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Heavy metal contamination in food and water is a major public health concern because heavy metals are toxic in minute amounts. DNAzyme sensors are emerging as a promising tool for rapid onsite detection of heavy metals, which can aid in minimizing exposure. However, DNAzyme activity toward its target metal is not absolute and has cross-reactivity with similar metals, which is a major challenge in the wide-scale application of DNAzyme sensors for environmental monitoring. To address this, we constructed a four DNAzyme array (17E, GR-5, EtNA, and NaA43) and used a pattern-based readout to improve sensor accuracy. We measured cross-reactivity between three metal cofactors (Pb2+, Ca2+, and Na+) and common interferents (Mg2+, Zn2+, Mn2+, UO22+, Li+, K+, and Ag+) and then used t-SNE analysis to identify and quantify the metal ion. We further showed that this method can be used for distinguishing mixtures of metals and detecting Pb2+ in environmental soil samples at micromolar concentrations.
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ADN Catalítico , Metales Pesados , ADN Catalítico/química , ADN Catalítico/metabolismo , Metales Pesados/análisis , Técnicas Biosensibles/métodos , Monitoreo del Ambiente/métodosRESUMEN
PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
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Fallo Hepático Agudo , Fallo Hepático , Adolescente , Niño , Preescolar , Humanos , Lactante , Adulto Joven , Acetilcisteína/uso terapéutico , Fallo Hepático/tratamiento farmacológico , Fallo Hepático/genética , Fallo Hepático Agudo/tratamiento farmacológico , Fallo Hepático Agudo/genética , Proteínas Mitocondriales/genética , Mutación , Estudios Retrospectivos , ARNt Metiltransferasas/genéticaRESUMEN
San Antonio Water System (SAWS) developed its Aquifer Storage Recovery (ASR) program in the Carrizo aquifer to provide potable water supply reliability for San Antonio during droughts while protecting natural ecosystems and threatened and endangered species at Comal Springs and San Marcos Springs and augmenting downstream flows in the San Antonio River and estuarine ecosystems. It enables SAWS to completely optimize use of its Edwards Aquifer Withdrawal Permit with no wasted water, leveling out seasonal demand stresses on the Edwards aquifer. The SAWS Carrizo ASR wellfield recovery hydraulic capacity was designed to provide 64 million gallons per day (MGD) (0.24 Mm3 /D). However, as built, the briefly tested recovery capacity, in practice, is approximately 80 MGD (Kirk Nixon and Kevin Morrison, verbal communication, 2022). Almost 200,000 acre feet (AF) (247 Mm3 ) of drinking water have been stored to date. The water recovered from storage requires only re-disinfection prior to transmission and distribution to customers. During the period 2011 to 2014, a drought of near record intensity required SAWS to recover a total volume exceeding 50,000 AF (61.7 Mm3 ) over the 4-year period. The ASR wellfield area and H2Oaks treatment facility serve as a central location for integration of two other long-term water supply strategies including desalination of brackish groundwater from the underlying Wilcox aquifer and groundwater production from the local Carrizo aquifer. Several lessons have been learned during 18 years of ASR operation, as addressed in this article.
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Agua Subterránea , Ecosistema , Reproducibilidad de los Resultados , Ríos , Texas , Agua , Abastecimiento de AguaRESUMEN
OBJECTIVES: Although electronic patient portals are offered by most health care organizations, poor usability and poor fit to patient needs may pose barriers to adoption. We collaborated with an academic hospital to conduct iterative user evaluation of a newly deployed portal designed to deliver inpatient data upon hospital discharge. METHODS: Three evaluators applied heuristic usability evaluation and conducted 23 individual user testing sessions with patients with chronic disease or managing the care of family members with chronic disease. Evaluation and development/improvement were conducted iteratively. User testing and analysis of qualitative data were both conducted from the perspective of a task-technology fit framework, to assess the degree of fit between the portal and patient work. RESULTS: Ability to complete health information management tasks, perceived usability, and positive comments from users improved over the course of the iterative development. However, patients still encountered significant difficulties accomplishing certain tasks such as setting up proxy accounts. The problems were most severe when patients did not start with a clear understanding of tasks that they could accomplish. In exploring the portal, novice users frequently described anecdotes from their own medical history or constructed fictional narratives about a hypothetical patient. CONCLUSION: Chronic illness imposes a significant workload on patients, and applying a task-technology framework for evaluation of a patient portal helped improve the portal's fit to patient needs. However, it also revealed that patients often lack a clear understanding of tasks that would help them accomplish personal health information management. Portal developers may need to educate patients about types of patient work involving medical centers, in a way that developers of clinical information systems do not need to do. An approach to doing this might be to provide narratives about hypothetical patients.
