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1.
J Invasive Cardiol ; 2024 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-39150435

RESUMO

Radial artery occlusion (RAO), a complication of transradial access, has an incidence of 4.0% to 9.1% in patients with advanced chronic kidney disease (CKD) and may preclude its use creation of arteriovenous fistula. Distal transradial access (dTRA) has lower rates of RAO compared with TRA, but prior studies excluded patients with advanced CKD. This was a single center study of patients with advanced CKD who underwent coronary procedures with dTRA from January 1, 2019 to May 12, 2022 who were retrospectively evaluated for radial artery patency in follow-up with reverse Barbeau testing or repeat access of the artery. Of 71 patients, 66% were on hemodialysis and the remainder had CKD 3 to 5. Access was ultrasound-guided, and all received adequate spasmolytic therapy and patent hemostasis. Proximal radial arteries were patent in 100% of the patients at follow-up. Our data suggest that dTRA is safe for patients with advanced CKD and preserves radial artery patency.

2.
JACC Case Rep ; 29(12): 102339, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38984206

RESUMO

Patients, often with underlying rheumatologic disease, may present with pericardial effusions in the setting of pulmonary hypertension (PHTN). Pericardial drainage in PHTN is associated with significant morbidity and mortality. We describe a patient with PHTN who developed cardiac tamponade that was managed safely and effectively with pulmonary artery catheter-guided pericardiocentesis.

3.
Curr Cardiol Rep ; 25(11): 1611-1622, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37804391

RESUMO

PURPOSE OF REVIEW: Peripheral artery disease (PAD) is an increasingly prevalent but frequently underdiagnosed condition that can be associated with high rates of morbidity and mortality. While an initial noninvasive approach is the cornerstone of management, revascularization is often pursued for patients with treatment-refractory claudication or chronic limb-threatening ischemia (CLTI). In this review, we discuss the current state of endovascular interventions for PAD and explore the many new emerging technologies. RECENT FINDINGS: The last decade has resulted in numerous advances in PAD interventions including the ongoing evolution of drug-coated devices, novel approaches to complex lesions, and contemporary evidence from large clinical trials for CLTI. Advances in endovascular management have allowed for increasingly complex lesions to be tackled percutaneously. Future directions for the field include the continued evolution in device technology, continued development of state-of-the-art techniques to revascularization of complex lesions, and increased collaboration between a largely multidisciplinary field.


Assuntos
Procedimentos Endovasculares , Doença Arterial Periférica , Humanos , Fatores de Risco , Procedimentos Endovasculares/métodos , Resultado do Tratamento , Doença Arterial Periférica/cirurgia , Doença Arterial Periférica/diagnóstico , Claudicação Intermitente/terapia , Isquemia/terapia , Salvamento de Membro/métodos , Estudos Retrospectivos , Doença Crônica
5.
Artigo em Inglês | MEDLINE | ID: mdl-36268042

RESUMO

Peripheral arterial disease is an increasingly prevalent condition with significant associated morbidity, mortality, and health care expenditure. Endovascular interventions are appropriate for most patients with either ongoing symptoms of intermittent claudication despite lifestyle and medical optimization or chronic limb-threatening ischemia. The femoropopliteal segment is the most common arterial culprit responsible for claudication and the most commonly revascularized segment. Endovascular approaches to revascularization of the femoropopliteal segment are advancing with an evolving landscape of techniques for arterial access, device-based therapies, vessel preparation, and intraprocedural imaging. These advances have been marked by debate and controversy, notably related to the safety of paclitaxel-based devices and necessity of atherectomy. In this review, we provide a critical overview of the current evidence, practice patterns, emerging evidence, and technological advances for endovascular intervention of the femoropopliteal arterial segment.

