RESUMO
BACKGROUND AND PURPOSE: Numerous studies have shown longer pre-hospital and in-hospital workflow times and poorer outcomes in women after acute ischemic stroke (AIS) in general and after endovascular treatment (EVT) in particular. We investigated sex differences in acute stroke care of EVT patients over 5 years in a comprehensive Canadian provincial registry. METHODS: Clinical data of all AIS patients who underwent EVT between January 2017 and December 2022 in the province of Saskatchewan were captured in the Canadian OPTIMISE registry and supplemented with patient data from administrative data sources. Patient baseline characteristics, transport time metrics, and technical EVT outcomes between female and male EVT patients were compared. RESULTS: Three-hundred-three patients underwent EVT between 2017 and 2022: 144 (47.5%) women and 159 (52.5%) men. Women were significantly older (median age 77.5 [interquartile range: 66-85] vs.71 [59-78], p < 0.001), while men had more intracranial internal carotid artery occlusions (48/159 [30.2%] vs. 26/142 [18.3%], p = 0.03). Last-known-well to comprehensive stroke center (CSC)-arrival time (median 232 min [interquartile range 90-432] in women vs. 230 min [90-352] in men), CSC-arrival-to-reperfusion time (median 108 min [88-149] in women vs. 102 min [77-141] in men), reperfusion status (successful reperfusion 106/142 [74.7%] in women vs. 117/158 [74.1%] in men) as well as modified Rankin score at 90 days did not differ significantly. This held true after adjusting for baseline variables in multivariable analyses. CONCLUSION: While women undergoing EVT in the province of Saskatchewan were on average older than men, they were treated just as fast and achieved similar technical and clinical outcomes compared to men.
RESUMO
Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx (P < 0.01) and a 29% increase in minutes of impaired autoregulation (P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.
Assuntos
Encéfalo/fisiopatologia , Homeostase/fisiologia , Hipotensão Ortostática/etiologia , Hipoventilação/congênito , Oxigênio/metabolismo , Postura/fisiologia , Apneia do Sono Tipo Central/fisiopatologia , Adolescente , Biomarcadores/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Criança , Feminino , Humanos , Hipotensão Ortostática/fisiopatologia , Hipoventilação/metabolismo , Hipoventilação/fisiopatologia , Masculino , Oximetria , Apneia do Sono Tipo Central/metabolismo , Teste da Mesa Inclinada , Adulto JovemRESUMO
There are ~463 million diabetics worldwide, and more than half have diabetic retinopathy. Yet, treatments are still lacking for non-proliferative diabetic retinopathy. We and others previously provided evidence that Interleukin-17A (IL-17A) plays a pivotal role in non-proliferative diabetic retinopathy. However, all murine studies used Type I diabetes models. Hence, it was the aim of this study to determine if IL-17A induces non-proliferative diabetic retinopathy in Type II diabetic mice, as identified for Type I diabetes. While examining the efficacy of anti-IL-17A as a potential therapeutic in a short-term Type I and a long-term Type II diabetes model; using different routes of administration of anti-IL-17A treatments. Retinal inflammation was significantly decreased (p < 0.05) after Type I-diabetic mice received 1 intravitreal injection, and Type II-diabetic mice received seven intraperitoneal injections of anti-IL-17A. Further, vascular tight junction protein Zonula Occludens-1 (ZO-1) was significantly decreased in both Type I and II diabetic mice, which was significantly increased when mice received anti-IL-17A injections (p < 0.05). Similarly, tight junction protein Occludin degradation was halted in Type II diabetic mice that received anti-IL-17A treatments. Finally, retinal capillary degeneration was halted 6 months after diabetes was confirmed in Type II-diabetic mice that received weekly intraperitoneal injections of anti-IL-17A. These findings provide evidence that IL-17A plays a pivotal role in non-proliferative diabetic retinopathy in Type II diabetic mice, and suggests that anti-IL-17A could be a good therapeutic candidate for non-proliferative diabetic retinopathy.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Camundongos , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Interleucina-17/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Injeções Intravítreas , Proteínas de Junções ÍntimasRESUMO
Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Neovascularização Retiniana , Camundongos , Animais , Neovascularização Retiniana/metabolismo , Retinopatia Diabética/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Retina/metabolismoRESUMO
Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.