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Registros Electrónicos de Salud , Informática Médica , Modelos Teóricos , Portales del Paciente , Adolescente , Adulto , Anciano , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.
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Antineoplásicos/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tiazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Ciclofosfamida/farmacología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Interferón Tipo I/efectos de los fármacos , Interferón Tipo I/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Recurrencia Local de Neoplasia/inmunología , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Tiazoles/farmacologíaRESUMEN
Inhibition of central nervous system axon growth is reportedly mediated in part by calcium-dependent phosphorylation of axonal epidermal growth factor receptor, with local administration of the epidermal growth factor receptor kinase inhibitors AG1478 and PD168393 to an optic nerve lesion site promoting adult retinal ganglion cell axon regeneration. Here, we show that epidermal growth factor receptor was neither constitutively expressed, nor activated in optic nerve axons in our non-regenerating and regenerating optic nerve injury models, a finding that is inconsistent with phosphorylated epidermal growth factor receptor-dependent intra-axonal signalling of central nervous system myelin-related axon growth inhibitory ligands. However, epidermal growth factor receptor was localized and activated within most glia in the retina and optic nerve post-injury, and thus an indirect glial-dependent mechanism for stimulated retinal ganglion cell axon growth by epidermal growth factor receptor inhibitors seemed plausible. Using primary retinal cultures with added central nervous system myelin extracts, we confirmed previous reports that AG1478/PD168393 blocks epidermal growth factor receptor activation and promotes disinhibited neurite outgrowth. Paradoxically, neurites did not grow in central nervous system myelin extract-containing cultures after short interfering ribonucleic acid-mediated knockdown of epidermal growth factor receptor. However, addition of AG1478 restored neurite outgrowth to short interfering ribonucleic acid-treated cultures, implying that epidermal growth factor receptor does not mediate AG1478-dependent effects. TrkA-/B-/C-Fc fusion proteins and the kinase blocker K252a abrogated the neuritogenic activity in these cultures, correlating with the presence of the neurotrophins brain derived neurotrophic factor, nerve growth factor and neurotrophin-3 in the supernatant and increased intracellular cyclic adenosine monophosphate activity. Neurotrophins released by AG1478 stimulated disinhibited retinal ganglion cell axon growth in central nervous system myelin-treated cultures by the induction of regulated intramembraneous proteolysis of p75(NTR) and Rho inactivation. Retinal astrocytes/Müller cells and retinal ganglion cells were the source of neurotrophins, with neurite outgrowth halved in the presence of glial inhibitors. We attribute AG1478-stimulated neuritogenesis to the induced release of neurotrophins together with raised cyclic adenosine monophosphate levels in treated cultures, leading to axon growth and disinhibition by neurotrophin-induced regulated intramembraneous proteolysis of p75(NTR). These off-target effects of epidermal growth factor receptor kinase inhibition suggest a novel therapeutic approach for designing treatments to promote central nervous system axon regeneration.
