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Since its initial description by Japanese investigators 30 years ago, TakoTsubo Syndrome (TTS) has variously been regarded as a form of acute coronary syndrome and also as a form of cardiomyopathy (or more accurately, a myocarditis). There is actually good evidence that TTS embodies both of these concepts, and the main purpose of this review is to present data that they occur sequentially. The initial phase of the disorder (over perhaps the first 48 hours post onset of symptoms) represents a form of vasculitis, with associated damage to the endothelial glycocalyx and associated permeabilization of blood vessels. This is followed by a more prolonged phase of myocardial inflammation and oedema, associated with inflammatory activation and energetic impairment within the entire myocardium. Although this phase subsides after several months, it may be followed by longstanding impairment of myocardial function, reflecting residual fibrosis. Understanding of this gradual transition in TTS pathogenesis from vasculature towards myocardium remains an important limitation of patient management, especially as many patients are still told that their hearts have "recovered" within 1-2 weeks. A number of important uncertainties remain. These include development of specific early and ongoing therapeutic strategies to be used to match the sequential pathogenesis of TTS. "And so these men of Indostan Disputed loud and long, Each in his own opinion Exceeding stiff and strong, Though each was partly in the right, And all were in the wrong!" From: Six wise men of Hindustan.
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BACKGROUND: Aortic valve stenosis is an increasingly prevalent degenerative and inflammatory disease. Transcatheter aortic valve implantation (TAVI) has revolutionized its treatment, thereby avoiding its life-threatening/disabling consequences. Whether aortic valve stenosis is accelerated by inflammation and whether it is itself a cause of inflammation are unclear. We hypothesized that the large shear forces exerted on circulating cells, particularly on the largest circulating cells, monocytes, while passing through stenotic aortic valves result in proinflammatory effects that are resolved with TAVI. METHODS: TAVI provides a unique opportunity to compare the activation status of monocytes under high shear stress (before TAVI) and under low shear stress (after TAVI). The activation status of monocytes was determined with a single-chain antibody, MAN-1, which is specific for the activated ß2-integrin Mac-1. Monocyte function was further characterized by the adhesion of myocytes to stimulated endothelial cells, phagocytic activity, uptake of oxidized low-density lipoprotein, and cytokine expression. In addition, we designed a microfluidic system to recapitulate the shear rate conditions before and after TAVI. We used this tool in combination with functional assays, Ca2+ imaging, siRNA gene silencing, and pharmacological agonists and antagonists to identify the key mechanoreceptor mediating the shear stress sensitivity of monocytes. Last, we stained for monocytes in explanted stenotic aortic human valves. RESULTS: The resolution of high shear stress through TAVI reduces Mac-1 activation, cellular adhesion, phagocytosis, oxidized low-density lipoprotein uptake, and expression of inflammatory markers in monocytes and plasma. Using microfluidics and pharmacological and genetic studies, we could recapitulate high shear stress effects on isolated human monocytes under highly controlled conditions, showing that shear stress-dependent calcium influx and monocyte adhesion are mediated by the mechanosensitive ion channel Piezo-1. We also demonstrate that the expression of this receptor is shear stress dependent and downregulated in patients receiving TAVI. Last, we show monocyte accumulation at the aortic side of leaflets of explanted aortic valves. CONCLUSIONS: We demonstrate that high shear stress, as present in patients with aortic valve stenosis, activates multiple monocyte functions, and we identify Piezo-1 as the mainly responsible mechanoreceptor, representing a potentially druggable target. We demonstrate an anti-inflammatory effect and therefore a novel therapeutic benefit of TAVI.
