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Autism spectrum disorder (ASD) is a common neurodevelopmental condition. The American Academy of Paediatrics and American Academy of Neurology do not recommend routine brain magnetic resonance imaging (MRI) in the assessment of ASD. The need for a brain MRI should be decided on atypical features in the clinical history and examination. However, many physicians continue to use brain MRI routinely in the assessment process. We performed a retrospective review of indications for requesting brain MRI in our institution over a 5-year period. The aim was to identify the yield of MRI in children with ASD and calculate the prevalence of significant neuroimaging abnormalities in children with ASD and identify clinical indications for neuroimaging. One hundred eighty-one participants were analysed. An abnormal brain MRI was identified in 7.2% (13/181). Abnormal brain MRI was more likely with an abnormal neurological examination (OR 33.1, p = 0.001) or genetic/metabolic abnormality (OR 20, p = 0.02). In contrast, abnormal MRI was not shown to be more likely in children with a variety of other indications such as behavioural issues and developmental delay. Conclusion: Thus, our findings support that MRI should not be a routine investigation in ASD, without additional findings. The decision to arrange brain MRI should be made on a case-by-case basis following careful evaluation of potential risks and benefits. The impact of any findings on the management course of the child should be considered prior to arranging imaging. What is Known: ⢠Incidental brain MRI findings are common in children with and without ASD. ⢠Many children with ASD undergo brain MRI in the absence of neurological comorbidities. What is New: ⢠Brain MRI abnormalities in ASD are more likely with an abnormal neurological examination and genetic or metabolic conditions. ⢠Prevalence of significant brain MRI abnormalities in ASD alone is low.
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Trastorno del Espectro Autista , Encefalopatías , Niño , Humanos , Estados Unidos , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , NeuroimagenRESUMEN
Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease-causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE.
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Epilepsia/epidemiología , Epilepsia/genética , Proteínas SNARE/metabolismo , Edad de Inicio , Niño , Exoma/genética , Femenino , HumanosRESUMEN
Spiromesifen is a novel insecticide and is classed as a tetronic acid derivative. It targets the insects' acetyl-coenzyme A carboxylase (ACCase) enzyme, causing a reduction in lipid biosynthesis. At the time of this publication, there are no reports of resistance to this class of insecticides in insects although resistance has been observed in several mite species. The greenhouse whitefly Trialeurodes vaporariorum (Westwood) is a serious pest of protected vegetable and ornamental crops in temperate regions of the world and spiromesifen is widely used in its control. Mortality rates of UK and European populations of T. vaporariorum to spiromesifen were calculated and up to 26-fold resistance was found. We therefore sought to examine the molecular mechanism underlying spiromesifen resistance in this important pest. Pre-treatment with piperonyl butoxide did not synergize spiromesifen, suggesting a target-site resistance mechanism. The full length ACCase gene was sequenced for a range of T. vaporariorum strains and a strong association was found between spiromesifen resistance and a glutamic acid substitution with lysine in position 645 (E645K) of this gene. A TaqMan allelic discrimination assay confirmed these findings. Although this resistance is not considered sufficient to compromise the field performance of spiromesifen, this association of E645K with resistance is the first report of a potential target site mechanism affecting an ACCase inhibitor in an arthropod species.
