RESUMO
Cantharidin and sodium fluoride inhibit the activity of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) and increase the force of contraction in human atrial preparations. R-phenylisopropyl adenosine (R-PIA) acts as an agonist at A1-adenosine receptors. R-PIA exerts a negative inotropic effect on human atria. The effect of R-PIA-and its various manifestations-are currently explained as a function of the inhibition of sarcolemmal adenylyl cyclase activity and/or opening of sarcolemmal potassium channels. We hypothesise that cantharidin and sodium fluoride may attenuate the negative inotropic effect of R-PIA. During open heart surgery, trabeculae carneae from the right atrium were obtained for human atrial preparations (HAPs). These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. Furthermore, we studied isolated electrically stimulated left atrial (LA) preparations from female wild-type mice (CD1). The force of contraction was recorded under isometric conditions. R-PIA (1 µM) exerted a rapid negative inotropic effect in the HAPs and mice LA preparations. These negative inotropic effects of R-PIA were attenuated by pre-incubation for 30 min with 100-µM cantharidin in HAPs, but not in mice LA preparations. Adenosine signals via A1 receptors in a species-specific pathway in mammalian atria. We postulate that R-PIA, at least in part, exerts a negative inotropic effect via activation of serine/threonine phosphatases in the human atrium.
RESUMO
At present, the best optical lattice clocks are based on the spectroscopy of trapped alkaline-earth-like atoms such as ytterbium and strontium. The development of mobile or even space-borne clocks necessitates concepts for the compact laser-cooling and trapping of these atoms with reduced laser requirements. Here, we present two compact and robust achromatic mirror structures for single-beam magneto-optical trapping of alkaline-earth-like atoms using two widely separated optical cooling frequencies. We have compared the trapping and cooling performance of a monolithic aluminum structure that generates a conventional trap geometry to a quasi-planar platform based on a periodic mirror structure for different isotopes of Yb. Compared to prior work with strontium in non-conventional traps, where only bosons were trapped on a narrow line transition, we demonstrate two-stage cooling and trapping of a fermionic alkaline-earth-like isotope in a single-beam quasi-planar structure.
RESUMO
We present a novel achromatic, planar, periodic mirror structure for single-beam magneto-optical trapping and demonstrate its use in the first- and second-stage cooling and trapping for different isotopes of strontium. We refer to it as a Fresnel magneto-optical trap (MOT) as the structure is inspired by Fresnel lenses. By design, it avoids many of the problems that arise for multi-color cooling using planar structures based on diffraction gratings, which have been the dominant planar structures to be used for single-beam trapping thus far. In addition to a complex design process and cost-intensive fabrication, diffraction gratings suffer from their inherent chromaticity, which causes different axial displacements of trap volumes for different wavelengths and necessitates trade-offs in their diffraction properties and achievable trap depths. In contrast, the Fresnel-reflector structure presented here is a versatile, easy-to-manufacture device that combines achromatic beam steering with the advantages of a planar architecture. It enables miniaturizing trapping systems for alkaline-earth-like atoms with multiple cooling transitions as well as multi-species trapping in the ideal tetrahedral configuration and within the same volume above the structure. Our design presents a novel approach for the miniaturization of cold-atom systems based on single-beam MOTs and enables the widespread adoption of these systems.
RESUMO
Cantharidin, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), is known to increase the force of contraction and shorten the time to relaxation in human ventricular preparations. We hypothesized that cantharidin has similar positive inotropic effects in human right atrial appendage (RAA) preparations. RAA were obtained during bypass surgery performed on human patients. These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. For comparison, we studied isolated electrically stimulated left atrial (LA) preparations and isolated spontaneously beating right atrial (RA) preparations from wild-type mice. Cumulatively applied (starting at 10 to 30 µM), cantharidin exerted a positive concentration-dependent inotropic effect that plateaued at 300 µM in the RAA, LA, and RA preparations. This positive inotropic effect was accompanied by a shortening of the time to relaxation in human atrial preparations (HAPs). Notably, cantharidin did not alter the beating rate in the RA preparations. Furthermore, cantharidin (100 µM) increased the phosphorylation state of phospholamban and the inhibitory subunit of troponin I in RAA preparations, which may account for the faster relaxation observed. The generated data indicate that PP1 and/or PP2A play a functional role in human atrial contractility.
