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1.
Cell Stem Cell ; 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39232559

RESUMEN

It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.

3.
Retina ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39163734

RESUMEN

PURPOSE: To evaluate the systemic and ocular outcomes of patients with branch retinal artery occlusion (BRAO) and central retinal artery occlusion (CRAO) after hyperbaric oxygen therapy (HBOT). METHODS: This is a single-institution study of 75 subjects diagnosed with BRAO (28, 37.3%) and CRAO (47, 62.7%) who visited the emergency department or stroke clinic. Twenty-seven (36%) subjects received HBOT on initial presentation (BRAO-14.3%, CRAO-48.9%). The primary outcome was the best corrective visual acuity (BCVA) change in non-HBOT and HBOT subjects. Secondary outcomes included subsequent development of an acute cerebrovascular accident (CVA)/stroke or neovascular glaucoma (NVG). RESULTS: Overall BCVA did not change from the initial presentation to the final timepoint (logMAR 1.5) in either the conservative management or HBOT cohorts for either BRAO subjects (non-HBOT-logMAR 0.4 vs. 0.6, p=0.658; HBOT-logMAR 0.1 vs. 0.4, p=0.207) or CRAO subjects (non-HBOT-logMAR 2.1 vs. 2.2, p=0.755; HBOT-logMAR 2.1 vs. 2.0, p=0.631). Seven (9.3%) subjects developed CVA (BRAO: non-HBOT-4.2% and HBOT-25.0%, p=0.207; CRAO: non-HBOT-16.7% and HBOT-4.3%, p=0.348) and five subjects (6.7%) developed NVG (BRAO: non-HBOT-4.2% and HBOT-0%, p=1.00; CRAO: non-HBOT-16.7% and HBOT-0%, p=0.109). CONCLUSIONS: Our findings suggest that HBOT does not significantly improve BCVA or mitigate the subsequent development of stroke and NVG in patients with RAOs.

4.
Case Rep Ophthalmol ; 15(1): 483-489, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39015227

RESUMEN

Introduction: Cytomegalovirus (CMV) retinitis in the setting of pediatric retinoblastoma is exceedingly unusual. Here, we present the first reported case of CMV retinitis in an enucleated eye with retinoblastoma after chemotherapy in the western hemisphere. Case Presentation: A 2-year-old Hispanic male without a family history of retinoblastoma presented with a 3-month history of right eye exotropia and squinting. Clinical examination revealed dense white vitreous opacities in the right eye. Ocular oncology evaluation unveiled an exudative retinal detachment with vitreous seeds, subretinal seeding, and a tumor emanating from the retina in the superonasal quadrant of the right eye. The patient was diagnosed with unilateral Group D retinoblastoma, and RB1 sequencing revealed a pathogenic variant with mosaicism. Treatment involved systemic chemotherapy, intravitreal chemotherapy, and cryotherapy. However, the patient developed a rhegmatogenous retinal detachment with diffuse vitreous hemorrhage and ultimately underwent right eye enucleation. Interestingly, histopathological analysis of the enucleated eye revealed concomitant CMV retinitis alongside retinoblastoma. After consultation with infectious disease, antiviral treatment was not initiated as the patient remained asymptomatic and maintained a recovered immune system. Repeat CMV PCR confirmed viral clearance. The patient received a prosthetic eye and continues to be monitored for retinoblastoma recurrence. Conclusion: Clinicians should be aware of the potential for CMV retinitis to develop in retinoblastoma patients receiving chemotherapy, which may complicate clinical decision-making and management. Timely identification of CMV retinitis in this setting may improve patient ocular outcomes and overall prognosis.

5.
Cureus ; 16(6): e63409, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39070418

RESUMEN

Implantable medical devices, such as pacemakers, have significantly improved the quality of life for patients with cardiac conditions, allowing them to maintain active lifestyles. Nonetheless, these devices can present unique challenges when interacting with the wearer's physical activities, potentially leading to unforeseen complications. Here, we present a case of an 81-year-old male golfer, with a history of atrial fibrillation, congestive heart failure, and sick sinus syndrome, who experienced atrial lead noise from his pacemaker, exclusively triggered by his golf swing. This incident, which led to multiple interventions including lead extraction, reimplantation, and eventually a switch to a unipolar lead configuration, represents the first documented case of its kind. It underscores the intricate relationship between the biomechanical forces of certain sports and the functionality of implanted cardiac devices. Through detailed electrophysiology testing, this case demonstrates how specific movements inherent to the patient's golf swing could induce micro-damage to the pacemaker leads, causing noise and malfunction. The findings from this case emphasize the need for healthcare providers to perform sport-specific biomechanical evaluations and create tailored rehabilitation strategies that consider the unique physical demands placed on patients with implanted devices. This approach is important not only for diagnosing and managing similar cases but also for advancing our understanding of how to best support the active lifestyles of patients with implanted cardiac devices, ensuring their safety and longevity.

