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1.
Mol Genet Metab ; 142(1): 108455, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38531184

RESUMO

Creatine transporter deficiency has been described with normal or uninformative levels of creatine and creatinine in plasma, while urine has been the preferred specimen type for biochemical diagnosis. We report a cohort of untreated patients with creatine transporter deficiency and abnormal plasma creatine panel results, characterized mainly by markedly decreased plasma creatinine. We conclude that plasma should be considered a viable specimen type for the biochemical diagnosis of this disorder, and abnormal results should be followed up with further confirmatory testing.


Assuntos
Encefalopatias Metabólicas Congênitas , Creatina , Creatina/deficiência , Creatinina , Deficiência Intelectual Ligada ao Cromossomo X , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Humanos , Creatina/sangue , Creatina/urina , Creatinina/sangue , Creatinina/urina , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/sangue , Masculino , Feminino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Criança , Pré-Escolar , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/deficiência , Lactente , Adolescente , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/sangue , Adulto
2.
Mol Genet Metab ; 143(1-2): 108564, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39216211

RESUMO

Transferrin isoform analysis is an established laboratory test for congenital disorders of glycosylation (CDG). Despite its long history of clinical use, little has been published about its empirical sensitivity for specific conditions. We conducted a retrospective analysis of ten years of testing data and report our experience with transferrin testing for type I profiles and its sensitivity for the most common congenital disorder of glycosylation, PMM2-CDG. The data demonstrate 94% overall test sensitivity for PMM2-CDG and importantly demonstrate two known, recurrent variants enriched in false positive cases highlighting an important limitation of the test. The data confirm the clinical validity of transferrin isotype analysis as a screening test for disorders of protein N-linked glycosylation and as functional test for PMM2 genotypes of uncertain significance.


Assuntos
Defeitos Congênitos da Glicosilação , Fosfotransferases (Fosfomutases) , Isoformas de Proteínas , Transferrina , Humanos , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Transferrina/metabolismo , Transferrina/análise , Transferrina/genética , Estudos Retrospectivos , Fosfotransferases (Fosfomutases)/deficiência , Fosfotransferases (Fosfomutases)/genética , Isoformas de Proteínas/genética , Glicosilação , Sensibilidade e Especificidade , Genótipo
3.
Am J Med Genet A ; 191(3): 842-845, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36495139

RESUMO

Biallelic pathogenic variants in the COASY gene have been associated with two distinct disease phenotypes, that is, COASY-protein associated neurodegeneration (CoPAN) and pontocerebellar hypoplasia type 12 (PCH 12). We present two siblings that independently presented with significant hypotonia and respiratory insufficiency at birth. Comprehensive genetic testing revealed homozygous variants within COASY, however, the progressive clinical and neuroradiologic findings described here are unique and have not been described previously. Magnetic resonance imaging showed progressive diffuse parenchymal loss throughout the bilateral cerebral hemispheres and atrophy of the basal ganglia and brainstem. As such, this article brings forth two additional cases of COASY-related disorder with abnormal newborn screening acylcarnitine profiles resembling carnitine palmitoyl transferase 1a (CPT1a) deficiency in two siblings who presented at birth with contractures, marked hypotonia and absent respiratory drive.


Assuntos
Doenças do Sistema Nervoso Central , Doenças Neurodegenerativas , Humanos , Hipotonia Muscular/genética , Irmãos , Encéfalo/diagnóstico por imagem , Atrofia/genética , Fenótipo , Imageamento por Ressonância Magnética , Transferases
4.
J Inherit Metab Dis ; 46(6): 1159-1169, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37747296

