ABSTRACT
INTRODUCTION: Studying innate sensitivity to ethanol can be an important first step toward understanding alcohol use disorders. In brain, we investigated transcripts, with evidence of miRNA modulation related to a predisposition to the hypnotic effect of ethanol, as measured by loss of righting reflex (LORR). METHODS: Expression of miRNAs (12 samples) and expression of mRNAs (353 samples) in brain were independently analyzed for an association with LORR in mice from the LXS recombinant inbred panel gathered across several small studies. These results were then integrated via a meta-analysis of miRNA-mRNA target pairs identified in miRNA-target interaction databases. RESULTS: We found 112 significant miRNA-mRNA pairs where a large majority of miRNAs and mRNAs were highly interconnected. Most pairs indicated a pattern of increased levels of miRNAs and reduced levels of mRNAs being associated with more alcohol-sensitive strains. For example, CaMKIIn1 was targeted by multiple miRNAs associated with LORR. CAMK2N1 is an inhibitor of CAMK2, which among other functions, phosphorylates, or binds to GABAA and NMDA receptors. CONCLUSIONS: Our results suggest a novel role of miRNA-mediated regulation of an inhibitor of CAMK2 and its downstream targets including the GABAA and NMDA receptors, which have been previously implicated to have a role in ethanol-induced sedation and sensitivity.
Subject(s)
Alcoholism/genetics , Ethanol/pharmacology , Hypnotics and Sedatives/pharmacology , MicroRNAs/physiology , Transcription, Genetic/genetics , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Female , GABA-A Receptor Antagonists/pharmacology , Gene Expression Regulation , Genetic Predisposition to Disease/genetics , Mice , Mice, Inbred Strains , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Messenger/metabolism , Receptors, GABA-A/drug effects , Receptors, GABA-A/genetics , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/genetics , Reflex, Righting/drug effects , Reflex, Righting/geneticsABSTRACT
Leukemic cells from 29 cases of acute lymphocytic leukemia (ALL), studied for T and B cell markers by the use of sheep erythrocyte rosetting and surface immunoglobulin determinations, were examined by electron microscopy. The majority of patients (76%) were found to have non-T, non-B neoplasms composed predominantly of relatively small, inactive-appearing cells with frequent nuclear folds. T cell cases (21%) were associated with mediastinal masses and were predominantly composed of large, active-appearing cells with nuclear irregularity and little rough endoplasmic reticulum. One case of B cell origin was not morphologically distinct from the non-T, non-B cell cases.
Subject(s)
Leukemia, Lymphoid/ultrastructure , Adolescent , Adult , B-Lymphocytes/ultrastructure , Cell Nucleus/ultrastructure , Child , Child, Preschool , Endoplasmic Reticulum/ultrastructure , Female , Humans , Infant , Leukemia, Lymphoid/immunology , Male , Middle Aged , Polyribosomes/ultrastructure , Rosette Formation , T-Lymphocytes/ultrastructureABSTRACT
On two occasions, a 3 1/2-year-old black girl had severe hypoglycemia associated with transient hepatomegaly. The plasma insulin level during the second hypoglycemic episode was excessive and led to a diagnosis of malicious insulin administration. We suggest that plasma be obtained for insulin determination in children with hypoglycemia, and that transient hepatomegaly may be a helpful sign in cases of insulin overdose.
Subject(s)
Child Abuse , Hepatomegaly/chemically induced , Hypoglycemia/chemically induced , Insulin/adverse effects , Child, Preschool , Female , Humans , Hypoglycemia/diagnosisABSTRACT
Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.
