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PURPOSE OF REVIEW: Given the recent increase in the profile and use of Janus kinase inhibitors (JAKinibs) in adult patients with rheumatic diseases, we aimed to review the current evidence accruing for use in paediatric rheumatology patients. RECENT FINDINGS: Significant advances have been made in the management of rheumatic diseases in the past two decades. The introduction of biologic agents in both adults and children has provided significant improvements to patient outcomes and led to better quality of life. Moreover, responses to similar agents allude to common effector pathways operating across juvenile and adult synovitis especially. However, inefficacy and intolerance of these agents leads to a subset of children with limited treatment options. Since 2012, Janus kinase (JAK) inhibitors (JAKinibs), a novel group of oral small molecule inhibitors, have demonstrated their efficacy in several forms of adult inflammatory arthritis, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). There are hopes that these successes will be transferable to the paediatric population. In the following review, we discuss the development and progress of JAKinibs in this regard.
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Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Criança , Humanos , ReumatologiaRESUMO
BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.
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Antineoplásicos/efeitos adversos , Avaliação de Resultados da Assistência ao Paciente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Qualidade de Vida , Autorrelato , Resultado do TratamentoRESUMO
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.
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Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Transversais , Nível de Saúde , Humanos , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Resultado do TratamentoRESUMO
INTRODUCTION: Many patients with intracranial tumours have cognitive deficits that might affect their mental capacity to give valid consent to neurosurgical treatment. The aim of this study was to determine the incidence of mental incapacity, as assessed by neurosurgeons, in patients with intracranial tumours undergoing neurosurgery. METHODS: The case notes of successive patients undergoing brain tumour surgery between 16 October 2008 and 16 October 2010 were reviewed. The frequency of use of standard consent forms and Certificates of Incapacity was recorded. In addition, the frequency and scores of pre-operative cognitive assessments were recorded. RESULTS: Case notes of 247 of 262 patients undergoing surgery for intracranial tumours were reviewed since there was no record of either a standard consent form or a Certificate of Incapacity in the case notes for 15 patients. Nine of 247 brain tumour patients were issued with a Certificate of Incapacity (3.6%, 95% CI 1.6-6.8%), while 238 (96.4%) signed a standard consent form. Seven of these nine had high-grade gliomas, for an incidence of incapacity of 5.9% (95% CI 2.8-11.8%), while the remaining two Certificates of Incapacity were issued for patients with meningiomas (incidence 3%; 95% CI 0.04-10.4%). Fifty of the 262 patients (19%) had some form of pre-operative cognitive assessment documented, but only three of these were issued with a Certificate of Incapacity. All three patients issued with a Certificate of Incapacity had Mini-Mental State Examination scores suggestive of cognitive impairment. CONCLUSIONS: Incapacity to consent to brain tumour surgery, as assessed by neurosurgeons, is uncommon. The incidence of incapacity is less than might be expected given the level of cognitive impairment known in this population. Decisions about capacity by neurosurgeons are often made in the absence of any documented assessment of cognition or other objective evidence that could support their decision in the event of dispute.
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Neoplasias Encefálicas/psicologia , Transtornos Cognitivos/psicologia , Consentimento Livre e Esclarecido , Competência Mental , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/cirurgia , Termos de Consentimento/estatística & dados numéricos , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Adulto JovemRESUMO
Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry. CF patients between 6-18 yrs of age with FEV(1 )≥ 80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used. The mean ± sd age was 10.32 ± 3.35 yrs. Dornase alfa improved LCI versus placebo (0.90 ± 1.44; p = 0.022). Forced expiratory flow at 25-75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1% ± 10.34%; p = 0.03 and 0.28 ± 0.46 z-score; p = 0.03). Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.
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Fibrose Cística/tratamento farmacológico , Desoxirribonuclease I/farmacologia , Adolescente , Burkholderia cepacia/metabolismo , Criança , Estudos Cross-Over , Feminino , Humanos , Pulmão/patologia , Masculino , Placebos , Projetos de Pesquisa , Testes de Função Respiratória , Espirometria/métodos , Fatores de Tempo , VentilaçãoRESUMO
The management of rheumatic and musculoskeletal diseases has transformed over two decades of exciting discoveries regarding pathogenesis and innovative drug development. The introduction of sophisticated immunomodulatory therapies has given renewed hope to many patients, but notable challenges remain within the field of rheumatology. Before the advent of biologic therapies, conventional synthetic DMARDs (csDMARDs) provided effective disease control for some patients, although a comprehensive understanding of the mechanisms by which these drugs exert their effects remained elusive. Reflecting upon the efficacy and mechanisms of action of csDMARDs can provide intriguing insights. First, contemplating past approaches brings our remarkable current approaches concerning pathogenesis-driven discovery and drug development into sharper focus. Second, increased understanding of the mode of action of these older drugs might in turn provide exciting opportunities for the understanding of disease and for the development of future therapies.
