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1.
Ann Vasc Surg ; 98: 182-193, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37802139

RESUMO

BACKGROUND: Distal muscle stabilization, such as myodesis (suturing muscles to bone) or myoplasty (suturing agonistic-antagonistic muscles together), can aid residual limb stabilization, provide a good soft-tissue covering, and increase rehabilitation potential. However, surgical practice varies due to scant clinical data. The aim of this review is to summarize and evaluate the literature regarding techniques and associated outcomes of distal muscle stabilization in transfemoral amputation (TFA). METHODS: A systematic review and narrative synthesis was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Resources, including observational studies, nonobservational scientific papers, conference proceedings, and textbooks, detailing techniques of TFA distal muscle stabilization were identified from standard medical repositories and library search. A supplementary search of YouTube and Google was undertaken to identify additional resources. Quality assessment was undertaken using Risk Of Bias In Nonrandomized Studies-of Interventions; Authority, Accuracy, Coverage, Objectivity, Date, Significance; and modified-Discern tools. RESULTS: Forty seven resources were identified, including 17 journal articles, 17 textbooks, 5 educational websites/eBooks, 5 videos, 2 online presentations, and 1 webpage. Thirty seven described myodesis, 11 described myoplasty, and 6 described closure without distal muscle stabilization. Eight observational studies presented outcome data for 302 TFAs. No studies comparing closure with or without distal muscle stabilization were identified. All papers describing myodesis secured the adductors to the femur, and most also secured the quadriceps and/or hamstrings to this complex. Number of femoral drill holes varied from 1 to 6. Early wound complications occurred in 17% of amputations, whereas myodesis failure occurred in 9.5%. Prosthetic fitting rates were 73% and, where reported, 100% of patients maintained neutral femoral alignment. CONCLUSIONS: Distal muscle stabilization, particularly myodesis, is a commonly described technique for TFA, although operative techniques are heterogenous. There is a paucity of outcome data, and no studies comparing it to closures without distal muscle stabilization. However, these low-quality data suggest wound healing rates are equivalent to TFA without distal muscle stabilization while demonstrating improvement to patients' rehabilitation potential.


Assuntos
Amputação Cirúrgica , Fêmur , Humanos , Resultado do Tratamento , Extremidades , Músculos
2.
Hum Factors ; 65(2): 275-287, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33934614

RESUMO

OBJECTIVE: To understand how aspects of vishing calls (phishing phone calls) influence perceived visher honesty. BACKGROUND: Little is understood about how targeted individuals behave during vishing attacks. According to truth-default theory, people assume others are being honest until something triggers their suspicion. We investigated whether that was true during vishing attacks. METHODS: Twenty-four participants read written descriptions of eight real-world vishing calls. Half included highly sensitive requests; the remainder included seemingly innocuous requests. Participants rated visher honesty at multiple points during conversations. RESULTS: Participants initially perceived vishers to be honest. Honesty ratings decreased before requests occurred. Honesty ratings decreased further in response to highly sensitive requests, but not seemingly innocuous requests. Honesty ratings recovered somewhat, but only after highly sensitive requests. CONCLUSIONS: The present results revealed five important insights: (1) people begin vishing conversations in the truth-default state, (2) certain aspects of vishing conversations serve as triggers, (3) other aspects of vishing conversations do not serve as triggers, (4) in certain situations, people's perceptions of visher honesty improve, and, more generally, (5) truth-default theory may be a useful tool for understanding how targeted individuals behave during vishing attacks. APPLICATION: Those developing systems that help users deal with suspected vishing attacks or penetration testing plans should consider (1) targeted individuals' truth-bias, (2) the influence of visher demeanor on the likelihood of deception detection, (3) the influence of fabricated situations surrounding vishing requests on the likelihood of deception detection, and (4) targeted individuals' lack of concern about seemingly innocuous requests.