RESUMO

Measurement of plasmalogens is useful for the biochemical diagnosis of rhizomelic chondrodysplasia punctata (RCDP) and is also informative for Zellweger spectrum disorders (ZSD). We have developed a test method for the simultaneous quantitation of C16:0, C18:0, and C018:1 plasmalogen (PG) species and their corresponding fatty acids (FAs) in dried blood spots (DBS) and erythrocytes (RBC) by using capillary gas chromatography-mass spectrometry. Normal reference ranges for measured markers and 10 calculated ratios were established by the analysis of 720 and 473 unaffected DBS and RBC samples, respectively. Determination of preliminary disease ranges was made by using 45 samples from 43 unique patients: RCDP type 1 (DBS: 1 mild, 17 severe; RBC: 1 mild, 6 severe), RCDP type 2 (DBS: 2 mild, 1 severe; RBC: 2 severe), RCDP type 3 (DBS: 1 severe), RCDP type 4 (RBC: 2 severe), and ZSD (DBS: 3 severe; RBC: 2 mild, 7 severe). Postanalytical interpretive tools in Collaborative Laboratory Integrated Reports (CLIR) were used to generate an integrated score and a likelihood of disease. In conjunction with a review of clinical phenotype, phytanic acid, and very long-chain FA test results, the CLIR analysis allowed for differentiation between RCDP and ZSD. Data will continue to be gathered to improve CLIR analysis as more samples from affected patients with variable disease severity are analyzed. The addition of DBS analysis of PGs may allow for at-home specimen collection and second-tier testing for newborn screening programs.


Assuntos
Condrodisplasia Punctata Rizomélica , Transtornos Peroxissômicos , Síndrome de Zellweger , Recém-Nascido , Humanos , Plasmalogênios , Condrodisplasia Punctata Rizomélica/genética , Transtornos Peroxissômicos/diagnóstico , Ácido Fitânico
5.
J Med Genet ; 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35790351

RESUMO

PURPOSE: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. METHODS: Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. RESULTS: Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. CONCLUSION: The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

6.
Pharmacol Res ; 182: 106329, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35772645

RESUMO

Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials.


Assuntos
Neoplasias Hepáticas , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/patologia , Linfócitos T , Microambiente Tumoral
7.
J Surg Res ; 280: 114-122, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35964483

RESUMO

INTRODUCTION: The rate of mastectomy in lumpectomy-eligible patients with unilateral breast cancer is increasing. We sought to investigate the association between magnetic resonance imaging (MRI) and surgical management of patients with early-stage breast cancer by comparing the rate of mastectomy as first surgery in patients with and without preoperative MRI. METHODS: A bi-institutional retrospective study included patients diagnosed between 2016 and 2020. Lumpectomy-eligible patients with in situ and invasive cancer were included. Those receiving preoperative therapy, MRI before diagnosis, or with known bilateral cancer were excluded. The risk factors for bilateral and multicentric disease were accounted for. Fisher's exact and chi-square tests compared categorical variables, Wilcoxon two-sample test analyzed continuous variables, and multivariate analyses were performed with Poisson regression. RESULTS: Four hundred twenty-eight participants met inclusion criteria. Patients who received MRI were younger (58 versus 67 y; P < 0.001) and had denser breasts (group 3 or 4; 61% versus 25%; P < 0.001). Mastectomy rate was twice as high in patients undergoing MRI (32% versus 15%, rate ratio 2.16; P < 0.001), which remained significant in multivariate analysis (rate ratio 2.0; P < 0.001). Contralateral mastectomy (12% versus 4%; P = 0.466) and reexcision (13% versus 12%; P = 0.519) rates were similar. Time to surgery was greater in those receiving MRI alone and MRI biopsy (34 [no MRI] versus 45 [MRI] versus 62 [MRI biopsy]; P < 0.001 for both). CONCLUSIONS: MRI receipt is associated with a doubled rate of mastectomy in lumpectomy-eligible patients. Future work is needed to standardize patient selection for MRI to those with the highest likelihood of having additional undiagnosed disease.


Assuntos
Neoplasias da Mama , Mastectomia , Humanos , Feminino , Mastectomia/métodos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Mastectomia Segmentar , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Cuidados Pré-Operatórios
8.
Am J Hum Genet ; 102(6): 1158-1168, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861105

RESUMO

ßIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into ßIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na+ channels and no nodal KCNQ2 K+ channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and ßI spectrin can cluster Na+ channels and partially compensate for the loss of AnkG and ßIV spectrin at nodes of Ranvier, AnkR and ßI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K+ channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction.


Assuntos
Axônios/patologia , Deficiência Intelectual/genética , Doença dos Neurônios Motores/genética , Hipotonia Muscular/congênito , Hipotonia Muscular/genética , Proteínas do Tecido Nervoso/genética , Espectrina/genética , Alelos , Animais , Axônios/metabolismo , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Lipídeos , Masculino , Camundongos Knockout , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/fisiopatologia , Hipotonia Muscular/complicações , Hipotonia Muscular/fisiopatologia , Proteínas Mutantes/metabolismo , Mutação/genética , Ratos Sprague-Dawley
9.
Genet Med ; 22(6): 1108-1118, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32089546

RESUMO

PURPOSE: Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations. METHODS: PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry. RESULTS: Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT). CONCLUSION: This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.


