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BACKGROUND AND AIMS: Impact of type 2 diabetes mellitus (T2DM) in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT) remains poorly defined. The objective of the present study is to evaluate the relationship between T2DM and clinical outcomes among patients with LT waitlist registrants. We hypothesize that the presence of T2DM will be associated with worse clinical outcomes. METHODS: 593 patients adult (age 18 years or older) who were registered for LT between 1/2010 and 1/2017 were included in this retrospective analysis. The impact of T2DM on liver-associated clinical events (LACE), survival, hospitalizations, need for renal replacement therapy, and likelihood of receiving LT were evaluated over a 12-month period. LACE was defined as variceal hemorrhage, hepatic encephalopathy, and ascites. Kaplan-Meier and Cox regression analysis were used to determine the association between T2DM and clinical outcomes. RESULTS: The baseline prevalence of T2DM was 32% (n = 191) and patients with T2DM were more likely to have esophageal varices (61% vs. 47%, p = 0.002) and history of variceal hemorrhage (23% vs. 16%, p = 0.03). The presence of T2DM was associated with increased risk of incident ascites (HR 1.91, 95% CI 1.11, 3.28, p = 0.019). Patients with T2DM were more likely to require hospitalizations (56% vs. 49%, p = 0.06), hospitalized with portal hypertension-related complications (22% vs. 14%; p = 0.026), and require renal replacement therapy during their hospitalization. Patients with T2DM were less likely to receive a LT (37% vs. 45%; p = 0.03). Regarding MELD labs, patients with T2DM had significantly lower bilirubin at each follow-up; however, no differences in INR and creatinine were noted. CONCLUSION: Patients with T2DM are at increased risk of clinical outcomes. This risk is not captured in MELD score, which may potentially negatively affect their likelihood of receiving LT.
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Proximity labeling provides a powerful in vivo tool to characterize the proteome of subcellular structures and the interactome of specific proteins. The nematode Caenorhabditis elegans is one of the most intensely studied organisms in biology, offering many advantages for biochemistry. Using the highly active biotin ligase TurboID, we optimize here a proximity labeling protocol for C. elegans. An advantage of TurboID is that biotin's high affinity for streptavidin means biotin-labeled proteins can be affinity-purified under harsh denaturing conditions. By combining extensive sonication with aggressive denaturation using SDS and urea, we achieved near-complete solubilization of worm proteins. We then used this protocol to characterize the proteomes of the worm gut, muscle, skin, and nervous system. Neurons are among the smallest C. elegans cells. To probe the method's sensitivity, we expressed TurboID exclusively in the two AFD neurons and showed that the protocol could identify known and previously unknown proteins expressed selectively in AFD. The active zones of synapses are composed of a protein matrix that is difficult to solubilize and purify. To test if our protocol could solubilize active zone proteins, we knocked TurboID into the endogenous elks-1 gene, which encodes a presynaptic active zone protein. We identified many known ELKS-1-interacting active zone proteins, as well as previously uncharacterized synaptic proteins. Versatile vectors and the inherent advantages of using C. elegans, including fast growth and the ability to rapidly make and functionally test knock-ins, make proximity labeling a valuable addition to the armory of this model organism.
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Mapeamento de Interação de Proteínas/métodos , Proteômica/métodos , Coloração e Rotulagem/métodos , Animais , Biotina/química , Biotinilação , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteoma/metabolismo , Sinapses/metabolismoRESUMO
G-quadruplexes (G4s) are four-stranded DNA secondary structures that occur in the human genome and play key roles in transcription, replication, and genome stability. G4-specific molecular probes are of vital importance to elucidate the structure and function of G4s. The scFv antibody BG4 has been a widely used G4 probe but has various limitations, including relatively poor in vitro expression and the inability to be expressed intracellularly to interrogate G4s in live cells. To address these considerations, we describe herein the development of SG4, a camelid heavy-chain-only derived nanobody that was selected against the human Myc DNA G4 structure. SG4 exhibits low nanomolar affinity for a wide range of folded G4 structures in vitro. We employed AlphaFold combined with molecular dynamics simulations to construct a molecular model for the G4-nanobody interaction. The structural model accurately explains the role of key amino acids and Kd measurements of SG4 mutants, including arginine-to-alanine point mutations that dramatically diminish G4 binding affinity. Importantly, predicted amino acid-G4 interactions were subsequently confirmed experimentally by biophysical measurements. We demonstrate that the nanobody can be expressed intracellularly and used to image endogenous G4 structures in live cells. We also use the SG4 protein to positionally map G4s in situ and also on fixed chromatin. SG4 is a valuable, new tool for G4 detection and mapping in cells.