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Antiinflamatorios/administración & dosificación , Estenosis de la Válvula Aórtica , Canales Iónicos/sangre , Monocitos/metabolismo , Resistencia al Corte , Estrés Mecánico , Reemplazo de la Válvula Aórtica Transcatéter , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/cirugía , Femenino , Humanos , MasculinoRESUMEN
Thrombocytosis is usually seen in myeloproliferative neoplasms (MPNs) and associated with thrombohemorrhagic complications. Therapeutic thrombocytapheresis using an automatic cell separator can help to achieve prompt platelet count reduction to decrease the rate of thrombotic events. In this study, we report a single center's experience in managing MPN patients with thrombocytapheresis prior to chemotherapy. Thrombocytapheresis procedures were performed in 185 MPN patients with thrombocytosis between January 2016 and June 2017. The median percentage reduction of platelets was 44.5% and the median percentage removal efficiency was 65.2% for 83 procedures where the waste bag was sampled. Procedures were generally well tolerated with few patients having mild adverse events (13 out of 185 patients).
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Trastornos Mieloproliferativos/terapia , Plaquetoferesis/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Estudios Prospectivos , Adulto JovenRESUMEN
It is now 30 years since Japanese investigators first described Takotsubo Syndrome (TTS) as a disorder occurring mainly in ageing women, ascribing it to the impact of multivessel coronary artery spasm. During the intervening period, it has become clear that TTS involves relatively transient vascular injury, followed by prolonged myocardial inflammatory and eventually fibrotic changes. Hence symptomatic recovery is generally slow, currently an under-recognised issue. It appears that TTS is induced by aberrant post-ß2-adrenoceptor signalling in the setting of "surge" release of catecholamines. Resultant activation of nitric oxide synthases and increased inflammatory vascular permeation lead to prolonged myocardial infiltration with macrophages and associated oedema formation. Initially, the diagnosis of TTS was made via exclusion of relevant coronary artery stenoses, plus the presence of regional left ventricular hypokinesis. However, detection of extensive myocardial oedema on cardiac MRI imaging offers a specific basis for diagnosis. No adequate methods are yet available for definitive diagnosis of TTS at hospital presentation. Other major challenges remaining in this area include understanding of the recently demonstrated association between TTS and antecedent cancer, the development of effective treatments to reduce risk of short-term (generally due to shock) and long-term mortality, and also to accelerate symptomatic recovery.
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Ventrículos Cardíacos/fisiopatología , Imagen por Resonancia Cinemagnética/métodos , Cardiomiopatía de Takotsubo/fisiopatología , Función Ventricular Izquierda/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Cardiomiopatía de Takotsubo/diagnósticoRESUMEN
BACKGROUND: Although Takotsubo syndrome (TS) was once considered to be rare and largely benign, it is now recognized to represent a major cause of cardiac morbidity and mortality, especially in ageing women. The biochemical precipitant of attacks of TS is an increase in catecholamine concentrations within the myocardium, engendering inflammatory activation via biased post-receptor signalling at myocardial ß2-adrenoceptor level. Cases of TS have been reported in patients treated with catecholamines, and with antidepressants which limit catecholamine re-uptake. In the current investigation, we sought to delineate the extent and potential impact of this "iatrogenic" form of TS. METHODS/RESULTS: Patients' data from a regional registry of 301 consecutive cases of TS were evaluated after exclusion of patients (n = 20) in whom TS had occurred in association with life threatening extracardiac disease states. A total of 55 (18%) of patients were identified as having antecedent exposure to potentially "iatrogenic" agents (tricyclic antidepressants in 24 cases, ß2-adrenoceptor agonists in 15). Demographics, including proportion of male patients, did not differ significantly between patients with and without "iatrogenic" TS, but plasma concentrations of the catecholamine metabolite normetanephrine tended to be greater (median 1149 pmol/L vs 938 pmol/L; p = 0.03). Long-term survival (median follow-up 3 years) was marginally (p = 0.13) worse for patients with "iatrogenic" TS. CONCLUSION: Potentially iatrogenic precipitation of TS attacks (via iatrogenic elevation of catecholamine levels and ß2-adrenoceptor stimulation) is common, associated with greater elevation of plasma normetanephrine concentrations, and also with a trend towards increased long-term mortality when compared to the remainder of TS patients.