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Axones , Receptores ErbB/antagonistas & inhibidores , Quinazolinas/farmacología , Células Ganglionares de la Retina , Tirfostinos/farmacología , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animales , Axones/efectos de los fármacos , Axones/fisiología , Axones/ultraestructura , Proliferación Celular , Células Cultivadas , Medios de Cultivo Condicionados/química , AMP Cíclico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Factores de Crecimiento Nervioso/metabolismo , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Neuroglía/citología , Neuroglía/fisiología , Nervio Óptico/citología , Nervio Óptico/metabolismo , Nervio Óptico/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Ratas Wistar , Receptor trkA/genética , Receptor trkA/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptor trkC/genética , Receptor trkC/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/fisiologíaRESUMEN
INTRODUCTION: Potential long-term sequelae of hypospadias and its surgical correction include difficulties in voiding, sexual function, psychosexual adjustment and self-appraisal. These difficulties often evolve long after surgical repair as children grow to adulthood. Despite this, patient-driven data on long-term functional outcomes and satisfaction are limited, leaving the true success of hypospadias surgery essentially unknown. The aim of this study was to address these deficiencies. METHODS: We conducted a chart review for all patients operated on by a single urologist from 1981 to 1988. Extensive efforts were made to obtain accurate current address information for patients. A database of patient demographics and pathology, operative details and complications was created. A 22-item questionnaire was mailed to study subjects. Telephone follow-up by an independent research nurse bolstered response rates. Responses from returned questionnaires were pooled and analyzed. RESULTS: The chart review included 115 patients. Of 100 patients (with address information) who were sent questionnaires, 28 ultimately responded. The chart review group was comparable to groups in other published studies. Despite a slightly higher initial major complication rate (57.2%), respondents reported few long-term complications (11% fistula, 29% persistent chordee and 10% stricture) and excellent urinary and sexual functional results. The most common functional complaints were spraying and hesitancy during micturition. Overall, 86% of patients were satisfied with their surgical result, and 52% wished they had been provided longer follow-up. CONCLUSION: Long-term outcomes data are critical to an honest account of success rates for hypospadias surgery. Obtaining these data remains challenging. In this series, despite high initial complication rates, most patients reported excellent long-term functional results and were quite satisfied with their overall outcome.
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BACKGROUND: In Canada and the United States, the relevance and utility of training objectives as perceived by practising surgeons is rarely examined. We sought to determine if urology residency training objectives reflect the broad realities of urologic practice. METHODS: A survey, based on the Royal College of Physicians and Surgeons of Canada training objectives for urology, was designed and validated. All 418 full-time practising members of the Canadian Urological Association were surveyed. RESULTS: The overall response rate was 63%. Many specialized clinical areas of urology that receive little emphasis in the training objectives were rated as useful by the majority: laparoscopic surgery (92%), percutaneous renal access (86%), transrectal ultrasonography (84%), pediatric urology (81%), extracorporeal shockwave lithotripsy (70%), urethral reconstruction (66%) and adrenal surgery (62%). Microsurgery and transplantation were perceived as less useful (54% and 22% respectively). Virtually all nonsurgical training objectives were regarded as useful components of training; however, in the opinion of the majority of respondents residency did not prepare them for many of these: the challenges of office and hospital administration (91% and 89% not prepared [NP]), building a referral base (67% NP), time management (60% NP) and providing care under financial constraints (60% NP). CONCLUSION: The study results support the current training objectives and indicate areas requiring increased emphasis.
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Competencia Clínica , Internado y Residencia/normas , Urología/educación , Canadá , Competencia Clínica/estadística & datos numéricos , Educación de Postgrado en Medicina/normas , Encuestas de Atención de la Salud , Humanos , Laparoscopía , Objetivos Organizacionales , Encuestas y Cuestionarios , Urología/normasRESUMEN
Renal leiomyoma is a rare smooth muscle tumor of the kidney. An association between Epstein-Barr virus and smooth muscle tumors in immunocompromised patients recently has been recognized. We describe a pediatric renal transplant patient who developed an Epstein-Barr virus-associated renal leiomyoma in his transplant kidney 5 years posttransplantation. Possible factors involved in the tumor pathogenesis in our patient are discussed, including immunosuppression, growth hormone therapy, and Epstein-Barr virus induction.
