RESUMO
We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G>A. This variant creates an alternative 3' splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.
Assuntos
Modelos Animais de Doenças , Fenilalanina Hidroxilase , Fenilcetonúrias , Animais , Camundongos , Fenilcetonúrias/genética , Fenilcetonúrias/patologia , Fenilcetonúrias/metabolismo , Humanos , Fenilalanina Hidroxilase/genética , Fenilalanina Hidroxilase/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas CRISPR-Cas , Autofagia/genética , Mutação , Fígado/metabolismo , Fígado/patologiaRESUMO
Given that treatment for secondary prevention in patients undergoing cardiac surgery is underused, we devised a hospital intervention to increase its implementation. The intervention involved all physicians in the department of cardiac surgery agreeing to complete a report on each patient before hospital discharge. The document recorded the indications for the recommended treatments, and prompted for details of the drugs prescribed, the doses used, the reasons for not prescribing the recommended drugs, if that was the case, and the use of alternative medicines. The efficacy of the intervention was evaluated by comparing the rate of drug use in the year in which it was introduced (2003, n=341) with retrospective data on the rate in the previous year (n=369). The rates of use of aspirin, statins, angiotensin-converting enzyme inhibitors, and beta-blockers by patients who required them all showed an absolute increase, of 13.4%, 38.3%, 21.8%, and 21.5%, respectively. In conclusion, the introduction of a simple and inexpensive intervention was able to significantly increase the use of drugs for secondary prevention in patients undergoing cardiac surgery.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Doenças Cardiovasculares/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RegistrosRESUMO
INTRODUCTION AND OBJECTIVES: Some patients, such as Jehovah's Witnesses, refuse to use blood products, which can make it difficult to achieve the same outcomes as in the general population. The objective of this study was to determine whether clinical characteristics and surgical outcomes in Jehovah's Witnesses undergoing cardiac surgery are similar to those in other patients. METHODS: Paired-group retrospective cohort study. All Jehovah's Witnesses undergoing cardiac surgery between January 1998 and September 2006 were included (n=59). Cases were matched on a 1:1 basis according to sex, age (5) years, year and type of surgery, and need for repeat surgery. Preoperative, intraoperative and postoperative data were analyzed. RESULTS: The mean age of cases was 62.5 (11.1) years with 57.6% being female. Some 30.5% had had at least one previous cardiac intervention. The clinical characteristics of the two groups were similar. Hemoglobin and hematocrit levels were higher in Jehovah's Witnesses both before (13.6 g/dL vs 12.9 g/dL; P=.01, and 40.7% vs 39%; P=.09) and after (11 g/dL vs 10 g/dL; P=.003, and 34.2% vs 30.7%; P=.001) surgery. Jehovah's Witnesses experienced significantly less bleeding, were intubated for fewer hours, and had shorter stays in both intensive care and the hospital. There was no difference in the rate of postoperative complications or mortality. CONCLUSIONS: The clinical characteristics of Jehovah's Witnesses were similar to those of the control group. The complication rate was also similar in these patients, though the number of hours of mechanical ventilation was less, 24-hour bleeding was less, and the hospital stay was shorter. Mortality was similar in the two groups.