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Antirreumáticos/uso terapêutico , Terapia Biológica/métodos , Gerenciamento Clínico , Doenças Musculoesqueléticas/terapia , Doenças Reumáticas/tratamento farmacológico , Reumatologia , HumanosRESUMO
BACKGROUND: It has been hypothesised that abnormal functioning of the mirror neuron system (MNS) may lead to deficits in imitation and the internal representation of movement, potentially contributing to the motor impairments associated with developmental coordination disorder (DCD). AIMS: Using fMRI, this study examined brain activation patterns in children with and without DCD on a finger adduction/abduction task during four MNS activation states: observation; motor imagery; execution; and imitation. METHODS AND PROCEDURES: Nineteen boys (8.25-12.75 years) participated, including 10 children with DCD (≤16th percentile on MABC-2; no ADHD/ASD), and nine typically developing controls (≥25th percentile on MABC-2). OUTCOMES AND RESULTS: Even though children with DCD displayed deficits behaviourally on imitation (Sensory Integration & Praxis Test Subtests) and motor imagery assessments prior to scanning, no differences in MNS activation were seen between the DCD and control groups at a neurological level, with both groups activating mirror regions effectively across conditions. Small clusters of decreased activation during imitation were identified in non-mirror regions in the DCD group, including the thalamus, caudate, and posterior cingulate - regions involved in motor planning and attentional processes. CONCLUSIONS AND IMPLICATIONS: The results of this study do not provide support for the MNS dysfunction theory as a possible causal mechanism for DCD. Further research to explore attentional and motor planning processes and how they may interact at a network level may enhance our understanding of this complex disorder.
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Encéfalo/diagnóstico por imagem , Neurônios-Espelho/fisiologia , Transtornos das Habilidades Motoras/diagnóstico por imagem , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Criança , Dedos , Neuroimagem Funcional , Humanos , Imaginação , Comportamento Imitativo , Imageamento por Ressonância Magnética , Masculino , Transtornos das Habilidades Motoras/fisiopatologia , Reprodutibilidade dos TestesRESUMO
Essentials Staphylococcus aureus (S. aureus) binds and impairs function of vascular endothelial cells (EC). We investigated the molecular signals triggered by S. aureus adhesion to EC. Inhibition of the EC integrin αVß3 reduces S. aureus binding and rescues EC function. αVß3 blockade represents an attractive target to treat S. aureus bloodborne infections. SUMMARY: Background Vascular endothelial dysfunction with associated edema and organ failure is one of the hallmarks of sepsis. Although a large number of microorganisms can cause sepsis, Staphylococcus aureus (S. aureus) is one of the primary etiologic agents. Currently, there are no approved specific treatments for sepsis, and the initial management bundle is therefore focused on cardiorespiratory resuscitation and mitigation of the immediate threat of uncontrolled infection. The continuous emergence of antibiotic-resistant strains of bacteria necessitates the development of new therapeutic approaches for this disease. Objective To identify the molecular mechanisms leading to endothelial dysfunction as a result of S. aureus binding. METHODS: Binding of wild type and Clumping factor A (ClfA) deficient S. aureus Newman to the endothelium was measured in vitro and in the mesenteric circulation of C57Bl/6 mice. The effects of the αV ß3 blocker-cilengitide-on bacterial binding, endothelial VE-cadherin expression, apoptosis, proliferation and permeability were assessed. Results The major S. aureus cell wall protein ClfA bound to endothelial cell αV ß3 in the presence of fibrinogen. This interaction resulted in disturbances in barrier function mediated by VE-cadherin in endothelial cell monolayers, and ultimately cell death by apoptosis. With a low concentration of cilengitide, ClfA binding to αV ß3 was significantly inhibited both in vitro and in vivo. Moreover, preventing S. aureus from attaching to αV ß3 resulted in a significant reduction in endothelial dysfunction following infection. Conclusion Inhibition of S. aureus ClfA binding to endothelial cell αV ß3 by cilengitide prevents endothelial dysfunction.
