Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted ...plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses.
Summary
There is a need to expand the current temporomandibular disorders' (TMDs) classification to include less common but clinically important disorders. The immediate aim was to develop a ...consensus‐based classification system and associated diagnostic criteria that have clinical and research utility for less common TMDs. The long‐term aim was to establish a foundation, vis‐à‐vis this classification system, that will stimulate data collection, validity testing and further criteria refinement. A working group members of the International RDC/TMD Consortium Network of the International Association for Dental Research (IADR), members of the Orofacial Pain Special Interest Group (SIG) of the International Association for the Study of Pain (IASP), and members from other professional societies reviewed disorders for inclusion based on clinical significance, the availability of plausible diagnostic criteria and the ability to operationalise and study the criteria. The disorders were derived from the literature when possible and based on expert opinion as necessary. The expanded TMDs taxonomy was presented for feedback at international meetings. Of 56 disorders considered, 37 were included in the expanded taxonomy and were placed into the following four categories: temporomandibular joint disorders, masticatory muscle disorders, headache disorders and disorders affecting associated structures. Those excluded were extremely uncommon, lacking operationalised diagnostic criteria, not clearly related to TMDs, or not sufficiently distinct from disorders already included within the taxonomy. The expanded TMDs taxonomy offers an integrated approach to clinical diagnosis and provides a framework for further research to operationalise and test the proposed taxonomy and diagnostic criteria.
Summary Temporomandibular Disorder (TMD) is the main cause of pain of non‐dental origin in the oro‐facial region including head, face and related structures. The aetiology and the pathophysiology of ...TMD is poorly understood. It is generally accepted that the aetiology is multifactorial, involving a large number of direct and indirect causal factors. Among such factors, occlusion is frequently cited as one of the major aetiological factors causing TMD. It is well known from epidemiologic studies that TMD‐related signs and symptoms, particularly temporomandibular joint (TMJ) sounds, are frequently found in children and adolescents and show increased prevalence among subjects between 15 and 45 years old. Aesthetic awareness, the development of new aesthetic orthodontic techniques and the possibility of improving prosthetic rehabilitation has increased the number of adults seeking orthodontic treatment. The shift in patient age also has increased the likelihood of patients presenting with signs and symptoms of TMD. Because orthodontic treatment lasts around 2 years, orthodontic patients may complain about TMD during or after treatment and orthodontists may be blamed for causing TMD by unsatisfied patients. This hypothesis of causality has led to legal problems for dentists and orthodontists. For these reasons, the interest in the relationship between occlusal factors, orthodontic treatment and TMD has grown and many studies have been conducted. Indeed, claims that orthodontic treatment may cause or cure TMD should be supported by good evidence. Hence, the aim of this article is to critically review evidence for a possible association between malocclusion, orthodontic treatment and TMD.
Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. ...Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC.
Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging.
Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality.
Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
Summary The frequency of diurnal clenching and/or grinding and nail‐biting habits was assessed in patients affected by temporomandibular disorders (TMDs) and in healthy controls in order to ...investigate the possible association between these oral parafunctions and different diagnostic subgroups of TMDs. The case group included 557 patients (127 men, mean age ± SD = 34·5 ± 15·4 years; 430 women, mean age ± SD = 32·9 ± 14·1 years) affected by myofascial pain or disc displacement or arthralgia/arthritis/arthrosis. The control group included 111 healthy subjects (55 men, mean age ± SD = 37 ± 15·2 years; 56 women, mean age ± SD = 38·2 ± 13·8 years). Multinomial logistic regression analysis was used to assess the association between oral parafunctions and TMDs, after adjusting for age and gender. Daytime clenching/grinding was a significant risk factor for myofascial pain (odds ratio (OR) = 4·9, 95% confidence interval (CI): 3·0–7·8) and for disc displacement (OR = 2·5, 95% CI: 1·4–4·3), nail biting was not associated to any of the subgroups investigated. Female gender was a significant risk factor for myofascial pain (OR = 3·8; 95% CI: 2·4–6·1), whereas the risk factor for developing disc displacement decreased with ageing. No association was found between gender, age and arthralgia/arthritis/arthrosis.
Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been ...carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH.
Liver repair involves phenotypic changes in hepatic stellate cells (HSCs) and reactivation of morphogenic signaling pathways that modulate epithelial‐to‐mesenchymal/mesenchymal‐to‐epithelial ...transitions, such as Notch and Hedgehog (Hh). Hh stimulates HSCs to become myofibroblasts (MFs). Recent lineage tracing studies in adult mice with injured livers showed that some MFs became multipotent progenitors to regenerate hepatocytes, cholangiocytes, and HSCs. We studied primary HSC cultures and two different animal models of fibrosis to evaluate the hypothesis that activating the Notch pathway in HSCs stimulates them to become (and remain) MFs through a mechanism that involves an epithelial‐to‐mesenchymal–like transition and requires cross‐talk with the canonical Hh pathway. We found that when cultured HSCs transitioned into MFs, they activated Hh signaling, underwent an epithelial‐to‐mesenchymal–like transition, and increased Notch signaling. Blocking Notch signaling in MFs/HSCs suppressed Hh activity and caused a mesenchymal‐to‐epithelial–like transition. Inhibiting the Hh pathway suppressed Notch signaling and also induced a mesenchymal‐to‐epithelial–like transition. Manipulating Hh and Notch signaling in a mouse multipotent progenitor cell line evoked similar responses. In mice, liver injury increased Notch activity in MFs and Hh‐responsive MF progeny (i.e., HSCs and ductular cells). Conditionally disrupting Hh signaling in MFs of bile‐duct–ligated mice inhibited Notch signaling and blocked accumulation of both MF and ductular cells. Conclusions: The Notch and Hedgehog pathways interact to control the fate of key cell types involved in adult liver repair by modulating epithelial‐to‐mesenchymal–like/mesenchymal‐to‐epithelial–like transitions. (Hepatology 2013;58:1801–1813)
Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of ...apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH.
To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies.
In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes.
TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.
Summary
The aim was to assess the quality and to summarise the findings of the Systematic Reviews (SRs) and Meta‐Analyses (MAs) on the dental and skeletal effects of maxillary expansion. Electronic ...and manual searches have been independently conducted by two investigators, up to February 2015. SRs and MAs on the dentoalveolar and skeletal effects of fixed expanders were included. The methodological quality was assessed using the AMSTAR (A Measurement Tool to Assess Systematic Reviews). The design of the primary studies included in each SR/MA was assessed with the LRD (Level of Research Design scoring). The evidence for each outcome was rated applying a pre‐determined scale. Twelve SRs/MAs were included. The AMSTAR scores ranged from 4 to 10. Two SRs/MAs included only RCTs. The current findings from SRs/MAs support with high evidence a significant increase in the short‐term of maxillary dentoalveolar transversal dimensions after Rapid Maxillary Expansion (RME). The same effect is reported with moderate evidence after Slow Maxillary Expansion (SME). However, there is moderate evidence of a non‐significant difference between the two expansion modalities concerning the short‐term dentoalveolar effects. With both RME and SME, significant increase of skeletal transversal dimension in the short‐term is reported, and the skeletal expansion is always smaller than the dentoalveolar. Even though dental relapse to some extent is present, long‐term results of the dentoalveolar effects show an increase of the transversal dimension, supported by moderate evidence for RME and low evidence for SME. Skeletal long‐term effects are reported only with RME, supported by very low evidence.
Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are ...required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes‐associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1‐ and Hedgehog‐regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma‐derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up‐regulating Yap1‐ and Hedgehog‐regulated transcription factors that normally promote their proliferation. Conclusions: Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post‐PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. (Hepatology 2016;64:232–244)
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