6.
JACC Cardiovasc Interv ; 15(15): 1558-1568, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35926922

RESUMO

BACKGROUND: There has been growing use of intravascular ultrasound (IVUS) during lower extremity arterial and venous revascularization. Observational data suggest that the use of IVUS can improve periprocedural and long-term outcomes, but largescale prospective data remain limited. Consensus opinion regarding the appropriate use of IVUS during peripheral intervention is needed. OBJECTIVES: The purpose of this consensus document is to provide guidance on the appropriate use of IVUS in various phases of peripheral arterial and venous interventions. METHODS: A 12-member writing committee was convened to derive consensus regarding the appropriate clinical scenarios for use of peripheral IVUS. The group iteratively created a 72-question survey representing 12 lower extremity arterial interventional scenarios. Separately, a 40-question survey representing 8 iliofemoral venous interventional scenarios was constructed. Clinical scenarios were categorized by interventional phases: preintervention, intraprocedure, and postintervention optimization. Thirty international vascular experts (15 for each survey) anonymously completed the survey instrument. Results were categorized by appropriateness using the median value and disseminated to the voting panel to reevaluate for any disagreement. RESULTS: Consensus opinion concluded that IVUS use may be appropriate during the preintervention phase for evaluating the etiology of vessel occlusion and plaque morphology in the iliac and femoropopliteal arteries. IVUS was otherwise rated as appropriate during iliac and femoropopliteal revascularization in most other preintervention scenarios, as well as intraprocedural and postprocedural optimization phases. IVUS was rated appropriate in all interventional phases for the tibial arteries. For iliofemoral venous interventions, IVUS was rated as appropriate in all interventional phases. CONCLUSIONS: Expert consensus can help define clinical procedural scenarios in which peripheral IVUS may have value during lower extremity arterial and venous intervention while additional prospective data are collected.


Assuntos
Procedimentos Endovasculares , Extremidade Inferior , Ultrassonografia de Intervenção , Consenso , Artéria Femoral/diagnóstico por imagem , Humanos , Extremidade Inferior/irrigação sanguínea , Extremidade Inferior/diagnóstico por imagem , Estudos Prospectivos , Resultado do Tratamento , Ultrassonografia de Intervenção/métodos
7.
Vasc Med ; 27(4): 392-400, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35546056

RESUMO

Although angiography has been the primary imaging modality used in peripheral vascular intervention, this technique has major limitations due to the evaluation of three-dimensional vessels in two dimensions. Intravascular ultrasound (IVUS) is an important adjunctive tool that can address some of these limitations. This systematic review assesses the appropriateness of IVUS as an imaging modality for guiding peripheral intervention through evidence collection and clinical appraisal of studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a cohort of 48 studies (29 arterial; 19 venous) detailing IVUS use in peripheral vascular intervention were extracted. Qualitative assessment of the studies evaluated pre- and postprocedure efficacy of IVUS and revealed that IVUS-guided peripheral intervention in arterial and venous diagnosis and treatment was superior to other imaging techniques alone. Each study in the cohort was further assessed for reliability and validity using the Oxford Centre for Evidence Based Medicine (CEBM) level of evidence scale. The majority of both arterial (79.3%) and venous (73.7%) studies received a 2b rating, the second highest level of evidence rating. The evidence to date indicates that IVUS results in better clinical outcomes overall and should be more widely adopted as an adjunctive imaging modality during peripheral intervention. (PROSPERO Registration No.: CRD42021232353).


Assuntos
Angiografia , Ultrassonografia de Intervenção , Artérias/diagnóstico por imagem , Humanos , Reprodutibilidade dos Testes , Resultado do Tratamento
8.
PLoS One ; 17(4): e0265767, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35390017

RESUMO

BACKGROUND: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. METHODS: We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. RESULTS: Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26). CONCLUSION: Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy.


Assuntos
Vasoespasmo Coronário , Neoplasias , Bloqueadores dos Canais de Cálcio/uso terapêutico , Vasoespasmo Coronário/induzido quimicamente , Vasoespasmo Coronário/tratamento farmacológico , Fluoruracila/efeitos adversos , Humanos , Neoplasias/tratamento farmacológico , Nitratos/uso terapêutico , Estudos Retrospectivos
9.
J Am Coll Cardiol ; 79(13): 1223-1235, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35361344