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Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Antidepresivos Tricíclicos/efectos adversos , Enfermedad Iatrogénica , Miocardio/metabolismo , Normetanefrina/sangre , Cardiomiopatía de Takotsubo/inducido químicamente , Función Ventricular Izquierda/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Cardiomiopatía de Takotsubo/sangre , Cardiomiopatía de Takotsubo/mortalidad , Cardiomiopatía de Takotsubo/fisiopatología , Factores de TiempoRESUMEN
INTRODUCTION: Glycodelin is a glycoprotein with different oligosaccharides that are responsible for its diverse biological functions in contraception and immunosuppression. Therefore, it is necessary to have access to adequate amounts of glycodelin with retained carbohydrate structure for functional studies because the carbohydrate part can be lacking or be insufficient in recombinant glycodelin from prokaryotic and eukaryotic cell systems. METHODS AND RESULTS: Native glycodelin was purified from amniotic fluid by a series of affinity chromatography steps and had many glycosylated forms verified by mass spectrometry. About 7.5 mg glycodelin was obtained from 1.5 L amniotic fluid. No high molecular mass forms of glycodelin were found in amniotic fluid. Aliquots of the purified glycodelin were used as an immunogen in rabbits for antibody production against glycodelin and a calibrator in a highly sensitive glycodelin enzyme-linked immunosorbent assay (ELISA) with a detection limit of about 1 µg/L. CONCLUSIONS: Native glycodelin was purified from amniotic fluid and used as an immunogen for raising a rabbit antibody against glycodelin and a calibrator in a highly sensitive glycodelin ELISA. We found no high molecular mass forms of glycodelin in amniotic fluid. Aliquots of the purified glycodelin were set aside for functional studies which are in progress.
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Líquido Amniótico/química , Anticuerpos/química , Cromatografía de Afinidad/métodos , Glicodelina , Animales , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Glicodelina/análisis , Glicodelina/química , Glicodelina/aislamiento & purificación , Humanos , ConejosRESUMEN
BACKGROUND: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course. METHOD/DESIGN: This is a prospective multi-centre observational study aiming to enrol 7-8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later. DISCUSSION: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for "Integrated Management of Childhood Illness" used in dengue-endemic countries. TRIAL REGISTRATION: NCT01550016. Registration Date: March 7, 2012.
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Dengue/epidemiología , Adolescente , Adulto , Asia/epidemiología , Niño , Dengue/diagnóstico , Dengue/tratamiento farmacológico , Virus del Dengue/aislamiento & purificación , Diagnóstico Diferencial , Manejo de la Enfermedad , Femenino , Humanos , América Latina/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Aedes albopictus is secondary to Aedes aegypti as a vector of dengue viruses (DENVs) in settings of endemicity, but it plays an important role in areas of dengue emergence. This study compared the susceptibility of these 2 species to DENV infection by performing 232 direct blood-feeding experiments on 118 viremic patients with dengue in Vietnam. Field-derived A. albopictus acquired DENV infections as readily as A. aegypti after blood feeding. Once infected, A. albopictus permitted higher concentrations of DENV RNA to accumulate in abdominal tissues, compared with A. aegypti. However, the odds of A. albopictus having infectious saliva were lower than the odds observed for A. aegypti (odds ratio, 0.70; 95% confidence interval, .52-.93). These results quantitate the susceptibility of A. albopictus to DENV infection and will assist parameterization of models for predicting disease risk in settings where A. albopictus is present.