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Acetil-CoA Carboxilasa/genética , Sustitución de Aminoácidos/genética , Hemípteros/enzimología , Hemípteros/genética , Resistencia a los Insecticidas/genética , Insecticidas/toxicidad , Compuestos de Espiro/toxicidad , Acetil-CoA Carboxilasa/química , Acetil-CoA Carboxilasa/metabolismo , Alelos , Secuencia de Aminoácidos , Animales , Secuencia Conservada/genética , Femenino , Hemípteros/efectos de los fármacos , Resistencia a los Insecticidas/efectos de los fármacos , Larva/enzimología , Masculino , Datos de Secuencia Molecular , Butóxido de Piperonilo/toxicidad , Mutación Puntual/genética , Estructura Terciaria de Proteína , Alineación de Secuencia , Análisis de Secuencia de Proteína , Análisis de SupervivenciaRESUMEN
AIM: To quantify the proportion of children who develop dystonia after acquired brain injury (ABI) admitted to a tertiary paediatric intensive care unit (PICU) and analyse the trajectory of dystonia over a 6 month period. METHODS: Children's Health Ireland at Temple Street PICU electronic database was searched for key terms related to ABI from January 1, 2016 to March 14, 2021. Individuals meeting inclusion criteria were analysed, and clinical data pertinent to ABI, dystonia, treatment and outcomes were reviewed. RESULTS: Six-hundred and forty-three PICU episodes (580 patients) met search criteria for ABI, with 379 included in the final analysis. Twelve patients developed dystonia following ABI, giving an incidence of 3.2%. The incidence was higher in the hypoxia/anoxia and TBI cohort at 8.3% and 6.2%, respectively. All patients developed dystonia within the first month following ABI (50% by a week). Patients who developed dystonia compared to non-dystonia cohort had a median lower GCS on admission (4.5 versus 7.0, p value 0.032), longer median length of PICU stay (14.0 versus 3.0 days, p value < 0.001) and were older (median age 9.08 versus 4.68 years, p value 0.06). Dystonia persisted in the majority at 6 months (10/11), requiring on-going medical therapies. CONCLUSION: In our retrospective study, the estimated incidence of dystonia following ABI admitted to the PICU was 3.2%, highest in the hypoxia/anoxia (8.3%) and TBI (6.2%) cohorts. Dystonia emerged early and persisted at 6 months in the majority. This is the first review of dystonia, clinical trajectory and outcomes conducted post-PICU admission for ABI. Future prospective studies are required to determine the true prevalence and burden of disease in the PICU setting.
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Lesiones Encefálicas , Trastornos Distónicos , Niño , Humanos , Lactante , Estudios Retrospectivos , Tiempo de Internación , Unidades de Cuidado Intensivo Pediátrico , HipoxiaRESUMEN
A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1, and a p (Pro222Leu) variant in PRKRA, respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in â¼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis.
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The brown planthopper, Nilaparvata lugens, is an economically significant pest of rice throughout Asia and has evolved resistance to many insecticides including the neonicotinoid imidacloprid. The resistance of field populations of N. lugens to imidacloprid has been attributed to enhanced detoxification by cytochrome P450 monooxygenases (P450s), although, to date, the causative P450(s) has (have) not been identified. In the present study, biochemical assays using the model substrate 7-ethoxycoumarin showed enhanced P450 activity in several resistant N. lugens field strains when compared with a susceptible reference strain. Thirty three cDNA sequences encoding tentative unique P450s were identified from two recent sequencing projects and by degenerate PCR. The mRNA expression level of 32 of these was examined in susceptible, moderately resistant and highly resistant N. lugens strains using quantitative real-time PCR. A single P450 gene (CYP6ER1) was highly overexpressed in all resistant strains (up to 40-fold) and the level of expression observed in the different N. lugens strains was significantly correlated with the resistance phenotype. These results provide strong evidence for a role of CYP6ER1 in the resistance of N. lugens to imidacloprid.
