbing, active lunchbreak, relaxation, detachment at work, physical detachment at work, relaxation and detachment at home. In the multiple model, a lower NFR was independently positively associated with frequency of stair climbing, minutes spent in leisure activities, detachment at work, physical detachment at work, relaxation and detachment at home (p<0.05). Significant effect modification indicated that the positive association between relaxation at home and NFR was stronger with high job demands. CONCLUSION: Although prospective evidence is necessary to confirm the causal relationships, our findings suggest that engaging in stair climbing, leisure activities, (physical) detachment at work, relaxation and detachment after work is associated with a lower NFR. For future worksite health promotion initiatives, interventions might be targeted at improving physical activity and relaxation