Assuntos
Comunicação , Enganação , Humanos
3.
Anesth Analg ; 134(2): 242-252, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33684091

RESUMO

Ensuring a productive clinical and research workforce requires bringing together physicians and communities to improve health, by strategic targeting of initiatives with clear and significant public health relevance. Within anesthesiology, the traditional perspective of the field's health impact has focused on providing safe and effective intraoperative care, managing critical illness, and treating acute and chronic pain. However, there are limitations to such a framework for anesthesiology's public health impact, including the transient nature of acute care episodes such as the intraoperative period and critical illness, and a historical focus on analgesia alone-rather than the complex psychosocial milieu-for pain management. Due to the often episodic nature of anesthesiologists' interactions with patients, it remains challenging for anesthesiologists to achieve their full potential for broad impact and leadership within increasingly integrated health systems. To unlock this potential, anesthesiologists should cultivate new clinical, research, and administrative roles within the health system-transcending traditional missions, seeking interdepartmental collaborations, and taking measures to elevate anesthesiologists as dynamic and trusted leaders. This special article examines 3 core themes for how anesthesiologists can enhance their impact within the health care system and pursue new collaborative health missions with nonanesthesiologist clinicians, researchers, and administrative leaders. These themes include (1) reframing of traditional anesthesiologist missions toward a broader health system-wide context; (2) leveraging departmental and institutional support for professional career development; and (3) strategically prioritizing leadership attributes to enhance system-wide anesthesiologist contributions to improving overall patient health.


Assuntos
Anestesiologistas/tendências , Anestesiologia/tendências , Mobilidade Ocupacional , Liderança , Relações Médico-Paciente , Humanos
4.
Genome Res ; 28(9): 1345-1352, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30087104

RESUMO

To enable the characterization of genetic heterogeneity in tumor cell populations, we developed a novel microfluidic approach that barcodes amplified genomic DNA from thousands of individual cancer cells confined to droplets. The barcodes are then used to reassemble the genetic profiles of cells from next-generation sequencing data. By using this approach, we sequenced longitudinally collected acute myeloid leukemia (AML) tumor populations from two patients and genotyped up to 62 disease relevant loci across more than 16,000 individual cells. Targeted single-cell sequencing was able to sensitively identify cells harboring pathogenic mutations during complete remission and uncovered complex clonal evolution within AML tumors that was not observable with bulk sequencing. We anticipate that this approach will make feasible the routine analysis of AML heterogeneity, leading to improved stratification and therapy selection for the disease.


Assuntos
Leucemia Mieloide Aguda/genética , Microfluídica/métodos , Análise de Sequência de DNA/métodos , Análise de Célula Única/métodos , Idoso , Células Cultivadas , Evolução Clonal , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Mutação
5.
Bioorg Med Chem Lett ; 42: 128050, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33887439

RESUMO

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.


Assuntos
Aminopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Oligopeptídeos/farmacologia , Ácidos Fosfínicos/farmacologia , Aminopeptidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Antígenos de Histocompatibilidade Menor/metabolismo , Modelos Moleculares , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/química , Relação Estrutura-Atividade
6.
Anesth Analg ; 132(5): 1438-1449, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33724961

