ObjectiveFactors that lead to metabolic dysregulation are associated with increased risk of early-onset colorectal cancer (CRC diagnosed under age 50). However, the association between metabolic ...syndrome (MetS) and early-onset CRC remains unexamined.DesignWe conducted a nested case–control study among participants aged 18–64 in the IBM MarketScan Commercial Database (2006–2015). Incident CRC was identified using pathologist-coded International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and controls were frequency matched. MetS was defined as presence of ≥3 conditions among obesity, hypertension, hyperlipidaemia and hyperglycaemia/type 2 diabetes, based on ICD-9-CM and use of medications. Multivariable logistic regressions were used to estimate ORs and 95% CIs.ResultsMetS was associated with increased risk of early-onset CRC (n=4673; multivariable adjusted OR 1.25; 95% CI 1.09 to 1.43), similar to CRC diagnosed at age 50–64 (n=14 928; OR 1.21; 95% CI 1.15 to 1.27). Compared with individuals without a metabolic comorbid condition, those with 1, 2 or ≥3 conditions had a 9% (1.09; 95% CI 1.00 to 1.17), 12% (1.12; 95% CI 1.01 to 1.24) and 31% (1.31; 95% CI 1.13 to 1.51) higher risk of early-onset CRC (ptrend <0.001). No associations were observed for one or two metabolic comorbid conditions and CRC diagnosed at age 50–64. These positive associations were driven by proximal (OR per condition 1.14; 95% CI 1.06 to 1.23) and distal colon cancer (OR 1.09; 95% CI 1.00 to 1.18), but not rectal cancer (OR 1.03; 95% CI 0.97 to 1.09).ConclusionsMetabolic dysregulation was associated with increased risk of early-onset CRC, driven by proximal and distal colon cancer, thus at least in part contribute to the rising incidence of early-onset CRC.
The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) and protodeboronation (ArB(OR)2 → ArH) of a series of boronic esters, encompassing eight different polyols and 10 ...polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (19F, 1H, and 11B), pH-rate dependence, isotope entrainment, 2H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous–organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. Moreover, hydrolysis of the ester to the boronic acid can be a dominant component of the overall protodeboronation process, augmented by self-, auto-, and oxidative (phenolic) catalysis when the pH is close to the pK a of the boronic acid/ester.
The Internet is now all-pervasive across much of the globe. While it has positive uses (e.g. prompt access to information, rapid news dissemination), many individuals develop Problematic Use of the ...Internet (PUI), an umbrella term incorporating a range of repetitive impairing behaviours. The Internet can act as a conduit for, and may contribute to, functionally impairing behaviours including excessive and compulsive video gaming, compulsive sexual behaviour, buying, gambling, streaming or social networks use. There is growing public and National health authority concern about the health and societal costs of PUI across the lifespan. Gaming Disorder is being considered for inclusion as a mental disorder in diagnostic classification systems, and was listed in the ICD-11 version released for consideration by Member States (http://www.who.int/classifications/icd/revision/timeline/en/). More research is needed into disorder definitions, validation of clinical tools, prevalence, clinical parameters, brain-based biology, socio-health-economic impact, and empirically validated intervention and policy approaches. Potential cultural differences in the magnitudes and natures of types and patterns of PUI need to be better understood, to inform optimal health policy and service development. To this end, the EU under Horizon 2020 has launched a new four-year European Cooperation in Science and Technology (COST) Action Programme (CA 16207), bringing together scientists and clinicians from across the fields of impulsive, compulsive, and addictive disorders, to advance networked interdisciplinary research into PUI across Europe and beyond, ultimately seeking to inform regulatory policies and clinical practice. This paper describes nine critical and achievable research priorities identified by the Network, needed in order to advance understanding of PUI, with a view towards identifying vulnerable individuals for early intervention. The network shall enable collaborative research networks, shared multinational databases, multicentre studies and joint publications.
•Technology use items were factor analyzed to yield 11 usage subscales.•Four attitude subscales included: positive, negative, anxiety, task-switching.•60 Item “Media and Technology Usage and ...Attitudes Scale” created.•Scale showed strong reliability and validity.
Current approaches to measuring people’s everyday usage of technology-based media and other computer-related activities have proved to be problematic as they use varied outcome measures, fail to measure behavior in a broad range of technology-related domains and do not take into account recently developed types of technology including smartphones. In the present study, a wide variety of items, covering a range of up-to-date technology and media usage behaviors. Sixty-six items concerning technology and media usage, along with 18 additional items assessing attitudes toward technology, were administered to two independent samples of individuals, comprising 942 participants. Factor analyses were used to create 11 usage subscales representing smartphone usage, general social media usage, Internet searching, e-mailing, media sharing, text messaging, video gaming, online friendships, Facebook friendships, phone calling, and watching television in addition to four attitude-based subscales: positive attitudes, negative attitudes, technological anxiety/dependence, and attitudes toward task-switching. All subscales showed strong reliabilities and relationships between the subscales and pre-existing measures of daily media usage and Internet addiction were as predicted. Given the reliability and validity results, the new Media and Technology Usage and Attitudes Scale was suggested as a method of measuring media and technology involvement across a variety of types of research studies either as a single 60-item scale or any subset of the 15 subscales.