RESUMO

BACKGROUND: Mortality rates for patients presenting with acute myocardial infarction (AMI) and cardiogenic shock (CS) remain high despite advances in revascularization strategies and mechanical circulatory support (MCS) devices. OBJECTIVES: This study sought to elucidate the association between comorbid lower extremity peripheral artery disease (PAD) and outcomes in CS and AMI. METHODS: PAD status was defined in Medicare beneficiaries hospitalized with CS and AMI from October 1, 2015 to June 30, 2018. Primary outcomes ascertained through December 31, 2018 included in- and out-of-hospital mortality. Secondary outcomes included bleeding, amputation, stroke, and lower extremity revascularization. Multivariable regression models with adjustment for confounders were used to estimate risk. Subgroup analyses included patients treated with MCS and those who underwent coronary revascularization. RESULTS: Among 71,690 patients, 5.9% (N = 4,259) had PAD. Mean age was 77.8 ± 7.9 years, 58.7% were male, and 84.3% were White. Cumulative in-hospital mortality was 47.2%, with greater risk among those with PAD (56.3% vs 46.6% without PAD; adjusted OR: 1.50; 95% CI: 1.40-1.59). PAD patients also had greater risk of in-hospital amputation (1.6% vs 0.2%; adjusted OR: 7.0; 95% CI: 5.26-9.37) and out-of-hospital mortality (67.9% vs 40.7%; adjusted HR: 1.78; 95% CI: 1.67-1.90). MCS was less frequently utilized in PAD patients (21.5% vs 38.6% without PAD; P < 0.001) and was associated with higher mortality, need for lower extremity revascularization, and amputation risk. Findings were consistent in patients who underwent coronary revascularization. CONCLUSIONS: Among patients presenting with AMI and CS, PAD was associated with worse limb outcomes and survival. In addition to lower MCS utilization rates, those with PAD who received MCS had increased mortality, lower extremity revascularization, and amputation rates.


Assuntos
Infarto do Miocárdio , Doença Arterial Periférica , Idoso , Idoso de 80 Anos ou mais , Mortalidade Hospitalar , Humanos , Masculino , Medicare , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia , Doença Arterial Periférica/complicações , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/cirurgia , Choque Cardiogênico/epidemiologia , Choque Cardiogênico/etiologia , Choque Cardiogênico/terapia , Estados Unidos/epidemiologia
10.
JACC CardioOncol ; 4(5): 660-669, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36636443

RESUMO

Background: The use of immune checkpoint inhibitors (ICI) is associated with cardiovascular (CV) events, and patients with pre-existing autoimmune disease are at increased CV risk. Objectives: The aim of this study was to characterize the risk for CV events in patients with pre-existing autoimmune disease post-ICI. Methods: This was a retrospective study of 6,683 patients treated with ICIs within an academic network. Autoimmune disease prior to ICI was confirmed by chart review. Baseline characteristics and risk for CV and non-CV immune-related adverse events were compared with a matched control group (1:1 ratio) of ICI patients without autoimmune disease. Matching was based on age, sex, history of coronary artery disease, history of heart failure, and diabetes mellitus. CV events were a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, or myocarditis. Univariable and multivariable Cox proportional hazards models were used to determine the association between autoimmune disease and CV events. Results: Among 502 patients treated with ICIs, 251 patients with and 251 patients without autoimmune disease were studied. During a median follow-up period of 205 days, there were 45 CV events among patients with autoimmune disease and 22 CV events among control subjects (adjusted HR: 1.77; 95% CI: 1.04-3.03; P = 0.0364). Of the non-CV immune-related adverse events, there were increased rates of psoriasis (11.2% vs 0.4%; P < 0.001) and colitis (24.3% vs 16.7%; P = 0.045) in patients with autoimmune disease. Conclusions: Patients with autoimmune disease have an increased risk for CV and non-CV events post-ICI.

11.
Front Cardiovasc Med ; 8: 709396, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34820427

RESUMO

Aortic stiffness (AoS) is a maladaptive response to hemodynamic stress and both modifiable and non-modifiable risk factors, and elevated AoS increases afterload for the heart. AoS is a non-invasive marker of cardiovascular health and metabolic dysfunction. Implementing AoS as a diagnostic tool is challenging as it increases with age and varies amongst races. AoS is associated with lifestyle factors such as alcohol and smoking, as well as hypertension and comorbid conditions including metabolic syndrome and its components. Multiple studies have investigated various biomarkers associated with increased AoS, and this area is of particular interest given that these markers can highlight pathophysiologic pathways and specific therapeutic targets in the future. These biomarkers include those involved in the inflammatory cascade, anti-aging genes, and the renin-angiotensin aldosterone system. In the future, targeting AoS rather than blood pressure itself may be the key to improving vascular health and outcomes. In this review, we will discuss the current understanding of AoS, measurement of AoS and the challenges in interpretation, associated biomarkers, and possible therapeutic avenues for modulation of AoS.