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Sistema Enzimático del Citocromo P-450/metabolismo , Hemípteros/enzimología , Imidazoles , Proteínas de Insectos/metabolismo , Insecticidas , Nitrocompuestos , Secuencia de Aminoácidos , Animales , Sistema Enzimático del Citocromo P-450/genética , ADN Complementario/química , Femenino , Dosificación de Gen , Hemípteros/genética , Proteínas de Insectos/genética , Resistencia a los Insecticidas/genética , Datos de Secuencia Molecular , Neonicotinoides , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Difficulties in inhibition and self-monitoring are early features of incipient Alzheimer's disease and may manifest as susceptibility to proactive semantic interference. However, due to limitations of traditional memory assessment paradigms, recovery from interference effects following repeated learning opportunities has not been explored. OBJECTIVE: This study employed a novel computerized list learning test consisting of repeated learning trials to assess recovery from proactive and retroactive semantic interference. DESIGN: The design was cross-sectional. SETTING: Participants were recruited from the community as part of a longitudinal study on normal and abnormal aging. PARTICIPANTS: The sample consisted of 46 cognitively normal individuals and 30 participants with amnestic mild cognitive impairment. MEASUREMENTS: Participants were administered the Cognitive Stress Test and traditional neuropsychological measures. Step-wise logistic regression was applied to determine which Cognitive Stress Test measures best discriminated between diagnostic groups. This was followed by receiver operating characteristic analyses. RESULTS: Cued A3 recall, Cued B3 recall and Cued B2 intrusions were all independent predictors of diagnostic status. The overall predictive utility of the model yielded 75.9% sensitivity, 91.1% specificity, and an overall correct classification rate of 85.1%. When these variables were jointly entered into receiver operating characteristic analyses, the area under the curve was .923 (p<.001). CONCLUSIONS: This novel paradigm's use of repeated learning trials offers a unique opportunity to assess recovery from proactive and retroactive semantic interference. Participants with mild cognitive impairment exhibited a continued failure to recover from proactive interference that could not be explained by mere learning deficits.
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Cognición/fisiología , Disfunción Cognitiva/psicología , Aprendizaje/fisiología , Memoria/fisiología , Semántica , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
Cloned CTLs show an unusually high resistance to lysis by effector CTLs. Several cloned CTL lines in our laboratories are absolutely refractory to lysis by other cloned CTLs, either (a) directly, (b) in the presence of lectin, or (c) by PMA-induced CTLs. They can be lysed to some extent by primary CTL, although they are less than 5% as sensitive as target cells normally used to assay primary CTL lytic activity. Lysis of cloned CTLs by primary CTL effector cells is not enhanced by the presence of lectin, and cloned T cells are also highly resistant to lysis by primary lymphokine-activated killer cells. Cloned CTLs are highly resistant to lysis by isolated CTL granules that contain the membranolytic pore-forming protein (PFP or perforin), while non-CTL targets are highly susceptible to granule-mediated killing, indicating that cloned CTLs resist lysis not only at the intact effector cell level but also when soluble effector proteins are used. This resistance mechanism may explain how CTLs kill but spare themselves from being killed during the cytolytic event.
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Citotoxicidad Celular Dependiente de Anticuerpos , Células Clonales/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Supervivencia Celular , Éteres/farmacología , Antígenos H-2/análisis , Ionomicina , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
We developed new methods for analyzing inheritance of insecticide resistance in haplodiploid arthropods and applied them to elucidate resistance of the whitefly Bemisia tabaci (Gennadius) to an insect growth regulator, pyriproxyfen. Two invasive biotypes of this devastating crop pest, the B biotype in Arizona and the Q biotype in Israel, have evolved resistance to pyriproxyfen. Here, we incorporated data from laboratory bioassays and crossing procedures exploiting haplodiploidy into statistical and analytical models to estimate the number of loci affecting pyriproxyfen resistance in strains of both biotypes. In tests with models of one to ten loci, the best fit between expected and observed mortality occurred with a two-locus model for the B biotype strain (QC-02) and for one- and two-locus models for the Q biotype strain (Pyri-R). The estimated minimum number of loci affecting resistance was 1.6 for the B biotype strain and 1.0 for the Q biotype strain. The methods used here can be applied to insecticide resistance and other traits in haplodiploid arthropods.
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Hemípteros/genética , Patrón de Herencia/genética , Resistencia a los Insecticidas/genética , Animales , Bioensayo , Hemípteros/efectos de los fármacos , Hemípteros/fisiología , Hormonas Juveniles/toxicidad , Dosificación Letal Mediana , Modelos Genéticos , Piridinas/toxicidad , Especificidad de la EspecieRESUMEN
BACKGROUND: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. CONCLUSIONS: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.