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Aedes/virología , Virus del Dengue/fisiología , Dengue/transmisión , Insectos Vectores/virología , Adulto , Animales , Dengue/virología , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Salud Pública , Vietnam , Viremia/virología , Adulto JovenRESUMEN
BACKGROUND: Takotsubo cardiomyopathy (TTC) is often associated with hypotension and shock. However, development of hypotension/shock in TTC is not closely related to extent of left ventricular (LV) hypokinesis. We sought to determine whether additional right ventricular (RV) involvement in TTC might contribute to hypotension and shock development and thus to prolonged hospital stay (PHS). METHODS: We evaluated 102 consecutive TTC patients with acute transthoracic echocardiography (TTE) to detect RV hypokinesis. Correlates of hypotension, shock and PHS were identified by univariate and multivariate analyses. RESULTS: Of the 102 patients evaluated, 33% had RV hypokinesis but only 9% had extensive RV involvement. Within the first 24 hours of admission, severe hypotension (systolic blood pressure (SBP) ≤ 90 mmHg) occurred in 21% of the patients and shock (hypotension + peripheral organ hypo-perfusion) in 16.6% of cases. RV involvement was a univariate but not a multivariate correlate of either hypotension or shock and did not result in PHS. On the other hand, RV involvement predicted more extensive LV hypokinesis and LV systolic dysfunction. CONCLUSIONS: In TTC, RV hypokinesis occurs in approximately 33% of cases and correlates with more severe LV wall motion abnormality but not with development of hypotension or shock. These data therefore reinforce previous findings that hypotension/shock in TTC are not purely by impaired cardiac output.
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Presión Sanguínea , Ecocardiografía , Choque Cardiogénico , Cardiomiopatía de Takotsubo , Disfunción Ventricular Izquierda , Disfunción Ventricular Derecha , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipotensión/diagnóstico por imagen , Hipotensión/etiología , Hipotensión/fisiopatología , Masculino , Persona de Mediana Edad , Choque Cardiogénico/diagnóstico por imagen , Choque Cardiogénico/etiología , Choque Cardiogénico/fisiopatología , Cardiomiopatía de Takotsubo/complicaciones , Cardiomiopatía de Takotsubo/diagnóstico por imagen , Cardiomiopatía de Takotsubo/fisiopatología , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Derecha/complicaciones , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Deuterium labelling of the non-labile protium atoms in starch granules has been achieved for the first time, by growing genetically modified yeast on deuterated media. Mass spectrometry of the glucose monomers from digested starch showed 44 % average deuteration of the non-labile protium when grown on partially deuterated raffinose (with average deuteration 48 %); yielding starch with 26 % average overall deuteration. Non-labile deuteration was also demonstrated using D2O solvent in the culture medium. Solid-state NMR revealed that deuteration was not evenly distributed across the monomer, being highest at the C6 carbon and lowest at the C1 carbon. SANS revealed two structural features at q = 0.05 Å-1 and 0.4 Å-1, the first corresponding to a lamellar repeat of approximately 12-13 nm while the latter is consistent with B-type crystalline polymer packing. Furthermore, solvent contrast variation SANS analysis yielded a contrast match point of 66 mol% D2O indicative of approximately 30-35 % average deuteration of the bulk granules, consistent with mass spectroscopy. When coupled with the more traditional process of exchange of labile protium in the hydroxyl groups by D2O solvent exchange, the biosynthesis of highly deuterated starch opens new opportunities for neutron scattering experiments involving multicomponent starch-based systems.