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Quadruplex G , Humanos , DNA/química , CromatinaRESUMO
Cardiovascular disease (CVD) is an important cause of mortality among liver transplantation (LT) recipients; however, the data on CVD risk stratification following LT are limited. Thus, the primary aim of this study was to evaluate the association between decline in renal function early after LT and atherosclerotic events. This retrospective study included all patients receiving LT between 2007 and 2019. Early renal function was quantified as estimated glomerular filtration rate (GFR) 6 months after LT. The primary endpoint for the study was a composite atherosclerotic cardiovascular event of three-point major adverse cardiovascular events (MACEs), which includes nonfatal myocardial infarction (MI), nonfatal stroke, or death from CVD. A total of 553 LT recipients met entry criteria. After a median follow-up of 74 months (interquartile range 46-111), 94 (17%) LT recipients died and CVD-associated death occurred in 20 patients. MACE-3 occurred in 66 (12%) patients, with nonfatal MI being the most common event (n = 30). A strong inverse relationship between early GFR and MACE-3 was noted in unadjusted analysis with hazard ratio (HR) 0.96 (95% confidence interval [CI] 0.95-0.98; p = 0.0001) and remained significant even after accounting for age, sex, coronary artery disease, diabetes mellitus, hypertension, calcineurin inhibitor use, and Framingham Risk Score (FRS; HR 0.96, 95% CI 0.95-0.97; p = 0.0001 per unit increase in GFR). Furthermore, an independent interaction between GFR, FRS, and likelihood of developing an MACE-3 was noted. GFR 6 months following LT is a strong predictor of developing atherosclerotic events. This relationship is independent of traditional CVD risk stratification models (e.g. FRS) and thus has the potential to be incorporated into CVD risk assessment after LT but requires further validation.
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Doenças Cardiovasculares , Transplante de Fígado , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Taxa de Filtração Glomerular , Humanos , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Perioperative intravenous (IV) TA has become routine in knee and hip arthroplasty. Less evidence exists on the administration of oral TA in the post- operative period. Our study aims to identify the efficacy and safety of combined perioperative IV and post-operative oral TA on blood loss and Hemoglobin (Hb) drop compared to perioperative IV TA alone. Patients undergoing primary elective knee arthro- plasty at our institution were invited to participate in the study (n=50). A computer-generated randomisation sequence was created online (www.randomization. org), with an allocation ratio of 1:1 and a block size of 50. Group A received perioperative IV TA alone and post-operative oral TA (n= 26) and Group B received perioperative IV TA plus 48 hours additional oral placebo (n= 24). Day 3 total blood loss and Hb drop was calculated. Continuous, normally distributed data (total blood loss) was compared utilising using one-way analysis of variance with post hoc Tukey test. Continuous skewed data (Hb drop) was compared using the Kruskal-Wallis test. P <0.05 was considered statistically significant. Group A demonstrated a trend in decreased total blood loss that was close to statistical significance ( p = 0.072). No difference in Hb drop was identified between the 2 groups. Increased nausea was also observed in Group A. The administration of oral TA to post-operative knee arthroplasty patients does not improve further blood loss compared to patients receiving perioperative IV TA pre-operatively and at wound closure.
