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81.
Karina V. Bunting Francesco Formisano Jennifer Green Richard P. Steeds Lucy Hudsmith Paul Clift 《Congenital heart disease》2020,15(2):89-100
Objective: To determine the accuracy of assessing univentricular
function in adult Fontan patients using three-dimensional (3D) volumetric
echocardiography. Design: A prospective observational study in an adult Fontan
patient cohort. Setting: University Hospitals Birmingham, NHS Foundation
Trust. Patients: 26 patients were enrolled in the study all aged over 18 years,
possessing the Fontan anatomy, with no contraindications to Cardiac Magnetic
Resonance (CMR) imaging and in sinus rhythm. Intervention: All patients
underwent transthoracic echocardiography using a Philips EPIQ 7 and X5-1
transducer. End diastolic volume (EDV), end systolic volume (ESV), stroke
volume (SV) and ejection fraction (EF) were obtained using two dimensional
(2D) and 3D acquisitions. CMR was performed within 3 months according to
standard protocols. Outcome Measures: The agreement and correlation between
2D, 3D and CMR derived parameters were determined by Bland and Altman
analysis and Pearson’s correlation coefficient method. The inter-observer
variability was also assessed for all three modalities. Results: 3D volumetric
acquisitions of the single ventricle were feasible in 18/26 (69%) patients. 3D
volumes strongly correlated with CMR but with a systematic bias to underestimation: EDV r = 0.66, bias = –47.1 (–109.6 to 15.2); ESV r = 0.82, bias = –
19.4 (–59.9 to 21.1); EF r = 0.73, –1.56 (–18.8 to 15.7) and SV r = 0.32, –27.7 (–
70.2 to 14.7). Inter-observer variability was lowest with CMR, when compared
to echocardiographic techniques. The inter-observer variability for 3D when
compared with 2D echocardiography was lower across all parameters except
EDV. Conclusions: 3D volumes correlate strongly with CMR and may be used
for serial assessment of univentricular function. However, 3D volumes on echo
are not interchangeable with CMR due to systematic underestimation of volume. 相似文献
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Elymir S Galvis-Garc a Sergio Sobrino-Coss o Arturo Reding-Bernal Yesica Contreras-Mar n Karina Sol rzano-Acevedo Patricia Gonz lez-Zavala Rosa M Quispe-Siccha 《World journal of gastroenterology : WJG》2020,26(34):5169-5180
BACKGROUND Endoscopic ultrasound(EUS) and endoscopic ultrasound elastography(EUS-E) simulation lessens the learning curve; however, models lack realism, diminishing competitiveness.AIM To standardize the mechanical properties of polyvinyl alcohol(PVA) hydrogel for simulating organs and digestive lesions.METHODS PVA hydrogel(Sigma Aldrich, degree of hydrolysis 99%) for simulating EUS/EUS-E lesions was investigated in Unidad de Investigación y Desarrollo Tecnológico at Hospital General de México "Dr. Eduardo Liceaga", Mexico City. We evaluated physical, contrast, elasticity and deformation coefficient characteristics in lesions, applying Kappa's concordance and satisfaction questionnaire(Likert 4-points).RESULTS PVA hydrogel showed stable mechanical properties. Density depended on molecular weight(MW) and concentration(C). PVA bblocks with the greatest density showed lowest tensile strength(r =-0.8, P = 0.01). Lesions were EUSgraphically visible. Homogeneous and heterogeneous examples were created from PVA blocks or PVA phantoms, exceeding(MW_2 = 146000-186000, C_9 = 15% and C_(10) = 20%) with a density under(MW_1 = 85000-124000, C_1 = 7% and C_2 = 9%). We calculated elasticity and deformation parameters of solid(blue) areas, contrasting with the norm(Kappa = 0.8; high degree of satisfaction).CONCLUSION PVA hydrogels were appropriate for simulating organs and digestive lesions using EUS/EUS-E, facilitating practice and reducing risk. Repetition amplified skills, while reducing the learning curve. 相似文献
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Andreas Janzer Natalie J. German Karina N. Gonzalez-Herrera John M. Asara Marcia C. Haigis Kevin Struhl 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(29):10574-10579
Metformin, a first-line diabetes drug linked to cancer prevention in retrospective clinical analyses, inhibits cellular transformation and selectively kills breast cancer stem cells (CSCs). Although a few metabolic effects of metformin and the related biguanide phenformin have been investigated in established cancer cell lines, the global metabolic impact of biguanides during the process of neoplastic transformation and in CSCs is unknown. Here, we use LC/MS/MS metabolomics (>200 metabolites) to assess metabolic changes induced by metformin and phenformin in an Src-inducible model of cellular transformation and in mammosphere-derived breast CSCs. Although phenformin is the more potent biguanide in both systems, the metabolic profiles of these drugs are remarkably similar, although not identical. During the process of cellular transformation, biguanide treatment prevents the boost in glycolytic intermediates at a specific stage of the pathway and coordinately decreases tricarboxylic