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1.
Am J Clin Dermatol ; 25(4): 559-584, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38744780

RESUMO

The heterogeneity of atypical wounds can present diagnostic and therapeutic challenges; however, as the prevalence of atypical wounds grows worldwide, prompt and accurate management is increasingly an essential skill for dermatologists. Addressing the underlying cause of an atypical wound is critical for successful outcomes. An integrated approach with a focus on pain management and patient engagement is recommended to facilitate enduring wound closure. Advances in treatment, in addition to further research and clinical training, are necessary to address the expanding burden of atypical wounds.


Assuntos
Cicatrização , Humanos , Manejo da Dor/métodos , Ferimentos e Lesões/terapia , Ferimentos e Lesões/diagnóstico
2.
Surg Clin North Am ; 104(3): 701-709, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677831

RESUMO

The detection rate of dysplastic colorectal polyps has significantly increased with improved screening programs. Treatment of dysplastic polyps attempt to limit morbidity of a procedure while also considering the risk of occult lymph node metastasis. Therefore, a variety of methods have been developed to predict the rate of lymph node metastasis to help identify the optimal treatment of patients. These include both the endoscopic and pathologic assessment of the lesion. In order to reduce the morbidity of surgery for patients with low-risk lesions, multiple endoscopic therapies have been developed, including endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic intermuscular dissection, and transanal endoscopic surgery.


Assuntos
Pólipos do Colo , Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgia , Pólipos do Colo/cirurgia , Pólipos do Colo/patologia , Pólipos do Colo/diagnóstico , Colonoscopia/métodos , Ressecção Endoscópica de Mucosa/métodos
3.
Psychopathology ; : 1-11, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38657572

RESUMO

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a tremendous psychiatric illness with a variety of severe symptoms. Feelings of shame and guilt are universal social emotions that fundamentally shape the way people interact with each other. Mental illness is therefore often related to pronounced feelings of shame and guilt in a maladaptive form. METHODS: A total of 62 participants (38 women and 24 men) were clinically and psychometrically investigated. RESULTS: The OCD patients (n = 31) showed a maladaptive guilt and shame profile, characterized by increased interpersonal feelings of guilt accompanied by a stronger tendency to self-criticism and increased punitive sense of guilt with a simultaneous prevailing tendency to perfectionism, as well as an increased concern for the suffering of others. The proneness to profuse shame in OCD patients seems to be in the context of the violation of inner values and a negative self-image with persistent self-criticism. CONCLUSION: Although there are limitations with a small sample size in this monocentric approach, our study underlines the importance of an individual consideration of the leading obsessive-compulsive symptomatology, especially in the context of very personal feelings of guilt and shame. Further multidimensional studies on guilt and shame could contribute to their implementation more strongly in individualized psychotherapy.

4.
Arch Dermatol Res ; 316(4): 98, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38446235

RESUMO

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum mainly affecting stoma sites of patients with inflammatory bowel disease. While surgical treatments are often used to assist healing, little is known about the relationship between surgical interventions and the rate of recurrence of peristomal pyoderma gangrenosum. The aim of this study was to identify patient and clinical factors associated with peristomal pyoderma gangrenosum recurrence following surgical intervention. A multi-institutional retrospective case series and literature review was conducted to evaluate patient characteristics and perioperative treatment. Patients of any age with peristomal pyoderma gangrenosum undergoing surgical operations related to their pyoderma gangrenosum or due to another comorbidity were included. Descriptive statistics were used to characterize demographic information. Associations were evaluated using Wilcoxon's rank-sum test for continuous variables and Fisher's exact test for categorical data. Thirty-seven cases were included, 78.3% of which had a history of inflammatory bowel disease. Overall, 13 (35.1%) cases experienced recurrence at 30 days. There was no significant association identified between patient demographics, stoma location, surgical intervention, or perioperative treatment with rate of recurrence at 30 days post-operation. While no clinical risk factors or treatments were associated with recurrence, our work underscores the importance of a multidisciplinary approach to this disease to address gastrointestinal, dermatologic, and surgical components of treatment.