Assuntos
Anemia/complicações , Anemia/tratamento farmacológico , Glicina/análogos & derivados , Isoquinolinas/uso terapêutico , Síndromes Mielodisplásicas/complicações , Idoso , Método Duplo-Cego , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Efeito Placebo , Resultado do TratamentoRESUMO
BACKGROUND: Constipation is a common diagnosis in adults and children. Emergency department (ED) visits for constipation increased from 1980 to 2010. Since then, efforts have aimed to reduce resource utilization for constipation in the ED setting. Our objective is to examine contemporary ED practice patterns in the context of updated care guidelines. METHODS: We conducted a cross-sectional study using the National Hospital Ambulatory Medical Care Survey from 2006 to 2017. Encounters with a constipation diagnosis were included. We examined rates of ED visits, diagnostic testing, and medication use. We also compared general and pediatric ED practice patterns for children. RESULTS: Approximately 1.3 million ED visits with a diagnosis of constipation occurred annually, with pediatric encounters comprising one-third of all visits. There was a 114% increase in ED visits for constipation over the study period. Urinalysis and imaging increased by 17% and 15%, respectively. Older patients were more likely to undergo diagnostic testing. No significant changes in laboratory testing, radiographs, or osmotic laxative prescriptions were observed among children. Compared to pediatric EDs, general EDs were more likely to perform CBC (29% vs. 15%) and urinalysis testing (42% vs 31%). General EDs were less likely to prescribe osmotic laxatives for children compared to pediatric EDs (26% vs. 37%). CONCLUSION: ED visits for constipation have increased significantly since 2006. Rates of diagnostic tests and prescriptions have not changed despite published evidence and guidelines that the diagnosis of constipation does not require imaging, and that the management of constipation requires consistent outpatient treatment. Opportunities exist to reduce ED resource utilization through knowledge dissemination and implementation.
Assuntos
Constipação Intestinal , Serviço Hospitalar de Emergência , Adulto , Assistência Ambulatorial , Criança , Constipação Intestinal/diagnóstico , Constipação Intestinal/epidemiologia , Constipação Intestinal/terapia , Estudos Transversais , Pesquisas sobre Atenção à Saúde , Humanos , Laxantes/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Dehydration is a common concern in children presenting to pediatric emergency departments and other acute care settings. Ultrasound (US) of the inferior vena cava (IVC) may be a fast, noninvasive tool to gauge volume status, but its utility is unclear. Our objectives were to determine the interobserver agreement of IVC collapse and collapse duration, then correlate IVC collapse with the outcome of intravenous (IV) versus oral (PO) rehydration. METHODS: We conducted a prospective study by enrolling patients 0 to 21 years old with emesis requiring ondansetron or diarrhea requiring IV hydration. Clinical operators interpreted US examinations in real time to determine whether the IVC was collapsed. Two blinded reviewers interpreted the US videos to determine IVC collapse and collapse duration. Cohen's kappa(κ) was calculated for reviewer-reviewer and reviewer-operator agreement. Primary outcomes were PO versus IV rehydration, and admitted versus discharged. RESULTS: One hundred twelve patients were enrolled, and 102 had complete data for analysis. The mean age was 7.2 years with 51% female. Twenty-nine patients received IV hydration. The reviewer-operator agreement for IVC collapse was κ = 0.57 (95% confidence interval [CI], 0.38-0.75) and interreviewer agreement was κ = 0.93 (95% CI, 0.83-1.0). The interreviewer agreement for collapse duration was κ = 0.66 (95% CI, 0.51-0.82). All patients with noncollapsed IVCs tolerated PO hydration. The likelihood of receiving IV hydration was correlated with the duration of IVC collapse (P = 0.034). CONCLUSIONS: Based on a novel dynamic measure of IVC collapse duration, children with increasing duration of IVC collapse correlated positively with the need for IV rehydration. Noncollapsing IVCs on US were associated with successful PO rehydration without need for IV fluids or emergency department revisits.