RESUMO

BACKGROUND: Postoperative pulmonary complications can have a significant impact on the morbidity and mortality of patients undergoing major surgeries. Intraoperative lung protective strategies using low tidal volume (TV) ventilation and positive end-expiratory pressure (PEEP) have been demonstrated to reduce the incidence of pulmonary injury and infection while improving oxygenation and respiratory mechanics. The purpose of this study was to develop decision support systems designed to optimize behavior of the attending anesthesiologist with regards to adherence with established intraoperative lung-protective ventilation (LPV) strategies. METHODS: Over a 4-year period, data were obtained from 49,386 procedures and 109 attendings. Cases were restricted to patients aged 18 years or older requiring general anesthesia that lasted at least 60 minutes. We defined protective lung ventilation as a TV of 6-8 mL/kg ideal body weight and a PEEP of ≥4 cm H2O. There was a baseline period followed by 4 behavioral interventions: education, near real-time feedback, individualized post hoc feedback, and enhanced multidimensional decision support. Segmented logistic regression using generalized estimating equations was performed in order to assess temporal trends and effects of interventions on adherence to LPV strategies. RESULTS: Consistent with improvement in adherence with LPV strategies during the baseline period, the predicted probability of adherence with LPV at the end of baseline was 0.452 (95% confidence interval [CI], 0.422-0.483). The improvements observed for each phase were relative to the preceding phase. Education alone was associated with an 8.7% improvement (P < .01) in adherence to lung-protective protocols and was associated with a 16% increase in odds of adherence (odds ratio [OR] = 1.16; 95% CI, 1.01-1.33; P = .04). Near real-time, on-screen feedback was associated with an estimated 15.5% improvement in adherence (P < .01) with a 69% increase in odds of adherence (OR = 1.69; 95% CI, 1.46-1.96; P < .01) over education alone. The addition of an individualized dashboard with personal adherence and peer comparison was associated with a significant improvement over near real-time feedback (P < .01). Near real-time feedback and dashboard feedback systems were enhanced based on feedback from the in-room attendings, and this combination was associated with an 18.1% (P < .01) increase in adherence with a 2-fold increase in the odds of adherence (OR = 2.23; 95% CI, 1.85-2.69; P < .0001) between the end of the previous on-screen feedback phase and the start of the individualized post hoc dashboard reporting phase. The adherence with lung-protective strategies using the multidimensional approach has been sustained for over 24 months. The difference between the end of the previous phase and the start of this last enhanced multidimensional decision support phase was not significant (OR = 1.08; 95% CI, 0.86-1.34; P = .48). CONCLUSIONS: Consistent with the literature, near real-time and post hoc reporting are associated with positive and sustained behavioral changes aimed at adopting evidence-based clinical strategies. Many decision support systems have demonstrated impact to behavior, but the effect is often transient. The implementation of near real-time feedback and individualized post hoc decision support tools has resulted in clinically relevant improvements in adherence with LPV strategies that have been sustained for over 24 months, a common limitation of decision support solutions.


Assuntos
Anestesia/normas , Anestesiologistas/normas , Técnicas de Apoio para a Decisão , Feedback Formativo , Cuidados Intraoperatórios/normas , Pneumopatias/prevenção & controle , Padrões de Prática Médica/normas , Respiração Artificial/normas , Adulto , Idoso , Anestesia/efeitos adversos , Anestesiologistas/educação , Anestesiologistas/psicologia , Registros Eletrônicos de Saúde , Feminino , Fidelidade a Diretrizes/normas , Conhecimentos, Atitudes e Prática em Saúde , Sistemas de Informação Hospitalar , Humanos , Cuidados Intraoperatórios/efeitos adversos , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Respiração com Pressão Positiva/normas , Guias de Prática Clínica como Assunto/normas , Fatores de Proteção , Respiração Artificial/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume de Ventilação Pulmonar , Resultado do Tratamento
7.
Regul Toxicol Pharmacol ; 126: 105029, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34455009

RESUMO

In drug development, nonclinical safety assessment is pivotal for human risk assessment and support of clinical development. Selecting the relevant/appropriate animal species for toxicity testing increases the likelihood of detecting potential effects in humans, and although recent regulatory guidelines state the need to justify or dis-qualify animal species for toxicity testing, individual companies have developed decision-processes most appropriate for their molecules, experience and 3Rs policies. These generally revolve around similarity of metabolic profiles between toxicology species/humans and relevant pharmacological activity in at least one species for New Chemical Entities (NCEs), whilst for large molecules (biologics) the key aspect is similarity/presence of the intended human target epitope. To explore current industry practice, a questionnaire was developed to capture relevant information around process, documentation and tools/factors used for species selection. Collated results from 14 companies (Contract Research Organisations and pharmaceutical companies) are presented, along with some case-examples or over-riding principles from individual companies. As the process and justification of species selection is expected to be a topic for continued emphasis, this information could be adapted towards a harmonized approach or best practice for industry consideration.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/métodos , Modelos Animais , Testes de Toxicidade/métodos , Produtos Biológicos/toxicidade , Indústria Farmacêutica/normas , Especificidade da Espécie , Testes de Toxicidade/normas
8.
Med Teach ; 43(7): 758-764, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34061700