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Antifibrinolíticos , Artroplastia de Quadril , Artroplastia do Joelho , Ácido Tranexâmico , Antifibrinolíticos/uso terapêutico , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Perda Sanguínea Cirúrgica/prevenção & controle , Humanos , Ácido Tranexâmico/uso terapêuticoRESUMO
BACKGROUND: Peripheral arterial occlusive disease (PAOD) continues to be a vexing problem despite the advent of endovascular techniques augmenting traditional open repair. At our institution, we have found there is a growing number of patients with PAOD who are vein-challenged and have undergone prosthetic bypass previously for infrainguinal arterial reconstruction. When occluded, these grafts have been abandoned for a new bypass strategy or amputation. We present a novel technique of reestablishing flow through chronically occluded prosthetic bypass grafts. METHODS: A retrospective review of a prospectively maintained database compiled at 2 institutions between 2016 and 2019 was performed. Six patients had previous prosthetic bypass grafts with 4 patients having femoral to popliteal grafts, 1 patient with a femoral to femoral graft, and 1 with a femoral to posterior tibial bypass graft. All patients had an attempted single-stage intervention to clear chronically occluded grafts. RESULTS: A total of 6 patients were included in the study. Indications for intervention were chronic, critical limb ischemia with tissue loss (3), severe claudication (2), and acute on chronic limb ischemia (1). Average time from bypass to suction thrombectomy was 29 months (6-60 months). Mean patency duration is 13 months (1-28 months). Adjunctive procedures include overnight lysis to improve outflow in 1 patient (16.6%), drug-coated balloon angioplasty (83.3%), or stents (83.3%). There were no embolic complications during these procedures. All (2) wounds healed and all are maintained on full-dose anticoagulation and/or antiplatelet therapy. CONCLUSIONS: Often, the timing of bypass graft occlusion is unknown, and the risk of embolism with lysis for chronically occluded bypass grafts is concerning with traditional peripheral intervention techniques. We report a new and unique minimally invasive approach to resurrect chronically occluded prosthetic bypass grafts often successful in just one stage. This tool offers an alternative technique for limb salvage in complex patients and as use increases, requires further interrogation.
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Implante de Prótese Vascular/efeitos adversos , Oclusão de Enxerto Vascular/terapia , Trombectomia , Trombose/terapia , Idoso , Doença Crônica , Bases de Dados Factuais , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Oclusão de Enxerto Vascular/etiologia , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombectomia/efeitos adversos , Trombose/diagnóstico por imagem , Trombose/etiologia , Trombose/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
BACKGROUND: Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. METHODS: We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. RESULTS: Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRß and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. CONCLUSIONS: The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.
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Isotretinoína/administração & dosagem , Neuroblastoma/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isotretinoína/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Piridinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismoRESUMO
BACKGROUND: Transcarotid artery revascularization (TCAR) is a novel, hybrid approach to treating carotid disease in the treatment of stroke and stroke prevention. Early results of this hybrid approach to carotid stenting using flow reversal have been promising, with reported stroke rates around 1-2.8%.1,2 Currently, carotid stenting, regardless of approach, is performed with uncovered stents, which incurs the risk of plaque protrusion through the stent and in-stent restenosis. Overall, plaque protrusion is a rare event, with a reported incidence of 2.8% on angiography, but it is associated a high rate of ischemic complications (up to 66.7%).3 The use of covered stents could eliminate the risk of plaque protrusion and therefore short to midterm embolic phenomenon during the remodeling process. It also may improve rates of in-stent restenosis as it is a fully covered stent. Adoption of this technique has the potential to further improve the safety, efficacy, and durability of TCAR. METHODS: We performed a retrospective review of a prospectively maintained database of patients undergoing TCAR with covered stents between September 2018 and December 2019. Procedures were performed by the same operator at 2 separate institutions. Indications included severe asymptomatic or symptomatic carotid stenosis with high-risk lesions defined as lesions 2 cm lesions or longer and/or >50% of the lesion containing soft plaque or bleeding carotid pseudoaneurysm. Our primary outcomes included periprocedural and 30-day stroke rates. Secondary outcomes included stent patency and other procedure-related complications. All patients were maintained on clopidogrel postprocedure for 3 months and then transitioned to aspirin, unless otherwise indicated. RESULTS: A total of 6 patients underwent TCAR with covered stent angioplasty during this time period. Patient demographics included 5 males and 1 female, with an average age of 70.8 ± 4.6 years. Indications for stenting included 4 patients with asymptomatic >70% carotid stenosis and 1 patient with transient ischemic attack-like symptoms and >70% stenosis, and 1 patient with bleeding carotid pseudoaneurysm. Gore Viabahn covered stents were used in all patients. There were no periprocedural or postprocedural ischemic events at 30 days. All 6 stents remained patent at follow-up on duplex ultrasound, and all patients remained asymptomatic on clinical follow-up (average 3.4 [1.4-6.9] months). CONCLUSIONS: The use of covered stents for TCAR appears to be a safe and effective in select patients requiring carotid intervention. It holds the potential to decrease ischemic events from plaque protrusion and in-stent restenosis in the long-term. Further investigation in device design or clinical evaluation is warranted.