6.
Antioxidants (Basel) ; 13(5)2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38790724

RESUMEN

1,4-naphthoquinones (NQs) catalytically oxidize H2S to per- and polysufides and sulfoxides, reduce oxygen to superoxide and hydrogen peroxide, and can form NQ-SH adducts through Michael addition. Here, we measured oxygen consumption and used sulfur-specific fluorophores, liquid chromatography tandem mass spectrometry (LC-MS/MS), and UV-Vis spectrometry to examine H2S oxidation by NQs with various substituent groups. In general, the order of H2S oxidization was DCNQ ~ juglone > 1,4-NQ > plumbagin >DMNQ ~ 2-MNQ > menadione, although this order varied somewhat depending on the experimental conditions. DMNQ does not form adducts with GSH or cysteine (Cys), yet it readily oxidizes H2S to polysulfides and sulfoxides. This suggests that H2S oxidation occurs at the carbonyl moiety and not at the quinoid 2 or 3 carbons, although the latter cannot be ruled out. We found little evidence from oxygen consumption studies or LC-MS/MS that NQs directly oxidize H2S2-4, and we propose that apparent reactions of NQs with inorganic polysulfides are due to H2S impurities in the polysulfides or an equilibrium between H2S and H2Sn. Collectively, NQ oxidation of H2S forms a variety of products that include hydropersulfides, hydropolysulfides, sulfenylpolysulfides, sulfite, and thiosulfate, and some of these reactions may proceed until an insoluble S8 colloid is formed.

7.
PLoS One ; 19(5): e0296570, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38728277

RESUMEN

In Zimbabwe, the ZAZIC consortium employs two-way, text-based (2wT) follow-up to strengthen post-operative care for voluntary medical male circumcision (VMMC). 2wT scaled nationally with evidence of client support and strengthened follow-up. However, 2wT uptake among healthcare providers remains suboptimal. Understanding the gap between mobile health (mHealth) potential for innovation expansion and scale-up realization is critical for 2wT and other mHealth innovations. Therefore, we conducted an exploratory qualitative study with the objective of identifying 2wT program strengths, challenges, and suggestions for scale up as part of routine VMMC services. A total of 16 in-depth interviews (IDIs) with diverse 2wT stakeholders were conducted, including nurses, monitoring & evaluation teams, and technology partners-a combination of perspectives that provide new insights. We used both inductive and deductive coding for thematic analysis. Among 2wT drivers of expansion success, interviewees noted: 2wT care benefits for clients; effective hands-on 2wT training; ease of app use for providers; 2wT saved time and money; and 2wT strengthened client/provider interaction. For 2wT scale-up challenges, staff shortages; network infrastructure constraints; client costs; duplication of paper and electronic reporting; and complexity of digital tools integration. To improve 2wT robustness, respondents suggested: more staff training to offset turnover; making 2wT free for clients; using 2wT to replace paper VMMC reporting; integrating with routine VMMC reporting systems; and expanding 2wT to other health areas. High stakeholder participation in app design, implementation strengthening, and evaluation were appreciated. Several 2wT improvements stemmed from this study, including enrollment of multiple people on one number to account for phone sharing; 2wT inclusion of minors ages 15+; clients provided with $1 to offset SMS costs; and reduced SMS messages to clients. Continued 2wT mentoring for staff, harmonization of 2wT with Ministry e-health data systems, and increased awareness of 2wT's client and provider benefits will help ensure successful 2wT scale-up.


Asunto(s)
Circuncisión Masculina , Investigación Cualitativa , Envío de Mensajes de Texto , Humanos , Zimbabwe , Masculino , Telemedicina/métodos , Personal de Salud , Estudios de Seguimiento , Adulto
8.
Br Dent J ; 236(9): 680-682, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38730155

RESUMEN

Nitrous oxide is a widely used and well-established form of inhalation sedation in dentistry. Its properties have a wide margin of safety and allow for anxious, paediatric and adult patients to receive dental treatment with minimal impact upon discharge. Nitrous oxide has drawbacks, however, including its environmental impact and need for specialist equipment. Methoxyflurane is another drug which could prove to be an alternative to nitrous oxide. Methoxyflurane's use has proved popular within emergency medicine in Australia and New Zealand for its potent analgesic effects and recognition of its anxiolytic effect. As a result, its use in invasive outpatient procedures has now become popular. Unfortunately, there is very limited evidence of its use within dentistry as a form of inhalation sedation and analgesic. A wider evidence base should be established, as methoxyflurane could prove to be an effective and environmentally friendly alternative to nitrous oxide.


