Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response

Objective: Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease. Methods and results: The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, -765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The -765C allele had significantly lower promoter activity compared with -765G, basally (28±3% lower, P<0.005) and in serum-stimulated cells (31±2% lower, P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with -765G homozygotes, patients carrying the -765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3, P<0.05 for all time points). Conclusions: For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed

Convulsões não epilépticas psicogênicas em sala de recuperação pós‐anestésica

ResumoIntroduçãoAs convulsões não epilépticas psicogênicas (CNEP ou “pseudoconvulsões”) permanecem como tema obscuro no cenário perioperatório. Trata‐se de distúrbios motores e cognitivos súbitos, mas por tempo limitado, que imitam as convulsões epilépticas, mas que são psicogenicamente mediados. Pseudoconvulsões ocorrem com mais frequência do que epilepsia em cenário perioperatório. O diagnóstico e o tratamento precoces podem evitar lesões iatrogênicas.CasoPaciente do sexo feminino, 48 anos, com história de depressão e “convulsões”, apresentou‐se para cirurgia ginecológica. A paciente descreveu sua história de convulsões “controladas” sem o uso de terapia anticonvulsivante. Foi submetida à anestesia geral sem intercorrências e recuperou‐se neurologicamente intacta. Durante as duas primeiras horas de pós‐operatório, apresentou três episódios semelhantes à convulsão, com tremores generalizados das extremidades e impulso pélvico; seus olhos estavam bem fechados. Não observamos mordedura da língua ou incontinência. Os episódios duraram cerca de trêsminutos cada; um dos episódios resolveu espontaneamente e os outros dois após a administração de lorazepam por via intravenosa. Durante os episódios, a condição hemodinâmica da paciente era estável e a ventilação adequada, de modo que a intubação traqueal foi considerada injustificável. Após a convulsão, a paciente estava neurologicamente intacta. Tomografia axial da cabeça, teste metabólico e eletroencefalograma não mostraram alterações. O diagnóstico de provável CNEP foi feito.DiscussãoAs convulsão não epilépticas psicogênicas imitam o tremor e devem ser inicialmente consideradas no diagnóstico diferencial de tremor pós‐operatório, pois podem ser mais prováveis do que a epilepsia nesse cenário. Os padrões da pseudoconvulsão incluem episódios convulsivos assíncronos que duram mais de 90segundos, olhos forçadamente fechados com resistência à abertura e respostas pupilares mantidas. Manifestações autonômicas, como taquicardia, cianose e incontinência, normalmente estão ausentes. Uma história psiquiátrica é comum. O conhecimento e o diagnóstico correto de pseudoconvulsões são muito importantes para os anestesiologistas para a prevenção de morbidade e lesões iatrogênicas, como a parada respiratória causada por terapia anticonvulsivante, além dos riscos associados à intubação orotraqueal e internação prolongada. O diagnóstico de pseudoconvulsões deve ser cuidadosamente documentado e retransmitido nas trocas de equipes médicas para evitar erros de diagnóstico e complicações iatrogênicas. As recomendações de tratamento são anedóticas; intervenções psiquiátricas são o pilar do tratamento. As recomendações anestésicas incluem técnicas que envolvem o uso de agentes de ação curta, juntamente com altos níveis de apoio e amparo psicológico no período perioperatório.AbstractIntroductionPsychogenic non‐epileptic seizures (PNES or “pseudoseizures”) remain an obscure topic in the peri‐operative setting. They are sudden and time‐limited motor and cognitive disturbances, which mimic epileptic seizures, but are psychogenically mediated. Pseudoseizures occur more frequently than epilepsy in the peri‐operative setting. Early diagnosis and management may prevent iatrogenic injury.Case48 year‐old female with a history of depression and “seizures” presented for gynecologic surgery. She described her seizure history as “controlled” without anticonvulsant therapy. The patient underwent uneventful general anesthesia and recovered neurologically intact. During the first two postoperative hours, the patient experienced 3 episodes of seizure‐like activity with generalized shaking of extremities and pelvic thrusting; her eyes were firmly closed. No tongue biting or incontinence was noted. The episodes lasted approximately 3min each, one of which resolved spontaneously and the other two following intravenous lorazepam. During these episodes, the patient had stable hemodynamics and adequate ventilation such that endotracheal intubation was deemed unwarranted. Post‐ictally, the patient was neurologically intact. Computed axial tomography of the head, metabolic assay, and electroencephalogram showed no abnormalities. A presumptive diagnosis of PNES was made.DiscussionPsychogenic non‐epileptic seizures mimic shivering, and should be considered early in the differential diagnosis of postoperative shaking, as they may be more likely than epilepsy in this setting. Pseudoseizure patterns include asynchronous convulsive episodes lasting more than 90s, forced eye closure with resistance to opening, and retained pupillary responses. Autonomic manifestations such as tachycardia, cyanosis and incontinence are usually absent. A psychiatric background is common. Knowledge and correct diagnosis of pseudoseizures is of great importance for anesthesiologists to prevent morbidity and iatrogenic injury such as respiratory arrest caused by anticonvulsant therapy, in addition to the risks associated with endotracheal intubation and prolonged hospital stays. The diagnosis of pseudoseizures must be thoroughly documented and relayed in transfer of care to avoid misdiagnosis and iatrogenic complications. Treatment recommendations are anecdotal; psychiatric interventions are the hallmark of treatment. Anesthetic recommendations include techniques involving the minimum required short‐acting agents, along with high levels of peri‐operative psychological support and reassurance