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Angioplastia/instrumentação , Estenose das Carótidas/terapia , Stents , Idoso , Angioplastia/efeitos adversos , Doenças Assintomáticas , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Bases de Dados Factuais , Feminino , Humanos , Ataque Isquêmico Transitório/etiologia , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Chronic iliocaval obstruction is a challenging clinical entity to treat. Endovenous iliocaval stenting is becoming the treatment of choice for central vein stenosis and occlusion. However, outcomes in thrombotic disease have not been as robust as nonthrombotic disease. In this article, we describe our experience utilizing covered stents as a novel tool for chronic total occlusions of the iliocaval veins. METHODS: We performed a retrospective review of a prospectively maintained database of all patients undergoing endovenous stenting with a covered stent for chronic occlusive iliocaval disease over a 3-year period at our institution. Patients were followed clinically and with venous duplexes to assess the feasibility, safety, and outcomes of iliocaval endovenous stenting with covered stents. RESULTS: A total of 10 patients (8 men and 2 women) underwent iliocaval stenting with covered stents from July 2015 to May 2018. A total of 20 self-expanding covered stents (SECS) and 13 balloon expandable covered stents (BECS) were deployed in the central veins of the 10 patients. Six SECS and 5 BECS were deployed in the inferior vena cava, 10 SECS and 6 BECS were deployed in the common iliac veins (CIVs) (5 patients had bilateral CIV BECS and 2 patients had bilateral CIV SECS), and 4 SECS and 2 BECS were deployed in the external iliac veins (2 patients had bilateral SECS placed). Median follow-up time was 12.1 (range 0.5-35.0) months. There were no perioperative or postoperative complications. Nine (90%) patients maintained primary stent patency during our follow-up time. One patient (10%) had rethrombosis of his stent due to undertreated common femoral vein disease in the setting of a new myeloproliferative neoplasm and an inappropriate cessation of therapeutic anticoagulation. All patients who were symptomatic preoperatively had improvement in their pain, venous ulceration, and venous claudication. Eight of nine (89%) patients had improvement in their lower extremity edema. CONCLUSIONS: Covered endovenous stenting of chronically occluded central veins is a safe and promising procedure. Their use may improve the short- and long-term outcomes in this challenging patient population. Further studies are required to evaluate the long-term efficacy and cost of their use.
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Angioplastia com Balão/instrumentação , Veia Ilíaca , Stents , Doenças Vasculares/terapia , Veia Cava Inferior , Adulto , Angioplastia com Balão/efeitos adversos , Doença Crônica , Constrição Patológica , Bases de Dados Factuais , Estudos de Viabilidade , Feminino , Humanos , Veia Ilíaca/diagnóstico por imagem , Veia Ilíaca/fisiopatologia , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/fisiopatologia , Grau de Desobstrução Vascular , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVES: Carnoy's fixation and compression represents a novel technique to enhance lymph node evaluation and accuracy of staging after colorectal cancer resection. METHODS: This study was performed in all adults undergoing colorectal cancer operations by Kaiser Permanente surgeons at two separate facilities. Patients were assigned to either location based upon surgeon and patient availability. One group of patients had their lymph nodes examined with current standard manual technique (MT). The other group had their specimens fixed with Carnoy's solution and then compressed (CT) to assess for lymph nodes. RESULTS: A total of 157 patients were enrolled. Seventy-eight patient specimens underwent MT and 79 patient specimens underwent the new compression technique (CT). CT resulted in a significant increase in total lymph node yield per specimen (37.6 ± 18.5 nodes with CT vs 18.9 ± 8.8 nodes with MT; P < 0.0001). CT also resulted in sufficient lymph node sampling (>12 nodes) in all 79 patients in the group compared with 13 of 78 patients (17%) with an insufficient lymph node evaluation in the MT group ( P = 0.0002). CONCLUSION: This study demonstrated that Carnoy's fixation with compression can significantly increase lymph node yields in colorectal cancer specimens and allow for a higher rate of adequate lymph node sampling.
