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1.
Mol Psychiatry ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39048645

RESUMO

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

2.
Acta Haematol ; 136(4): 210-218, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27632567

RESUMO

Telomeres are the capping ends of chromosomes that protect the loss of genetic material and prevent chromosomal instability. In human tissue-specific stem/progenitor cells, telomere length (TL) is maintained by the telomerase complex, which consists of a reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Very short telomeres and loss-of-function mutations in the TERT and TERC genes have been reported in acute myeloid leukemia, but the role of telomeres in acute promyelocytic leukemia (APL) has not been well established. We report the results for a large cohort of 187 PML/RARα-positive APL patients. No germline mutations in the TERT or TERC genes were identified. Codon 279 and 1062 TERT polymorphisms were present at a frequency similar to that in the general population. TL measured in blood or marrow mononuclear cells at diagnosis was significantly shorter in the APL patients than in healthy volunteers, and shorter telomeres at diagnosis were significantly associated with high-risk disease. For patients who achieved complete remission, the median increase in TL from diagnosis to remission (delta TL) was 2.0 kilobase (kb), and we found delta TL to be the most powerful predictor of overall survival when compared with well-established risk factors for poor outcomes in APL.


Assuntos
Códon , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Polimorfismo Genético , Telomerase/genética , Homeostase do Telômero/genética , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , RNA/genética , Taxa de Sobrevida , Homeostase do Telômero/efeitos dos fármacos
3.
N Engl J Med ; 366(12): 1079-89, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22417203

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. METHODS: We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. RESULTS: We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). CONCLUSIONS: We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).


Assuntos
Análise Mutacional de DNA , Quimioterapia de Indução , Leucemia Mieloide Aguda/genética , Mutação , Medição de Risco/métodos , Adolescente , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Impressões Digitais de DNA , Daunorrubicina/administração & dosagem , Duplicação Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Translocação Genética , Adulto Jovem
4.
Blood ; 121(11): 1935-43, 2013 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-23319575

RESUMO

Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.


Assuntos
Redes Comunitárias/organização & administração , Países em Desenvolvimento , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/terapia , Melhoria de Qualidade/organização & administração , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Chile/epidemiologia , Consenso , Países em Desenvolvimento/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Internacionalidade , Leucemia Promielocítica Aguda/mortalidade , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Uruguai/epidemiologia , Adulto Jovem
5.
Br J Haematol ; 166(4): 540-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24796963

RESUMO

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71-30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08-0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49-43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05-0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99-1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ligação a DNA/metabolismo , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Antraciclinas/administração & dosagem , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
6.
Blood ; 120(10): 2098-108, 2012 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-22734072

RESUMO

Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.


Assuntos
Antineoplásicos/administração & dosagem , Aberrações Cromossômicas , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Tretinoína/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Lactente , Cariotipagem , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/mortalidade , Pessoa de Meia-Idade , Mutação , Recidiva , Análise de Sobrevida , Tretinoína/efeitos adversos
7.
Ann Hematol ; 93(12): 2001-10, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24981688

RESUMO

Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Criança , DNA de Neoplasias/genética , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Hemoglobinas/análise , Humanos , Idarubicina/administração & dosagem , Estimativa de Kaplan-Meier , América Latina/epidemiologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
8.
J Nat Prod ; 77(3): 631-9, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24456028

RESUMO

Nine new withanolides (1-9), withahisolides A-I, were isolated along with nine known compounds (10-18) from the aerial parts of Physalis hispida. The structures of 1-9 were elucidated through a variety of spectroscopic techniques, while the structures of 1 and 2 were confirmed by X-ray crystallographic analysis. Compounds 1-3 are the first withanolides with nonaromatic six-membered ring D moieties. In addition, withanolide 8 represents a novel withanolide skeleton due to the absence of a C-13-C-17 bond within the steroidal nucleus.