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Deuterio , Almidón , Almidón/química , Almidón/metabolismo , Almidón/biosíntesis , Deuterio/química , Saccharomyces cerevisiae/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Rafinosa/química , Rafinosa/metabolismoRESUMEN
BACKGROUND: In previous trials, point-of-care testing of C-reactive protein (CRP) concentrations safely reduced antibiotic use in non-severe acute respiratory infections in primary care. However, these trials were done in a research-oriented context with close support from research staff, which could have influenced prescribing practices. To better inform the potential for scaling up point-of-care testing of CRP in respiratory infections, we aimed to do a pragmatic trial of the intervention in a routine care setting. METHODS: We did a pragmatic, cluster-randomised controlled trial at 48 commune health centres in Viet Nam between June 1, 2020, and May 12, 2021. Eligible centres served populations of more than 3000 people, handled 10-40 respiratory infections per week, had licensed prescribers on site, and maintained electronic patient databases. Centres were randomly allocated (1:1) to provide point-of-care CRP testing plus routine care or routine care only. Randomisation was stratified by district and by baseline prescription level (ie, the proportion of patients with suspected acute respiratory infections to whom antibiotics were prescribed in 2019). Eligible patients were aged 1-65 years and visiting the commune health centre for a suspected acute respiratory infection with at least one focal sign or symptom and symptoms lasting less than 7 days. The primary endpoint was the proportion of patients prescribed an antibiotic at first attendance in the intention-to-treat population. The per-protocol analysis included only people who underwent CRP testing. Secondary safety outcomes included time to resolution of symptoms and frequency of hospitalisation. This trial is registered with ClinicalTrials.gov, NCT03855215. FINDINGS: 48 commune health centres were enrolled and randomly assigned, 24 to the intervention group (n=18 621 patients) and 24 to the control group (n=21 235). 17 345 (93·1%) patients in the intervention group were prescribed antibiotics, compared with 20 860 (98·2%) in the control group (adjusted relative risk 0·83 [95% CI 0·66-0·93]). Only 2606 (14%) of 18 621 patients in the intervention group underwent CRP testing and were included in the per-protocol analysis. When analyses were restricted to this population, larger reductions in prescribing were noted in the intervention group compared with the control group (adjusted relative risk 0·64 [95% CI 0·60-0·70]). Time to resolution of symptoms (hazard ratio 0·70 [95% CI 0·39-1·27]) and frequency of hospitalisation (nine in the intervention group vs 17 in the control group; adjusted relative risk 0·52 [95% CI 0·23-1·17]) did not differ between groups. INTERPRETATION: Use of point-of-care CRP testing efficaciously reduced prescription of antibiotics in patients with non-severe acute respiratory infections in primary health care in Viet Nam without compromising patient recovery. The low uptake of CRP testing suggests that barriers to implementation and compliance need to be addressed before scale-up of the intervention. FUNDING: Australian Government, UK Government, and the Foundation for Innovative New Diagnostics.
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Antibacterianos , Proteína C-Reactiva , Pruebas en el Punto de Atención , Infecciones del Sistema Respiratorio , Humanos , Antibacterianos/uso terapéutico , Australia , Proteína C-Reactiva/análisis , Atención Primaria de Salud , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Pueblos del Sudeste Asiático , Vietnam/epidemiología , Análisis por ConglomeradosRESUMEN
The experimental electron density distribution (EDD) in 8-hydroxyquinoline cocrystallized with salicylic acid, 1, has been determined from a multipole refinement of high-resolution X-ray diffraction data collected at 100 K. The experimental EDD is compared with theoretical densities resulting from high-level ab initio and BHandH calculations using Atoms in Molecules theory. 1 crystallizes in the triclinic crystal system, and the asymmetric unit consists of a neutral salicylic acid molecule, a salicylate anion, and an 8-hydroxyquinolinium cation exhibiting a number of inter- and intramolecular hydrogen bonds and π-π interactions. Topological analysis reveals that π-π interactions are of the "closed-shell" type, characterized by rather low and flat charge density. In general, the agreement of the topological values (ρ(bcp) and ∇(2)ρ(bcp)) between experiment and theory is good, with mean differences of 0.010 e Å(-3) and 0.036 e Å(-5), respectively. The energetics of the π-π interactions have been estimated, and excellent agreement is observed between the relative energy and the strength of π-stacking derived from the Espinosa approach, with an average difference of only 4.4 kJ mol(-1).
