Mutations in the VHL gene in sporadic apparently congenital polycythemia

The congenital polycythemic disorders with elevated erythropoietin (Epo) have been until recently an enigma, and abnormality in the hypoxia-sensing pathway has been hypothesized as a possible mechanism. The tumor suppressor von Hippel-Lindau (VHL) participates in the hypoxia-sensing pathway, as it binds to the proline-hydroxylated form of the hypoxia-inducible factor 1alpha (HIF-1alpha) and mediates its ubiquitination and proteosomal degradation. The loss of VHL function may result in the accumulation of HIF-1alpha and overproduction of HIF-1 downstream target genes including Epo. VHL syndrome is an autosomal dominant disorder predisposing to the development of tumors, due to inherited mutations in the VHL gene. Some rare patients with VHL syndrome have polycythemia, which has been attributed to Epo production by a tumor. It was recently found that homozygosity for the VHL Arg200Trp mutation is the cause of Chuvash polycythemia, an autosomal recessive polycythemic disorder characterized by elevated serum Epo and hypersensitivity of erythroid cells to Epo. We evaluated the role of VHL in 8 children with a history of polycythemia and an elevated serum Epo level and found 3 different germline VHL mutations in 4 of them. One child was homozygous for the Arg200Trp VHL mutation, and another compound heterozygous for the Arg200Trp and the Val130Leu mutations. Two children (siblings) were heterozygous for an Asp126Tyr mutation, one of them fulfilling some criteria of VHL syndrome. We propose that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum Epo concentration.     

Behavior‐associated Neuronal Activation After Kainic Acid‐induced Hippocampal Neurotoxicity is Modulated in Time

Kainic acid‐induced (KA) hippocampal damage leads to neuronal death and further synaptic plasticity. Formation of aberrant as well as of functional connections after such procedure has been documented. However, the impact of such structural plasticity on cell activation along time after damage and in face of a behavioral demand has not been explored. We evaluated if the mRNA and protein levels of plasticity‐related protein synaptophysin (Syp and SYP, respectively) and activity‐regulated cytoskeleton‐associated protein mRNA and protein levels (Arc and Arc, respectively) in the dentate gyrus were differentially modulated in time in response to a spatial‐exploratory task after KA‐induced hippocampal damage. In addition, we analyzed Arc+/NeuN+ immunopositive cells in the different experimental conditions. We infused KA intrahippocampally to young‐adult rats and 10 or 30 days post‐lesion (dpl) animals performed a hippocampus‐activating spatial‐exploratory task. Our results show that Syp mRNA levels significantly increase at 10dpl and return to control levels after 30dpl, whereas SYP protein levels are diminished at 10dpl, but significantly increase at 30dpl, as compared to 10dpl. Arc mRNA and protein levels are both increased at 30dpl as compared to sham. Also the number of NeuN+/Arc+ cells significantly increases at 30dpl in the group with a spatial‐exploratory demand. These results provide information on the long‐term modifications associated to structural plasticity and neuronal activation in the dentate gyrus after excitotoxic damage and in face of a spatial‐exploratory behavior. Anat Rec, 300:425–432, 2017. © 2016 Wiley Periodicals, Inc.     

Interaction between warfarin and Chinese herbal medicines

In traditional Chinese medicine (TCM), the human body is divided into Yin and Yang. Diseases occur when the Yin and Yang balance is disrupted. Different herbs are used to restore this balance, achieving the goal of treatment. However, inherent difficulties in designing experimental trials have left much of TCM yet to be substantiated by science. Despite that, TCM not only remains a popular form of medical treatment among the Chinese, but is also gaining popularity in the West. This phenomenon has brought along with it increasing reports on herb-drug interactions, beckoning the attention of Western physicians, who will find it increasingly difficult to ignore the impact of TCM on Western therapies. This paper aims to facilitate the education of Western physicians on common Chinese herbs and raise awareness about potential interactions between these herbs and warfarin, a drug that is especially susceptible to herb-drug interactions due to its narrow therapeutic range.     

Preliminary Study of Brain Glucose Metabolism Changes in Patients with Lung Cancer of Different Histological Types

Background:Cerebral glucose metabolism changes are always observed in patients suffering from malignant tumors.This preliminary study aimed to investigate the brain glucose metabolism changes in patien...     

Adverse Effects of Osteocytic Constitutive Activation of ß‐Catenin on Bone Strength and Bone Growth

The activation of the canonical Wnt/β‐catenin signaling pathway in both mesenchymal stem cells and osteoblasts has been demonstrated to increase bone mass, showing promise for the treatment of low bone volume conditions such as osteoporosis. However, the possible side effects of manipulating this pathway have not been fully addressed. Previously, we reported that the constitutive activation of ß‐catenin in osteoblasts impaired vertebral linear growth. In the present study, β‐catenin was constitutively activated in osteocytes by crossing Catnb+/lox(exon 3) mice with dentin matrix protein 1(DMP1)‐Cre transgenic mice, and the effects of this activation on bone mass, bone growth and bone strength were then observed. DMP1‐Cre was found to be predominantly expressed in osteocytes, with weak expression in a small portion of osteoblasts and growth plate chondrocytes. After the activation, the cancellous bone mass was dramatically increased, almost filling the entire bone marrow cavity in long bones. However, bone strength decreased significantly. Thinner and more porous cortical bone along with impaired mineralization were responsible for the decrease in bone strength. Furthermore, the mice showed shorter stature with impaired linear growth of the long bones. Moreover, the concentration of serum phosphate decreased significantly after the activation of ß‐catenin, and a high inorganic phosphate (Pi) diet could partially rescue the phenotype of decreased mineralization level and impaired linear growth. Taken together, the constitutive activation of β‐catenin in osteocytes may increase cancellous bone mass; however, the activation also had adverse effects on bone strength and bone growth. These adverse effects should be addressed before the adoption of any therapeutic clinical application involving adjustment of the Wnt/β‐catenin signaling pathway. © 2015 American Society for Bone and Mineral Research.