Assuntos
Desidratação , Veia Cava Inferior , Adolescente , Adulto , Criança , Pré-Escolar , Desidratação/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Variações Dependentes do Observador , Estudos Prospectivos , Ultrassonografia , Veia Cava Inferior/diagnóstico por imagem , Adulto JovemRESUMO
PURPOSE: CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype-phenotype correlations that will guide anticipatory management. METHODS: An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher's exact test; further pairwise comparisons were made on significant results. RESULTS: Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function. CONCLUSION: This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype-phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.
Assuntos
Genes Homeobox , Proteínas de Homeodomínio , Estudos de Associação Genética , Proteínas de Homeodomínio/genética , Humanos , Hipoventilação/congênito , Mutação , Apneia do Sono Tipo CentralRESUMO
OBJECTIVE: 17-α-hydroxyprogesterone caproate (17-OHP) has been recommended by professional societies for the prevention of recurrent preterm birth, but subsequent clinical studies have reported conflicting efficacy results. This study aimed to contribute to the evidence base regarding the effectiveness of 17-OHP in clinical practice using real-world data. STUDY DESIGN: A total of 4,422 individuals meeting inclusion criteria representing recurrent spontaneous preterm birth (sPTB) were identified in a database of insurance claims, and 568 (12.8%) received 17-OHP. Crude and propensity score-matched recurrence rates and risk ratios (RRs) for the association of receiving 17-OHP on recurrent sPTB were calculated. RESULTS: Raw sPTB recurrence rates were higher among those treated versus not treated; after propensity score matching, no association was detected (26.3 vs. 23.8%, RR = 1.1, 95% CI: 0.9-1.4). CONCLUSION: We failed to identify a beneficial effect of 17-OHP for the prevention of spontaneous recurrent preterm birth in our observational, U.S. based cohort. KEY POINTS: · â¢We observed higher risk for sPTB in the group receiving 17-OHP in the unmatched analysis. · â¢After propensity-score matching, we still failed to identify a beneficial effect of 17-OHP on sPTB. · â¢Sensitivity analyses demonstrated robustness to the inclusion criteria and modeling assumptions..
RESUMO
Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients. The rapid spread of multi-drug-resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore-unexplored discovery pathway for novel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF- EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF- EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF- NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.-Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.-C., Ye, Q., Haselhorst, T., Jennings, M. P., Seib, K. L., Zhou, Y. Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.
Assuntos
Aminopeptidases/antagonistas & inibidores , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Proliferação de Células/efeitos dos fármacos , Gonorreia/tratamento farmacológico , Metionina/metabolismo , Neisseria gonorrhoeae/efeitos dos fármacos , Células Cultivadas , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Colo do Útero/microbiologia , Farmacorresistência Bacteriana Múltipla , Feminino , Gonorreia/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/enzimologiaRESUMO
PURPOSE: To determine if variables of the pupillary light response mature with age and sex in a healthy pediatric cohort and the utility of pupillometry in assessment among pediatric participants. METHODS: After 1 min in a dark room to establish baseline, pupillometry was performed on 323 healthy, pediatric participants (646 eyes; 2-21 years; 175 females). Variables included initial pupil diameter, pupil diameter after light stimulus, percent pupillary constriction, latency to onset of constriction, average constriction velocity, maximum constriction velocity, average dilation velocity, and time from light stimulus to 75% of the initial pupil diameter. Data analyses employed ANOVAs and non-linear regressions. RESULTS: Analyses of age group differences revealed that participants 12-21 years old had a larger initial pupil diameter and pupil diameter after light stimulus, with males aged 12-18 years demonstrating a larger pupil diameter than all younger participants (ps < 0.05). Participants 12-18 years old had a slower maximum constriction velocity than participants 6-11 years old, with no sex differences (ps < 0.05). Furthermore, males aged 12-18 years old had a smaller percent constriction than males 6-11 years old (ps < 0.05). Regressions revealed that percent constriction and dilation velocity seemed to mature linearly, initial pupil diameter and ending pupil diameter matured quadratically, and the constriction velocity terms matured cubically. CONCLUSIONS: Results revealed maturation of the pupillary light response by age and sex in healthy pediatric participants. Given the value of the pupillary light response as a biomarker, the results provide normative benchmarks for comparison in health and disease, including opiate-exposed and concussion patients.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Nível de Saúde , Pupila/fisiologia , Reflexo Pupilar/fisiologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Adulto JovemRESUMO
Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease characterized by autonomic nervous system dysregulation. Central hypoventilation is the most prominent and clinically important presentation. CCHS is caused by mutations in paired-like homeobox 2b (PHOX2B) and is inherited in an autosomal dominant pattern. A co-occurrence of two asymptomatic PHOX2B variants with a classical CCHS presentation highlights the importance of clinical PHOX2B testing in parents and family members of all CCHS probands. Despite being an autosomal dominant disease, once a polyalanine repeat expansion mutation has been identified, sequencing of the other allele should also be considered.