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Oxiquinolina/química , Teoría Cuántica , Ácido Salicílico/química , Cristalización , Cristalografía por Rayos X , Modelos Moleculares , Estructura MolecularRESUMEN
The experimental charge density distributions in a host-guest complex have been determined. The host, 1,4-bis[[(6-methylpyrid-2-yl)amino]carbonyl]benzene (1) and guest, adipic acid (2). The molecular geometries of 1 and 2 are controlled by the presence in the complex of intermolecular hydrogen bonding interactions and the presence in the host 1 of intramolecular hydrogen bonding motifs. This system therefore serves as an excellent model for studying noncovalent interactions and their effects on structure and electron density, and the transferability of electron distribution properties between closely related molecules. For the complex, high resolution X-ray diffraction data created the basis for a charge density refinement using a pseudoatomic multipolar expansion (Hansen-Coppens formalism) against extensive low-temperature (T = 100 K) single-crystal X-ray diffraction data and compared with a selection of theoretical DFT calculations on the same complex. The molecules crystallize in the noncentrosymmetric space group P2(1)2(1)2(1) with two independent molecules in the asymmetric unit. A topological analysis of the resulting density distribution using the atoms in molecules methodology is presented along with multipole populations, showing that the host and guest structures are relatively unaltered by the geometry changes on complexation. Three separate refinement protocols were adopted to determine the effects of the inclusion of calculated hydrogen atom anisotropic displacement parameters on hydrogen bond strengths. For the isotropic model, the total hydrogen bond energy differs from the DFT calculated value by ca. 70 kJ mol(-1), whereas the inclusion of higher multipole expansion levels on anisotropic hydrogen atoms this difference is reduced to ca. 20 kJ mol(-l), highlighting the usefulness of this protocol when describing H-bond energetics.
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Adipatos/química , Derivados del Benceno/química , Anisotropía , Simulación por Computador , Cristalización , Cristalografía por Rayos X , Electrones , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Teoría Cuántica , Difracción de Rayos XRESUMEN
INTRODUCTION: Takotsubo syndrome (TTS) is an acute inflammatory disorder involving first the vasculature and then the myocardium. It occurs relatively frequently, especially in aging women after acute physical and emotional stress. There is also increasing recognition that TTS attacks are sometimes precipitated by pharmacotherapy. AREAS COVERED: The pathogenesis of TTS is described, including components of a complex biochemical 'cascade' centering on aberrant post-receptor signaling following ß2-adrenoceptors stimulation and resultant nitric oxide (NO) release and development of nitrosative stress. Examples and significance of drug-induced TTS are also described. Currently available therapeutic information regarding TTS is presented, both for management of patients acutely and in the long-term. Furthermore, development of specific therapies to block components of the pathogenetic TTS 'cascade' is discussed. EXPERT OPINION: The biochemical 'cascade' in TTS revolves around an aberrant post-receptor response to ß2-adrenoceptor stimulation, increased responsiveness to NO and triggering of activation of poly(ADP-ribose) polymerase (PARP). In theory, interruption of this 'cascade' represents a logical approach to improving both symptomatic status and survival post TTS. Currently, there is some evidence supporting routine long-term treatment post TTS with either ACE inhibitors or angiotensin receptor antagonists, both to reduce risk of recurrence and to improve survival. Results of ongoing controlled clinical trials are awaited.
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Cardiomiopatía de Takotsubo , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Femenino , Humanos , Óxido Nítrico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas , Receptores Adrenérgicos , Factores de Riesgo , Cardiomiopatía de Takotsubo/inducido químicamente , Cardiomiopatía de Takotsubo/tratamiento farmacológicoRESUMEN
Plasmid-Mediated Colistin Resistance 1 (mcr-1) was first reported in 2015 and is a great concern to human health. In this study, we investigated the prevalence of mcr-1 and mcr-1-positive Escherichia coli (MCRPEC) and the association in infection status among various reservoirs connected to livestock. The study was conducted in 70 poultry and swine farms in a commune in Ha Nam province, northern Vietnam. Samples were collected from farmers, food animals, domestic animals, and farm environments (flies and wastewater) for polymerase chain reaction (PCR) screening for mcr-1 gene and species identification of PCR positive isolates. Among 379 obtained mcr-1 positives isolates, Escherichia coli was the major identified, varying from 50% (2/4) in dog feces to 100% (31/31) in humans feces isolates. The prevalence of MCRPEC was 14.4% (20/139), 49.7% (96/193), 31.3% (25/80), 36.7% (40/109), 26.9% (18/67), and 3.9% (2/51) in humans, chickens, pigs, flies, wastewater, and dogs, respectively. The study identified association between MCRPEC infection status in humans and flies (OR = 3.4), between flies and chickens (OR = 5.3), and between flies and pigs (OR = 9.0). Farmers' age and farm livestock unit were also associated factors of MCRPEC infection status in humans (OR = 5.1 and 1.05, respectively). These findings bring new knowledge on antibiotic resistance in livestock setting and important suggestions on potential role of flies in the transmission of mcr-1 resistance gene.