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Coagulase/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Integrina alfaVbeta3/antagonistas & inibidores , Staphylococcus aureus/patogenicidade , Animais , Antibacterianos/uso terapêutico , Antígenos CD/metabolismo , Apoptose , Aderência Bacteriana/efeitos dos fármacos , Caderinas/metabolismo , Cálcio/química , Proliferação de Células , Células Endoteliais/microbiologia , Endotélio Vascular/microbiologia , Citometria de Fluxo , Humanos , Integrina alfaVbeta3/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Venenos de Serpentes/químicaRESUMO
Staphylococcus epidermidis is the leading etiologic agent of orthopaedic implant infection. Contamination of the implanted device during insertion allows bacteria gain entry into the sterile bone environment leading to condition known as osteomyelitis. Osteomyelitis is characterised by weakened bones associated with progressive bone loss. The mechanism through which S. epidermidis interacts with bone cells to cause osteomyelitis is poorly understood. We demonstrate here that S. epidermidis can bind to osteoblasts in the absence of matrix proteins. S. epidermidis strains lacking the cell wall protein SdrG had a significantly reduced ability to bind to osteoblasts. Consistent with this, expression of SdrG in Lactococcus lactis resulted in significantly increased binding to the osteoblasts. Protein analysis identified that SdrG contains a potential integrin recognition motif. αVß3 is a major integrin expressed on osteoblasts and typically recognises RGD motifs in its ligands. Our results demonstrate that S. epidermidis binds to recombinant purified αVß3, and that a mutant lacking SdrG failed to bind. Blocking αVß3 on osteoblasts significantly reduced binding to S. epidermidis. These studies are the first to identify a mechanism through which S. epidermidis binds to osteoblasts and potentially offers a mechanism through which implant infection caused by S. epidermidis leads to osteomyelitis.
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Proteínas de Bactérias/metabolismo , Proteínas de Transporte/metabolismo , Integrina alfaVbeta3/metabolismo , Osteoblastos/metabolismo , Staphylococcus epidermidis/crescimento & desenvolvimento , Proteínas de Transporte/imunologia , Humanos , Osteomielite/etiologia , Osteomielite/imunologia , Osteomielite/terapia , Ligação Proteica/imunologia , Serina/antagonistas & inibidores , Serina/imunologia , Staphylococcus epidermidis/imunologiaRESUMO
Polyclonal antibodies raised against the hallucinogenic drug, lysergic acid diethylamide (LSD), were used to detect and extract drug from whole blood samples. An indirect ELISA was used to detect as little as 1 pg of total drug in 25 microl blood. The limit of detection of the immunoassay, calculated from the mean - 3 SD was 39 pg/ml. The analytical recovery of LSD (2.5-0.2 ng/ml) from whole blood was 102-113%. Within-run CVs for LSD spiked in blood at 1.25, 0.16 and 0.04 ng/ml were 5.6, 3.1, and 8.9%, respectively (n = 4). There was an overall decrease in precision when whole blood was used in place of urine, due to the increased complexity of the matrix. However, using this technique LSD was calibrated in blood in the sub-ng/ml region of forensic interest. Immunoaffinity extraction was used to isolate LSD from blood and urine samples. The affinity support was prepared by covalently attaching anti-LSD antibodies to Protein A-coated agarose beads. No pre-treatment of the sample was required other than the addition of neutral buffer. Sub-ng/ml concentrations of LSD were routinely extracted from blood and urine samples with greater than 80% recovery of drug. This technique, which could be used to extract LSD from blood and urine samples prior to confirmatory drug analysis, could be completed in about 10 min.
