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1.
Cell ; 185(24): 4507-4525.e18, 2022 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-36356582

RESUMEN

The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.


Asunto(s)
Enfermedades Óseas , Mycobacterium marinum , Mycobacterium tuberculosis , Tuberculosis , Animales , Humanos , Pez Cebra , Tuberculosis/microbiología , Macrófagos/microbiología , Proteínas Bacterianas/genética
2.
Cell ; 154(6): 1300-13, 2013 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-24034252

RESUMEN

Radial glial progenitors (RGPs) are elongated epithelial cells that give rise to neurons, glia, and adult stem cells during brain development. RGP nuclei migrate basally during G1, apically using cytoplasmic dynein during G2, and undergo mitosis at the ventricular surface. By live imaging of in utero electroporated rat brain, we find that two distinct G2-specific mechanisms for dynein nuclear pore recruitment are essential for apical nuclear migration. The "RanBP2-BicD2" and "Nup133-CENP-F" pathways act sequentially, with Nup133 or CENP-F RNAi arresting nuclei close to the ventricular surface in a premitotic state. Forced targeting of dynein to the nuclear envelope rescues nuclear migration and cell-cycle progression, demonstrating that apical nuclear migration is not simply correlated with cell-cycle progression from G2 to mitosis, but rather, is a required event. These results reveal that cell-cycle control of apical nuclear migration occurs by motor protein recruitment and identify a role for nucleus- and centrosome-associated forces in mitotic entry. PAPERCLIP:


Asunto(s)
Encéfalo/embriología , Núcleo Celular/metabolismo , Dineínas/metabolismo , Mitosis , Células-Madre Neurales/citología , Poro Nuclear/metabolismo , Animales , Encéfalo/citología , Proteínas Portadoras/metabolismo , Centrosoma/metabolismo , Embrión de Mamíferos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos , Células-Madre Neurales/metabolismo , Neurogénesis , Ratas
3.
Am J Emerg Med ; 83: 109-113, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39002496

RESUMEN

BACKGROUND: Inefficient supply chain management within the US healthcare industry results in significant financial and environmental impact. Unopened medical supplies may routinely be discarded in the Emergency Department (ED), contributing as a source of unnecessary medical waste. OBJECTIVES: Quantify the financial and environmental impact of unopened medical supplies that are routinely discarded in two EDs. METHODS: The study utilized a waste audit of collection bins targeting unopened medical supplies that would have otherwise been discarded. Associated financial cost was calculated using data from the purchasing department and from an online search. End-of-life (EOL) environmental impact was calculated using the M+ Wastecare calculator. A lifecycle analysis was performed on a supplier-packaged intubation kit, which the study identified as a significant source of waste. RESULTS: High volumes of unused, unopened supplies (143.48 kg) were collected during the study period with a yearly extrapolated value of 1337 kg. Purchasing costs over 44 days at Hospital A and 37 days at Hospital B for these items amounted to $16,159.71 across both sites with a yearly extrapolated value of $150,631.73. Yearly extrapolated EOL impact yielded 5.79 tons per year of CO2eq. Components from supplier-packaged intubation kits were found to contribute to 45.2% of collected items at one site which purchased them. Lifecycle analysis of an intubation kit yields 23.6 kg of CO2eq. CONCLUSION: This study demonstrates that the disposal of unopened medical supplies contributes a significant source of financial and environmental waste in the ED setting. The results continue to support the trend of procedure kits generating significant environmental and financial waste.


Asunto(s)
Servicio de Urgencia en Hospital , Servicio de Urgencia en Hospital/economía , Humanos , Residuos Sanitarios/economía , Equipos y Suministros de Hospitales/economía , Ambiente , Eliminación de Residuos Sanitarios/economía , Eliminación de Residuos Sanitarios/métodos
4.
Nucleic Acids Res ; 50(4): e22, 2022 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-34850128