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Infecciones por Escherichia coli , Proteínas de Escherichia coli , Animales , Antibacterianos/farmacología , Pollos , Colistina/farmacología , Perros , Farmacorresistencia Bacteriana/genética , Escherichia coli/genética , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/veterinaria , Proteínas de Escherichia coli/genética , Granjas , Humanos , Ganado , Pruebas de Sensibilidad Microbiana , Plásmidos/genética , Porcinos , Vietnam/epidemiología , Aguas ResidualesRESUMEN
INTRODUCTION: Bloodstream infections (BSIs) are a leading cause of sepsis, which is a life-threatening condition that significantly contributes to the mortality of bacterial infections. Aminoglycoside antibiotics such as gentamicin or amikacin are essential medicines in the treatment of BSIs, but their clinical efficacy is increasingly being compromised by antimicrobial resistance. The aminoglycoside apramycin has demonstrated preclinical efficacy against aminoglycoside-resistant and multidrug-resistant (MDR) Gram-negative bacilli (GNB) and is currently in clinical development for the treatment of critical systemic infections. METHODS: This study collected a panel of 470 MDR GNB isolates from healthcare facilities in Cambodia, Laos, Singapore, Thailand and Vietnam for a multicentre assessment of their antimicrobial susceptibility to apramycin in comparison with other aminoglycosides and colistin by broth microdilution assays. RESULTS: Apramycin and amikacin MICs ≤ 16 µg/mL were found for 462 (98.3%) and 408 (86.8%) GNB isolates, respectively. Susceptibility to gentamicin and tobramycin (MIC ≤ 4 µg/mL) was significantly lower at 122 (26.0%) and 101 (21.5%) susceptible isolates, respectively. Of note, all carbapenem and third-generation cephalosporin-resistant Enterobacterales, all Acinetobacter baumannii and all Pseudomonas aeruginosa isolates tested in this study appeared to be susceptible to apramycin. Of the 65 colistin-resistant isolates tested, four (6.2%) had an apramycin MIC > 16 µg/mL. CONCLUSION: Apramycin demonstrated best-in-class activity against a panel of GNB isolates with resistances to other aminoglycosides, carbapenems, third-generation cephalosporins and colistin, warranting continued consideration of apramycin as a drug candidate for the treatment of MDR BSIs.
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Amicacina , Colistina , Aminoglicósidos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Asia Sudoriental , Cultivo de Sangre , Carbapenémicos , Cefalosporinas , Colistina/farmacología , Farmacorresistencia Bacteriana Múltiple , Gentamicinas , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Nebramicina/análogos & derivados , Pseudomonas aeruginosa , TobramicinaRESUMEN
AIMS: Takotsubo syndrome (TTS) is a form of acute myocardial inflammation, often triggered by catecholamine release surges, which accounts for approximately 10% of 'myocardial infarctions' in female patients above the age of 50. Its associated substantial risk of in-hospital mortality is mainly driven by the development of hypotension and shock. While hypotension is induced largely by factors other than low cardiac output, its precise cause is unknown, and clinical parameters associated with hypotension have not been identified previously. We therefore sought to identify the incidence and clinical/laboratory correlates of early hypotension in TTS. METHODS AND RESULTS: We analysed the in-hospital data of patients recruited to the South Australian TTS Registry. Associations between the development of hypotension, patient demographics, severity of the acute TTS attack, and key biochemical markers were sought. One hundred thirteen out of 319 patients (35%) were hypotensive (median systolic blood pressure 80 mmHg) during their index hospitalization. Development of hypotension preceded all in-hospital deaths (n = 8). On univariate analyses, patients who developed hypotension had lower left ventricular ejection fraction (P = 0.009), and higher plasma N-terminal pro brain natriuretic peptide and troponin-T concentrations (P = 0.046 and 0.008, respectively), all markers of severity of the TTS attack; hypotension also occurred less commonly in male than in female patients (P = 0.014). On multivariate linear regression analysis, female sex and lower left ventricular ejection fraction were independent correlates of the development of hypotension (P = 0.009 and 0.010, respectively). CONCLUSIONS: Early development of hypotension is very common in TTS, and its presence is associated with a substantial risk of in-hospital mortality. Hypotension is a marker of severe TTS attacks and occurs more commonly in female TTS patients.