Assuntos
Fibrilação Atrial , Cantaridina , Humanos , Camundongos , Animais , Cantaridina/farmacologia , Fosforilação , Contração Miocárdica , Átrios do CoraçãoRESUMO
For almost 160 years, it has been known that Helmholtz oscillations, unique to vibrating strings in bowed instruments (violin, cello, etc.), have two distinct regimes: "slip" and "stick." During the slip regime, the force at the bow-string interaction is attributed to friction between the sliding bow hair and the vibrating string, with a friction coefficient that decreases with increasing relative velocity. Yet the hair-string interaction during the stick regime is less understood. We propose that the interaction force during the stick regime is proportional to the product of the longitudinal acoustic impedance of the bow hair to the relative bow-string velocity. We validate this hypothesis by solving the string's differential equation of motion, including an enhanced formulation to avoid parasitic high-frequency oscillations. This physical model enables us to analyze, in real time, the characteristics of the Helmholtz oscillations, including the string shape, excitation of harmonics, Schelleng ripples, and string energy, showing that the bowed string gains energy during the stick regime and loses energy during the slip regime.
RESUMO
Ultrastable lasers are essential tools in optical frequency metrology enabling unprecedented measurement precision that impacts on fields such as atomic timekeeping, tests of fundamental physics, and geodesy. To characterise an ultrastable laser it needs to be compared with a laser of similar performance, but a suitable system may not be available locally. Here, we report a comparison of two geographically separated lasers, over the longest ever reported metrological optical fibre link network, measuring 2220 km in length, at a state-of-the-art fractional-frequency instability of 7 × 10-17 for averaging times between 30 s and 200 s. The measurements also allow the short-term instability of the complete optical fibre link network to be directly observed without using a loop-back fibre. Based on the characterisation of the noise in the lasers and optical fibre link network over different timescales, we investigate the potential for disseminating ultrastable light to improve the performance of remote optical clocks.
RESUMO
The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.
RESUMO
BACKGROUND: Children and adolescents with severe hemophilia commonly suffer from acute and chronic pain as a consequence of hemophilia-related bleeding. Intervention-related pain also plays a major role. Despite its high prevalence in this patient group, hemophilia-related pain is not always adequately addressed and sufficiently treated. OBJECTIVES: This paper discusses how to improve pain management for children and adolescents (0-18 years) with hemophilia and which specific features in this population should influence decisions in pain management. MATERIALS AND METHODS: An expert panel discussed challenges in pain treatment in children and adolescents with hemophilia. Recommendations are based on evidence and clinical experience. RESULT: Pain management in children with hemophilia needs improvement. Children with hemophilia are at risk of developing chronic pain and of suffering traumatization due to insufficient pain management. Pain therapy can be challenging in these children as both their age and the underlying disease limit the options in particular in pain medication. The expert panel developed recommendations to improve pain management in children with hemophilia.
Assuntos
Dor Crônica , Hemofilia A , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Manejo da DorRESUMO
PURPOSE: To compare the diagnostic performance of frequency-selective non-linear blending and conventional linear blending contrast-enhanced CT for the diagnosis of acute (AC) and gangrenous (GC) cholecystitis. MATERIALS AND METHODS: Following local ethics committee approval for retrospective data analysis, a database search derived 39 patients (26 men, mean age 67.8⯱â¯14.6 years) with clinical signs of acute cholecystitis, contrast enhanced CT (CECT) evaluation, cholecystectomy, and pathological examination of the resected specimen. The interval between CECT and surgery was 4.7⯱â¯4.1 days. Pathological gross examination was used to categorize the cases into AC and GC. Subsequently, two radiologists categorized the CECT studies in a blinded and independent fashion into AC and GC, during two different reading sessions using linear blending and frequency-selective non-linear blending CECT. RESULTS: Histologic analysis diagnosed 31/39 (79.4%) cases of GC and 8/39 (20.6%) cases of AC. Image interpretation of linear blending CECT resulted in classification of 7/39 (17.9%) patients as GC and 32/39 (82.1%) as AC, whereas image interpretation of frequency-selective non-linear blending CECT resulted in classification of 29/39 (74.3%) patients as GC and 10/39 (25.7%) as AC. Sensitivity/specificity/PPV/NPV for detection of GC were 22.6%/100%/100%/25% with linear blending CECT and 80.6%/50%/86.2%/40% with frequency-selective non-linear blending CECT, respectively. Based on the histopathologic diagnosis frequency-selective non-linear blending had a significant improvement (pâ¯>â¯0.0001) in the diagnostic accuracy of gangrenous cholecystitis compared with linear blending. CONCLUSION: Frequency-selective non-linear blending post-processing increases the diagnostic accuracy of gangrenous cholecystitis owing to improved visualization of absence of focal enhancement and mural ulcerations.