Assuntos
Physalis/química , Vitanolídeos/isolamento & purificação , Cristalografia por Raios X , Kansas , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Vitanolídeos/química
9.
World J Surg ; 38(6): 1343-52, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24763440

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis, as a majority of patients present with advanced disease. Current adjuvant strategies for metastatic patients include mitotane or other cytotoxic agents and carry a significant morbidity as well as a low (<10 %) 5-year survival. Withanolides, including withaferin A, are novel chemotherapeutic agents with potent targeted effects in medullary thyroid cancer and a number of solid malignancies with low toxicity in vivo. We hypothesize that novel naturally derived withanolides will have potent targeted anti-cancer activity against ACCs. METHODS: In vitro cell viability of ACC cell lines (Y1 and SW13) was measured using MTS cell proliferation assay. Cell cycle and apoptotic analysis studied using annexin V/propidium iodide staining on flow cytometry (FC) and targeted molecular mechanisms of withanolide cytotoxicity were assessed using standard Western blot analysis. RESULTS: All the withanolides potently reduced ACC cell viability on MTS assay with 7- to 185-fold higher selectivity than normal fibroblasts. Cell cycle analysis demonstrated a shift in cell cycle arrest from G1/G0 to G2/M with induction of apoptosis at nanomolar concentrations of withanolides. Unlike current ACC therapeutics, withanolides modulated expression of several key oncogenic pathway proteins in ACCs by Western blot, including Jagged 1, MAPK, and Akt/mTOR pathway proteins in a dose-dependent manner after 24 h drug treatment of SW13 cells. CONCLUSION: These results demonstrate the first evidence of the anticancer efficacy of withanolides in ACC cells and provide support for future translational evaluation of these compounds as novel therapeutic agents for ACC patients.


Assuntos
Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Vitanolídeos/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/cirurgia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Sensibilidade e Especificidade , Células Tumorais Cultivadas/efeitos dos fármacos
10.
Prim Care ; 51(1): 95-109, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38278576

RESUMO

Valvular heart disease is a common abnormality seen in the primary care setting. There are many causes of valvular heart disease including congenital, degenerative, infectious, traumatic, and many more. There is a wide variety of types of valvular heart disease with each valve having the ability to develop both regurgitation and stenosis by multiple mechanisms. All these complexities make diagnosis and management of valvular heart disease complicated, especially in the context of comorbidities. For this reason, it is important for primary care physicians to have a thorough understanding of how these diseases present and when interventions are indicated.


Assuntos
Doenças das Valvas Cardíacas , Insuficiência da Valva Mitral , Humanos , Doenças das Valvas Cardíacas/diagnóstico , Doenças das Valvas Cardíacas/terapia
11.
LGBT Health ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968344

RESUMO

Purpose: Sexually and racially minoritized people often have mistrust toward the healthcare system due to both perceived and actual experiences of discrimination. This may result in increased privacy concerns and a reluctance to share health-related information with health care providers. Drawing upon minority stress and an intersectionality framework, this study examines how rates of concealing health information differ between non-Hispanic White heterosexual people, non-Hispanic White lesbian, gay, and bisexual (LGB) people, racially minoritized heterosexual people, and those who are both sexually and racially minoritized. Methods: Using nationally representative cross-sectional data from the Health Information National Trends Survey from 2017 and 2018 (n = 4575), we fit logistic regression models to examine (1) whether sexually and racially minoritized people conceal health information from their providers more than their counterparts and (2) whether this tendency increases for those with multiple marginalized identities. Furthermore, we fit linear regression models to examine whether and how concealing health information from providers are linked to health outcomes. Results: Sexually and racially minoritized people had higher odds of concealing health information from providers than their counterparts. Those with multiple marginalized identities had even higher odds of withholding health information than other groups. Finally, we found a significant negative association between concealing health information and mental health. Conclusion: Our findings underscore the need to consider how the intersection of multiple marginalized identities shape health experiences and concerns over privacy in health care matters. We call for further research to better understand the complex dynamics of patient-provider relationships for marginalized populations.