RESUMO

Programmatic assessment as a concept is still novel for many in clinical education, and there may be a disconnect between the academics who publish about programmatic assessment and the front-line clinical educators who must put theory into practice. In this paper, we clearly define programmatic assessment and present high-level guidelines about its implementation in competency-based medical education (CBME) programs. The guidelines are informed by literature and by lessons learned from established programmatic assessment approaches. We articulate five steps to consider when implementing programmatic assessment in CBME contexts: articulate the purpose of the program of assessment, determine what must be assessed, choose tools fit for purpose, consider the stakes of assessments, and define processes for interpreting assessment data. In the process, we seek to offer a helpful guide or template for front-line clinical educators. We dispel some myths about programmatic assessment to help training programs as they look to design-or redesign-programs of assessment. In particular, we highlight the notion that programmatic assessment is not 'one size fits all'; rather, it is a system of assessment that results when shared common principles are considered and applied by individual programs as they plan and design their own bespoke model of programmatic assessment for CBME in their unique context.


Assuntos
Educação Baseada em Competências , Educação Médica , Humanos
9.
Development ; 144(19): 3475-3486, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28851706

RESUMO

Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on activation of the spindle assembly checkpoint, which results in anaphase-promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes of DNA damage checkpoint proteins are assembled at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min. Despite this robust response, there is no measurable loss in k-fibres, or tension across the bivalent. Through pharmacological inhibition we observed that the response is dependent on Mps1 kinase, aurora kinase and Haspin. Using oocyte-specific knockouts we find the response does not require the DNA damage response kinases ATM or ATR. Furthermore, checkpoint activation does not occur in response to DNA damage in fully mature eggs during meiosis II, despite the divisions being separated by just a few hours. Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA , Cinetocoros/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular , Meiose , Oócitos/citologia , Oócitos/metabolismo , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Animais , Aurora Quinases/metabolismo , Centrômero/efeitos dos fármacos , Centrômero/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinetocoros/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Meiose/efeitos dos fármacos , Camundongos , Modelos Biológicos , Oócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo
10.
Regul Toxicol Pharmacol ; 113: 104624, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32126256

RESUMO

An international expert working group representing 37 organisations (pharmaceutical/biotechnology companies, contract research organisations, academic institutions and regulatory bodies) collaborated in a data sharing exercise to evaluate the utility of two species within regulatory general toxicology studies. Anonymised data on 172 drug candidates (92 small molecules, 46 monoclonal antibodies, 15 recombinant proteins, 13 synthetic peptides and 6 antibody-drug conjugates) were submitted by 18 organisations. The use of one or two species across molecule types, the frequency for reduction to a single species within the package of general toxicology studies, and a comparison of target organ toxicities identified in each species in both short and longer-term studies were determined. Reduction to a single species for longer-term toxicity studies, as used for the development of biologicals (ICHS6(R1) guideline) was only applied for 8/133 drug candidates, but might have been possible for more, regardless of drug modality, as similar target organ toxicity profiles were identified in the short-term studies. However, definition and harmonisation around the criteria for similarity of toxicity profiles is needed to enable wider consideration of these principles. Analysis of a more robust dataset would be required to provide clear, evidence-based recommendations for expansion of these principles to small molecules or other modalities where two species toxicity testing is currently recommended.


Assuntos
Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos/efeitos adversos , Testes de Toxicidade , Animais , Bases de Dados Factuais , Humanos , Medição de Risco
11.
BMC Med Educ ; 20(1): 283, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854702

RESUMO

BACKGROUND: This study aimed to determine the current state of oncology education in Canadian family medicine postgraduate medical education programs (FM PGME) and examine opinions regarding optimal oncology education in these programs. METHODS: A survey was designed to evaluate ideal and current oncology teaching, educational topics, objectives, and competencies in FM PGMEs. The survey was sent to Canadian family medicine (FM) residents and program directors (PDs). RESULTS: In total, 150 residents and 17 PDs affiliated with 16 of 17 Canadian medical schools completed the survey. The majority indicated their programs do not have a mandatory clinical rotation in oncology (79% residents, 88% PDs). Low rates of residents (7%) and PDs (13%) reported FM residents being adequately prepared for their role in caring for cancer patients (p = 0.03). Residents and PDs believed the most optimal method of teaching oncology is through clinical exposure (65% residents, 80% PDs). Residents and PDs agreed the most important topics to learn (rated ≥4.7 on 5-point Likert scale) were: performing pap smears, cancer screening/prevention, breaking bad news, and approach to patient with increased cancer risk. According to residents, other important topics such as appropriate cancer patient referrals, managing cancer complications and post-treatment surveillance were only taught at frequencies of 52, 40 and 36%, respectively. CONCLUSIONS: Current FM PGME oncology education is suboptimal, although the degree differs in the opinion of residents and PDs. This study identified topics and methods of education which could be focussed upon to improve FM oncology education.