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Infecciones por Virus de Epstein-Barr/transmisión , Neoplasias Renales/virología , Trasplante de Riñón/efectos adversos , Leiomioma/virología , Complicaciones Posoperatorias/virología , Trasplante Homólogo/efectos adversos , Preescolar , Transmisión de Enfermedad Infecciosa , Femenino , Trastornos del Crecimiento/etiología , Humanos , Hidronefrosis/complicaciones , Riñón/anomalías , Riñón/química , Riñón/patología , Riñón/virología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/fisiopatología , Leiomioma/diagnóstico por imagen , Leiomioma/fisiopatología , Masculino , Persona de Mediana Edad , Nefrectomía , Nefritis Intersticial/etiología , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatología , ARN Viral/análisis , Radiografía , Recurrencia , Diálisis Renal , Ultrasonografía , Uretra/anomalías , Infecciones Urinarias/etiologíaRESUMEN
A seven centimeter supra-renal mass was discovered in a 62-year old patient who presented with gross hematuria and a superficial bladder tumor. The supra-renal mass was resected laparoscopically and the final pathology revealed a benign schwannoma. The epidemiology, diagnostic features and treatment options for this rare peripheral nerve sheath tumor are reviewed.
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Laparoscopía/métodos , Neurilemoma/cirugía , Neoplasias Retroperitoneales/cirugía , Carcinoma de Células Transicionales/complicaciones , Carcinoma de Células Transicionales/cirugía , Femenino , Humanos , Persona de Mediana Edad , Neurilemoma/complicaciones , Neurilemoma/diagnóstico por imagen , Neoplasias Retroperitoneales/complicaciones , Neoplasias Retroperitoneales/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
PURPOSE: In an effort to evaluate the perceived utility of specific Royal College of Physicians and Surgeons of Canada (RCPSC) urology residency training objectives we conducted a survey of the practicing urologists of British Columbia (BC). MATERIALS AND METHODS: A two page semi-structured survey was designed. Validity was evaluated for clarity, content and ease of completion. The survey was mailed-out to all 61 practicing urologists in BC. The survey population was divided into urban, rural, and academic according to location of practice. RESULTS: Survey response rate was 79% with varying subgroup rates: urban-69% (20/29), rural-94% (17/18) and academic 86% (12/14). Specific clinical components of training were rated as "useful" by the majority of all respondents: pediatric urology (93%), laparoscopy (88%), TRUS (77%), percutaneous renal access (74%), urethral surgery (72%), microsurgery (62%). Renal transplantation was rated "not useful" by 74% of respondents. TRUS, percutaneous renal access and adrenal surgery were perceived as useful by the majority of those practicing in rural and non-academic urban centers compared to those in academic centers where the majority rated these skills as "not useful". Virtually all non-clinical components of training were rated as "useful". The majority of respondents felt that residency training prepared them for the following challenges: accepting responsibility for patient care, assessing scientific literature, ethical decision-making and communication. The majority of respondents felt that residency did not prepare them for the following challenges: time and office management, hospital administration and providing care within a constrained system. CONCLUSION: Specific clinical and non-clinical areas of training have high perceived utility in all settings of practice. Certain clinical components of training have high perceived utility only in specific settings of practice. There are many non-clinical components of practice, which are perceived to be important, but for which BC urologists feel inadequately prepared for by their residency training programs. If consistent across Canada, these findings may facilitate a rational approach to the modification of the objectives for urology residency training.