Assuntos
Doenças Inflamatórias Intestinais , Pioderma Gangrenoso , Humanos , Pioderma Gangrenoso/etiologia , Pioderma Gangrenoso/cirurgia , Estudos Retrospectivos , Doenças Inflamatórias Intestinais/cirurgia , Período Pós-Operatório , Fatores de Risco
5.
Pediatr Allergy Immunol Pulmonol ; 37(1): 13-21, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38324020

RESUMO

Background: Poor adherence to inhaled corticosteroids (ICS) is a significant challenge in pediatric asthma, contributing to health inequities. Text-message reminders for ICS therapy are an evidence-based approach that improves pediatric asthma medication adherence, yet has not been widely adopted into practice, partly due to lack of (1) participant input on design and implementation and (2) use of sustainable community linkages. Remote Asthma Link™ (RAL) seeks to fill this gap as a school-linked text-message intervention wherein parents of children with poorly controlled asthma received daily, 2-way text-message reminders for preventive inhaler use. Responses were shared with school nurses who conducted remote check-ins with families. Enrolled children, largely from underserved backgrounds, experienced improvements in medication adherence and asthma health outcomes. While initial results were promising, we have yet to elicit participant input to refine the protocol for more widespread implementation. Objective: Examine participant perspectives on barriers and facilitators of RAL implementation. Methods: Semistructured interviews were conducted May-June 2022 with intervention participants: 10 parents, 7 school nurses, and 4 pediatric providers (n = 21) until thematic saturation was reached. Interview transcripts were coded using thematic analysis. Results: Several facilitators for RAL implementation were identified, including ease of use and accessibility, personal connection to the school nurse, and receipt of a visual notification for habit formation. Barriers included challenges with school nurses reaching parents, poor understanding of program expectations, and lack of reimbursement structure. Participant-proposed solutions to barriers included utilizing alternate communication methods (eg, social media), educational sessions, and meeting with payors to consider reimbursement models. Conclusion: RAL is a school-linked text-message intervention demonstrating promise in improving outcomes and equity in asthma care. Key implementation facilitators, barriers, and proposed solutions will inform protocol adaptations to promote successful implementation of this and other text-message interventions into clinical practice.


Assuntos
Asma , Envio de Mensagens de Texto , Humanos , Criança , Asma/tratamento farmacológico , Adesão à Medicação , Corticosteroides/uso terapêutico , Nebulizadores e Vaporizadores
7.
Adv Sci (Weinh) ; 11(9): e2308346, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38084435

RESUMO

Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.


Assuntos
Hidroxicloroquina , Neoplasias Pulmonares , Masculino , Humanos , Hidroxicloroquina/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Monóxido de Carbono/farmacologia , Próstata , Estudos Retrospectivos , Autofagia
8.
Am J Physiol Cell Physiol ; 326(2): C487-C504, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38145295

RESUMO

Blood-brain barrier (BBB) breakdown is one of the pathophysiological characteristics of ischemic stroke, which may contribute to the progression of brain tissue damage and subsequent neurological impairment. Human immunodeficiency virus (HIV)-infected individuals are at greater risk for ischemic stroke due to diminished immune function and HIV-associated vasculopathy. Studies have shown that astrocytes are involved in maintaining BBB integrity and facilitating HIV-1 infection in the brain. The present study investigated whether targeting astrocyte-endothelial cell signaling with cenicriviroc (CVC), a dual chemokine receptor (CCR)2 and CCR5 antagonist, may protect against dysregulation of cross talk between these cells after oxygen-glucose deprivation/reoxygenation (OGD/R) combined with HIV-1 infection. Permeability assay with 10 kDa fluorescein isothiocyanate (FITC)-dextran demonstrated that CVC alleviated endothelial barrier disruption in noncontact coculture of human brain microvascular endothelial cells (HBMECs) with HIV-1-infected human astrocytes, and reversed downregulation of tight junction protein claudin-5 induced by OGD/R- and HIV-1. Moreover, CVC attenuated OGD/R- and HIV-1-triggered upregulation of the NOD-like receptor protein-3 (NLRP3) inflammasome and IL-1ß secretion. Treatment with CVC also suppressed astrocyte pyroptosis by attenuating cleaved caspase-1 levels and the formation of cleaved N-terminal GSDMD (N-GSDMD). Secretome profiling revealed that CVC ameliorated secretion levels of chemokine CC chemokine ligand 17 (CCL17), adhesion molecule intercellular adhesion molecule-1 (ICAM-1), and T cell activation modulator T cell immunoglobulin and mucin domain 3 (TIM-3) by astrocytes synergistically induced by OGD/R and HIV-1. Overall, these results suggest that CVC contributes to restoring astrocyte-endothelial cross interactions in an astrocyte-dependent manner via protection against NLRP3 activation and pyroptosis.NEW & NOTEWORTHY The present study reveals the role of astrocytic NOD-like receptor protein-3 (NLRP3) inflammasome in dysfunctional astrocyte-endothelial cross interactions triggered in response to oxygen/glucose deprivation injury associated with human immunodeficiency virus type 1 (HIV-1) infection. Our results suggest that blocking NLRP3 inflammasome activation and pyroptosis-mediated inflammation with cenicriviroc (CVC) may constitute a potentially effective therapeutic strategy for blood-brain barrier (BBB) protection during HIV-1-associated ischemic stroke.