12.
Immunother Adv ; 1(1): ltab014, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34541581

RESUMO

OBJECTIVES: Skeletal myopathies are highly morbid, and in rare cases even fatal, immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI). Skeletal myopathies are also a recognized statin-associated side effect. It is unknown whether concurrent use of statins and ICIs increases the risk of skeletal myopathies. METHODS: This was a retrospective cohort study of all patients who were treated with an ICI at a single academic institution (Massachusetts General Hospital, Boston, MA, USA). The primary outcome of interest was the development of a skeletal myopathy. The secondary outcome of interest was an elevated creatine kinase level (above the upper limit of normal). RESULTS: Among 2757 patients, 861 (31.2%) were treated with a statin at the time of ICI start. Statin users were older, more likely to be male and had a higher prevalence of cardiovascular and non-cardiovascular co-morbidities. During a median follow-up of 194 days (inter quartile range 65-410), a skeletal myopathy occurred in 33 patients (1.2%) and was more common among statin users (2.7 vs. 0.9%, P < 0.001). Creatine kinase (CK) elevation was present in 16.3% (114/699) and was higher among statin users (20.0 vs. 14.3%, P = 0.067). In a multivariable Cox model, statin therapy was associated with a >2-fold higher risk for skeletal myopathy (HR, 2.19; 95% confidence interval, 1.07-4.50; P = 0.033). CONCLUSION: In this large cohort of ICI-treated patients, a higher risk was observed for skeletal myopathies and elevation in CK levels in patients undergoing concurrent statin therapy. Prospective observational studies are warranted to further elucidate the potential association between statin use and ICI-associated myopathies.

13.
JACC CardioOncol ; 3(1): 101-109, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33817666

RESUMO

BACKGROUND: Coronary vasospasm is a recognized side effect of 5-FU (fluorouracil). There are limited and conflicting data on the incidence, risk factors and prognostic effect of 5-FU associated vasospasm. OBJECTIVES: To assess the incidence, risk factors and prognostic implications of 5-FU coronary vasospasm among patients receiving 5-FU regimens at a single tertiary care center. METHODS: We conducted a retrospective analysis of all patients who received 5-FU at a single academic center from January 2009 to July 2019. Vasospasm was defined as the occurrence of a typical chest pain syndrome in the presence of 5-FU. The presence of associated electrocardiogram (ECG) changes and/or elevated biomarkers was used to further confirm the diagnosis. Patients with vasospasm were compared to patients treated with 5-FU without vasospasm in a 1:2 ratio. Data regarding demographics, medical history, and follow-up were collected by manual chart review. RESULTS: From approximately 4019 individual patients who received 5-FU from 2009 to 2019 at a single center, 87 (2.16%) developed vasospasm. Patients who developed vasospasm were younger (58±13 vs. 64±13 years, P = 0.001), and were less likely to have any cardiovascular risk factors (70.1% vs. 84.5%, P = 0.007). Patients with vasospasm and patients without vasospasm were otherwise similar in terms of types of cancer, stage of cancer, sex, and race. There was no significant difference in progression-free survival, overall mortality or cancer specific mortality between patients who developed vasospasm versus those who did not. CONCLUSION: In a large, single-center report of 5-FU associated vasospasm, patients who developed vasospasm were younger, had lower rates of traditional cardiovascular risk factors and had no significant difference in progression-free or overall survival compared to those who did not develop vasospasm.

