β-Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2

During bone marrow stromal cell (BMSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin plays a critical role in the Wnt signaling pathway to facilitate downstream effects on gene expression. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chromatin immunoprecipitation (ChIP)-sequencing demonstrated binding of β-catenin to the promoter of enhancer of zeste homolog 2 (EZH2), a key component of the polycomb repressive complex 2 (PRC2) complex that catalyzes histone methylation. Knockdown of β-catenin reduced EZH2 protein levels and decreased methylated histone 3 (H3K27me3) at osteogenic loci. Further, when EZH2 was inhibited, β-catenin's anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin's effects on BMSCs to preserve multipotentiality. © 2020 American Society for Bone and Mineral Research.     

Liquid diet induces memory impairment accompanied by a decreased number of hippocampal neurons in mice

It is suggested that masticatory dysfunction affects the central nervous system; however, the underlying mechanism remains unknown. Brain‐derived neurotrophic factor (BDNF) and its receptor, TrkB, are known to play important roles in memory and learning. In this study, we examined the effects of mastication on memory, the expression levels of BDNF and TrkB, and the number of neurons in the hippocampus of mice. Male C57 BL/6J mice (3 weeks old) were randomly divided into the control group (N = 7) fed chow pellets and the experimental group (N = 7) fed a liquid diet, which reduces mastication during eating. At 14 weeks of age, we performed a passive avoidance test and found that memory and learning ability were impaired in the experimental group compared with the control group. After the behavioral experiment, brains were harvested and analyzed morphologically and biochemically. In the hippocampus of the experimental group, the expression levels of BDNF were significantly higher, whereas those of TrkB were lower than those of the control group. In the cerebral cortex, these levels remained unchanged between the two groups. The ratio of phospho‐p44/42 ERK/pan ERK, a downstream molecule of BDNF/TrkB signaling, in the experimental group was significantly lower than that of the control group in the cortex and hippocampus. The number of pyramidal neurons in the hippocampus was lower in the experimental group than in the control group. These findings suggest that reduced mastication induced by a liquid diet in early childhood may impair memory and learning ability, accompanied by neuronal loss in the hippocampus. © 2014 Wiley Periodicals, Inc.     

Does abnormal interhemispheric inhibition play a role in mirror dystonia?

The presence of mirror dystonia (dystonic movement induced by a specific task performed by the unaffected hand) in the dominant hand of writer's cramp patients when the nondominant hand is moved suggests an abnormal interaction between the 2 hemispheres. In this study we compare the level of interhemispheric inhibition (IHI) in 2 groups of patients with writer's cramp, one with the presence of a mirror dystonia and the other without as well as a control group. The level of bidirectional IHI was measured in wrist muscles with dual‐site transcranial magnetic stimulation with a 10‐millisecond (short IHI) and a 40‐millisecond (long IHI) interstimulus interval during rest and while holding a pen in 9 patients with mirror dystonia 7 without mirror dystonia, and 13 controls. The group of patients without mirror dystonia did not differ from the controls in their IHI level. In contrast, IHI was significantly decreased in the group of patients with mirror dystonia in comparison with the group without mirror dystonia and the controls in both wrist muscles of both the dystonic and unaffected hand whatever the resting or active condition (P = 0.001). The decrease of IHI level in the group of patients with mirror dystonia was negatively correlated with the severity and the duration of the disease: the weaker the level of IHI, the more severe was the disease and the longer its duration. Interhemispheric inhibition disturbances are most likely involved in the occurrence of mirror dystonia. This bilateral deficient inhibition further suggests the involvement of the unaffected hemisphere in the pathophysiology of unilateral dystonia. © 2013 International Parkinson and Movement Disorder Society     

Association of calcium channel blocker use with clinical outcome of COVID-19: A meta-analysis

AimsThis meta-analysis aims to analyze the association of calcium channel blocker (CCB) use with COVID-19 clinical outcomes.MethodsPubMed, ProQuest, Science Direct, Scopus, and medRxiv databases were searched systematically in a limited period. The primary outcome was mortality.ResultsA total of 119,298 patients from 31 eligible studies were included. Pooled analysis of the random-effect model revealed CCB was not associated with reduced mortality (OR = 1.21 [95%CI: 0.98–1.49], p = 0.08). Interestingly, subgroup analysis in hypertensive patients revealed significantly reduced mortality (OR = 0.69 [95%CI: 0.52–0.91], p = 0.009).ConclusionCCB usage was not associated with the outcome of COVID-19. However, CCB was associated with a decreased mortality rate in hypertensive COVID-19 patients.     

A novel peroxisome proliferator-activated gamma (PPAR gamma) agonist,CLX-0921, has potent antihyperglycemic activity with low adipogenic potential

Agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) are pharmacologically active antihyperglycemic agents that act by increasing peripheral tissue sensitivity to insulin. Many of these agonists have antihyperglycemic activity that is directly proportional to their ability to bind and activate PPAR gamma; however, recent data bring this relationship into question. In this report we describe a new PPAR gamma agonist, CLX-0921, that is derived from a natural product. This thiazolidinedione (TZD) has a spectrum of activity that differs from commercially available TZDs. It is a weak activator of PPAR gamma (EC(50) of 0.284 micromol/L) compared to rosiglitazone (EC(50) 0.009 micromol/L). Despite this difference, the drug maintains potent glucose uptake activity in vitro and glucose-lowering activity in vivo that is equipotent to that of rosiglitazone. Moreover, CLX-0921 showed a 10-fold reduction in in vitro adipogenic potential compared to rosiglitazone. CLX-0921 also increases glycogen synthesis, an activity not typically associated with rosiglitazone or pioglitazone. Thus CLX-0921 appears to have a distinct spectrum of activity relative to other TZDs.     

Case report: peritoneal sarcoidosis in an unusual location

A 48-year-old woman underwent surgery for a lesion seen on ultrasound and interpreted as a uterine myoma. The surgery revealed multiple nodules that had seeded on the omentum, peritoneum, and ovaries. The macroscopic interpretation was either metastasis or tuberculosis. The biopsy showed noncaseating granulomas, and a diagnosis of peritoneal sarcoidosis was reported. The AFB (acid fast bacillus) and L?wenstein-Jensen culture were negative. She was treated with methylprednisolone for 1 year for pulmonary sarcoidosis progression, with a resulting decrease in her DLCO (diffusing lung capacity for carbon monoxide). Computed tomography showed only a slight decrease in the multiple nodules and cysts. She is currently symptom-free.     

Primary hyperparathyroidism associated to slipped capital femoral epiphysis in a teenager

Primary hyperparathyroidism (PHP) is an uncommon disease in children and adolescents. The association between PHP and slipped capital femoral epiphysis is rare, and so far only four cases have been reported in the literature. Herein, we report a case of PHP due to a parathyroid adenoma, with several painful skeletal deformities and associated with slipped capital femoral epiphysis in an 18-year-old male patient. Laboratory evaluation showed: calcium of 13.6 mg/dL, parathyroid hormone of 1,524 pg/mL and alkaline phosphatase of 3,449 U/L. Deformities were caused by late diagnosis during the growth spurt, and this association is the result of combinations between metabolic and mechanical factors. The patient underwent parathyroidectomy and, in agreement with the literature, since the removal of the adenoma is followed by prompt resolution of the slipped capital femoral epiphysis we decided for a conservative approach. We observed improvement of the pain and normalization of calcium and parathyroid hormone levels.