RESUMEN

MicroRNAs (miRNAs or miRs) are single-stranded, ∼22-nucleotide noncoding RNAs that regulate many cellular processes. While numerous miRNA quantification technologies are available, a recent analysis of 12 commercial platforms revealed high variations in reproducibility, sensitivity, accuracy, specificity and concordance within and/or between platforms. Here, we developed a universal hairpin primer (UHP) system that negates the use of miRNA-specific hairpin primers (MsHPs) for quantitative reverse transcription PCR (RT-qPCR)-based miRNA quantification. Specifically, we analyzed four UHPs that share the same hairpin structure but are anchored with two, three, four and six degenerate nucleotides at 3'-ends (namely UHP2, UHP3, UHP4 and UHP6), and found that the four UHPs yielded robust RT products and quantified miRNAs with high efficiency. UHP-based RT-qPCR miRNA quantification was not affected by long transcripts. By analyzing 14 miRNAs, we demonstrated that UHP4 closely mimicked MsHPs in miRNA quantification. Fine-tuning experiments identified an optimized UHP (OUHP) mix with a molar composition of UHP2:UHP4:UHP6 = 8:1:1, which closely recapitulated MsHPs in miRNA quantification. Using synthetic LET7 isomiRs, we demonstrated that the OUHP-based qPCR system exhibited high specificity and sensitivity. Collectively, our results demonstrate that the OUHP system can serve as a reliable and cost-effective surrogate of MsHPs for RT-qPCR-based miRNA quantification for basic research and precision medicine.


Asunto(s)
MicroARNs , Análisis Costo-Beneficio , Cartilla de ADN/genética , MicroARNs/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
Hosp Pharm ; 58(4): 350-352, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37360209

RESUMEN

Silver-containing products have been used for medicinal purposes since antiquity. Throughout the ages and indeed up until the present time, silver has been employed with the hopes of treating a myriad of diseases including the common cold, skin problems, infections, and even cancer. However, silver has no known biological role in human physiology, and taking silver may lead to adverse reactions. The better-known adverse reactions of silver include argyria, or a gray-blue cutaneous discoloration, which is a known effect of silver accumulation. Additionally renal or hepatic injury may also be experienced. Reports of neurological adverse reactions are rare, however, and the extant medical literature contains very few descriptions of such cases. We report herein a case of a 70 year old man who presented with seizures as the sole manifestation of silver toxicity after self-medicating with colloidal silver.

6.
Immunol Rev ; 277(1): 9-20, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28462532

RESUMEN

The differentiation of hematopoietic precursors into the many functionally distinct T-cell types produced by the thymus is a complex process. It proceeds through a series of stages orchestrated by a variety of thymic microenvironments that shape the T-cell developmental processes. Numerous cytokine and cell surface receptors direct thymocyte differentiation but the primary determinant of cell fate is the engagement of the T-cell antigen receptor (TCR). The strength of the TCR signal and the maturation stage of the thymocyte receiving it can direct the various differentiation programs or, alternatively, end the process by inducing cell death. The regulation of thymocyte death is critical for the efficiency of thymic T-cell differentiation and the preservation of immune tolerance. A detailed knowledge of mechanisms that eliminate thymocytes from the T-cell repertoire is essential to understand the "logic" of T-cell selection in the thymus. This review focuses on the central role of the BCL-2 family of proteins in the apoptotic checkpoints that punctuate thymocyte differentiation and the consequences of defects in these processes.


Asunto(s)
Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Linfocitos T/fisiología , Timocitos/fisiología , Timo/inmunología , Animales , Muerte Celular , Diferenciación Celular , Microambiente Celular , Tolerancia Central , Hematopoyesis , Humanos , Receptores de Antígenos de Linfocitos T/metabolismo
7.
Hosp Pharm ; 56(5): 462-465, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34720146

RESUMEN

Background: Cannabis withdrawal syndrome (CWS) is characterized by irritability, sleep disorders, and physical discomfort that typically peaks within 7 days of cessation. Case: A patient with a 30-year history of heavy cannabis developed prolonged symptoms of CWS that peaked at greater than 40 days after cessation, who was successfully managed with dexmedetomidine. Discussion: This case report documents an unusual case of significantly delayed CWS peak in symptoms, as well as the novel use of dexmedetomidine for inpatient management of CWS.

8.
J Am Pharm Assoc (2003) ; 60(4): 541-547.e2, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32115391

RESUMEN

OBJECTIVE: Graduating pharmacists are applying to postgraduate year 1 (PGY-1) and postgraduate year 2 (PGY-2) programs at a rate that is outpacing the number of programs available. Emergency department (ED) PGY-2 programs are gaining popularity, and competitions are increasing for applicants. Demand for ED pharmacists seems to be steady, although this has not yet been formally evaluated. This survey seeks to clarify current expectations from the ED pharmacist job market and those currently graduating from a PGY-2 ED program. DESIGN: Electronic surveys were sent via e-mail from January 2019 to February 2019. SETTING AND PARTICIPANTS: Directors of pharmacy (DOPs) and residency program directors (RPDs) of all PGY-2 ED programs available in the American Society of Health-System Pharmacists directory. OUTCOME MEASURES: Included residency position forecast and trends, program development, pharmacist position forecast and trends, perceptions of pharmacist market, and salary. RESULTS: RPDs stated that the number of PGY-2 ED resident applicants has increased over the past 5 years. Although RPDs did not plan to expand the number of PGY-2 ED resident positions in their program for the 2019-2020 cycle, they had strong plans to expand in the next 5 years. Although RPDs projected growth in the number of resident positions over the next 5 years, DOPs anticipated the number of full-time equivalents openings for ED pharmacists to remain constant over the next 5 years. CONCLUSION: A survey involving PGY-2 ED program RPDs and DOPs found that the market was perceived to be stable by DOPs with more anticipation of growth by RPDs in the number of PGY-2 ED resident positions. Salaries have increased, and demand was perceived to at least be in balance with supply, with RPD respondents generally believing it was easy to find ED pharmacist employment and most PGY-2 ED program graduates finding employment in ED positions following residency.