Assuntos
Infecções por HIV , HIV-1 , Imidazóis , AVC Isquêmico , Sulfóxidos , Humanos , Astrócitos/metabolismo , Inflamassomos/metabolismo , Inflamassomos/farmacologia , HIV-1/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Células Endoteliais/metabolismo , Piroptose , Proteínas NLR/metabolismo , Oxigênio/metabolismo , Isquemia/metabolismo , AVC Isquêmico/metabolismo , Glucose/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo
9.
Cancers (Basel) ; 15(23)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38067381

RESUMO

BACKGROUND: Chronic cancer-related fatigue is difficult to manage in breast cancer survivors. The tango trial showed that a six-week tango Argentino program was effective in reducing fatigue and improving quality of life, and here we investigated the sustainability of this tango program for breast cancer survivors. METHODS: Stage I-III breast cancer survivors with increased fatigue symptoms were analyzed. The fifty participants in the tango trial were compared with a control cohort (n = 108) who did not participate in the tango program. Using the European Organization for Research and Treatment of Cancer Questionnaire C30 (EORTC-QLQ-C30) and the German version of the cancer fatigue scale (CFS-D) self-reported quality of life parameters were assessed and longitudinal changes, correlations, and association factors were calculated. RESULTS: Significant improvements in fatigue (p = 0.006), physical functioning (p = 0.01), and diarrhea (p = 0.04) persisted in the 50 Tango participants at 6 months, but not in the control cohort. Twelve months after joining the tango program, increased fatigue was associated with reduced sporting activities (p = 0.0005), but this was not the case for tango dancing. CONCLUSIONS: The present results suggest that tango may be appropriate as a component of early supportive and follow-up care programs, to promote health-related quality of life and physical activity and also eventually to improve long-term clinical outcomes of breast cancer survivors. TRIAL REGISTRATION: Trial registration numbers DRKS00013335 on 27 November 2017 and DRKS00021601 on 21 August 2020 retrospectively registered.

10.
Omega (Westport) ; : 302228231215521, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37963233

RESUMO

Objective: Death anxiety has long been attributed a role as a psychopathologically decisive factor in the development of mental illnesses such as obsessive-compulsive disorder (OCD). For example, patients with washing compulsions associate their behavior with a fear of life-threatening diseases or patients with control compulsions report that the constant checking is driven by the fear of fatal or deadly consequences for the occupants.Method: The Bochum Questionnaire to Assess Death Anxiety and Attitudes Towards Death (BOFRETTA) was administered to 31 patients with OCD and 31 healthy volunteers within a semi-structured interview using broad psychometry.Results: OCD patients showed increased death anxiety and negative attitute to death in comparison to healthy volunteers. A significant correlation was found between BOFRETTA-anxiety and the currently present religious obsessive thoughts.Conclusions: Our investigation provides further findings on the role of death anxiety and the problematic attitude towards death in OCD patients.

11.
Open Forum Infect Dis ; 10(10): ofad485, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37869403

RESUMO

Background: To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations. Methods: We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations. Results: We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 109/L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 109/L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts. Conclusions: Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative.

12.
Clin Cosmet Investig Dermatol ; 16: 2143-2152, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37581011

RESUMO

Pyoderma gangrenosum (PG) is a rare, autoinflammatory disease leading to aseptic ulcers which carries a significant disease burden and is often difficult to treat, with many patients failing first-line treatment and requiring additional therapies. Such cases are typically referred to in the literature as "recalcitrant", "refractory", or "resistant", though little is known about the clinical characteristics of such cases. We performed a narrative literature review to characterize patient demographics and clinical course associated with difficult to treat pyoderma gangrenosum cases in order to identify trends to guide future clinical management and therapeutic innovation. We identified 148 cases with clinical manifestations and associated patient demographics stratified by ulcer and patient features. Consistent with previous work, a greater prevalence of PG was observed among female patients and those with a history of inflammatory bowel disease, however interestingly despite an aggressive course to their PG, few patients had comorbidities complicating their disease course. Additionally, despite the requirement of three or more treatments for most patients' disease to resolve, the majority healed within the typical window observed in previous clinical studies with low rates of recurrence. Biologics were the most common medication patients were on at time of remission. Collectively, our results suggest a potential benefit for a reduced threshold for biologic initiation in PG patients and a need for standardization of language in the field to facilitate treatment outcomes comparisons and interventions.