RESUMO
The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
Assuntos
Movimento Celular , Regulação Neoplásica da Expressão Gênica , Receptores CXCR4/metabolismo , Receptores de Interleucina-8B/metabolismo , Neoplasias Gástricas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Feminino , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptores CXCR4/genética , Receptores de Interleucina-8B/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Diarrheagenic E. coli (DEC) are one of the most common causes for diarrhea worldwide, especially in children. We evaluated the rapid RIDA ® GENE (RG) real-time multiplex PCR assays (R-Biopharm, Darmstadt, Germany) for the detection of the most important diarrheagenic E. coli. Three hundred fifteen liquid or non-formed stool specimens were examined. The results of the RG multiplex assays were compared to specific PCR methods. The sensitivity and specificity of the RG PCRs were as follows, 100%/100% for the detection of EHEC, 96.3% and 99% for EPEC, 100% and 100% for the detection of EAEC, ETEC and EIEC, respectively. Overall, the RG real-time PCR system for the detection of DEC tested in this study provided reliable and rapid results and shows the ability as a useful addendum for the detection of diarrheagenic E. coli in the medical laboratory.
Assuntos
Diarreia/diagnóstico , Infecções por Escherichia coli/diagnóstico , Escherichia coli/isolamento & purificação , Fezes/microbiologia , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Diarreia/microbiologia , Escherichia coli/classificação , Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
The goal of this randomized and controlled study was to examine whether whole-body vibration (WBV) training is able to reduce back pain and physical disability in seated working office employees with chronic low-back pain in a real-world setting. A total of 41 subjects (68.3% female/mean age 45.5±9.1 years/mean BMI 26.6±5.2) were randomly allocated to an intervention group (INT [n=21]) or a control group (CON [n=20]). The INT participated in WBV training 2.5 times per week for 3 months. The primary outcome was the change in the Roland and Morris disability questionnaire (RMQ) score over the study period. In addition, secondary outcomes included changes in the Oswestry Disability Index (ODI), the Work Ability Index Questionnaire, the quality of life questionnaire SF-36, the Freiburger activity questionnaire, and an isokinetic test of the musculature of the trunk. Compliance with the intervention in the INT reached a mean of 81.1%±31.2% with no long-lasting unwanted side effects. We found significant positive effects of 3 months of WBV training in the INT compared to the CON regarding the RMQ (P=.027), the ODI (P=.002), the SF-36 (P=.013), the Freiburger activity questionnaire (P=.022), the post-interventional sick-leave in the INT (P=.008), and trends regarding a positive effect of the intervention on the muscular capacity of the muscles of the trunk in flexion. WBV training seems to be an effective, safe, and suitable intervention for seated working employees with chronic low-back pain.
Assuntos
Dor Lombar/terapia , Modalidades de Fisioterapia , Vibração , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Saúde Ocupacional , Postura , Qualidade de Vida , Amplitude de Movimento Articular , Licença Médica , Inquéritos e Questionários , Tronco , Local de TrabalhoRESUMO
BACKGROUND: Resistance of uropathogenic bacteria against the common antibiotics is considerable-especially in the elderly. OBJECTIVES: In Germany nitroxoline is licensed for the treatment of acute urinary tract infections and for prophylaxis of recurrent infections. What is the actual resistance pattern of uropathogenic bacteria? MATERIALS AND METHODS: The in vitro susceptibility of 477 uropathogenic bacteria from patients in 2015 was determined by means of the agar diffusion method. RESULTS: Obviously, this agent is still active against the vast majority of uropathogenic bacteria and in particular against strains of Escherichia coli (E. coli). Pseudomonas aeruginosa and enterococci are not really within the spectrum of nitroxoline. One has to keep in mind, however, that even among E. coli and other enterobacteriaceae there are single resistant isolates. This applies in particular to problem strains resistant to many other antibiotics. DISCUSSION: Nitroxoline is a reasonable alternative and a promising option for calculated treatment of urinary tract infections-especially of the elderly, although this drug is not recommended in the current guideline. Laboratory testing of clinical isolates should be requested-at least when treatment fails.