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Ácido Acético , Clorofórmio , Etanol , Fixadores , Excisão de Linfonodo , Linfonodos/patologia , Manejo de Espécimes/métodos , Idoso , Colectomia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Patologia Clínica/métodos , Protectomia , Estudos RetrospectivosRESUMO
There is a well-described association between infantile epilepsy and pervasive cognitive and behavioral deficits, including a high incidence of autism spectrum disorders. Despite the robustness of the relationship between early-life seizures and the development of autism, the pathophysiological mechanism by which this occurs has not been explored. As a result of increasing evidence that autism is a disorder of brain connectivity we hypothesized that early-life seizures would interrupt normal brain connectivity during brain maturation and result in an autistic phenotype. Normal rat pups underwent recurrent flurothyl-induced seizures from postnatal (P)days 5-14 and then tested, along with controls, for developmental alterations of development brain oscillatory activity from P18-P25. Specifically we wished to understand how normal changes in rhythmicity in and between brain regions change as a function of age and if this rhythmicity is altered or interrupted by early life seizures. In rat pups with early-life seizures, field recordings from dorsal and ventral hippocampus and prefrontal cortex demonstrated marked increase in coherence as well as a decrease in voltage correlation at all bandwidths compared to controls while there were minimal differences in total power and relative power spectral densities. Rats with early-life seizures had resulting impairment in the sociability and social novelty tests but demonstrated no evidence of increased activity or generalized anxiety as measured in the open field. In addition, rats with early-life seizures had lower seizure thresholds than controls, indicating long-standing alterations in the excitatory/inhibition balance. Bumetanide, a pharmacological agent that blocks the activity of NKCC1 and induces a significant shift of ECl toward more hyperpolarized values, administration at the time of the seizures precluded the subsequent abnormalities in coherence and voltage correlation and resulted in normal sociability and seizure threshold. Taken together these findings indicate that early-life seizures alter the development of oscillations and result in autistic-like behaviors. The altered communication between these brain regions could reflect the physiological underpinnings underlying social cognitive deficits seen in autism spectrum disorders.
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Encéfalo/fisiologia , Bumetanida/uso terapêutico , Convulsões/patologia , Convulsões/prevenção & controle , Comportamento Social , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Contagem de Células , Modelos Animais de Doenças , Eletroencefalografia , Comportamento Exploratório/efeitos dos fármacos , Análise de Fourier , Masculino , Ratos , Ratos Sprague-Dawley , Estatística como Assunto , Ritmo TetaRESUMO
Refractory psychosis units currently have little information regarding which symptoms profiles should be expected to respond to treatment. In the current study, we provide this information using structural equation modeling of Positive and Negative Syndrome Scale (PANSS) ratings at admission and discharge on a sample of 610 patients admitted to a treatment refractory psychosis program at a Canadian tertiary care unit between 1990 and 2011. The hypothesized five-dimensional structure of the PANSS fit the data well at both admission and discharge, and the latent variable scores are reported as a function of symptom dimension and diagnostic category. The results suggest that, overall, positive symptoms (POS) responded to treatment better than all other symptoms dimensions, but for the schizoaffective and bipolar groups, greater response on POS was observed relative to the schizophrenia and major depression groups. The major depression group showed the most improvement on negative symptoms and emotional distress, and the bipolar group showed the most improvement on disorganization. Schizophrenia was distinct from schizoaffective disorder in showing reduced treatment response on all symptom dimensions. These results can assist refractory psychosis units by providing information on how PANSS symptom dimensions respond to treatment and how this depends on diagnostic category.
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Transtorno Bipolar/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Esquizofrenia/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Transtorno Bipolar/terapia , Canadá , Transtorno Depressivo Maior/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Transtornos Psicóticos/terapia , Esquizofrenia/terapia , Resultado do Tratamento , Adulto JovemRESUMO
TBRT and ATRP are orthogonal initiation chemistries used in vinyl polymerisations. Here, we present the first combination of these techniques to readily create high molecular weight branched polyester macroinitiators capable of forming star copolymers from a range of methacrylate monomers.