14.
J Emerg Med ; 58(5): 733-740, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32205000

RESUMO

BACKGROUND: Infectious disease-related factors that may contribute to or complicate falls have received relatively little attention in the literature. OBJECTIVE: Our aim was to determine the prevalence of, and risk factors for, coexisting systemic infections (CSIs) in patients admitted to the hospital because of a fall or its complications. METHODS: We conducted a retrospective cohort study of adult patients seen at a tertiary care hospital emergency department and subsequently hospitalized because of a fall or its complications. RESULTS: Of 1,456 evaluable cases, 775 patients (53.2%) were female. Mean age was 71.6 years (range 18-104 years). CSI was diagnosed in 303 patients (20.8%), of which 166 (54.8%) were urinary tract infections and 108 (35.6%) were pneumonia cases; 14 patients (4.6%) were bacteremic. CSI was not initially suspected by providers in 98 (32.5%) subsequently diagnosed cases. Age ≥50 years (odds ratio [OR] 5.6; 95% confidence interval [CI] 1.2-24.9), inability to get up on own after the index fall (OR 2.1; 95% CI 1.2-3.6), preexisting symptom(s) (OR 3.0; 95% CI 1.8-5.2), and systemic inflammatory response syndrome (SIRS) (OR 2.9; 95% CI 1.5-5.4), or confusion at presentation (OR 3.0; 95% CI 1.5-6.0) were independently associated with CSI. In-hospital mortality rate was significantly higher among patients with CSI (6.9% vs. 3.8 %, OR 1.9; 95% CI 1.1-3.3). CONCLUSIONS: CSIs are common among patients admitted to the hospital after a fall or its complications. Age ≥ 50 years, inability to get up on own, preexisting symptom(s), and the presence of SIRS or confusion at presentation are potential predictors of CSI in this patient population.


Assuntos
Acidentes por Quedas , Serviço Hospitalar de Emergência , Sepse , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
15.
J Am Coll Cardiol ; 73(11): 1336-1349, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30898209

RESUMO

Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins have been preferred for treatment of VTE, whereas warfarin has been the standard anticoagulant for stroke prevention in patients with atrial fibrillation (AF). More recently, direct oral anticoagulants (DOACs) have been demonstrated to reduce the risk of venous and arterial thromboembolism in large randomized clinical trials of patients with VTE and AF, respectively, thus providing an attractive oral dosing option that does not require routine laboratory monitoring. In this review, we summarize available clinical trial data and guideline recommendations, and outline a practical approach to anticoagulation management of VTE and AF in cancer.


Assuntos
Anticoagulantes , Fibrilação Atrial , Neoplasias , Tromboembolia , Anticoagulantes/classificação , Anticoagulantes/farmacologia , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Coagulação Sanguínea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Neoplasias/sangue , Neoplasias/complicações , Guias de Prática Clínica como Assunto , Tromboembolia/etiologia , Tromboembolia/prevenção & controle
16.
Am J Med ; 132(9): 1103-1105, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30851265

RESUMO

BACKGROUND: While open access publishing among cardiovascular journals has increased in scope over the last decade, the relationship between open access and article citation volume remains unclear. METHODS: We evaluated the association between open access publishing and citation number in 2017 among 4 major cardiovascular journals. Articles indexed to PubMed with ≥5 citations were identified among the following journals: Circulation, European Heart Journal, Journal of the American College of Cardiology, and JAMA Cardiology. Multivariable Poisson regression models were adjusted for journal and article type. RESULTS: Of the 916 articles published in 2017, original investigations accounted for most articles (66.7%), followed by reviews (14.5%), guideline/scientific statements (8.4%), research letters (3.7%), viewpoints (3.7%), and editorials (2.9%). Among all articles, 43% (n = 391) were open access. Citation number was higher among open access articles compared with those with subscription access (14 [25th-75th percentile: 9-23] vs 11 [25th-75th percentile: 7-17]; P < .001). Open access status was significantly associated with higher number of citations after multivariable adjustment (ß coefficient: +0.42; 95% confidence interval, 0.38-0.45, P < .001). Open access articles had consistently higher citations compared with subscription access articles across the 3 most frequent article types. CONCLUSION: Among contemporary articles published in major cardiovascular journals, open access publishing accounted for over 40% of articles and was significantly associated with increased short-term citations. Further research is required to assess the variation in long-term citation rates based on open access publishing status.


Assuntos
Cardiologia , Publicação de Acesso Aberto/estatística & dados numéricos , Publicações Periódicas como Assunto/estatística & dados numéricos , Editoração/estatística & dados numéricos , Bibliometria , Humanos
17.
PLoS Genet ; 11(11): e1005655, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26544867

RESUMO

Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects.


Assuntos
Proteínas de Ligação a DNA/genética , Síndrome de Cornélia de Lange/genética , Proteínas de Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/fisiologia , Modelos Biológicos , Mutação , Animais , Drosophila/genética , Heterozigoto
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