Assuntos
Doenças Assintomáticas , Variação Genética , Proteínas de Homeodomínio/genética , Hipoventilação/congênito , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/genética , Fatores de Transcrição/genética , Feminino , Humanos , Hipoventilação/diagnóstico , Hipoventilação/genética , Hipoventilação/terapia , Masculino , Mutação , Linhagem , Fenótipo , Apneia do Sono Tipo Central/terapiaRESUMO
This article examines how HIV policies and the funding priorities of global institutions affect practices in prenatal clinics and the quality of healthcare women receive. Data consist of observations at health centres in Lilongwe, Malawi and interviews with providers (N = 37). I argue that neoliberal ideology, which structures the global health field, produces a fragmented healthcare system on the ground. Findings show two kinds of healthcare practices within the same clinic: donor-funded NGOs took on HIV services while government providers focused on prenatal care. NGO practices were defined by surveillance, where providers targeted pregnant HIV-positive women and intensively monitored their adherence to drug treatment. In contrast, state-led practices were defined by rationing. Government providers worked with all pregnant women, but with staff and resource shortages, they limited time and services for each patient in order to serve everyone. This paper builds on concepts of therapeutic citizenship and clientship by exploring how global health priorities produce different conditions, practices and outcomes of NGO and state-led care.
Assuntos
Atenção à Saúde , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Pessoal de Saúde/estatística & dados numéricos , Cuidado Pré-Natal/organização & administração , Adulto , Feminino , Governo , Infecções por HIV/transmissão , Humanos , Entrevistas como Assunto , Malaui , Organizações , Política , GravidezRESUMO
Abdominal radiography and computed tomography scans are standard tests to diagnose pneumoperitoneum. With the growing availability of point-of-care ultrasound, pneumoperitoneum may be diagnosed in settings without easy access to radiography or computed tomography, such as in overcrowded emergency departments or resource-poor environments. The use of point-of-care ultrasound to diagnose or monitor pneumoperitoneum has been described in adult but not pediatric patients. We present a case of point-of-care ultrasound detection of pneumoperitoneum and monitoring for tension pneumoperitoneum, after failed air enema reduction for intussusception in an infant.
Assuntos
Enema/efeitos adversos , Doenças do Íleo/terapia , Intussuscepção/terapia , Pneumoperitônio/diagnóstico por imagem , Testes Imediatos , Ultrassonografia , Enema/métodos , Humanos , Lactente , Masculino , Pneumoperitônio/etiologiaRESUMO
Fibroblast growth factors (FGF) are essential signaling proteins that regulate diverse cellular functions in developmental and metabolic processes. In Drosophila, the FGF homolog, branchless (bnl) is expressed in a dynamic and spatiotemporally restricted pattern to induce branching morphogenesis of the trachea, which expresses the Bnl-receptor, breathless (btl). Here we have developed a new strategy to determine bnl- expressing cells and study their interactions with the btl-expressing cells in the range of tissue patterning during Drosophila development. To enable targeted gene expression specifically in the bnl expressing cells, a new LexA based bnl enhancer trap line was generated using CRISPR/Cas9 based genome editing. Analyses of the spatiotemporal expression of the reporter in various embryonic stages, larval or adult tissues and in metabolic hypoxia, confirmed its target specificity and versatility. With this tool, new bnl expressing cells, their unique organization and functional interactions with the btl-expressing cells were uncovered in a larval tracheoblast niche in the leg imaginal discs, in larval photoreceptors of the developing retina, and in the embryonic central nervous system. The targeted expression system also facilitated live imaging of simultaneously labeled Bnl sources and tracheal cells, which revealed a unique morphogenetic movement of the embryonic bnl- source. Migration of bnl- expressing cells may create a dynamic spatiotemporal pattern of the signal source necessary for the directional growth of the tracheal branch. The genetic tool and the comprehensive profile of expression, organization, and activity of various types of bnl-expressing cells described in this study provided us with an important foundation for future research investigating the mechanisms underlying Bnl signaling in tissue morphogenesis.