Asunto(s)
Anestesia Dental , Anestésicos por Inhalación , Metoxiflurano , Óxido Nitroso , Humanos , Anestesia Dental/métodos , Anestésicos por Inhalación/administración & dosificación , Sedación Consciente/métodos , Isoflurano/administración & dosificación , Metoxiflurano/administración & dosificación , Metoxiflurano/uso terapéutico , Metoxiflurano/farmacología , Óxido Nitroso/administración & dosificación
9.
Cureus ; 16(3): e56637, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38646322

RESUMEN

Cytomegalovirus (CMV) retinitis is commonly associated with immunosuppression and can cause irreversible vision loss. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective cancer treatment option but requires immunosuppression, thereby increasing the possibility of acquiring opportunistic infections such as CMV. We present the case of a 76-year-old female with a history of hypertension and type 2 diabetes mellitus who initially presented with shortness of breath and was diagnosed with the activated B-cell subset of diffuse large B-cell lymphoma (DLBCL). She received multiple cycles of chemotherapy and experienced relapses with cardiac involvement. The patient developed vision loss in the right eye and was diagnosed with bilateral posterior vitritis. She underwent various treatments, including radiotherapy, systemic chemotherapy, cataract extraction, and vitrectomy. After CAR-T therapy, she developed bilateral CMV retinitis, confirmed through polymerase chain reaction testing and managed by valganciclovir. Overall, this case report describes the first reported case of bilateral CMV retinitis following CAR-T therapy for DLBCL. It emphasizes the need for early recognition and treatment of CMV retinitis to prevent permanent vision loss. The report also underscores the importance of regular ocular screening and consideration of prophylactic measures in patients undergoing CAR-T therapy.

10.
bioRxiv ; 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38559081

RESUMEN

Problem: All trainees, especially those from historically minoritized backgrounds, experience stresses that may reduce their continuation in science, technology, engineering, math, and medicine (STEMM) careers. The Johns Hopkins University School of Medicine is one of ~45 institutions with a National Institutes of Health funded Postbaccalaureate Research Education Program (PREP) that provides mentoring and a year of fulltime research to prepare students from historically excluded groups for graduate school. Having experienced the conflation of stresses during the COVID-19 pandemic and related shutdown, we realized our program lacked a component that explicitly helped PREP Scholars recognize and cope with non-academic stresses (financial, familial, social, mental) that might threaten their confidence and success as scientists and future in STEMM. Intervention: We developed an early-intervention program to help Scholars develop life-long skills to become successful and resilient scientists. We developed a year-long series comprised of 9 workshops focused on community, introspection, financial fitness, emotional intelligence, mental health, and soft-skills. We recruited and compensated a cohort of PhD students and postdoctoral fellows to serve as Peer Mentors, to provide a community and the safest 'space' for Scholars to discuss personal concerns. Peer Mentors were responsible for developing and facilitating these Community-Building Wellness Workshops (CBWW). Context: CBWW were created and exectued as part of the larger PREP program. Workshops included a PowerPoint presentation by Peer Mentors that featured several case studies that prompted discussion and provided time for small-group discussions between Scholars and Peer Mentors. We also included pre- and post-work for each workshop. These touch-points helped Scholars cultivate the habit of introspection. Impact: The CBWW exceeded our goals. Both Peer Mentors and Scholars experienced strong mutual support, and Scholars developed life-long skills. Notably, several Scholars who had been experiencing financial, mental or mentor-related stress immediately brought this to the attention of program leadership, allowing early and successful intervention. At the completion of CBWW, PREP Scholars reported implementing many workshop skills into practice, were reshaping their criteria for choosing future mentors, and evaluating career decisions. Strikingly, Peer Mentors found they also benefitted from the program as well, suggesting a potential larger scope for the role of CBWW in academia. Lessons Learned: Peer Mentors were essential in creating a safe supportive environment that facilitated discussions, self-reflection, and self-care. Providing fair compensation to Peer Mentors for their professional mentoring and teaching contributions was essential and contributed meaningfully to the positive energy and impact of this program.