12.
Am Surg ; : 31348241241659, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563045

RESUMO

BACKGROUND: Unexpected ICU admissions are a key quality metric in trauma care. The purpose of this study is to identify the most common causes of unplanned ICU admissions among trauma patients at an ACS-verified level 1 trauma center. METHODS: A retrospective review was conducted of all trauma patients with unplanned admission to the ICU at a level 1 trauma center between 2019 and 2021. Unplanned ICU admissions were categorized into (1) "bounce-backs," patients previously admitted to the ICU and (2) "upgrades," patients who had not previously been cared for in the ICU. RESULTS: Of 300 unexpected ICU transfers, bounce-backs accounted for 69% and upgrades 31%. The most common injuries were traumatic brain injuries (40%) and rib fractures (41.3%). In-hospital mortality rate was 10% and did not significantly differ between bounce-backs and upgrades (12 vs 5%, P = .92). Respiratory distress was the most common cause of transfer (41.1%), followed by neurologic (29.6%) and cardiovascular decline (21.2%). Patients were on average 928 mL fluid positive 72 hours prior to transfer (t > 0, P < .0001), and 295 mL fluid positive in the 24 hours prior to transfer (t > 0, P .0003). Patients transferred for respiratory distress were no more fluid over-balanced than those transferred for other reasons. CONCLUSION: We found a large percent of unplanned transfers occurring within 48 hours of admission or transfer out of the ICU suggesting under-triage as a leading cause of bounce-backs and upgrades. Respiratory distress was the leading cause of transfer. These findings highlight opportunities for targeted interventions.

13.
Am J Case Rep ; 25: e941759, 2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38217283

RESUMO

BACKGROUND Capecitabine and other 5-fluorouracil prodrugs are medications widely employed in treating solid tumors, including breast and colorectal cancer. However, they carry a notable risk for cardiotoxicity, including coronary vasospasm, possibly related to their impact on vascular endothelium and smooth muscle. CASE REPORT We present a case of a 45-year-old male with a pancreatic neuroendocrine tumor who developed exertional chest pain after starting capecitabine. Initial evaluations in the emergency department, including a 12-lead electrocardiogram and cardiac enzymes, were normal, but suspicion for coronary vasospasm persisted due to the temporal relationship with drug initiation and symptom characteristics. A graded exercise test reproduced his symptoms, accompanied by hyperacute peaked T waves and subsequent ST segment elevations in the inferior leads. Coronary angiography revealed patent coronary arteries, rendering provocative testing unnecessary due to a high clinical suspicion of capecitabine-induced vasospasm. Discontinuing the patient's medication was a more efficient approach than continuing additional cardiac workup while the drug was still administered. After multidisciplinary discussion, capecitabine was discontinued, leading to symptom resolution and a negative repeat graded exercise test. CONCLUSIONS This case underscores the potential for capecitabine to induce coronary artery vasospasm, emphasizing the importance of prompt medication cessation. Patients receiving capecitabine therapy and experiencing chest pain should undergo an evaluation with consideration of capecitabine-induced vasospasm in the differential diagnosis. Prompt recognition and medication cessation are critical to prevent serious cardiovascular complications including death. In our patient, discontinuing capecitabine resolved his symptoms, emphasizing the significance of discontinuing the causative drug and seeking alternative chemotherapy regimens.


Assuntos
Aterosclerose , Vasoespasmo Coronário , Masculino , Humanos , Pessoa de Meia-Idade , Capecitabina/efeitos adversos , Vasoespasmo Coronário/induzido quimicamente , Vasoespasmo Coronário/diagnóstico , Vasoespasmo Coronário/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Dor no Peito/induzido quimicamente , Eletrocardiografia
14.
Injury ; 55(7): 111593, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38762943