Approximately 50 000 women of reproductive age in the United States are currently living after kidney transplantation (KT), and another 2800 undergo KT each year. Although KT improves reproductive ...function in women with ESRD, studies of post‐KT pregnancies are limited to a few voluntary registry analyses and numerous single‐center reports. To obtain more generalizable inferences, we performed a systematic review and meta‐analysis of articles published between 2000 and 2010 that reported pregnancy‐related outcomes among KT recipients. Of 1343 unique studies, 50 met inclusion criteria, representing 4706 pregnancies in 3570 KT recipients. The overall post‐KT live birth rate of 73.5% (95%CI 72.1–74.9) was higher than the general US population (66.7%); similarly, the overall post‐KT miscarriage rate of 14.0% (95%CI 12.9–15.1) was lower (17.1%). However, complications of preeclampsia (27.0%, 95%CI 25.2–28.9), gestational diabetes (8.0%, 95%CI 6.7–9.4), Cesarean section (56.9%, 95%CI 54.9–58.9) and preterm delivery (45.6%, 95%CI 43.7–47.5) were higher than the general US population (3.8%, 3.9%, 31.9% and 12.5%, respectively). Pregnancy outcomes were more favorable in studies with lower mean maternal ages; obstetrical complications were higher in studies with shorter mean interval between KT and pregnancy. Although post‐KT pregnancy is feasible, complications are relatively high and should be considered in patient counseling and clinical decision making.
This systematic review and meta‐analysis of pregnancy‐related outcomes in kidney transplant recipients shows that while pregnancies are viable, obstetric complications are relatively high and should be considered in patient counseling and clinical decision making. See editorial by Armenti on page 2275.
The aims of this cross-sectional study were (i) to compare the overall glucose metabolism between early onset and late onset Alzheimer's disease in a large sample of patients; and (ii) to investigate ...the pattern of glucose metabolism as a function of dementia severity in early onset versus late onset Alzheimer's disease, using a statistical parametric mapping (SPM) analysis. Subjects consisted of four groups: 74 patients with early onset Alzheimer's disease, 46 patients with late onset of the disease, and two control groups age matched to each patient group. All the subjects underwent 2-18Ffluoro-2-deoxy-d-glucose (FDG)-PET under the same scanning conditions. Severity of dementia was rated with the Clincial Dementia Rating (CDR). Voxel-based SPM99 was used for statistical analyses. Overall glucose hypometabolism of early onset Alzheimer's disease patients was much greater in magnitude and extent than that of late onset patients, though both groups were similar in dementia severity: the early onset group showed more severe hypometabolism in parietal, frontal and subcortical (basal ganglia and thalamus) areas. When the decline of glucose metabolism was compared as a function of CDR stage, the slope was steeper in early onset than in late onset Alzheimer's disease. The rapid decline occurred at CDR 0.5–1 in the early onset group, whereas similar changes occurred at CDR 2–3 in the late onset group. The greater hypometabolism in early onset than in late onset patients is required to reach the same severity of dementia, probably reflecting greater functional reserve in younger than in older subjects. Alternatively, the metabolic decline curve suggests that the early onset patients may take a more rapid course in the reduction of glucose metabolism than the late onset patients.
Abstract The response of the skeleton to loading appears to be mediated through the activation of the Wnt/β-catenin signaling pathway and osteocytes have long been postulated to be the primary ...mechanosensory cells in bone. To examine the kinetics of the mechanoresponse of bone and cell types involved in vivo , we performed forearm loading of 17-week-old female TOPGAL mice. β-catenin signaling was observed only in embedded osteocytes, not osteoblasts, at 1 h post-loading, spreading to additional osteocytes and finally to cells on the bone surface by 24 h. This early activation at 1 h appeared to be independent of receptor (Lrp5/6) mediated activation as it occurred in the presence of the inhibitors sclerostin and/or Dkk1. The COX-2 inhibitor, Carprofen, blocked the activation of β-catenin signaling and decline in sclerostin positive osteocytes post-loading implying an important role for prostaglandin. In vitro , PI3K/Akt activation was shown to be required for β-catenin nuclear translocation downstream from prostaglandin in MLO-Y4 osteocyte-like cells supporting this mechanism. Downstream targets of β-catenin signaling, sclerostin and Dkk1, were also examined and found to be significantly downregulated in osteocytes in vivo at 24 h post-loading. The pattern of initially activated osteocytes appeared random and in order to understand this heterogeneous expression, a novel finite element model of the strain field in the ulna was developed, which predicts highly variable local magnitudes of strain experienced by osteocytes. In summary, both in vivo and in vitro models show the rapid activation of β-catenin in response to load through the early release of prostaglandin and that strain fields in the bone are extremely heterogeneous resulting in heterogeneous activation of the β-catenin pathway in osteocytes in vivo.