11.
J Affect Disord ; 354: 302-308, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38479502

RESUMEN

BACKGROUND: Parenting stress has long been proposed as a major risk factor for child maltreatment. However, there is a lack of evidence from existing studies on the temporal sequence to establish a causal relationship. This study aims to examine bidirectional temporal relationships between parenting stress and child maltreatment. METHODS: Longitudinal data from two different sources were analysed: a pre-post study of an online parenting programme conducted across six countries - the ePLH Evaluation Study, and a prospective cohort study in the United States - LONGSCAN. Cross-lagged panel model on parenting stress and child maltreatment was used in each dataset. RESULTS: Based on repeatedly measured data of 484 caregivers in the ePLH study across five time points (every two weeks), we found that parenting stress at an earlier time point predicted later child maltreatment (IRR = 1.14, 95 % CI: 1.10,1.18). In addition, the occurrence of child maltreatment was associated with higher subsequent short-term parenting stress (IRR = 1.04, 95 % CI: 1.01,1.08) and thus could form a vicious circle. In the LONGSCAN analysis with 772 caregivers who were followed up from child age of 6 to child age of 16, we also found parenting stress at an earlier time point predicted later child maltreatment (ß = 0.11, 95 % CI: 0.01,0.20), but did not observe an association between child maltreatment and subsequent long-term parenting stress. LIMITATIONS: Potential information bias on the measurements. CONCLUSIONS: This study provides evidence for a bidirectional temporal relationship between parenting stress and child maltreatment, which should be considered in parenting intervention programmes.


Asunto(s)
Maltrato a los Niños , Responsabilidad Parental , Niño , Humanos , Estudios Prospectivos , Cuidadores
12.
J Clin Invest ; 134(5)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38426503

RESUMEN

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Intestinos/patología , Linfocitos T/patología , Células Epiteliales/patología
13.
Acad Med ; 99(5): 493-499, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38166321

RESUMEN

ABSTRACT: Outcome data from 6 National Institutes of Health-funded Postbaccalaureate Research Education Programs (PREPs) in the Mid-Atlantic region were combined to give a multi-institutional perspective on their scholars' characteristics and progress through biomedical research training. The institutions hosting these programs were Johns Hopkins University School of Medicine, the Medical University of South Carolina, the University of Maryland School of Medicine, the University of North Carolina at Chapel Hill, Virginia Commonwealth University, and Virginia Polytechnic Institute and State University. The authors summarize the institutional pathways, demographics, undergraduate institutions, and graduate institutions for a total of 384 PREP scholars who completed the programs by June 2021. A total of 228 (59.4%) of these PREP scholars identified as Black or African American, 116 (30.2%) as Hispanic or Latinx, and 269 (70.0%) as female. The authors found that 376 of 384 scholars (97.9%) who started PREP finished their program, 319 of 376 (84.8%) who finished PREP matriculated into PhD or MD/PhD programs, and 284 of 319 (89.0%) who matriculated have obtained their PhD or are successfully making progress toward their PhD.


Asunto(s)
Investigación Biomédica , Adulto , Femenino , Humanos , Masculino , Negro o Afroamericano/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Evaluación de Programas y Proyectos de Salud , Facultades de Medicina/organización & administración , South Carolina , Estados Unidos , Universidades
14.
Curr Opin Cell Biol ; 86: 102313, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38262116

RESUMEN

The nuclear lamina (NL) is a crucial component of the inner nuclear membrane (INM) and consists of lamin filaments and associated proteins. Lamins are type V intermediate filament proteins essential for maintaining the integrity and mechanical properties of the nucleus. In human cells, 'B-type' lamins (lamin B1 and lamin B2) are ubiquitously expressed, while 'A-type' lamins (lamin A, lamin C, and minor isoforms) are expressed in a tissue- and development-specific manner. Lamins homopolymerize to form filaments that localize primarily near the INM, but A-type lamins also localize to and function in the nucleoplasm. Lamins play central roles in the assembly, structure, positioning, and mechanics of the nucleus, modulating cell signaling and influencing development, differentiation, and other activities. This review highlights recent findings on the structure and regulation of lamin filaments, providing insights into their multifaceted functions, including their role as "mechanosensors", delving into the emerging significance of lamin filaments as vital links between cytoskeletal and nuclear structures, chromatin organization, and the genome.