Assuntos
Leucodistrofia de Células Globoides , Psicosina , Teste em Amostras de Sangue Seco , Galactosilceramidase/genética , Humanos , Recém-Nascido , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/genética , Triagem Neonatal
10.
Mol Genet Metab ; 129(2): 106-110, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31753749

RESUMO

PURPOSE: To describe an efficient and effective multiplex screening strategy for sulfatide degradation disorders and mucolipidosis type II/III (MLII/III) using 3 mL of urine. METHODS: Glycosaminoglycans were analyzed by liquid chromatography-tandem mass spectrometry. Matrix assisted laser desorption/ionization-time of flight tandem mass spectrometry was used to identify free oligosaccharides and identify 22 ceramide trihexosides and 23 sulfatides, which are integrated by 670 calculated ratios. Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) was used for post-analytical interpretation of the complex metabolite profile and to aid in the differential diagnosis of abnormal results. RESULTS: Multiplex analysis was performed on 25 sulfatiduria case samples and compiled with retrospective data from an additional 15 cases revealing unique patterns of biomarkers for each disorder of sulfatide degradation (MLD, MSD, and Saposin B deficiency) and for MLII/III, thus allowing the formulation of a novel algorithm for the biochemical diagnosis of these disorders. CONCLUSIONS: Comprehensive and integrated urine screening could be very effective in the initial workup of patients suspected of having a lysosomal disorder as it covers disorders of sulfatide degradation and narrows down the differential diagnosis in patients with elevated glycosaminoglycans.


Assuntos
Glicosaminoglicanos/urina , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/urina , Mucolipidoses/diagnóstico , Sulfoglicoesfingolipídeos/urina , Adolescente , Adulto , Algoritmos , Biomarcadores/urina , Criança , Pré-Escolar , Cromatografia Líquida , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mucolipidoses/urina , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Adulto Jovem
11.
Bioorg Med Chem Lett ; 28(14): 2451-2453, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29907393

RESUMO

Successful implementation of mRNA gene therapy is facing many hurdles, for example poor expression levels of the exogenously delivered mRNA transcripts. Herein we describe the synthesis of various 3'-modified RNA oligonucleotides, and we show that 3'-modification drastically stabilizes these oligonucleotides in cell extracts. Modification of the 3'-terminus of gaussia luciferase mRNA results in 3-fold increased and extended (>48 h) translation of the mRNA. Our findings suggest 3'-modification of RNA-transcripts as a valid approach to increase expression levels for application in mRNA gene therapy.


Assuntos
Terapia Genética , RNA Mensageiro/genética , Transcrição Gênica/genética , Animais , Copépodes/enzimologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Luciferases/genética , Luciferases/metabolismo , Estrutura Molecular , Oligonucleotídeos/síntese química , Oligonucleotídeos/química , Oligonucleotídeos/genética , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
12.
J Extra Corpor Technol ; 47(4): 245-50, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26834290

RESUMO

During orientation to the cardiac surgery operating room, new staff may not be exposed to emergent situations. Allowing team members the opportunity to practice their roles during less common, high-stakes emergency cardiac surgical scenarios may better prepare them when crises do arise in the OR. The Emergency Cardiopulmonary Bypass Course was developed to meet the needs of new staff starting in cardiac surgery. Recently, the course has expanded to include experienced staff. This communication describes a high fidelity simulation based course that includes four emergent cardiac surgery scenarios.


Assuntos
Procedimentos Cirúrgicos Cardíacos/educação , Ponte Cardiopulmonar/educação , Humanos
13.
RNA ; 18(3): 557-68, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22294662