acid (TCA) cycle intermediates. In contrast, in breast CSCs, biguanides have a modest effect on glycolytic and TCA cycle intermediates, but they strongly deplete nucleotide triphosphates and may impede nucleotide synthesis. These metabolic profiles are consistent with the idea that biguanides inhibit mitochondrial complex 1, but they indicate that their metabolic effects differ depending on the stage of cellular transformation.Altered metabolism is a hallmark of malignantly transformed cells. Cancer risk is linked to metabolic syndrome, a disease state that includes obesity, type 2 diabetes, high cholesterol, and atherosclerosis. Retrospective studies of type 2 diabetes patients treated with metformin, the most widely prescribed antidiabetic drug, show a strong correlation between drug intake and reduced tumor incidence or reduced cancer-related deaths (1–4).In the breast lineage, metformin inhibits growth of cancer cell lines (5–7), blocks transformation in a Src-inducible cell system (8, 9), and selectively inhibits the growth of cancer stem cells (CSCs) (8). As a consequence of its selective effects on CSCs, combinatorial therapy of metformin and standard chemotherapeutic drugs (doxorubicin, paclitaxel, and cisplatin) increases tumor regression and prolongs remission in mouse xenografts (8, 10). In addition, metformin can decrease the chemotherapeutic dose for prolonging tumor remission in xenografts involving multiple cancer types (10).Phenformin, a related biguanide and formerly used diabetes drug, acts as an anticancer agent in tumors including lung, lymphoma, and breast cancer with a greater potency than metformin. Phenformin mediates antineoplastic effects at a lower concentration than metformin in cell lines, a PTEN-deficient mouse model, breast cancer xenografts, and drug-induced mitochondrial impairment (11–14). The chemical similarities of these biguanides, as well as their similar effects in diabetes and cancer, have led to the untested assumption that phenformin is essentially a stronger version of metformin.In a Src-inducible model of cellular transformation and CSC formation, multiple lines of evidence suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response (15). In the context of atherosclerosis, metformin inhibits NF-κB activation and the inflammatory response via a pathway involving AMP kinase (AMPK) and the tumor suppressor PTEN (16, 17). As metformin alters energy metabolism in diabetics, we speculated that metformin might block a metabolic stress response that stimulates the inflammatory pathway (15). However, very little is known about the metabolic changes that inhibit the inflammatory pathway.Previous studies on metformin-induced metabolic effects in cancer have focused on single metabolic alterations or pathways in already established cancer cell lines. Metformin leads to activation of AMPK, which plays a key role in insulin signaling and energy sensing (18). Metformin can reduce protein synthesis via mTOR inhibition (19). In addition, metformin may directly impair mitochondrial respiration through complex I inhibition and has been described to boost glycolysis as a compensation mechanism (14, 20). In this regard, lactic acidosis can be a side effect of metformin and phenformin treatment of diabetic patients, presumably because inhibition of complex I prevents NADH oxidation, thereby leading to a requirement for cytosolic NADH to be oxidized by the conversion of pyruvate to lactate. There is some knowledge about the metabolic effects of metformin (21, 22), but very little is known about the specific metabolic alterations linking biguanides to inhibition of neoplastic transformation.Here, we perform a metabolomic analysis on the effects of metformin and phenformin in a Src-inducible model of transformation and in CSCs. This inducible model permits an analysis of the transition from nontransformed to transformed cells in an isogenic cell system and hence differs from analyses of already established cancer cell lines. We studied CSCs to address why this population, which is resistant to standard chemotherapeutics and hypothesized to be a major reason for tumor recurrence, is selectively inhibited by metformin. Our results indicate the metabolic effects of metformin and phenformin are remarkably similar to each other, with only a few differences. Both biguanides dramatically decrease tricarboxylic acid (TCA) cycle intermediates in the early stages of transformation, and they inhibit the boost in select glycolytic intermediates that normally occurs with transformation along with increases in glycerol 3-phosphate and lactate, which are metabolites branching from glycolysis. Unexpectedly, in CSCs, biguanides have only marginal effects on glycolytic and TCA cycle metabolites, but they severely decrease nucleotide triphosphates. These detailed metabolic analyses provide independent support for the idea that metformin inhibits mitochondrial complex 1 (14, 20), and they indicate that the metabolic effects of biguanides depend on the stage of the cellular transformation. 相似文献
86.