Assuntos
Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Nitroquinolinas/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Adolescente , Adulto , Idoso , Anti-Infecciosos Urinários/administração & dosagem , Bactérias/classificação , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The impact of immediate breast reconstruction on the time to first adjuvant therapy is controversial. METHODS: Retrospective study design comparing time to first treatment in women undergoing mastectomy with and without immediate reconstruction in a community cancer center. RESULTS: Seventy-six cases fit inclusion criteria of which 44 (58%) underwent mastectomy with immediate reconstruction. Women undergoing immediate reconstruction were younger, had more bilateral mastectomies and had fewer prior breast procedures. The median time to first adjuvant therapy was longer in the immediate reconstruction group [80.5days (36-343) versus 53.5 days (18-96), p = 0.003]. Fifteen of 44 patients had the start of adjuvant treatment over 90 days after resection, 14 of whom (93%) had immediate reconstruction versus 1 (7%) who did not (p = 0.01). CONCLUSION: In this study immediate breast reconstruction was associated with a longer time to first adjuvant treatment, with adjuvant therapies being more likely delayed over 90 days.
Assuntos
Neoplasias da Mama/terapia , Mamoplastia , Mastectomia , Tempo para o Tratamento , Fatores Etários , Institutos de Câncer , Quimioterapia Adjuvante , Centros Comunitários de Saúde , Feminino , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Radioterapia Adjuvante , Estudos RetrospectivosRESUMO
We present results from an analysis of all data taken by the BICEP2 and Keck Array cosmic microwave background (CMB) polarization experiments up to and including the 2014 observing season. This includes the first Keck Array observations at 95 GHz. The maps reach a depth of 50 nK deg in Stokes Q and U in the 150 GHz band and 127 nK deg in the 95 GHz band. We take auto- and cross-spectra between these maps and publicly available maps from WMAP and Planck at frequencies from 23 to 353 GHz. An excess over lensed ΛCDM is detected at modest significance in the 95×150 BB spectrum, and is consistent with the dust contribution expected from our previous work. No significant evidence for synchrotron emission is found in spectra such as 23×95, or for correlation between the dust and synchrotron sky patterns in spectra such as 23×353. We take the likelihood of all the spectra for a multicomponent model including lensed ΛCDM, dust, synchrotron, and a possible contribution from inflationary gravitational waves (as parametrized by the tensor-to-scalar ratio r) using priors on the frequency spectral behaviors of dust and synchrotron emission from previous analyses of WMAP and Planck data in other regions of the sky. This analysis yields an upper limit r_{0.05}<0.09 at 95% confidence, which is robust to variations explored in analysis and priors. Combining these B-mode results with the (more model-dependent) constraints from Planck analysis of CMB temperature plus baryon acoustic oscillations and other data yields a combined limit r_{0.05}<0.07 at 95% confidence. These are the strongest constraints to date on inflationary gravitational waves.
RESUMO
Enterobacteriaceae causing community-acquired urinary tract infections were examined in selected outpatient clinics and hospitals in Belgium, Germany and Spain using EUCAST breakpoints for susceptibility. A total of 1190 isolates were collected. Escherichia coli isolates were resistant to amoxicillin-clavulanic acid (28.1%), ciprofloxacin (23.4%) and trimethoprim-sulfamethoxazole (21.4%) compared with fosfomycin and nitrofurantoin (each, <1.5%). Ceftibuten (MIC50/90 0.25/0.5 mg/L) and ceftriaxone activity (MIC50/90 ≤0.25 mg/L) was comparable. Ceftibuten (MIC90 ≤0.25 mg/L) was also active against Proteus mirabilis and Klebsiella spp. Extended-spectrum ß-lactamase phenotypes were 7.1% for E. coli, 5.6% for Klebsiella pneumoniae and 0.4% for P. mirabilis. Resistance was common among men and elderly women.