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Dietilamida do Ácido Lisérgico/sangue , Animais , Calibragem , Bovinos , Ensaio de Imunoadsorção Enzimática , Dietilamida do Ácido Lisérgico/imunologia , Dietilamida do Ácido Lisérgico/isolamento & purificação , Dietilamida do Ácido Lisérgico/urina , CoelhosRESUMO
BACKGROUND: Quality of life (QOL) is an important consideration in healthcare decision-making for pets with cancer. To determine the effect of disease and treatment on pet QOL, this important variable should be objectively measured as an outcome in veterinary cancer studies. OBJECTIVES: To determine the prevalence and methodology of QOL measurement in a sample of recently published reports of prospective studies evaluating cancer treatments in client-owned dogs and cats; to characterize reporting of QOL outcomes and to identify article characteristics associated with QOL measurement. METHODS: English-language reports of prospective studies of cancer treatments in dogs and cats published from 2008 to 2013 were identified using medical research databases combined with a hand-searching strategy. Data pertaining to general article characteristics and QOL measurement were abstracted and summarized. RESULTS: Reports of 144 eligible studies were identified. QOL was measured in 16 (11.1%) studies, with 8 (5.6%) reporting the results. All studies that measured QOL reported using unvalidated instruments, or did not report how QOL was assessed. Only 1 study provided sufficient information for QOL measurements to be replicated. Recently published articles (2011-2013) were significantly more likely to report measuring QOL, compared with earlier articles. CONCLUSIONS: Quality of life of pets undergoing cancer treatment is largely unreported and cannot be meaningfully compared across treatments or disease states using the existing literature. Reliable, validated instruments are needed to facilitate the measurement and comparison of pet QOL in veterinary cancer research. Consistent reporting practices could improve transparency and interpretation of QOL results.
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Doenças do Gato/psicologia , Doenças do Cão/psicologia , Neoplasias/veterinária , Qualidade de Vida , Animais , Doenças do Gato/terapia , Gatos , Doenças do Cão/terapia , Cães , Neoplasias/psicologia , Neoplasias/terapia , Estudos ProspectivosRESUMO
BACKGROUND: Infective endocarditis (IE) is characterized by thrombus formation on a cardiac valve. The oral bacterium, Streptococcus oralis, is recognized for its ability to colonize damaged heart valves and is frequently isolated from patients with IE. Platelet interaction with S. oralis leads to the development of a thrombotic vegetation on heart valves, which results in valvular incompetence and congestive heart failure. OBJECTIVE: To investigate the mechanism through which platelets become activated upon binding S. oralis. PATIENTS AND METHODS: Platelet interactions with immobilized bacteria under shear conditions were assessed using a parallel flow chamber. S. oralis-inducible platelet reactivity was determined using light transmission aggregometry. Dense granule secretion was measured by luminometry using a luciferin/luciferase assay. RESULTS: Using shear rates that mimic physiological conditions, we demonstrated that S. oralis was able to support platelet adhesion under venous (50-200 s(-1) ) and arterial shear conditions (800 s(-1) ). Platelets rolled along immobilized S. oralis through an interaction with GPIbα. Following rolling, platelet microaggregate formation was observed on immobilized S. oralis. Aggregate formation was dependent on S. oralis binding IgG, which cross-links to platelet FcγRIIa. This interaction led to phosphorylation of the ITAM domain on FcγRIIa, resulting in dense granule secretion, amplification through the ADP receptor and activation of RAP1, culminating in platelet microaggregate formation. CONCLUSIONS: These results suggest a model of interaction between S. oralis and platelets that leads to the formation of a stable septic vegetation on damaged heart valves.
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Ativação Plaquetária/fisiologia , Complexo Glicoproteico GPIb-IX de Plaquetas/fisiologia , Receptores de IgG/fisiologia , Streptococcus oralis/fisiologia , Adesão Celular , Endocardite/sangue , Endocardite/microbiologia , Humanos , Agregação PlaquetáriaRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.
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Antineoplásicos/efeitos adversos , Avaliação da Deficiência , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Inquéritos e Questionários , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Consenso , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/psicologia , Valor Preditivo dos Testes , Qualidade de Vida , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
It has become clear that platelets are not simply cell fragments that plug the leak in a damaged blood vessel; they are, in fact, also key components in the innate immune system, which is supported by the presence of Toll-like receptors (TLRs) on platelets. As the cells that respond first to a site of injury, they are well placed to direct the immune response to deal with any resulting exposure to pathogens. The response is triggered by bacteria binding to platelets, which usually triggers platelet activation and the secretion of antimicrobial peptides. The main platelet receptors that mediate these interactions are glycoprotein (GP)IIb-IIIa, GPIbα, FcγRIIa, complement receptors, and TLRs. This process may involve direct interactions between bacterial proteins and the receptors, or can be mediated by plasma proteins such as fibrinogen, von Willebrand factor, complement, and IgG. Here, we review the variety of interactions between platelets and bacteria, and look at the potential for inhibiting these interactions in diseases such as infective endocarditis and sepsis.
