Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development

The WNT/β-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of β-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate β-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for β-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived β-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with β-catenin(fx(exon3)/wt) or β-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific β-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific β-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific β-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived β-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.     

Safety Practices in Relation to Home Ownership Among Urban Mexican Immigrant Families

We examined home safety hazards, comparing renter- to owner-occupied housing among urban, immigrant Mexican families. Methods: Interviews and home inspections were conducted among urban, Spanish-speaking immigrant families with children. We estimated weighted hazard prevalence and used logistic regression to compare owner- and renter-occupied homes. Of 313 eligible households, 250 (80%) enrolled. Respondents were predominantly Mexican-born (99%), low income (72.6%) and lower education (92.3%). Most homes had fire, burn, fall, poisoning, electrocution and fire escape hazards, including high tap water temperatures (76.4%; 95% CI: 69.0, 83.7%), no working smoke alarms (60.0%; 51.3, 68.8%), slippery bathtub/shower surfaces (58.7%; 49.9, 67.5%), blocked fire escape routes (55.9%; 47.2, 64.5%) and child-accessible medications (71.0%; 60.1, 81.3%). After adjustment for sociodemographics, fire escape (OR = 8.8; 95% CI: 2.8, 27.7), carbon monoxide poisoning (OR = 2.9; 1.4, 6.2) and drowning (OR = 3.5; 1.3, 9.4) hazards were more likely in owner- than renter-occupied homes. Housing age and type explained most differences. Many urban, immigrant Spanish-speaking families live in unsafe homes. For this population, housing safety programs should be targeted based on housing age and type rather than tenure.     

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-l-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application.     

Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis

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Efficacy of chalcone and xanthine derivatives on lipase inhibition: A systematic review

Losing weight has significant impact on chronic disease management. Orlistat, a lipase inhibitor, has alternative effect for weight controlling. To find more candidates, we conducted a review of chalcone and xanthine derivatives regarding their anti‐lipase activity. Eight databases were searched including PubMed, Scopus, Web of Science (ISI), Virtual Health Library (VHL), System for Information on Grey Literature in Europe (SIGLE), Global Health Library (GHL), EMBASE, and Google Scholar in August 2018. We found chalcone scaffold was more effective on lipase inhibition than xanthine scaffold. Among 19 investigated chalcones, only isoliquiritigenin and licuroside demonstrated an effect on preventing weight gain and increase in the total cholesterol and total triglycerides aside apart from their high activity on inhibiting lipase. Effect and type of inhibition of individual chalcones differed depending on their structure. In addition, very few studies investigated xanthine compounds and their activities were inconsistent. We suggest more studies investigate the ability of chalcones and modifying their structure to find out other compounds with higher efficacy.     

Progress in zero-fluoroscopy implantation of cardiac electronic device

Fluoroscopy is the imaging modality routinely used for cardiac device implantation. Due to the rising concern regarding the harmful effects of radiation exposure to both the patients and operation staffs, many efforts have been made to develop alternative techniques to achieve zero-fluoroscopy implantation. In this review, we describe the different methods aimed at avoiding the application of fluoroscopy in recent years, and evaluate their feasibility and safety in cardiac electronic device implantation.