Assuntos
Medicina de Família e Comunidade , Internato e Residência , Canadá , Educação de Pós-Graduação em Medicina , Feminino , Humanos , Avaliação das Necessidades , Inquéritos e Questionários
12.
Br J Cancer ; 121(10): 827-836, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611612

RESUMO

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Procedimentos Cirúrgicos Eletivos/métodos , Neoplasias Bucais/cirurgia , Esvaziamento Cervical/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/patologia , Pescoço/inervação , Pescoço/fisiopatologia , Pescoço/cirurgia , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
13.
Toxicol Pathol ; 47(7): 891-895, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31280706

RESUMO

Over the last decade, the minipig has been established as a species which can be used in biomedical research, including drug development safety assessment. There are no mandatory regulatory guidelines regarding species selection strategy for safety assessment; hence, choice is at the discretion of companies responsible for drug development. A survey of member companies by IQ DruSafe (2016) highlighted inconsistent and low use of the minipig. At the 12th Annual Minipig Research Forum in 2018, presentations and a workshop examined current practices and considered if the minipig could be utilized more from earliest drug development stages. Despite the agreed utility of scientific data and validity of the minipig, especially for small molecules, each company has its own approach in nonrodent species selection, without consistent rationale. The overall objective should be to ensure the most appropriate species is selected and is scientifically based, with the minipig systematically included from early screening stages.


Assuntos
Pesquisa Biomédica , Desenvolvimento de Medicamentos , Medição de Risco , Porco Miniatura , Animais , Modelos Animais , Suínos , Testes de Toxicidade
14.
Mol Cell ; 44(1): 29-38, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21981916

RESUMO

Insulators are multiprotein-DNA complexes thought to affect gene expression by mediating inter- and intrachromosomal interactions. Drosophila insulators contain specific DNA-binding proteins plus common components, such as CP190, that facilitate these interactions. Here, we examine changes in the distribution of Drosophila insulator proteins during the heat-shock and ecdysone responses. We find that CP190 recruitment to insulator sites is the main regulatable step in controlling insulator function during heat shock. In contrast, both CP190 and DNA-binding protein recruitment are regulated during the ecdysone response. CP190 is necessary to stabilize specific chromatin loops and for proper activation of transcription of genes regulated by this hormone. These findings suggest that cells may regulate recruitment of insulator proteins to DNA to activate insulator activity at specific sites and create distinct patterns of nuclear organization that are necessary to achieve proper gene expression in response to different stimuli.


Assuntos
Cromatina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Animais , Cromossomos/química , DNA/química , Proteínas de Ligação a DNA/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Ecdisona/farmacologia , Perfilação da Expressão Gênica , Genoma , Proteínas de Choque Térmico/metabolismo , Microscopia de Fluorescência/métodos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Ligação Proteica , Transcrição Gênica
15.
Small ; 14(19): e1800162, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29603624

RESUMO

Atomic force microscope (AFM) probes and AFM imaging by extension are the product of exceptionally refined silicon micromachining, but are also restricted by the limitations of these fabrication techniques. Here, the nanoscale additive manufacturing technique direct laser writing is explored as a method to print monolithic cantilevered probes for AFM. Not only are 3D printed probes found to function effectively for AFM, but they also confer several advantages, most notably the ability to image in intermittent contact mode with a bandwidth approximately ten times larger than analogous silicon probes. In addition, the arbitrary structural control afforded by 3D printing is found to enable programming the modal structure of the probe, a capability that can be useful in the context of resonantly amplifying nonlinear tip-sample interactions. Collectively, these results show that 3D printed probes complement those produced using conventional silicon micromachining and open the door to new imaging techniques.