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Hipotensión , Cardiomiopatía de Takotsubo , Australia , Femenino , Humanos , Hipotensión/epidemiología , Hipotensión/etiología , Incidencia , Laboratorios , Masculino , Volumen Sistólico , Cardiomiopatía de Takotsubo/diagnóstico , Cardiomiopatía de Takotsubo/epidemiología , Función Ventricular IzquierdaRESUMEN
INTRODUCTION: Since Prinzmetal first described a 'variant' form of angina pectoris, with predominantly resting episodes of pain and cyclic severity variations, it has gradually become apparent that this clinical presentation is caused by episodes of coronary artery spasm (CAS) involving focal or diffuse changes in large and/or small coronary arteries in the presence or absence of 'fixed' coronary artery stenoses. However, most clinicians have only limited understanding of this group of disorders. AREAS COVERED: We examine the clinical presentation of CAS, associated pathologies outside the coronary vasculature, impediments to making the diagnosis, provocative diagnostic tests, available and emerging treatments, and the current understanding of pathogenesis. EXPERT OPINION: CAS is often debilitating and substantially under-diagnosed and occur mainly in women. Many patients presenting with CAS crises have non-diagnostic ECGs and normal serum troponin concentrations, but CAS can be suspected on the basis of history and association with migraine, Raynaud's phenomenon and Kounis syndrome. Definitive diagnosis requires provocative testing at coronary angiography. Treatment still centers around the use of calcium antagonists, but with greater understanding of pathogenesis, new management options are emerging.
Asunto(s)
Angina Pectoris Variable , Vasoespasmo Coronario , Angina de Pecho/diagnóstico , Angina de Pecho/etiología , Angina Pectoris Variable/diagnóstico , Angina Pectoris Variable/terapia , Angiografía Coronaria , Vasoespasmo Coronario/diagnóstico , Vasoespasmo Coronario/terapia , Vasos Coronarios , Femenino , Humanos , EspasmoRESUMEN
TBR225 is one of the most popular commercial rice varieties in Northern Vietnam. However, this variety is highly susceptible to bacterial leaf blight (BLB), a disease caused by Xanthomonas oryzae pv. oryzae (Xoo) which can lead to important yield losses. OsSWEET14 belongs to the SWEET gene family that encodes sugar transporters. Together with other Clade III members, it behaves as a susceptibility (S) gene whose induction by Asian Xoo Transcription-Activator-Like Effectors (TALEs) is absolutely necessary for disease. In this study, we sought to introduce BLB resistance in the TBR225 elite variety. First, two Vietnamese Xoo strains were shown to up-regulate OsSWEET14 upon TBR225 infection. To investigate if this induction is connected with disease susceptibility, nine TBR225 mutant lines with mutations in the AvrXa7, PthXo3 or TalF TALEs DNA target sequences of the OsSWEET14 promoter were obtained using the CRISPR/Cas9 editing system. Genotyping analysis of T0 and T1 individuals showed that mutations were stably inherited. None of the examined agronomic traits of three transgene-free T2 edited lines were significantly different from those of wild-type TBR225. Importantly, one of these T2 lines, harboring the largest homozygous 6-bp deletion, displayed decreased OsSWEET14 expression as well as a significantly reduced susceptibility to a Vietnamese Xoo strains and complete resistance to another one. Our findings indicate that CRISPR/Cas9 editing conferred an improved BLB resistance to a Vietnamese commercial elite rice variety.