Assuntos
Movimento Celular/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Morfogênese/genética , Traqueia/metabolismo , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica/métodos , Hipóxia , Hibridização In Situ , Larva/genética , Larva/metabolismo , Microscopia Confocal , Técnicas de Cultura de Órgãos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Imagem com Lapso de Tempo/métodos , Traqueia/citologia , Traqueia/embriologiaRESUMO
PURPOSE: We assessed the risk of locally aggressive behavior in pure Gleason score 6 (Grade Group 1) prostate cancer using contemporary grading criteria. To our knowledge this has been studied in only 1 prior cohort. MATERIALS AND METHODS: We evaluated consecutive radical prostatectomy specimens from an academic institution, including those from 3,291 men with Gleason score 6 and 4,202 with Gleason score 3 + 4 = 7 (Grade Group 2) disease between 2005 and 2016. For dichotomous variables the Pearson chi-square test was used. RESULTS: Of the 3,288 Gleason score 6 cancer cases 128 (3.9%) showed focal extraprostatic extension compared to 593 of the 4,202 (14.1%) with Gleason score 3 + 4 = 7 (p <0.0001). Of the 3,288 Gleason score 6 cancer cases 79 (2.4%) showed nonfocal extraprostatic extension compared to 639 of the 4,202 (15.2%) with Gleason score 3 + 4 = 7 (p <0.0001). The incidence of focal extraprostatic extension with Gleason score 3 + 4 = 7 with less than 5% Gleason pattern 4 was 129 of 1,147 cases (11.2%), which was between Gleason scores 6 and 3 + 4 = 7 with greater than 5% Gleason pattern 4. The incidence of nonfocal extraprostatic extension in Gleason score 3 + 4 = 7 with less than 5% Gleason pattern 4 was 96 of 1,147 cases (8.4%), which was between Gleason scores 6 and 3 + 4 = 7 with greater than 5% Gleason pattern 4. One of the 3,290 Gleason score 6 cases (0.03%) showed seminal vesicle invasion compared to 93 of the 4,202 (2.2%) of Gleason score 3 + 4 = 7 (p <0.0001). A limitation of our study was its retrospective design. CONCLUSIONS: It is not rare for pure Gleason score 6 prostate cancer to locally extend out of the prostate 3.9% focally and 2.4% nonfocally. In extremely rare cases Gleason score 6 can be associated with seminal vesicle invasion and yet not lymph node metastases. Our overall findings support the argument for continuing to use the term cancer for these tumors.