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Ataxia/genética , Canal de Sodio Activado por Voltaje NAV1.2/genética , Acetazolamida/uso terapéutico , Adulto , Anticonvulsivantes/uso terapéutico , Ataxia/tratamiento farmacológico , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , MutaciónRESUMEN
BACKGROUND: A series of monozygotic (MZ) twin pairs discordant for premature ovarian failure presented an unusual opportunity to study ovarian transplantation. METHODS: Ten MZ twin pairs requested ovarian transplantation and eight have undergone transplantation with cryopreservation of spare tissue. Seven had a fresh cortical tissue transplant, one of whom received a second frozen-thawed transplant after the first ceased functioning at three years. One had a fresh microvascular transplant. RESULTS: All recipients reinitiated ovulatory menstrual cycles and normal Day 3 serum FSH levels by 77-142 days. Six have already conceived naturally (one twice). Currently, two healthy babies have been delivered, and another three pregnancies are ongoing. The oldest transplant functioned for 36 months, resulting in one child and one miscarriage. She conceived again after a frozen-thawed secondary transplant. There was no apparent difference in return of ovarian function between the eight fresh ovarian grafts and the one frozen graft. CONCLUSIONS: Ovarian transplantation appears to restore ovulatory function robustly. Successful pregnancies, including one after cryopreservation, bode well for application to fertility preservation.
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Criopreservación/métodos , Ovario/trasplante , Insuficiencia Ovárica Primaria/cirugía , Gemelos Monocigóticos , Adulto , Femenino , Humanos , Menstruación , Ovario/irrigación sanguínea , Ovario/fisiología , Embarazo , Índice de EmbarazoRESUMEN
In 2016, two research groups independently identified microdeletions and pathogenic variants in the lysine-specific histone methyltransferase 2B gene, KMT2B in patients with early-onset progressive dystonia. KMT2B-dystonia (DYT28) is emerging as an important and frequent cause of childhood-onset progressive generalised dystonia and is estimated to potentially account for up to 10% of early-onset generalised dystonia. Herein, we review variants in KMT2B associated with dystonia, as well as the clinical phenotype, treatment and underlying disease mechanisms. Furthermore, in context of this newly identified condition, we summarise our approach to the genetic investigation of paediatric dystonia.
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Trastornos Distónicos/genética , N-Metiltransferasa de Histona-Lisina/genética , Niño , Femenino , Humanos , Mutación , FenotipoRESUMEN
CG----TA transitions at CpG sequences account for many human point mutations and are thought to result from hydrolytic deamination of 5-methylcytosine residues in these sites. The gene for regulatory subunit of murine cyclic AMP-dependent protein kinase has two closely linked CpG sites, one of which is a strong hotspot for spontaneous CG----TA mutations leading to cyclic AMP resistance in S49 mouse lymphoma cells. About 5% of mutants with a spontaneous mutation at this CpG site had also acquired a second CG----TA mutation at the nearby CpG site. The two mutations were always at first positions of the Arg codons in which they occurred, and they were always together in a single regulatory subunit allele. Their linked appearance could be attributed to neither the selection conditions nor the preexistence of one mutation in the target cells. The high frequency of these double mutants suggests that their lesions result not from hydrolytic deamination but rather from an endogenous enzymatic mechanism.