13.
Ann Gastroenterol ; 36(4): 360-368, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37396009

RESUMO

One of the primary methods by which the gut microbiome interacts with its host is through the interactions that occur through the production of the metabolites produced, either directly, or indirectly, through microbial metabolism. Decades of research has demonstrated that these metabolic products play a vital role in human health, either for its benefit or detriment. This review article highlights the main metabolites produced by the interactions between diet and the gut microbiome, bile acids and the gut microbiome, and products produced by the gut microbiome alone. Additionally, this article reviews the literature on the effects that these metabolites play on human health.

14.
Cancers (Basel) ; 15(11)2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37296883

RESUMO

BACKGROUND: Persistent impairments of quality of life-in particular, cancer-associated fatigue-are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. METHODS: A randomized controlled trial was conducted with 60 breast cancer survivors diagnosed with stage I-III tumors 12-48 months prior to study enrollment and who had increased symptoms of fatigue. The participants were randomly assigned with a 1:1 allocation to either the tango or the waiting group. The treatment consisted of six weeks of supervised weekly one-hour tango group-sessions. Self-reported fatigue and further quality of life parameters were assessed at baseline and six weeks post-baseline. Longitudinal changes, correlations, Cohen's D (d) effect sizes, and association factors were also calculated. RESULTS: Superiority of the tango intervention over the waiting list control was found in terms of improvement in fatigue (d = -0.64; 95%CI, -1.2 to -0.08; p = 0.03), especially cognitive fatigue. In addition, a superiority of the tango intervention over the waiting list was found in the improvement of diarrhea (d = -0.69; 95%CI, -1.25 to -0.13; p = 0.02). A pooled pre-post analysis of the 50 participants completing the six-week tango program revealed a close to 10% improvement of fatigue (p = 0.0003), insomnia (p = 0.008) and further quality of life outcomes. Adjusted multivariate linear regression analyses revealed the greatest improvements for participants who were more active in sports. In particular, survivors who received endocrine therapies, were obese, or had no prior dance experience seemed to especially benefit from the tango program. CONCLUSIONS: This randomized controlled trial demonstrated that a six-week Argentine tango program improves fatigue in breast cancer survivors. Further trials are warranted to determine whether such improvements lead to better long-term clinical outcomes. TRIAL REGISTRATION: trial registration number DRKS00021601. Retrospectively registered on 21 August 2020.

15.
BMC Psychiatry ; 23(1): 146, 2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36890494

RESUMO

OBJECTIVE: Embitterment is a persistent emotion that is known to everybody in reaction to injustice and being let down, associated with feelings of helplessness and hopelessness. People with psychiatric disorders can develop bitterness, which is to be understood as a form of reactive embitterment to the illness. The aim of this explorative study was to investigate the occurrence of embitterment in obsessive-compulsive patients compared to healthy volunteers and in the context of their metacognitions and other biographical and clinical characteristics. METHOD: Following a semi-structured diagnostic interview, a number of measures were administered to 31 patients with obsessive-compulsive disorder (OCD) [ICD-10 F42.X: mean age 35.2 (SD = 10.7) years] and 31 healthy volunteers [mean age 39.1 (SD = 15.0) years]. These measures included the Post-Traumatic Embitterment Disorder questionaire (PTEDq) for measuring embitterment, the Yale-Brown Obsessive-Compulsive Scale, the Metacognition Questionnaire and other psychometric questionnaires such as the Beck Depression Inventory and the State-Trait Anxiety Inventory. RESULTS: Patients with OCD scored more than three times higher (mean = 2.0, SD = 1.1) than the healthy participants in the PTEDq (mean = 0.6, SD = 0.8; p < 0.001), but the cut-off of < 2.5 for a clinically relevant embitterment disorder was not reached. Dysfunctionally distorted metacognition (MCQ-30), which is a consistent finding in OCD, as well as a generally high degree of clinical impairment were significantly cor related to the degree of embitterment. CONCLUSION: Our findings suggest that embitterment as measured by PTEDq is important in patients with OCD, who are characterized by metacognitive distortions with an injustice of fate as well as a mortification of their self-image. In future, it would be necessary to screen patients with OCD not only for depressive symptoms but also specifically for feelings of embitterment in order to be able to initiate appropriate psychotherapeutic measures at an early stage.