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Competencia Clínica/estadística & datos numéricos , Objetivos , Internado y Residencia/métodos , Percepción Social , Urología/educación , Colombia Británica , Evaluación Educacional , Encuestas de Atención de la Salud , Humanos , Internado y Residencia/estadística & datos numéricos , Práctica Profesional/estadística & datos numéricos , Urología/estadística & datos numéricosRESUMEN
Activation of alternative growth factor pathways after androgen withdrawal is one mechanism mediating androgen-independent (AI) progression in advanced prostate cancer. Insulin-like growth factor (IGF) I activation is modulated by a family of IGF binding proteins (IGFBPs). Although IGFBP-2 is one of the most commonly overexpressed genes in hormone refractory prostate cancer, the functional significance of changes in IGF-I signaling during AI progression remains poorly defined. In this article, we characterize changes in IGFBP-2 in the LNCaP tumor model after androgen withdrawal and evaluate its functional significance in AI progression using gain-of-function and loss-of-function analyses. IGFBP-2 mRNA and protein levels increase 2-3-fold after androgen withdrawal in LNCaP cells in vitro in LNCaP tumors during AI progression in vivo. Increased IGFBP-2 levels after castration were also identified using a human prostate tissue microarray of untreated and posthormone therapy-treated prostatectomy specimens. LNCaP cell transfectants that stably overexpressed IGFBP-2 progressed more rapidly after castration than control tumors. Antisense oligonucleotides (ASOs) targeting the translation initiation site of IGFBP-2 reduced IGFBP-2 mRNA and protein expression by >70% in a dose-dependent and sequence-specific manner. ASO-induced decreases in IGFBP-2-reduced LNCaP cell growth rates and increased apoptosis 3-fold. LNCaP tumor growth and serum prostate-specific antigen levels in mice treated with castration plus adjuvant IGFBP-2 ASOs were significantly reduced compared with mismatch control oligonucleotides. Increased IGFBP-2 levels after androgen ablation may represent an adaptive response that helps potentiate IGF-I-mediated survival and mitogenesis and promote androgen-independent tumor growth. Inhibiting IGFBP-2 expression using ASO technology may offer a treatment strategy to delay AI progression.
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Andrógenos/fisiología , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Orquiectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Secuencia de Bases , División Celular , Cartilla de ADN , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Oligodesoxirribonucleótidos Antisentido/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , Biosíntesis de Proteínas , Transcripción Genética/efectos de los fármacosRESUMEN
Congenital fibrosarcoma (CFS) and cellular mesoblastic nephroma (CMN) are pediatric spindle cell malignancies that share two specific cytogenetic abnormalities: trisomy of chromosome 11 and a t(12;15)(p13;q25) translocation. The t(12;15) rearrangement creates a transcriptionally active fusion gene that encodes a chimeric oncoprotein, ETV6-NTRK3 (EN). EN transforms NIH3T3 fibroblasts through constitutive activation of both the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3'kinase (PI3K)-Akt pathway. However, the role of trisomy 11 in CFS and CMN remains unknown. In this study we demonstrate elevated expression of the chromosome 11p15.5 insulin-like growth factor 2 gene (IGF2) in CFS and CMN tumors. Moreover, we present evidence that an intact IGF signaling axis is essential for in vitro EN-mediated transformation. EN only very weakly transformed so-called R-murine fibroblasts derived from mice with a targeted disruption of the IGF1 receptor gene (IGFRI), but transformation activity was fully restored in R- cells engineered to re-express IGFRI (R+ cells). We also observed that the major IGFRI substrate, insulin-receptor substrate-1 (IRS-1), was constitutively tyrosine phosphorylated and could be co-immunoprecipitated with EN in either R- or R+ cells expressing the EN oncoprotein. IRS-1 association with Grb2 and PI3K p85, which link IGFRI to the Ras-MAPK and PI3K-Akt pathways, respectively, was enhanced in both cell types in the presence of EN. However, activation of the Ras-MAPK and PI3K-Akt pathways was markedly attenuated in EN-expressing R- cells compared to EN-transformed R+ cells. This suggests that IRS-1 may be functioning as an adaptor in EN signal transduction, but that a link to EN transformation pathways requires the presence of IGFRI. Our findings indicate that an intact IGF signaling axis is essential for EN transformation, and are consistent with a role for trisomy 11 in augmenting this pathway in EN expressing tumors.