RESUMO

Since the discovery of RNA interference (RNAi), researchers have identified a variety of small interfering RNA (siRNA) structures that demonstrate the ability to silence gene expression through the classical RISC-mediated mechanism. One such structure, termed "Dicer-substrate siRNA" (dsiRNA), was proposed to have enhanced potency via RISC-mediated gene silencing, although a comprehensive comparison of canonical siRNAs and dsiRNAs remains to be described. The present study evaluates the in vitro and in vivo activities of siRNAs and dsiRNAs targeting Phosphatase and Tensin Homolog (PTEN) and Factor VII (FVII). More than 250 compounds representing both siRNA and dsiRNA structures were evaluated for silencing efficacy. Lead compounds were assessed for duration of silencing and other key parameters such as cytokine induction. We identified highly active compounds from both canonical siRNAs and 25/27 dsiRNAs. Lead compounds were comparable in potency both in vitro and in vivo as well as duration of silencing in vivo. Duplexes from both structural classes tolerated 2'-OMe chemical modifications well with respect to target silencing, although some modified dsiRNAs demonstrated reduced activity. On the other hand, dsiRNAs were more immunostimulatory as compared with the shorter siRNAs, both in vitro and in vivo. Because the dsiRNA structure does not confer any appreciable benefits in vitro or in vivo while demonstrating specific liabilities, further studies are required to support their applications in RNAi therapeutics.


Assuntos
Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ribonuclease III/metabolismo , Animais , Sequência de Bases , Fator VII/genética , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/genética , Complexo de Inativação Induzido por RNA/metabolismo , Ratos
14.
Proc Natl Acad Sci U S A ; 108(34): 14163-8, 2011 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-21844366

RESUMO

Mir-290 through mir-295 (mir-290-295) is a mammalian-specific microRNA (miRNA) cluster that, in mice, is expressed specifically in early embryos and embryonic germ cells. Here, we show that mir-290-295 plays important roles in embryonic development as indicated by the partially penetrant lethality of mutant embryos. In addition, we show that in surviving mir-290-295-deficient embryos, female but not male fertility is compromised. This impairment in fertility arises from a defect in migrating primordial germ cells and occurs equally in male and female mutant animals. Male mir-290-295(-/-) mice, due to the extended proliferative lifespan of their germ cells, are able to recover from this initial germ cell loss and are fertile. Female mir-290-295(-/-) mice are unable to recover and are sterile, due to premature ovarian failure.


Assuntos
Perda do Embrião/genética , Perda do Embrião/patologia , Células Germinativas/metabolismo , Células Germinativas/patologia , MicroRNAs/metabolismo , Penetrância , Envelhecimento/patologia , Animais , Animais Recém-Nascidos , Apoptose , Contagem de Células , Ciclo Celular , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Fertilidade/genética , Regulação da Expressão Gênica no Desenvolvimento , Gônadas/crescimento & desenvolvimento , Gônadas/patologia , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Masculino , Camundongos , Camundongos Mutantes , MicroRNAs/genética
15.
HEC Forum ; 26(3): 225-36, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25108391

RESUMO

In this article, I argue that persons suffering from Body Integrity Identity Disorder (BIID) can give informed consent to surgical measures designed to treat this disorder. This is true even if the surgery seems radical or irrational to most people. The decision to have surgery made by a BIID patient is not necessarily coerced, incompetent or uninformed. If surgery for BIID is offered, there should certainly be a screening process in place to insure informed consent. It is beyond the scope of this work, however, to define all the conditions that should be placed on the availability of surgery. However, I argue, given the similarities between BIID and gender dysphoria and the success of such gatekeeping measures for the surgical treatment of gender dysphoria, it is reasonable that similar conditions be in place for BIID. Once other treatment options are tried and gatekeeping measures satisfied, A BIID patient can give informed consent to radical surgery.


Assuntos
Amputação Cirúrgica/ética , Transtornos Dismórficos Corporais/psicologia , Consentimento Livre e Esclarecido/psicologia , Humanos
16.
Commun Biol ; 7(1): 980, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39134612

RESUMO

Animal vigilance is often investigated under a narrow set of scenarios, but this approach may overestimate its contribution to animal lives. A solution may be to sample all looking behaviours and investigate numerous competing hypotheses in a single analysis. In this study, using a wild group of habituated chacma baboons (Papio ursinus griseipes) as a model system, we implemented a framework for predicting the key drivers of looking by comparing the strength of a full array of biological hypotheses. This included methods for defining individual-specific social threat environments, quantifying individual tolerance to human observers, and incorporating predator resource selection functions. Although we found evidence supporting reactionary and within-group (social) vigilance hypotheses, risk factors did not predict looking with the greatest precision, suggesting vigilance was not a major component of the animals' behavioural patterns generally. Instead, whilst some behaviours constrain opportunities for looking, many shared compatibility with looking, alleviating the pressure to be pre-emptively vigilant for threats. Exploring looking patterns in a thorough multi-hypothesis framework should be feasible across a range of taxa, offering new insights into animal behaviour that could alter our concepts of fear ecology.