Asunto(s)
Medicina de Emergencia , Internado y Residencia , Farmacia , Medicina de Emergencia/educación , Servicio de Urgencia en Hospital , Humanos , Percepción , Farmacéuticos , Estados Unidos
10.
Consult Pharm ; 33(8): 446-449, 2018 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-30068437

RESUMEN

PURPOSE: There are a limited number of case reports in the literature which describe hyponatremia/syndrome of inappropriate antidiuretic hormone (SIADH) induced by duloxetine. SUMMARY: This case report adds to the literature by describing a patient who developed hyponatremia/SIADH after two doses of duloxetine. CONCLUSION: Hyponatremia/SIADH can develop rapidly after initiation of duloxetine. Clinicians should be aware of the potential for this adverse drug reaction, particularly in elderly females.


Asunto(s)
Clorhidrato de Duloxetina/efectos adversos , Hiponatremia/inducido químicamente , Síndrome de Secreción Inadecuada de ADH/inducido químicamente , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Anciano de 80 o más Años , Clorhidrato de Duloxetina/uso terapéutico , Femenino , Humanos , Hiponatremia/diagnóstico , Síndrome de Secreción Inadecuada de ADH/diagnóstico , Trastornos del Humor/complicaciones , Trastornos del Humor/tratamiento farmacológico
11.
Hum Mol Genet ; 23(9): 2447-58, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24352790

RESUMEN

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulates RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here, a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon 1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity prior to death between 7 and 31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing, 96% amino acid identity, differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in subnuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole contributor to RTT with non-redundant functions.


Asunto(s)
Exones/genética , Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/genética , Animales , Western Blotting , Femenino , Técnica del Anticuerpo Fluorescente , Masculino , Ratones , Ratones Transgénicos , Mutación/genética
12.
Immunol Cell Biol ; 94(4): 357-66, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26510893

RESUMEN

Thymocytes that bind strongly to self-antigens are prevented from becoming naive T cells by several mechanisms. They undergo clonal deletion at two stages of development; wave 1 in immature thymocytes lacking the medulla-homing chemokine receptor, CCR7, or wave 2 in more mature CCR7(+) thymocytes. Alternatively, self-reactive thymocytes upregulate Foxp3 to become T-regulatory cells. Here, we describe the differential timing of the two waves of deletion and Foxp3 upregulation relative to the immature proliferating stage. Proliferating thymocytes were pulse-labeled in normal C57BL/6 mice with 5-ethynyl-2'-deoxyuridine (EdU). Thymocytes progressed into wave 1 (CCR7(-)) and wave 2 (CCR7(+)) of clonal deletion ~2 and 5 days after proliferation, respectively. Foxp3 upregulation occurred between 4 and 8 days after proliferation, predominantly in thymocytes with a Helios(+) CCR7(+) phenotype. These findings establish a timeline that suggests that wave 1 of clonal deletion occurs in the thymic cortex, whereas wave 2 and Foxp3 upregulation both occur in the thymic medulla.


Asunto(s)
Diferenciación Celular , Selección Clonal Mediada por Antígenos , Linfocitos T Reguladores/inmunología , Timocitos/inmunología , Timo/inmunología , Animales , Autoantígenos/inmunología , Proliferación Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR7/metabolismo , Timo/anatomía & histología , Factores de Transcripción/metabolismo , Regulación hacia Arriba
13.
Hosp Pharm ; 56(3): 139-140, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34024920
14.
Hosp Pharm ; 56(6): 624-625, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34732910
15.
N Engl J Med ; 375(22): 2205, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27959758
17.
J Am Soc Mass Spectrom ; 35(8): 2028-2031, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-38982799

RESUMEN

Quenching digestions in proteomics prior to analysis is routine in order to eliminate residual protease activity. Residual activity leads to overdigestion, nonspecific star-activity, and back-exchange in isotopic 18O quantitation. Chemical and isobaric labeling (e.g., TMT/iTRAQ) of proteins or peptides for mass spectrometry-based proteomics is generally incompatible with ubiquitous postdigestion acidification. This necessitates buffer exchange and pH adjustments. We demonstrate that quenching is unnecessary with peptides generated from protein filter-traps, as trypsin activity and intact trypsin are negligible in the eluate from these preparations. Labeling can be directly performed on enzymatic digests from these methods, improving recovery, throughput, and ease of automation.