16.
Biochem Soc Trans ; 46(4): 797-806, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29934303

RESUMO

Initiated by luteinizing hormone and finalized by the fertilizing sperm, the mammalian oocyte completes its two meiotic divisions. The first division occurs in the mature Graafian follicle during the hours preceding ovulation and culminates in an extreme asymmetric cell division and the segregation of the two pairs of homologous chromosomes. The newly created mature egg rearrests at metaphase of the second meiotic division prior to ovulation and only completes meiosis following a Ca2+ signal initiated by the sperm at gamete fusion. Here, we review the cellular events that govern the passage of the oocyte through meiosis I with a focus on the role of the spindle assembly checkpoint in regulating its timing. In meiosis II, we examine how the egg achieves its arrest and how the fertilization Ca2+ signal allows the initiation of embryo development.


Assuntos
Mamíferos/fisiologia , Meiose/fisiologia , Oócitos/citologia , Animais , Sinalização do Cálcio , Divisão Celular/fisiologia , Segregação de Cromossomos , Desenvolvimento Embrionário , Feminino , Fertilização/fisiologia , Masculino , Camundongos , Ovulação , Interações Espermatozoide-Óvulo , Fuso Acromático/fisiologia
17.
Bioorg Med Chem ; 26(11): 3021-3029, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29764757

RESUMO

Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity.


Assuntos
Aminopiridinas/química , Sistemas de Liberação de Medicamentos , Fragmentos de Peptídeos/síntese química , Inibidores de Proteínas Quinases , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Estrutura Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Biblioteca de Peptídeos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
18.
Anesth Analg ; 127(2): 420-423, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29933275

RESUMO

BACKGROUND: Known complications of endoscopic retrograde cholangiopancreatography (ERCP) include pancreatitis, bleeding, duodenal perforation, and venous air embolism (VAE). The aim of this study was to determine the incidence of VAE during ERCP and be able to differentiate high-risk versus low-risk ERCP procedures. METHODS: This is a prospective cohort study consisting of patients who underwent ERCP and were monitored with a precordial Doppler ultrasound (PDU) for VAE. PDU monitoring was digitally recorded and analyzed to confirm the suspected VAE. Demographic and clinical data related to the anesthetic care, endoscopic procedure, and intraoperative hemodynamics were analyzed. RESULTS: A total of 843 ERCP procedures were performed over a 15-month period. The incidence of VAE was 2.4% (20 patients). All VAE's occurred during procedures in which stent placement, sphincterotomy, biopsy, duct dilation, gallstone retrieval, cholangioscopy, or necrosectomy occurred. Ten of 20 (50%) of VAEs were associated with hemodynamic alterations. None occurred if the procedure was only diagnostic or for stent removal. Subanalysis for the type of procedure showed that VAE was statistically more frequent when stents were removed and then replaced or if a cholangioscopy was performed. CONCLUSIONS: The high incidence of VAE highlights the need for practitioners to be aware of this potentially serious event. Use of PDU can aid in the detection of VAE during ERCP and should be considered especially during high-risk therapeutic procedures. Detection may allow appropriate interventions before serious adverse events such as cardiovascular collapse occur.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Embolia Aérea/epidemiologia , Embolia Aérea/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia/efeitos adversos , Cateterismo/efeitos adversos , Feminino , Hemodinâmica , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pancreatite , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Fatores de Risco , Stents/efeitos adversos , Resultado do Tratamento , Ultrassonografia Doppler
19.
Ann Vasc Surg ; 47: 143-148, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28890060