Assuntos
Metacognição , Transtorno Obsessivo-Compulsivo , Humanos , Adulto , Transtorno Obsessivo-Compulsivo/psicologia , Psicometria , Escalas de Graduação Psiquiátrica , Emoções
16.
Clin Pediatr (Phila) ; 62(11): 1390-1397, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36908108

RESUMO

To examine the clinical outcomes of topical lidocaine exposures in pediatric patients reported to the National Poison Data System (NPDS). We performed a retrospective review of the NPDS in pediatric patients with topical lidocaine toxicity from 2000 to 2020. Specific data analyzed were age, exposure chronicity, medical outcome, clinical effects, treatments, and disposition. Narrative case records were requested from poison centers. Of 37 cases identified, mean age was 5 years with age distribution of 1- to 0 days (n = 8), 1 to 24 months (n = 11), and 2-18 years (n = 18). Exposure chronicity was acute in 33 (89.2%) or chronic in 4 (10.8%). Moderate effects were seen in 25 (67.6%), major effects in 10 (27%), and 2 deaths (5.4%). The most common clinical effects included cyanosis (29.7%), seizures (18.9%), central nervous systems (CNS) depression (13.5%), drowsiness/lethargy (13.5%), and tachycardia (10.8%). The most common treatments were dilution/irrigation (35.1%), intravenous (IV) fluids (29.7%), oxygen (29.7%), methylene blue (27%), benzodiazepines (13.5%), and intubation (10.8%). Non-intensive care unit (ICU) disposition occurred for 23 patients (62.2%) and ICU admission for 14 (37.8%). Case details were requested for 37 cases, 16 cases (43.2%) were provided. Of the 2 deaths, 1 had significant cardiac history. The most common use of topical lidocaine was at home prior to a dermatologic procedure (37.5%). Topical lidocaine can induce serious outcomes resulting in ICU level care or death; however, moderate/major effects were well tolerated without comorbidities. Most patients discharged home. Given frequent use of topical, especially in outpatient settings, greater vigilance should be taken with prescriptions, instructions for use, and anticipatory guidance.


Assuntos
Venenos , Humanos , Criança , Estados Unidos/epidemiologia , Pré-Escolar , Recém-Nascido , Sistemas de Dados , Centros de Controle de Intoxicações , Bases de Dados Factuais , Estudos Retrospectivos , Lidocaína/efeitos adversos
17.
Clin Cancer Res ; 29(14): 2651-2667, 2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-36780194

RESUMO

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.


Assuntos
Glioblastoma , Glioma , Camundongos , Animais , Quinase do Linfoma Anaplásico/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Estudos Retrospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Glioma/tratamento farmacológico
18.
Science ; 378(6620): 596-597, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36356135

RESUMO

Some tunas and billfishes are recovering, but sharks continue to decline.


Assuntos
Espécies em Perigo de Extinção , Extinção Biológica , Tubarões , Atum , Animais , Oceanos e Mares , Cadeia Alimentar , Crescimento Demográfico
19.
J Vis Exp ; (188)2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36282703

RESUMO

Ischemic stroke is a major cause of death and disability worldwide with limited therapeutic options. The neuropathology of ischemic stroke is characterized by an interruption in blood supply to the brain leading to cell death and cognitive dysfunction. During and after ischemic stroke, blood-brain barrier (BBB) dysfunction facilitates injury progression and contributes to poor patient recovery. Current BBB models primarily include endothelial monocultures and double co-cultures with either astrocytes or pericytes. Such models lack the ability to fully imitate a dynamic brain microenvironment, which is essential for cell-to-cell communication. Additionally, commonly used BBB models often contain immortalized human endothelial cells or animal-derived (rodent, porcine, or bovine) cell cultures that pose translational limitations. This paper describes a novel well-insert-based BBB model containing only primary human cells (brain microvascular endothelial cells, astrocytes, and brain vascular pericytes) enabling the investigation of ischemic brain injury in vitro. The effects of oxygen-glucose deprivation (OGD) on barrier integrity were assessed by passive permeability, transendothelial electrical resistance (TEER) measurements,and direct visualization of hypoxic cells. The presented protocol offers a distinct advantage inmimicking the intercellular environment of the BBB in vivo, serving as a more realistic in vitro BBB model for developing new therapeutic strategies in the setting of ischemic brain injury.


Assuntos
Lesões Encefálicas , AVC Isquêmico , Humanos , Animais , Bovinos , Suínos , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Cultura Primária de Células , Técnicas de Cocultura , Astrócitos/metabolismo , Oxigênio/metabolismo , Glucose/metabolismo , Lesões Encefálicas/patologia
20.
JAMA Netw Open ; 5(7): e2223253, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35867061

RESUMO

Importance: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. Objectives: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. Design, Setting, and Participants: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. Exposure: SARS-CoV-2 detected via nucleic acid testing. Main Outcomes and Measures: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. Results: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). Conclusions and Relevance: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.


Assuntos
COVID-19 , Doença Aguda , COVID-19/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Fadiga , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , SARS-CoV-2
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