RESUMO

BACKGROUND: Surgical stabilization of rib fractures (SSRF) improves outcomes in chest wall trauma. Geriatric patients are particularly vulnerable to poor outcomes; yet, this population is often excluded from SSRF studies. Further delineating patient outcomes by age is necessary to optimize care for the aging trauma population. METHODS: A retrospective cohort study was conducted examining outcomes among patients aged 40+ for whom an SSRF consult was placed between 2017 and 2022 at a level 1 trauma center. Patients were categorized into geriatric (65+) and adult (40-64), as well as 80 years and older (80+) and 79 and younger (40-79). Patient outcomes were assessed comparing non-operative and operative management of chest wall trauma. Propensity matched analysis was performed to evaluate mortality differences between adult and geriatric patients who did and did not undergo SSRF. RESULTS: A total of 543 patients had an SSRF consult. Of these, 227 were 65+, and 73 were 80+. A total of 129 patients underwent SSRF (24 %). The percentage of patients undergoing SSRF did not vary between 40 and 64 and 65+ (23.7 % and 23.6 %, respectively, p = 0.97) or 40-79 and 80+ (24.0 vs 21.9, p = 0.69). Patients undergoing SSRF had higher chest injury burden and were more likely to require mechanical ventilation and ICU level care on admission. Overall, in-hospital mortality rate was 4.6 %. Among patients who underwent SSRF, mortality rate did not significantly differ between 65+ and 40-64 (7.8% vs 2.7 %, p = 0.18) or 80+ and 40-79 (6.3% vs 4.6 %, p = 0.77). This remained true in propensity matched analysis. CONCLUSION: Geriatric and octogenarian patients with rib fractures underwent SSRF at similar rates and achieved equivalent outcomes to their younger counterparts. SSRF did not differentially affect mortality outcomes based on age group in propensity matched analysis. SSRF is safe for geriatric patients including octogenarians.


Assuntos
Pontuação de Propensão , Fraturas das Costelas , Centros de Traumatologia , Humanos , Fraturas das Costelas/cirurgia , Fraturas das Costelas/mortalidade , Feminino , Masculino , Estudos Retrospectivos , Idoso , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto , Fatores Etários , Mortalidade Hospitalar , Fixação Interna de Fraturas/métodos , Traumatismos Torácicos/cirurgia , Traumatismos Torácicos/mortalidade
15.
Am J Pathol ; 181(3): 1007-16, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22819534

RESUMO

Inactivation of the transcription factor/tumor suppressor Krüppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naïve PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy.


Assuntos
Androgênios/deficiência , Progressão da Doença , Fatores de Transcrição Kruppel-Like/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/genética , Processamento Alternativo/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Análise Mutacional de DNA , Éxons/genética , Humanos , Fator 6 Semelhante a Kruppel , Masculino , Transcrição Gênica , Ativação Transcricional/genética
16.
J Nat Prod ; 76(11): 2040-6, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24152046

RESUMO

Methanol solutions of the main withanolides (6-8) naturally present in Physalis longifolia yielded five artificial withanolides (1-5), including three new compounds (1-3). Withanolides 1 and 2 were identified as intramolecular Michael addition derivatives, while withanolides 3-5 were the result of intermolecular Michael addition. A comprehensive literature investigation was conducted to identify potential withanolide Michael addition artifacts isolated from Solanaceous species to date.


Assuntos
Metanol/química , Physalis/química , Vitanolídeos/química , Ergosterol/análogos & derivados , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Vitanolídeos/isolamento & purificação
17.
J Nat Prod ; 76(3): 445-9, 2013 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-23252848

RESUMO

A new withanolide, named withawrightolide (1), and four known withanolides (2-5) were isolated from the aerial parts of Datura wrightii. The structure of compound 1 was elucidated through 2D NMR and other spectroscopic techniques. In addition, the structure of withametelin L (2) was confirmed by X-ray crystallographic analysis. Using MTS viability assays, withanolides 1-5 showed antiproliferative activities against human glioblastoma (U251 and U87), head and neck squamous cell carcinoma (MDA-1986), and normal fetal lung fibroblast (MRC-5) cells with IC50 values in the range between 0.56 and 5.6 µM.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Datura/química , Vitanolídeos/isolamento & purificação , Vitanolídeos/farmacologia , Antineoplásicos Fitogênicos/química , Carcinoma de Células Escamosas/tratamento farmacológico , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Kansas , Pulmão/citologia , Pulmão/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Vitanolídeos/química
18.
J Card Surg ; 28(3): 321-4, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23445461