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Plaquetas/imunologia , Imunidade Inata , Ativação Plaquetária , Bactérias/imunologia , Plaquetas/microbiologia , HumanosRESUMO
The presence of alcohol (ethanol) is a common toxicological finding in alleged cases of drug-facilitated sexual assault (DFSA). Alcohol was identified as the most frequently encountered drug in DFSAs more than a decade ago, and epidemiological studies to date confirm this initial finding. There is no single substance that is uniquely associated with DFSA. Alcohol has been used by humans for thousands of years and its effect on sexual behavior is well established. Despite the fact that alcohol has been the subject of scientific investigation for several hundred years, DFSA casework involving alcohol remains complex and poses numerous challenges. The prevalence of alcohol in DFSAs is reviewed within the context of toxicological findings and blood alcohol concentration (BAC). Pharmacological aspects are briefly presented, including pharmacokinetics and retrograde extrapolation. The effects of alcohol are discussed within the context of the pharmacodynamics of alcohol and the mechanistic issues associated with alcohol's disruption of memory. The amnesic effects of alcohol are reviewed, with particular focus on the two distinct types of alcohol-induced blackout: fragmentary and en bloc. The prevalence of and the BACs associated with this type of alcohol-mediated memory loss are described. Finally, biological specimens (blood, serum, and urine) are reviewed from a toxicological standpoint, and the associated methodology for quantitative alcohol determination is presented.
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BACKGROUND: Sepsis is the most common manifestation of invasive pneumococcal disease and is characterized by a severe systemic inflammatory state that leads to circulatory compromise or end organ malperfusion or dysfunction. Patients suffering from sepsis often display low platelet counts characterized by thrombocytopenia as a result of platelet activation. OBJECTIVE: To investigate the mechanism through which platelets become activated in sepsis upon binding to Streptococcus pneumoniae. PATIENTS AND METHODS: We determined S. pneumoniae inducible platelet reactivity using light transmission aggregometry. Dense granule secretion was measured by luminometry using a luciferin/luciferase assay. RESULTS: Streptococcus pneumoniae induced platelet aggregation in a strain-dependent manner. Induction of aggregation was not attributable to capsule serotype, as unencapsulated strains also induced platelet aggregation. Platelet aggregation was not associated with pneumolysin toxin, as a pneumolysin-deficient mutant of S. pneumoniae induced aggregation equally as well as the parent strain. Platelet aggregation also occurred in the absence of plasma proteins or antibody, and was GPIIbIIIa dependent but aspirin independent. Toll-like receptor 2 (TLR2) is present on platelets and acts as a receptor for gram-positive bacterial lipoteichoic acid and peptidoglycan. Inhibition of TLR2 but not TLR4 (also present on platelets) completely abolished platelet aggregation. S. pneumoniae-induced platelet aggregation resulted in activation of the PI3kinase/RAP1 pathway, leading to integrin GPIIbIIIa activation and dense granule release. CONCLUSIONS: Our results demonstrate a novel interaction between S. pneumoniae and TLR2, which results in platelet activation that is likely to contribute to the thrombotic complications of sepsis.
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Ativação Plaquetária/fisiologia , Streptococcus pneumoniae/fisiologia , Receptor 2 Toll-Like/fisiologia , Plaquetas/microbiologia , Proteínas Sanguíneas/fisiologia , Ensaio de Imunoadsorção Enzimática , Humanos , Agregação Plaquetária/fisiologia , Transdução de SinaisRESUMO
A microchannel plate (MCP)/phosphor screen assembly has been used to destructively measure the radial profile of cold, confined antiprotons, electrons, and positrons in the ALPHA experiment, with the goal of using these trapped particles for antihydrogen creation and confinement. The response of the MCP to low energy (10-200 eV, <1 eV spread) antiproton extractions is compared to that of electrons and positrons.
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A photoreactive heterobifunctional linker was used to prepare an immunogen in which lysergic acid diethylamide was indirectly coupled to keyhole limpet hemocyanin at multiple sites on the drug. It was possible to attach approximately 35 drug molecules to each protein using approximately equal amounts of both species during the reaction. The presence of buffer components or water severely compromised reaction efficiency, as estimated from the molar substitution ratio. Factors such as excess linker, pH, irradiation of dry matrix in the absence of buffer, and the drug/protein ratio used during photolysis were shown to have pronounced effects on reaction efficiency. Structural insights regarding immunogen coupling were obtained by determining the specificities of antibodies which were raised against the immunogen. Cross-reactivity data indicated that haptenation of protein likely occurred at positions N1 and N6 of lysergic acid diethylamide, which is plausible given the electrophilicity of the photogenerated aryl nitrene.