Assuntos
Comportamento Animal , Medo , Papio ursinus , Animais , Masculino , Papio ursinus/fisiologia , Papio ursinus/psicologia , Feminino , Comportamento Social
17.
Mol Genet Metab Rep ; 40: 101110, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39022300

RESUMO

Treatment of phenylketonuria (PKU) has evolved since the initial introduction of a phenylalanine (Phe) restricted diet. The most recent option for adults affected with PKU is treatment with an alternate enzyme, phenylalanine ammonia lyase (PAL), that metabolizes excess Phe. Proper management of all patients with PKU relies on accurate measurement of Phe levels in blood, to comply with guidance intended to minimize the neurological symptoms. Recently, our laboratory was notified of discrepant results for a patient with PKU who is treated with pegvaliase. Two specimens were collected at the same time but yielded unexpectedly different Phe concentrations. After exclusion of specimen mix-ups or analytical errors, we suspected that there was residual pegvaliase activity in the specimens continuing to degrade Phe after collection. To investigate this possibility, we performed spiking studies that showed the degradation of Phe over time at ambient temperatures. Sample preparation by protein crash appears to deactivate pegvaliase and prevents further Phe degradation. However, because pegvaliase deactivation would be required immediately following blood collection, appropriate mitigation measures must be implemented, including stringent pre-analytical requirements, alternate sample matrices such as dried blood spots, or point of care testing. Until then, health care professionals need to be cautious in their interpretation of Phe levels in their patients with PKU that are treated with pegvaliase.

18.
Open Forum Infect Dis ; 11(5): ofae204, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38746950

RESUMO

Background: To end the HIV and hepatitis C virus (HCV) epidemics, people who use drugs (PWUD) need more opportunities for testing. While inpatient hospitalizations are an essential opportunity to test people who use drugs (PWUD) for HIV and HCV, there is limited research on rates of inpatient testing for HIV and HCV among PWUD. Methods: Eleven hospital sites were included in the study. Each site created a cohort of inpatient encounters associated with injection drug use. From these cohorts, we collected data on HCV and HIV testing rates and HIV testing consent policies from 65 276 PWUD hospitalizations. Results: Hospitals had average screening rates of 40% for HIV and 32% for HCV, with widespread heterogeneity in screening rates across facilities. State consent laws and opt-out testing policies were not associated with statistically significant differences in HIV screening rates. On average, hospitals that reflexed HCV viral load testing on HCV antibody testing did not have statistically significant differences in HCV viral load testing rates. We found suboptimal testing rates during inpatient encounters for PWUD. As treatment (HIV) and cure (HCV) are necessary to end these epidemics, we need to prioritize understanding and overcoming barriers to testing.

19.
Front Health Serv ; 3: 1166034, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37720845

RESUMO

This study explored the lived experiences of transitioning from Medicaid to private health insurance upon college graduation. Fifteen recent graduates of an urban, commuter, public college in the Mid-Atlantic were interviewed via Zoom® to understand what they regard as crucial aspects of the transition experience, especially during the COVID pandemic. The subjects all identified as being members of a minority racial or ethnic group, the average age was 33 years (SD = 10.96), and all but one interview subject majored in the health sciences. Every recent graduate reported experiencing difficulty in the transition. Subjects felt unprepared for the transition, alone, and without support. "Copays" was the most common response to questions, frequently said with arms in the air for emphasis, as if the word "copay" summarized all of the lack of preparation, difficulty, and expense of the healthcare system after previously receiving Medicaid (i.e., free healthcare). The findings inform how the private sector should on-board new college graduates. There is a need for Medicaid case officers to better prepare clients for the transition and for human resources personnel in the private sector to sufficiently explain how private health insurance works.

20.
Genet Med ; 14(1): 135-42, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22237443

RESUMO

PURPOSE: Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients. METHODS: Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA. RESULTS: In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts. CONCLUSION: The combination of rituximab with methotrexate ± intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naïve setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy.


Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/imunologia , Doença de Depósito de Glicogênio Tipo II/terapia , Tolerância Imunológica , Anticorpos/imunologia , Linfócitos B/imunologia , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Oligossacarídeos/urina , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/imunologia , alfa-Glucosidases/uso terapêutico
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