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Fosfatos de Dinucleósidos/genética , Proteínas Quinasas/genética , Animales , Arginina/genética , Secuencia de Bases , Clonación Molecular , Codón/genética , AMP Cíclico/metabolismo , Electroforesis en Gel Bidimensional , Cinética , Ratones , Datos de Secuencia Molecular , Mutación/genética , Proteínas Quinasas/metabolismo , Células Tumorales CultivadasRESUMEN
A series of mutant cell lines (Kin) were previously isolated from Y1 adrenocortical tumor cells based on their ability to resist the growth-inhibitory effects of 8-bromo cAMP. In these Kin clones, cAMP-dependent protein kinase (cAMPdPK) was resistant to activation by cAMP as the consequence of mutations affecting the type I regulatory subunit (RI) of the enzyme. This study shows that the cAMP-resistant phenotypes of mutant clones Kin-2, Kin-7, and Kin-8 were associated with single base changes causing substitutions, respectively, of Glu for Gly200, Trp for Arg334, and Asp for Gly324 in the RI protein. By expressing the mutant Trp334 and Asp324 forms of RI under the control of an inducible promoter in Y1 cells, the causal relationship between these RI mutations and impairment of cAMP-stimulated adrenocortical responses was studied. Expression of the mutant RI forms rendered cAMPdPK resistant to activation by cAMP and decreased cAMP-stimulated cell rounding, steroid production, and growth inhibition. These observations indicate that the cAMP-resistant phenotype of Kin mutant clones resulted specifically from single mutational events in RI and thus establish the importance of cAMPdPK as an essential regulator of adrenocortical function. Unlike the original Kin mutant clones, transformants expressing the mutant forms of RI had adenylyl cyclases that were resistant to activation by ACTH, forskolin, or sodium fluoride. These results indicate that there may be a hitherto unappreciated mechanism of regulation of adenylyl cyclase activity by cAMPdPK.
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Neoplasias de la Corteza Suprarrenal/patología , AMP Cíclico/farmacología , Mutación , Proteínas Quinasas/genética , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Adenilil Ciclasas/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Animales , Secuencia de Bases , Northern Blotting , División Celular/efectos de los fármacos , ADN/genética , Humanos , Ratones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Proteínas Quinasas/metabolismo , Sulfatos/farmacología , Células Tumorales Cultivadas , Zinc/farmacología , Sulfato de ZincRESUMEN
Mean plasma GH concentrations increase in normal boys during mid- to late-puberty. To investigate the nature of the pituitary secretory events and/or altered metabolic clearance responsible for these serum GH concentration changes, we performed multiple-parameter deconvolution analysis of 46 24-h serum GH concentration-time series obtained from normal boys at various stages of puberty and young adulthood. The subjects ranged in chronological age from 7-27 yr. The height and weight of each subject were between the 5th and 95th percentile for age. The calculated daily mass of GH secreted was greatest (P less than 0.001) in late pubertal boys (mean +/- SE, 1810 +/- 250 micrograms/24 h) and was triple the value in prepubertal boys (610 +/- 65 micrograms/24 h). When the values were normalized and expressed as mass of GH secreted per unit (m2) body surface area or per L distribution volume, GH secretion in late pubertal boys was still significantly greater than that in any other group (P less than 0.05). These values for late pubertal boys were nearly double the corresponding values for prepubertal boys (1160 +/- 160 vs. 600 +/- 58 micrograms GH/m2.24 h and 440 +/- 63 vs. 270 +/- 25 micrograms GH/L vol.24 h, respectively). When the effect of clearance mechanics on serum GH concentrations was removed mathematically, the primary change in predicted GH secretory burst parameters during pubertal development was an increase in GH mass released per burst resulting from an increase in the maximal rate of GH secretion attained within the bursts. These changes in the amplitude of GH release events were specific, in that they were largely independent of any accompanying alterations in duration or frequency of the GH secretory bursts or in serum GH half-life. Correlation analysis revealed that the 24-h GH secretion rate varied inversely with the subjects' body mass index SD score (r = -0.65; P less than 0.01), suggesting that differences in body mass, even within the normal range, contribute to the wide variability in daily GH secretion rates among normally growing children. The plasma insulin-like growth factor-I concentrations of all subjects correlated positively with the calculated 24-h GH secretion rate (r = 0.51; P less than 0.001). In summary, the primary neuroendocrine alteration responsible for the augmented serum GH concentrations characterizing mid- to late-puberty in boys is an increased mass of GH released per pituitary secretory episode resulting from an increased maximal rate of GH secretion within each burst.(ABSTRACT TRUNCATED AT 400 WORDS)