Asunto(s)
Lamina Tipo B , Lámina Nuclear , Humanos , Laminas/metabolismo , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Lámina Nuclear/metabolismo , Membrana Nuclear/metabolismo , Núcleo Celular/metabolismo , Filamentos Intermedios/metabolismo , Diferenciación Celular
15.
Front Microbiol ; 14: 1282949, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37954237

RESUMEN

Introduction: The aim of this international project was to establish a species-specific Clinical Breakpoint for interpretation of Antimicrobial Susceptibility Testing of benzylpenicillin (BP) in horses. Methods: A population pharmacokinetic model of BP disposition was developed to compute PK/PD cutoff values of BP for different formulations that are commonly used in equine medicine around the world (France, Sweden, USA and Japan). Investigated substances were potassium BP, sodium BP, procaine BP, a combination of procaine BP and benzathine BP and penethamate, a prodrug of BP. Data were collected from 40 horses that provided 63 rich profiles of BP corresponding to a total of 1022 individual BP plasma concentrations. Results: A 3-compartment disposition model was selected. For each of these formulations, the PK/PD cutoff was estimated for different dosage regimens using Monte Carlo simulations. The fAUC/MIC or fT>MIC were calculated with a free BP fraction set at 0.4. For fAUC/MIC, a target value of 72 h (for a 72h treatment) was considered. For fT>MIC, efficacy was assumed when free plasma concentrations were above the explored MIC (0.0625-2 mg/L) for 30 or 40 % of the dosing interval. For continuous infusion, a fT>MIC of 90 % was considered. It was shown that a PK/PD cutoff of 0.25 mg/L can be achieved in 90 % of horses with routine regimen (typically 22,000 IU/kg or 12.4 mg/kg per day) with IM procaine BP once a day (France, Japan, Sweden but not USA1) and with IM sodium BP at 14.07 mg/kg, twice a day or IV sodium BP infusion of 12.4 mg/kg per day. In contrast, penethamate and the combination of procaine BP and benzathine BP were unable to achieve this PK/PD cutoff not even an MIC of 0.125 mg/L. Discussion: The PK/PD cutoff of 0.25 mg/L is one dilution lower than the clinical breakpoint released by the CLSI (0.5 mg/ L). From our simulations, the CLSI clinical breakpoint can be achieved with IM procaine BP twice a day at 22,000 IU i.e. 12.4 mg/kg.

16.
Front Cell Dev Biol ; 11: 1240285, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37936983

RESUMEN

Clinical frailty affects ∼10% of people over age 65 and is studied in a chronically inflamed (Interleukin-10 knockout; "IL10-KO") mouse model. Frailty phenotypes overlap the spectrum of diseases ("laminopathies") caused by mutations in LMNA. LMNA encodes nuclear intermediate filament proteins lamin A and lamin C ("lamin A/C"), important for tissue-specific signaling, metabolism and chromatin regulation. We hypothesized that wildtype lamin A/C associations with tissue-specific partners are perturbed by chronic inflammation, potentially contributing to dysfunction in frailty. To test this idea we immunoprecipitated native lamin A/C and associated proteins from skeletal muscle, hearts and brains of old (21-22 months) IL10-KO versus control C57Bl/6 female mice, and labeled with Tandem Mass Tags for identification and quantitation by mass spectrometry. We identified 502 candidate lamin-binding proteins from skeletal muscle, and 340 from heart, including 62 proteins identified in both tissues. Candidates included frailty phenotype-relevant proteins Perm1 and Fam210a, and nuclear membrane protein Tmem38a, required for muscle-specific genome organization. These and most other candidates were unaffected by IL10-KO, but still important as potential lamin A/C-binding proteins in native heart or muscle. A subset of candidates (21 in skeletal muscle, 30 in heart) showed significantly different lamin A/C-association in an IL10-KO tissue (p < 0.05), including AldoA and Gins3 affected in heart, and Lmcd1 and Fabp4 affected in skeletal muscle. To screen for binding, eleven candidates plus prelamin A and emerin controls were arrayed as synthetic 20-mer peptides (7-residue stagger) and incubated with recombinant purified lamin A "tail" residues 385-646 under relatively stringent conditions. We detected strong lamin A binding to peptides solvent exposed in Lmcd1, AldoA, Perm1, and Tmem38a, and plausible binding to Csrp3 (muscle LIM protein). These results validated both proteomes as sources for native lamin A/C-binding proteins in heart and muscle, identified four candidate genes for Emery-Dreifuss muscular dystrophy (CSRP3, LMCD1, ALDOA, and PERM1), support a lamin A-interactive molecular role for Tmem38A, and supported the hypothesis that lamin A/C interactions with at least two partners (AldoA in heart, transcription factor Lmcd1 in muscle) are altered in the IL10-KO model of frailty.