Assuntos
Anti-Infecciosos/farmacologia , Infecções Comunitárias Adquiridas/microbiologia , Farmacorresistência Bacteriana , Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Infecções Urinárias/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Bélgica , Enterobacteriaceae/isolamento & purificação , Feminino , Alemanha , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Espanha , Adulto JovemRESUMO
BACKGROUND: Population-based data on pediatric patients on long-term respiratory support (LTRS) in Austria are lacking. This study aimed to record the pediatric departments active in this field, as well as number and characteristics of patients on LTRS. METHODS: A national cross-sectional study was carried out by means of questionnaires sent to all pediatric departments in Austria. RESULTS: All departments answered to the questionnaires. On June 1st, 2013, the reference day for this study, 12 of the 41 pediatric departments in Austria were active in the field. At this time, these centers were caring for 143 patients, 111 (77.6%) of them under 18 years, which corresponds to a prevalence of 7.4 per 100 000. The patients suffered from neuromuscular disorders (44%), other neurological disorders (18.9%), disorders of respiratory drive (9.1%), obstructive sleep apnea (8.4%), thoracal and spinal diseases (8.4%), pulmonary disorders (4.9%) and other diseases (6.3%). Continuous positive airway pressure was used in 6.3%, non-invasive ventilation in 60.1% and invasive ventilation in 33.6% of the patients, respectively. LTRS was performed at home in 92.3%. CONCLUSION: LTRS represents a common management strategy in children and adolescents with a variety of disorders. Census reports such as this one provide the basis for appropriate planning of resource allocation. The age distribution of our patients shows the need for structured transition into adult care.
Assuntos
Assistência de Longa Duração/métodos , Assistência de Longa Duração/tendências , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/terapia , Adolescente , Áustria , Criança , Pré-Escolar , Doença Crônica , Estudos Transversais , Feminino , Serviços Hospitalares de Assistência Domiciliar/estatística & dados numéricos , Serviços Hospitalares de Assistência Domiciliar/tendências , Humanos , Recém-Nascido , Assistência de Longa Duração/estatística & dados numéricos , Masculino , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/etiologia , Inquéritos e Questionários , Revisão da Utilização de Recursos de Saúde/estatística & dados numéricosRESUMO
INTRODUCTION: Disturbances of circadian rhythms occur in all episodes of bipolar disorder (BD). Lithium, as gold-standard in the maintenance treatment of BD, is known to influence circadian processes. METHODS: In a pilot study lymphoblastoid cell lines (LCLs) were generated from 8 BD patients and 6 healthy controls. The LCLs were treated with lithiumchloride (LiCl) for 3 weeks. Cell cycles were then synchronized and expressional analysis by quantitative Real Time PCR was done. RESULTS: BD and controls differed in the period length regarding DBP (albumin D-box binding protein) expression and DBP expression was also influenced by lithium treatment. Furthermore, baseline DBP expression was significantly different between non-treated BD and healthy controls. None of the other analyzed circadian genes showed to be influenced by chronic lithium treatment or to be differentially regulated due to the diagnosis. DISCUSSION: We here show that chronic lithium treatment of LCLs leads to decreased expression of the clock gene DBP, rendering DBP a lithium-regulated gene. We could confirm the role of the circadian clock as well in lithium mode of action as in the pathomechanisms of BD although future studies with a greater number of participants and cell lines are needed.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Relógios Circadianos , Proteínas de Ligação a DNA/biossíntese , Expressão Gênica/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Fatores de Transcrição/biossíntese , Linhagem Celular , Feminino , Humanos , Masculino , Projetos PilotoRESUMO
BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Adolescente , Neoplasias Ósseas/cirurgia , Criança , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Terapia Neoadjuvante , Osteossarcoma/cirurgia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Qualidade de Vida , Projetos de Pesquisa , Adulto JovemRESUMO
BACKGROUND: The aim of this multicenter study was to establish a diagnostic algorithm using molecular methods for the diagnosis of C. difficile-associated infection (CDI). In addition patient specific data were taken into consideration for the interpretation of the results. METHODS: We compared the performance of six different commercially available PCR-tests, two toxin immunoassays, and a glutamat-dehydrogenase test by analysing liquid stool specimens from patients with suspected CDI. Toxigenic culture on CLO-agar was used as reference method. RESULTS: In total 250 stool specimens were collected at two study sites. 77 (30.8%) stool samples were culture-positive for toxigenic C. difficile. 173 (69.2%) specimens showed no growth of C. difficile. As a result, each of the PCR assays tested for C. difficile had a significantly higher sensitivity (94.8% - 100%) and NPV (97.6% - 100%) than the TOX-EIA with a sensitivity of 57.1% and NPV of 83.8%. Specificity of the PCR tests was 94.1% to 96.0% and PPV between 86.5% and 91.6%. The analysis of the patient data revealed a significant difference (p-value 0.0202) between toxin-positive and toxin-negative patients regarding prior antibiotic treatment, especially for cephalosporins. CONCLUSIONS: Our findings support the recommendation to restrict the use of antibiotics as a cornerstone in the prevention of CDI. We conclude that all of the PCR assays evaluated in this study can be applied in a diagnostic algorithm.