RESUMO
Nausea and vomiting (NVP) affect most pregnant women. At the severe end of the clinical spectrum, hyperemesis gravidarum (HG) can be life-threatening. The condition is fraught with misconceptions that have slowed progress and left women undertreated. Herein, recent scientific advances are presented that dispel common myths associated with HG related to maternal/offspring outcomes, etiology, and evolution. There is now strong evidence that (i) HG is associated with poor outcomes, (ii) a common cause of NVP and HG has been identified, and (iii) NVP is likely a protective evolutionary mechanism that occurs throughout the animal kingdom but is no longer necessary for human survival. Therefore, it is encouraging that we are finally on the cusp of testing treatments that may put an end to unnecessary suffering.
Assuntos
Hiperêmese Gravídica , Humanos , Hiperêmese Gravídica/terapia , Gravidez , Feminino , AnimaisAssuntos
Depressão , Hiperêmese Gravídica , Ansiedade , Transtornos de Ansiedade , Transtorno Depressivo , Feminino , Humanos , GravidezRESUMO
Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.
Assuntos
Cálcio/metabolismo , Predisposição Genética para Doença , Hiperêmese Gravídica/genética , Espaço Intracelular/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Austrália , Estudos de Coortes , Exoma/genética , Família , Feminino , Deleção de Genes , Dosagem de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Noruega , Nutrição Parenteral , Linhagem , Gravidez , Análise de Sequência de DNA , Estados UnidosRESUMO
Tissue microarray technology is a new method used to analyze 100s to 1,000s of tumor samples on a single slide allowing high throughput analysis of genes and proteins on a large cohort. The original methodology involves coring tissues from paraffin-embedded tissue donor blocks and placing them into a single paraffin block. One difficulty with paraffin-embedded tissue relates to antigenic changes in proteins and mRNA degradation induced by the fixation and embedding process. We modified this technology by using frozen tissues embedded in OCT compound as donor samples and arraying the specimens into a recipient OCT block. Tumor tissue is not fixed before embedding, and sections from the array are evaluated without fixation or postfixed according to the appropriate methodology used to analyze a specific gene at the DNA, RNA, and/or protein levels. While paraffin tissue arrays can be problematic for immunohistochemistry and for RNA in situ hybridization analyses, this method allows optimal evaluation by each technique and uniform fixation across the array panel. Frozen tissue microarrays work well for DNA, RNA, and protein analyses, and may have significant advantages over the original technology for the assessment of some genes and proteins by improving both qualitative and quantitative results.