Timothy R. Leahy Michelle Goode Paul Lynam Patrick J. Gavin Karina M. Butler 《Influenza and other respiratory viruses》2014,8(3):360-366
Design
Children with HIV are especially susceptible to complications from influenza infection, and effective vaccines are central to reducing disease burden in this population. We undertook a prospective, observational study to investigate the safety and immunogenicity of the inactivated split-virion AS03-adjuvanted pandemic H1N1(2009) vaccine in children with HIV.Setting
National referral centre for Paediatric HIV in Ireland.Sample
Twenty four children with HIV were recruited consecutively and received two doses of the vaccine. The serological response was measured before each vaccine dose (Day 0 and Day 28) and 2 months after the booster dose. Antibody titres were measured using a haemagglutination inhibition (HAI) assay. Seroprotection was defined as a HAI titre ≥ 1:40; seroconversion was defined as a ≥ fourfold increase in antibody titre and a postvaccination titre ≥ 1:40.Main outcome measures
The seroconversion rates after prime and booster doses were 75% and 71%, respectively. HIV virological suppression at the time of immunization was associated with a significantly increased seroconversion rate (P = 0·009), magnitude of serological response (P = 0·02) and presence of seroprotective HAI titres (P = 0·017) two months after the booster dose. No other factor was significantly associated with the seroconversion/seroprotection rate. No serious adverse effects were reported. Vaccination had no impact on HIV disease progression. The AS03-adjuvanted pandemic H1N1 vaccine appears to be safe and immunogenic among HIV-infected children. A robust serological response appears to be optimized by adherence to a HAART regimen delivering virological suppression. 相似文献87.
Igor Bastos Polonio Milena Marques Pagliareli Acencio Rogério Pazetti Francine Maria de Almeida Bárbara Soares da Silva Karina Aparecida Bonifácio Pereira Rogério Souza 《Jornal brasileiro de pneumologia》2014,40(4):421-424
We assessed the effects of lodenafil on hemodynamics and inflammation in the rat
model of monocrotaline-induced pulmonary hypertension (PH). Thirty male
Sprague-Dawley rats were randomly divided into three groups: control; monocrotaline
(experimental model); and lodenafil (experimental model followed by lodenafil
treatment, p.o., 5 mg/kg daily for 28 days) Mean pulmonary artery pressure (mPAP) was
obtained by right heart catheterization. We investigated right ventricular
hypertrophy (RVH) and IL-1 levels in lung fragments. The number of cases of RVH was
significantly higher in the monocrotaline group than in the lodenafil and control
groups, as were mPAP and IL-1 levels. We conclude that lodenafil can prevent
monocrotaline-induced PH, RVH, and inflammation. 相似文献
88.
89.