RESUMO

BACKGROUND: Complete device and lead removal is recommended for management of infected implantable cardiac device. Management of large lead vegetation (2 cm) is still in debate. METHODS: We report a series of patients involving percutaneous extraction of large vegetations (>2 cm) from ICD/pacing leads using the AngioVac Cannula in patients with infective endocarditis. This approach was used to debulk the ICD/pacing lead vegetations in order to minimize the risk of septic pulmonary embolism during lead explantation. CONCLUSION: AngioVac Cannula can be used safely and effectively as an adjunctive method for patients with large lead vegetation.


Assuntos
Cateterismo Cardíaco/instrumentação , Catéteres , Desfibriladores Implantáveis , Remoção de Dispositivo/instrumentação , Eletrodos Implantados , Endocardite Bacteriana/cirurgia , Corpos Estranhos/cirurgia , Átrios do Coração/cirurgia , Marca-Passo Artificial , Infecções Relacionadas à Prótese/cirurgia , Sucção/instrumentação , Idoso de 80 Anos ou mais , Bacteriemia/diagnóstico , Bacteriemia/microbiologia , Bacteriemia/cirurgia , Comportamento Cooperativo , Desfibriladores Implantáveis/microbiologia , Ecocardiografia , Ecocardiografia Transesofagiana , Eletrodos Implantados/microbiologia , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/microbiologia , Desenho de Equipamento , Feminino , Corpos Estranhos/diagnóstico , Corpos Estranhos/microbiologia , Átrios do Coração/microbiologia , Ventrículos do Coração/microbiologia , Ventrículos do Coração/cirurgia , Humanos , Comunicação Interdisciplinar , Masculino , Staphylococcus aureus Resistente à Meticilina , Pessoa de Meia-Idade , Marca-Passo Artificial/microbiologia , Pacientes , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/cirurgia , Staphylococcus aureus , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/cirurgia , Streptococcus agalactiae
19.
Clin Case Rep ; 11(2): e6963, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36814712

RESUMO

We report a case of incidental detection of severe aortic coarctation, severe secundum atrial septal defect, and bicuspid aortic valve in an active-duty military service member. A single complex minimally invasive procedure successfully corrected his coarctation and atrial septal defect allowing this patient to continue military service.

20.
Plast Reconstr Surg Glob Open ; 11(6): e5064, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37325370

RESUMO

With high success rates of autologous breast reconstruction, the focus has shifted from flap survival to improved patient outcomes. Historically, a criticism of autologous breast reconstruction has been the length of hospital stay. Our institution has progressively shortened the length of stay after deep inferior epigastric artery perforator (DIEP) flap reconstruction and began discharging select patients on postoperative day 1 (POD1). The purpose of this study was to document our experience with POD1 discharges and to identify preoperative and intraoperative factors that may identify patients as candidates for earlier discharge. Methods: An institutional review board-approved, retrospective chart review of patients undergoing DIEP flap breast reconstruction from January 2019 to March 2022 at Atrium Health was completed, consisting of 510 patients and 846 DIEP flaps. Patient demographics, medical history, operative course, and postoperative complications were collected. Results: Twenty-three patients totaling 33 DIEP flaps were discharged on POD1. The POD1 group and the group of all other patients (POD2+) had no difference in age, ASA score, or comorbidities. BMI was significantly lower in the POD1 group (P = 0.039). Overall operative time was significantly lower in the POD1 group, and this remained true when differentiating into unilateral operations (P = 0.023) and bilateral operations (P = 0.01). No major complications occurred in those discharged on POD1. Conclusions: POD1 discharge after DIEP flap breast reconstruction is safe for select patients. Lower BMI and shorter operative times may be predictive in identifying patients as candidates for earlier discharge.

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