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BACKGROUND: Loss of skeletal muscle can be accompanied by an increase in adipose tissue leading to sarcopenic obesity. There are limited data on how liver transplantation (LT) might impact adipose tissue compartments, particularly among patients with metabolically active disease, such as nonalcoholic steatohepatitis (NASH) and subsequent metabolic sequela. METHODS: Skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured using cross-sectional imaging performed in 190 patients pre-LT, 6 mo post-LT and 12 mo post-LT. Changes in adipose tissue and their impact on metabolic diseases were determined in patients transplanted for NASH versus non-NASH. RESULTS: Skeletal muscle, VAT, and SAT were similar in patients with NASH and non-NASH pre-LT despite a higher burden of metabolic diseases in patients with NASH. Following LT, no significant differences between skeletal muscle and SAT were observed in the entire cohort and among patients with NASH (versus non-NASH). LT recipients with the highest muscle mass pre-LT were at the greatest risk for muscle loss post-LT. A time-dependent increase in VAT was noted post-LT, which was more robust among patients with a history of NASH cirrhosis. In adjusted multivariate analysis, NASH versus non-NASH was a strong predictor of post-LT increase in VAT (ß-coefficient 3.00, P = 0.04). Pre-LT VAT was an independent predictor of post-LT serum triglycerides (ß-coefficient 5.49 ± 2.78, P = 0.05) and low-density lipoprotein cholesterol (ß-coefficient 1.80 ± 0.75, P = 0.02). A trend between pre-LT VAT and diabetes was noted but did not reach statistical significance. CONCLUSIONS: VAT but not SAT increases rapidly after LT, especially among patients transplanted for NASH cirrhosis and predicts future metabolic burden.
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Diabetes Mellitus , Transplante de Fígado , Hepatopatia Gordurosa não Alcoólica , Humanos , Transplante de Fígado/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/cirurgia , Diabetes Mellitus/patologia , Tecido Adiposo , Cirrose Hepática/diagnóstico , Cirrose Hepática/cirurgia , Cirrose Hepática/complicações , Progressão da Doença , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismoAssuntos
Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/terapia , Força Muscular/fisiologia , Resistência Física/fisiologia , Adulto , Idoso , Neoplasias da Mama/sangue , Carcinoma Ductal de Mama/sangue , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Ácido Láctico/sangue , Pessoa de Meia-Idade , Projetos Piloto , Estudos RetrospectivosRESUMO
Background: Tapered, fluted, titanium (TFT) stems have shown good clinical outcomes in revision total hip arthroplasty (rTHA), however concerns exist regarding early subsidence. This study compares subsidence between a modern monoblock 3-degree and a modular 2-degree TFT stem in rTHA. Methods: A retrospective, international multicentre comparative study was conducted including 64 rTHA in 63 patients. A monoblock TFT stem was used in 37 cases and a modular TFT stem was used in 27 cases. Patient demographics, Paprosky femoral bone loss classification, bicortical contact and stem subsidence were recorded at minimum four week follow up. Results: There was no statistically significant difference in overall subsidence (p = 0.318) or the rate of subsidence >10 mm between stems. Mean subsidence was 2.13 mm in the monoblock group and 3.15 mm in the modular group. Two stems subsided >10 mm: one in each group. There was no difference in bicortical contact between groups (p = 0.98). No re-revisions were performed. Conclusions: We found no difference in subsidence between the two stems. Surgeons may consider the use of monoblock stems in rTHA as they have comparably low rates of subsidence and eliminate the small but potentially catastrophic risk of implant fracture at modular junctions associated with modular stems.
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The establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation.
Assuntos
Linhagem da Célula/genética , Epigênese Genética , Quadruplex G , Histonas/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Pluripotentes/metabolismo , Processamento de Proteína Pós-Traducional , Biomarcadores/metabolismo , Diferenciação Celular , Linhagem Celular , DNA/genética , DNA/metabolismo , Metilação de DNA , Elementos Facilitadores Genéticos , Expressão Gênica , Histonas/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina/genética , Nestina/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fator de Transcrição PAX6/genética , Fator de Transcrição PAX6/metabolismo , Células-Tronco Pluripotentes/citologia , Regiões Promotoras Genéticas , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismoRESUMO
Transfer-dominated Branching Radical Telomerisation (TBRT) enables the production of branched polymers with step-growth backbones using radical telomerisation chemistry. By conducting identical TBRTs over a broad temperature range, the role of temperature in telomer formation and branching has been evaluated. Elevated temperature limits telomer length, thereby allowing a >10% reduction in the amount of telogen required to produce near identical high molecular weight branched polymers.