17.
JAMA ; 330(17): 1694-1695, 2023 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-37934224
18.
FEBS Lett ; 597(22): 2806-2822, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37953467

RESUMEN

Lamina-associated domains are large regions of heterochromatin positioned at the nuclear periphery. These domains have been implicated in gene repression, especially in the context of development. In mammals, LAD organization is dependent on nuclear lamins, inner nuclear membrane proteins, and chromatin state. In addition, chromatin readers and modifier proteins have been implicated in this organization, potentially serving as molecular tethers that interact with both nuclear envelope proteins and chromatin. More recent studies have focused on teasing apart the rules that govern dynamic LAD organization and how LAD organization, in turn, relates to gene regulation and overall 3D genome organization. This review highlights recent studies in mammalian cells uncovering factors that instruct the choreography of LAD organization, re-organization, and dynamics at the nuclear lamina, including LAD dynamics in interphase and through mitotic exit, when LAD organization is re-established, as well as intra-LAD subdomain variations.


Asunto(s)
Núcleo Celular , Lámina Nuclear , Animales , Núcleo Celular/metabolismo , Lámina Nuclear/genética , Lámina Nuclear/metabolismo , Cromatina/genética , Cromatina/metabolismo , Membrana Nuclear , Heterocromatina/genética , Heterocromatina/metabolismo , Mamíferos/genética
19.
Cureus ; 15(9): e45911, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37885556

RESUMEN

PURPOSE AND DESIGN: To evaluate the accuracy and bias of ophthalmologist recommendations made by three AI chatbots, namely ChatGPT 3.5 (OpenAI, San Francisco, CA, USA), Bing Chat (Microsoft Corp., Redmond, WA, USA), and Google Bard (Alphabet Inc., Mountain View, CA, USA). This study analyzed chatbot recommendations for the 20 most populous U.S. cities. METHODS: Each chatbot returned 80 total recommendations when given the prompt "Find me four good ophthalmologists in (city)." Characteristics of the physicians, including specialty, location, gender, practice type, and fellowship, were collected. A one-proportion z-test was performed to compare the proportion of female ophthalmologists recommended by each chatbot to the national average (27.2% per the Association of American Medical Colleges (AAMC)). Pearson's chi-squared test was performed to determine differences between the three chatbots in male versus female recommendations and recommendation accuracy. RESULTS: Female ophthalmologists recommended by Bing Chat (1.61%) and Bard (8.0%) were significantly less than the national proportion of 27.2% practicing female ophthalmologists (p<0.001, p<0.01, respectively). ChatGPT recommended fewer female (29.5%) than male ophthalmologists (p<0.722). ChatGPT (73.8%), Bing Chat (67.5%), and Bard (62.5%) gave high rates of inaccurate recommendations. Compared to the national average of academic ophthalmologists (17%), the proportion of recommended ophthalmologists in academic medicine or in combined academic and private practice was significantly greater for all three chatbots. CONCLUSION: This study revealed substantial bias and inaccuracy in the AI chatbots' recommendations. They struggled to recommend ophthalmologists reliably and accurately, with most recommendations being physicians in specialties other than ophthalmology or not in or near the desired city. Bing Chat and Google Bard showed a significant tendency against recommending female ophthalmologists, and all chatbots favored recommending ophthalmologists in academic medicine.

20.
Int J Surg Case Rep ; 111: 108896, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37812959

RESUMEN

INTRODUCTION AND IMPORTANCE: Small bowel diverticular disease (DD) is encountered and managed much less frequently than colonic DD, leading to a significantly less developed body of evidence for managing small bowel diverticulum and its associated complications. CASE PRESENTATION: This case report discusses a rare occurrence of simultaneous perforated jejunal diverticulitis and mechanical small bowel obstruction (SBO) due to a migrating diverticular enterolith. The patient's condition was ultimately managed operatively through laparoscopically assisted small bowel resection. CLINICAL DISCUSSION: A review of the literature reveals only eight reported cases of jejunal diverticulitis with simultaneous enterolith obstruction. All cases were managed operatively, with approaches including small bowel resection encompassing both pathologies, milking the enterolith back to the diverticulitis site and resecting en bloc to avoid extensive resection, or enterotomy and enterolith retrieval. CONCLUSION: The prevalence of small bowel diverticular disease is increasing, and as a result, clinicians may encounter more complications associated with this condition in the future. This case highlights the importance of considering alternate complications of small bowel DD.

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