Assuntos
Próstata/patologia , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Glândulas Seminais/cirurgia , Conduta Expectante/normas , Humanos , Metástase Linfática/patologia , Masculino , Gradação de Tumores , Seleção de Pacientes , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Medição de Risco , Glândulas Seminais/patologiaRESUMO
Background: Combined hepatocellular-cholangiocarcinoma tumors (cHCC-CCA) are a heterogeneous group of rare malignancies that have no established optimal treatment. Patients and Methods: We identified patients with cHCC-CCA treated at a tertiary center and retrospectively examined their histology, interventions, and outcomes. We calculated disease control rate (DCR), disease progression, overall survival, and progression-free survival (PFS) between treatment subgroups. Results: A total of 123 patients were evaluable. Interventions included resection, locoregional therapy, transplant, chemotherapy, and targeted agents. Ultimately, 68 patients received systemic treatment-57 with gemcitabine plus either 5-fluoropyrimidine (5-FU) or a platinum combination. Disease progression was more common in the gemcitabine/5-FU group versus gemcitabine/platinum (P=.028), whereas DCR favored gemcitabine/platinum (78.4% vs 38.5%; P=.0143). Median PFS from time of initial diagnosis favored the gemcitabine/platinum group, but the difference did not reach statistical significance. Targeted agents had minimal to no effect on survival metrics. Conclusions: Gemcitabine/platinum seems to be a superior regimen for patients with cHCC-CCA who require systemic treatment. Further studies are needed to clarify the regimen's efficacy and applicability in patient subgroups.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/terapia , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioterapia Adjuvante/métodos , Colangiocarcinoma/complicações , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Hepatectomia , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Compostos Organoplatínicos/uso terapêutico , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Adulto Jovem , GencitabinaRESUMO
The "bedside-to-bench" Congenital Central Hypoventilation Syndrome (CCHS) research journey has led to increased phenotypic-genotypic knowledge regarding autonomic nervous system (ANS) regulation, and improved clinical outcomes. CCHS is a neurocristopathy characterized by hypoventilation and ANS dysregulation. Initially described in 1970, timely diagnosis and treatment remained problematic until the first large cohort report (1992), delineating clinical presentation and treatment options. A central role of ANS dysregulation (2001) emerged, precipitating evaluation of genes critical to ANS development, and subsequent 2003 identification of Paired-Like Homeobox 2B (PHOX2B) as the disease-defining gene for CCHS. This breakthrough engendered clinical genetic testing, making diagnosis exact and early tracheostomy/artificial ventilation feasible. PHOX2B genotype-CCHS phenotype relationships were elucidated, informing early recognition and timely treatment for phenotypic manifestations including Hirschsprung disease, prolonged sinus pauses, and neural crest tumors. Simultaneously, cellular models of CCHS-causing PHOX2B mutations were developed to delineate molecular mechanisms. In addition to new insights regarding genetics and neurobiology of autonomic control overall, new knowledge gained has enabled physicians to anticipate and delineate the full clinical CCHS phenotype and initiate timely effective management. In summary, from an initial guarantee of early mortality or severe neurologic morbidity in survivors, CCHS children can now be diagnosed early and managed effectively, achieving dramatically improved quality of life as adults.
Assuntos
Hipoventilação/congênito , Pneumologia/história , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/terapia , Animais , Encéfalo/patologia , Estudos de Associação Genética , Testes Genéticos , Genótipo , História do Século XX , História do Século XXI , Proteínas de Homeodomínio/genética , Humanos , Hipoventilação/diagnóstico , Hipoventilação/terapia , Camundongos , Camundongos Knockout , Modelos Biológicos , Mutação , Qualidade de Vida , Recidiva , Fatores de Transcrição/genética , Resultado do TratamentoRESUMO
OBJECTIVES: Racially targeted healthcare provides racial minorities with culturally and linguistically appropriate health services. This mandate, however, can conflict with the professional obligation of healthcare providers to serve patients based on their health needs. The dilemma between serving a particular population and serving all is heightened when the patients seeking care are racially diverse. This study examines how providers in a multi-racial context decide whom to include or exclude from health programs. DESIGN: This study draws on 12 months of ethnographic fieldwork at an Asian-specific HIV organization. Fieldwork included participant observation of HIV support groups, community outreach programs, and substance abuse recovery groups, as well as interviews with providers and clients. RESULTS: Providers managed the dilemma in different ways. While some programs in the organization focused on an Asian clientele, others de-emphasized race and served a predominantly Latino and African American clientele. Organizational structures shaped whether services were delivered according to racial categories. When funders examined client documents, providers prioritized finding Asian clients so that their documents reflected program goals to serve the Asian population. In contrast, when funders used qualitative methods, providers could construct an image of a program that targets Asians during evaluations while they included other racial minorities in their everyday practice. Program services were organized more broadly by health needs. CONCLUSION: Even within racially targeted programs, the meaning of race fluctuates and is contested. Patients' health needs cross cut racial boundaries, and in some circumstances, the boundaries of inclusion can expand beyond specific racial categories to include racial minorities and underserved populations more generally.