To provide a better understanding of rheological properties of mantle rocks under lithospheric conditions, we carried out a series of experiments on the creep behavior of polycrystalline olivine at ...high pressures (∼4–9 GPa), relatively low temperatures (673 ≤ T ≤ 1273 K), and anhydrous conditions, using a deformation‐DIA. Differential stress and sample displacement were monitored in situ using synchrotron X‐ray diffraction and radiography, respectively. Experimental results were fit to the low‐temperature plasticity flow law, . On the basis of this analysis, the low‐temperature plasticity of olivine deformed under anhydrous conditions is well constrained by our data with a Peierls stress of σP = 5.9 ± 0.2 GPa, a zero‐stress activation energy of Ek(0) = 320 ± 50 kJ mol−1, and AP = 1.4 × 10−7 s−1 MPa−2. Compared with published results for high‐temperature creep of olivine, a transition from low‐temperature plasticity to high‐temperature creep occurs at ∼1300 K for a strain rate of ∼10−5 s−1. For a geological strain rate of 10−14 s−1, extrapolation of our low‐temperature flow law to 873 K, the cutoff temperature for earthquakes in the mantle, yields a strength of ∼600 MPa. The low‐temperature, high‐stress flow law for olivine in this study provides a solid basis for modeling tectonic processes occurring within Earth's lithosphere.
Because DTI can provide good markers of white matter pathology, it could be useful in differentiating white matter changes of INPH from those of other dementias. The aim of this study was, by using ...DTI, to compare the characteristic white matter changes in INPH with those in AD, subcortical vascular dementia, and healthy control subjects.
Sixteen patients with presurgical INPH, 10 with AD, 10 with subcortical vascular dementia, and 20 healthy control subjects underwent DTI. All patients with INPH showed clinical improvement after shunt surgery, and 9 of them also underwent postshunting DTI. Regions of interest were selected at the periventricular white matter, the anterior limb of the internal capsule, the posterior limb of the internal capsule, the genu and the splenium of the corpus callosum, the superior longitudinal fasciculus, and the inferior longitudinal fasciculus. FA and MD were obtained from each region of interest and were compared among the groups.
Presurgical INPH showed significantly higher FA than all the other groups in the posterior limb of the internal capsule, which was decreased after shunt surgery. Presurgical MD of the INPH group was higher than that in the AD and healthy control groups but lower than that in the subcortical vascular dementia group in the anterior periventricular white matter, the anterior limb of the internal capsule, and the superior longitudinal fasciculus. In differentiating INPH, the sensitivity and specificity of FA in the posterior limb of the internal capsule was 87.5% and 95.0%, respectively.
Patients with shunt-responsive INPH showed higher FA in the posterior limb of the internal capsule compared with healthy controls and those in other groups of dementia that was reversible with shunt surgery. With this parameter, shunt-responsive INPH could be distinguished from AD, subcortical vascular dementia, and healthy conditions with high diagnostic accuracy.
Presently, co-culture of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) with BV2 microglia under amyloid-β42 (Aβ42) exposure induced a reduction of Aβ42 in the medium as well as an ...overexpression of the Aβ-degrading enzyme neprilysin (NEP) in microglia. Cytokine array examinations of co-cultured media revealed elevated release of soluble intracellular adhesion molecule-1 (sICAM-1) from hUCB-MSCs. Administration of human recombinant ICAM-1 in BV2 cells and wild-type mice brains induced NEP expression in time- and dose-dependent manners. In co-culturing with BV2 cells under Aβ42 exposure, knockdown of ICAM-1 expression on hUCB-MSCs by small interfering RNA (siRNA) abolished the induction of NEP in BV2 cells as well as reduction of added Aβ42 in the co-cultured media. By contrast, siRNA-mediated inhibition of the sICAM-1 receptor, lymphocyte function-associated antigen-1 (LFA-1), on BV2 cells reduced NEP expression by ICAM-1 exposure. When hUCB-MSCs were transplanted into the hippocampus of a 10-month-old transgenic mouse model of Alzheimer's disease for 10, 20, or 40 days, NEP expression was increased in the mice brains. Moreover, Aβ42 plaques in the hippocampus and other regions were decreased by active migration of hUCB-MSCs toward Aβ deposits. These data suggest that hUCB-MSC-derived sICAM-1 decreases Aβ plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway.
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