Asunto(s)
Proteómica , Tripsina , Tripsina/metabolismo , Tripsina/química , Proteómica/métodos , Marcaje Isotópico/métodos , Filtración , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Espectrometría de Masas/métodos , Humanos , Concentración de Iones de Hidrógeno , Animales , Péptidos/química , Péptidos/análisis
18.
Med Sci Educ ; 34(2): 327-330, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38686138

RESUMEN

Purpose: To describe gender diversity and research productivity among medical education boards. Methods: We examined gender, training status, and research productivity of board members of Journal Citation Reports-listed medical education journals and affiliated professional societies. We determined gender using gendered pronouns and-if unavailable-software. We evaluated differences using χ2 and t-tests. Results: Overall, half of board members but 44% of editors-in-chief and 20% of society leaders were female. Female-led journals and societies had higher female representation than their non-female-led counterparts; trainee board members were more likely to be female. Conclusions: Gender disparities exist among executives on journal and affiliated professional society boards in medical education.

19.
J Grad Med Educ ; 16(2): 151-165, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38993318

RESUMEN

Background Although the selection interview is a standard admission practice for graduate medical education (GME) programs in the United States, there is a dearth of recent reviews on optimizing the trainee interview process, which has low reliability, high cost, and major risk of bias. Objective To investigate the evidence base for different selection interview practices in GME. Methods We searched 4 literature databases from inception through September 2022. Two investigators independently conducted title/abstract screening, full-text review, data extraction, and quality assessment. Disagreements were mediated by discussion. We used backward reference searching of included articles to identify additional studies. We included studies of different interview methods and excluded literature reviews, non-GME related publications, and studies comparing different applicant populations. We examined study characteristics, applicant and interviewer preferences, and interview format. We evaluated study quality using the Medical Education Research Study Quality Instrument (MERSQI). Results Of 2192 studies, 39 (2%) met our inclusion criteria. The evidence base was rated as moderately low quality using MERSQI criteria. Applicants reported preferences for several one-on-one interviews lasting 15 to 20 minutes, interviews by current trainees, and interviews including social events with only trainees. Applicants had mixed perceptions of virtual versus in-person interviews and reported that virtual interviews saved costs. The multiple mini interview (MMI) required more applicant and interviewer time than individual interviews but demonstrated construct and predictive validity and was preferred by applicants and interviewers. Conclusions Based on moderately low-quality evidence, using the MMI, training interviewers, and providing applicants with basic program information in advance should be considered for GME selection interviews.


Asunto(s)
Educación de Postgrado en Medicina , Internado y Residencia , Entrevistas como Asunto , Criterios de Admisión Escolar , Humanos , Práctica Clínica Basada en la Evidencia , Estados Unidos , Selección de Personal/métodos
20.
bioRxiv ; 2024 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-39416176

RESUMEN

Organs in the abdominal cavity are covered by a peritoneal membrane, which is comprised of a monolayer of mesothelial cells (MC). Diseases involving the peritoneal membrane include peritonitis, primary cancer (mesothelioma), and metastatic cancers (ovarian, pancreatic, colorectal). These diseases have gender- and/or age-related pathologies; however, the impact of gender and age on the peritoneal MC is not well evaluated. To address this, we identified and characterized gender- and age-related differences in the proteomes of murine primary peritoneal MC. Primary peritoneal MC were isolated from young female (FY) or male (MY) mice (3-6 months) and aged female (FA) or male (MA) mice (20-23 months), lysed, trypsin digested using S-Traps, then subjected to bottom-up proteomics using an LC-Orbitrap mass spectrometer. In each cohort, we identified >1000 protein groups. Proteins were categorized using Gene Ontology and pairwise comparisons between gender and age cohorts were conducted. This study establishes baseline information for studies on peritoneal MC in health and disease at two physiologic age/gender points. Segregation of the data by gender and age could reveal novel factors to specific disease states involving the peritoneum. [This in vitro primary cell model has utility for future studies on the interaction between the mesothelium and foreign materials.].

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