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Peso Corporal , Hormona del Crecimiento/metabolismo , Pubertad/fisiología , Adolescente , Adulto , Factores de Edad , Niño , Humanos , Masculino , Tasa de Depuración Metabólica , Valores de ReferenciaRESUMEN
In an effort to determine the total one-year cost of liver transplantation, the underlying drivers of that cost, and any cost differences between alternative immunosuppressive regimens, an analysis was performed comparing the average one-year posttransplant charges of 322 patients participating in the "U.S. Multi-center Prospective Randomized Trial Comparing FK-506 to Cyclosporine in Liver Transplantation." Total one-year inpatient charges including all readmissions were examined. Professional fees and outpatient charges were excluded. Costs for tacrolimus drug and blood assays were assumed to be equal to those in the CsA group. For patients completing the study, the tacrolimus group had an average length of stay and average one-year cost seven days (P = .06) and $19,290 (P = .05) lower than the CsA group. The difference in rejection profiles between the two arms seems to largely account for the lower costs. The tacrolimus arm consistently had fewer patients in the more severe rejection groups. Increased incidence and severity of rejection were directly related to higher average lengths of stay and costs of transplantation (P < .001). Tacrolimus immunosuppression during the first year after liver transplantation is more cost-effective than CsA in achieving similar patient and graft survival rates. Differing incidence and severity of rejection can dramatically affect the first-year cost of liver transplantation.
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Ciclosporina/uso terapéutico , Costos de la Atención en Salud , Inmunosupresores/uso terapéutico , Trasplante de Hígado/economía , Tacrolimus/uso terapéutico , Análisis Costo-Beneficio , Rechazo de Injerto , Humanos , Tiempo de InternaciónRESUMEN
One of the primary manifestations of ageing is a reduced ability to respond to physiologic challenges. With aging, the ability to perform exercise and physical work declines and is reflected in the reduction in maximal oxygen consumption. Although this decline is influenced to some degree by the state of health and age, it seems that maintenance of regular physical activity significantly counteracts the loss of aerobic capacity. In healthy old age, the cardiovascular system is able to compensate for certain age-associated declines in cardiac function. A program of endurance training, even when begun in old age, can restore more youthful levels of physical fitness and results in tangible improvements in certain resting, submaximal and maximal indicators of exercise capacity. With comprehensive preexercise clinical screening, physical training can be conducted safely with minimal musculoskeletal problems in the aged. The long-term effects of exercise on morbidity, mortality and psychologic function in old age are unknown.
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Anciano , Esfuerzo Físico , Adulto , Envejecimiento , Anaerobiosis , Presión Sanguínea , Gasto Cardíaco , Femenino , Humanos , Lactatos/sangre , Ácido Láctico , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Educación y Entrenamiento Físico , Volumen SistólicoRESUMEN
Because of the low abundance of the two major isoforms (C alpha and C beta) of catalytic (C) subunit of cAMP-dependent protein kinase, it has been difficult to monitor their expression and virtually impossible to quantify their synthesis, phosphorylation, and turnover in intact mammalian cells. We now describe sensitive and quantitative immunochemical methods using a goat antibody raised against the recombinant C alpha isoform of murine C subunit that enable studies of the expression and metabolism of C subunit in cultured cells. The antibody reacts well with C alpha and C beta isoforms of murine C subunit and with C subunits from rat, hamster, and human cell lines, so it should have widespread utility. Immunoreactivity with bovine heart C subunit was substantially weaker. For quantitation of C subunit radioactivity in extracts of cells labeled metabolically with [35S]methionine, we developed a two-cycle immunoadsorption protocol that reduces nonspecific adsorption to negligible levels. A tritium-labeled, truncated C subunit marker protein is added to extracts as an internal marker to monitor C subunit recoveries in different samples. For analysis of expression of C subunit isoforms in different cells or tissues, we describe a nonradioactive Western immunoblot procedure that can quantitate C subunit in amounts as low as 12 pg. Using extraction conditions that either stabilize or destabilize the phosphate on Thr-197, we show how the relative expression and phosphorylation of C alpha and C beta isoforms can be estimated from SDS-gel patterns resulting from either immunoblot or immunoadsorption procedures.