RESUMO

BACKGROUND: This study evaluates differences in wound complication rate when transverse versus longitudinal incision is utilized to expose femoral vessels in managing patients with peripheral vascular disease. METHODS: A retrospective review from 2013 to 2015 was conducted of 150 patients undergoing 156 lower extremity revascularizations with femoral artery exposure through a groin incision. Patients were stratified into 2 groups, transverse versus longitudinal groin incision. Data were reviewed for 3 surgeons that utilize either transverse or longitudinal groin incision in patients undergoing common or iliofemoral endarterectomies, or where femoral artery was used as inflow and/or outflow vessel for limb revascularization. Each group had a comparative outcomes analysis based on incision type. The primary outcome was wound complication, defined as any wound infection, lymphocele, hematoma, dehiscence, pseudoaneurysm, or necrosis. Other outcomes studied included unplanned return to operating room for wound complication, wound vacuum therapy, and soft-tissue flap closure. Data were analyzed using 2-tailed chi-squared test and Student's t-test. RESULTS: Patients in the transverse (n = 85 cases) versus longitudinal (n = 71 cases) cohorts were similar in relation to demographics and comorbidities. Overall mean follow-up was 220 days. Patients with a transverse as compared to longitudinal incision had a significantly lower overall wound complication rate, 7% vs. 42%, respectively (P < 0.001). Furthermore, transverse incisions were associated with lower incidence of unplanned return to the operating room to manage wound complications than patients with a longitudinal incision (5% vs. 23%, respectively; P < 0.001). Transverse versus longitudinal incisions were also associated with significantly lower need for wound vacuum therapy (6% vs. 15%, respectively; P < 0.05) and muscle flap closure (0% vs. 13%, respectively; P < 0.001) for wound complications. CONCLUSIONS: Transverse groin incisions for femoral artery exposure may offer a lower risk of wound complications for open procedures as compared to a longitudinal incision. While longitudinal incisions may have higher wound complication rates, incisional approach is contingent on anatomical circumstance and treated disease pattern. Patients should undergo appropriate preoperative counseling regarding wound healing in preparation for limb revascularization.


Assuntos
Artéria Femoral/cirurgia , Doenças Vasculares Periféricas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Vasculares/métodos , Idoso , Feminino , Virilha/cirurgia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Procedimentos Cirúrgicos Vasculares/efeitos adversos
20.
Ann Vasc Surg ; 47: 121-127, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28887253

RESUMO

BACKGROUND: Ultrasound-guided thrombin injection (UGTI) of femoral artery pseudoaneurysms after endovascular procedures is an effective therapy. There is controversy in the literature regarding injecting pseudoaneurysms with short and/or wide necks. This article reports our experience in UGTI of pseudoaneurysms in 1 hospital regarding the efficacy of this treatment in all pseudoaneurysms regardless of the size of the necks. METHODS: A retrospective review of 46 patients diagnosed between 2011 and 2016 with groin pseudoaneurysms using established duplex ultrasound criteria. Mean age was 68 years (range 27-87). Ten pseudoaneurysms thrombosed spontaneously, 5 were thrombosed by ultrasound-guided compression, and 2 were treated surgically due to disqualifying criteria. In this retrospective review, we analyzed the remaining 29 pseudoaneurysms regarding the dimensions of their neck lengths and outcomes after attempting thrombin injection. RESULTS: The mean aneurysm neck length and width were 1.03 ± 0.9 cm and 0.30 ± 0.1 cm, respectively. All 29 patients were evaluated with respect to pseudoaneurysm size, neck length, neck width, and complexity. Successful treatment of 29 pseudoaneurysms (2 external iliac, 20 common femoral, 2 deep femoral, and 5 superficial femoral) with UGTI was achieved without complications in 100% of the cases, regardless of pseudoaneurysm size, neck dimensions, or complexity. Anticoagulation status did not affect the efficacy of the procedure. Nine of the 29 pseudoaneurysms (31.0%) had neck length less than 0.5 cm. CONCLUSIONS: This study demonstrates the safety and efficacy of UGTI in treating iatrogenic pseudoaneurysm in 29 of 29 patients, even in patients with pseudoaneurysm with short neck lengths. Our experiences support injecting all pseudoaneurysms irrespective of dimension.


Assuntos
Falso Aneurisma/tratamento farmacológico , Procedimentos Endovasculares/efeitos adversos , Artéria Femoral/patologia , Trombina/administração & dosagem , Ultrassonografia de Intervenção , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/patologia , Cateterismo Periférico/efeitos adversos , Feminino , Artéria Femoral/diagnóstico por imagem , Humanos , Doença Iatrogênica , Injeções Intra-Arteriais , Masculino , Estudos Retrospectivos , Ultrassonografia Doppler em Cores
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