Karina Leal Sumiko Mochida Todd Scheuer William A. Catterall 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(42):17069-17074
Modulation of P/Q-type Ca2+ currents through presynaptic voltage-gated calcium channels (CaV2.1) by binding of Ca2+/calmodulin contributes to short-term synaptic plasticity. Ca2+-binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca2+ sensor proteins that differentially modulate CaV2.1 channels, but how they contribute to short-term synaptic plasticity is unknown. Here, we show that activity-dependent modulation of presynaptic CaV2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion neurons. Expression of CaBP1, which blocks Ca2+-dependent facilitation of P/Q-type Ca2+ current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca2+-dependent inactivation of P/Q-type Ca2+ current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent regulation of presynaptic CaV2.1 channels by differentially expressed Ca2+ sensor proteins can fine-tune synaptic responses to trains of action potentials and thereby contribute to the diversity of short-term synaptic plasticity.Neurons fire repetitively in different frequencies and patterns, and activity-dependent alterations in synaptic strength result in diverse forms of short-term synaptic plasticity that are crucial for information processing in the nervous system (1–3). Short-term synaptic plasticity on the time scale of milliseconds to seconds leads to facilitation or depression of synaptic transmission through changes in neurotransmitter release. This form of plasticity is thought to result from residual Ca2+ that builds up in synapses during repetitive action potentials and binds to a Ca2+ sensor distinct from the one that evokes neurotransmitter release (1, 2, 4, 5). However, it remains unclear how changes in residual Ca2+ cause short-term synaptic plasticity and how neurotransmitter release is regulated to generate distinct patterns of short-term plasticity.In central neurons, voltage-gated calcium (CaV2.1) channels are localized in high density in presynaptic active zones where their P/Q-type Ca2+ current triggers neurotransmitter release (6–11). Because synaptic transmission is proportional to the third or fourth power of Ca2+ entry through presynaptic CaV2.1 channels, small changes in Ca2+ current have profound effects on synaptic transmission (2, 12). Studies at the calyx of Held synapse have provided important insights into the contribution of presynaptic Ca2+ current to short-term synaptic plasticity (13–17). CaV2.1 channels are required for synaptic facilitation, and Ca2+-dependent facilitation and inactivation of the P/Q-type Ca2+ currents are correlated temporally with synaptic facilitation and rapid synaptic depression (13–17).Molecular interactions between Ca2+/calmodulin (CaM) and CaV2.1 channels induce sequential Ca2+-dependent facilitation and inactivation of P/Q-type Ca2+ currents in nonneuronal cells (18–21). Facilitation and inactivation of P/Q-type currents are dependent on Ca2+/CaM binding to the IQ-like motif (IM) and CaM-binding domain (CBD) of the CaV2.1 channel, respectively (20, 21). This bidirectional regulation serves to enhance channel activity in response to short bursts of depolarizations and then to decrease activity in response to long bursts. In synapses of superior cervical ganglion (SCG) neurons expressing exogenous CaV2.1 channels, synaptic facilitation is induced by repetitive action potentials, and mutation of the IM and CBD motifs prevents synaptic facilitation and inhibits the rapid phase of synaptic depression (22). Thus, in this model synapse, regulation of presynaptic CaV2.1 channels by binding of Ca2+/CaM can contribute substantially to the induction of short-term synaptic plasticity by residual Ca2+.CaM is expressed ubiquitously, but short-term plasticity has great diversity among synapses, and the potential sources of this diversity are unknown. How could activity-dependent regulation of presynaptic CaV2.1 channels contribute to the diversity of short-term synaptic plasticity? CaM is the founding member of a large family of Ca2+ sensor (CaS) proteins that are differentially expressed in central neurons (23–25). Two CaS proteins, Ca2+-binding protein-1 (CaBP1) and Visinin-like protein-2(VILIP-2), modulate facilitation and inactivation of CaV2.1 channels in opposite directions through interaction with the bipartite regulatory site in the C-terminal domain (26, 27), and they have varied expression in different types of central neurons (23, 25, 28). CaBP1 strongly enhances inactivation and prevents facilitation of CaV2.1 channel currents, whereas VILIP-2 slows inactivation and enhances facilitation of CaV2.1 currents during trains of stimuli (26, 27). Molecular analyses show that the N-terminal myristoylation site and the properties of individual EF-hand motifs in CaBP1 and VILIP-2 determine their differential regulation of CaV2.1 channels (27, 29–31). However, the role of CaBP1 and VILIP-2 in the diversity of short-term synaptic plasticity is unknown, and the high density of Ca2+ channels and unique Ca2+ dynamics at the presynaptic active zone make extrapolation of results from studies in nonneuronal cells uncertain. We addressed this important question directly by expressing CaBP1 and VILIP-2 in presynaptic SCG neurons and analyzing their effects on synaptic plasticity. Our results show that CaM-related CaS proteins can serve as sensitive bidirectional switches that fine-tune the input–output relationships of synapses depending on their profile of activity and thereby maintain the balance of facilitation versus depression by the regulation of presynaptic CaV2.1 channels. 相似文献
90.