Polonesa /

Música manuscritaOrgánico: 3[1.2.Pic] 2 2 2 -- 4 2 3 1 -- tmp + 4 -- strperc: tambn, sd, tri, bd, cymCopia digital. España : Ministerio de Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, s2021Tít. de la carp.: `Polonesa`, tít. en la port. de la partitura: `Polaca de concierto`Partes: Fl 1, 2, Pic, Ob 1, 2, Cl 1, 2, Bn 1, 2, Hn 1, 2, 3, 4, Crt 1, 2, Tbn 1, 2, 3, Tuba, Tmp, Tambn, Sd + Tri, Bd + Cym, Vn 1 (8), Vn 2 (7), Va (5), Vc (5), Db (4

Machine Learning Based Fall Detector with a Sensorized Tip

Fall detection has become an area of interest in recent years, as quick response to these events is critical to reduce the morbidity and mortality rate. In order to ensure proper fall detection, several technologies have been developed, including vision system, environmental detection systems, and wearable sensor based systems. However, in elderly or impaired people, it has been shown that the implementation of sensors in Assistive Devices for Walking, such as crutches or canes, can also be a promising alternative. In this work, a Support Vector Machine (SVM) based Fall Detection system is proposed, which uses the data provided by a Sensorized Tip which can be attached to different Assistive Devices for Walking (ADW). Unlike other approaches, the developed one is able to differentiate the fall of the ADW from the fall of the user. For that purpose, the developed Fall Detector uses two modules connected in series. The first one detects all falls, while the second differentiates between user and ADW falls. The proposed approach is validated in a set of experimental tests carried out by healthy volunteers that have simulated different falls. In addition, a comparative analysis is carried out by comparing the performance of the Sensorized Tip based Fall Detector and a state-of-the-art commercial accelerometer system. Results demonstrate that the proposed approach provides high Fall Detection Ratios (over 90%), similar or higher to wearable-sensor based approaches

Modelling and characterisation of a ultrasound-actuated needle for improved visibility in ultrasound-guided regional anaesthesia and tissue biopsy

AbstractClear needle visualisation is recognised as an unmet need for ultrasound guided percutaneous needle procedures including regional anaesthesia and tissue biopsy. With inadequate needle visibility, these procedures may result in serious complications or a failed operation. This paper reports analysis of the modal behaviour of a previously proposed ultrasound-actuated needle configuration, which may overcome this problem by improving needle visibility in colour Doppler imaging. It uses a piezoelectric transducer to actuate longitudinal resonant modes in needles (outer diameter 0.8–1.2mm, length>65mm). The factors that affect the needle’s vibration mode are identified, including the needle length, the transducer’s resonance frequency and the gripping position. Their effects are investigated using finite element modelling, with the conclusions validated experimentally. The actuated needle was inserted into porcine tissue up to 30mm depth and its visibility was observed under colour Doppler imaging. The piezoelectric transducer is able to generate longitudinal vibration with peak-to-peak amplitude up to 4μm at the needle tip with an actuating voltage of 20Vpp. Actuated in longitudinal vibration modes (distal mode at 27.6kHz and transducer mode at 42.2kHz) with a drive amplitude of 12–14Vpp, a 120mm needle is delineated as a coloured line in colour Doppler images, with both needle tip and shaft visualised. The improved needle visibility is maintained while the needle is advanced into the tissue, thus allowing tracking of the needle position in real time. Moreover, the needle tip is highlighted by strong coloured artefacts around the actuated needle generated by its flexural vibration. A limitation of the technique is that the transducer mode requires needles of specific lengths so that the needle’s resonance frequency matches the transducer. This may restrict the choice of needle lengths in clinical applications

In vivo magnetic resonance imaging of glucose - initial experience

A new noninvasive, nonradioactive approach for glucose imaging using spin hyperpolarization technology and stable isotope labeling is presented. A glucose analog labeled with 13C at all six positions increased the overall hyperpolarized imaging signal; deuteration at all seven directly bonded proton positions prolonged the spin-lattice relaxation time. High-bandwidth 13C imaging overcame the large glucose carbon chemical shift dispersion. Hyperpolarized glucose images in the live rat showed time-dependent organ distribution patterns. At 8s after the start of bolus injection, the inferior vena cava was demonstrated at angiographic quality. Distribution of hyperpolarized glucose in the kidneys, vasculature, and heart was demonstrated at 12 and 20s. The heart-to-vasculature intensity ratio at 20s suggests myocardial uptake. Cancer imaging, currently performed with 18F-deoxyglucose positron emission tomography (FDG-PET), warrants further investigation, and glucose imaging could be useful in a vast range of clinical conditions and research fields where the radiation associated with the FDG-PET examination limits its use. © 2012 John Wiley & Sons, Ltd

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

McArdle disease; Glycogen phosphorylase; Research modelsEnfermedad de McArdle; Glucógeno fosforilasa; Modelos de investigaciónMalaltia de McArdle; Glicogen fosforilasa; Models de recercaMcArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.The present manuscript was funded by grants received from the Fondo de Investigaciones Sanitarias (FIS, grant PI19/01313 and PI17/2052) and co-funded by “Fondos FEDER”

A cortical potential reflecting cardiac function

Emotional trauma and psychological stress can precipitate cardiac arrhythmia and sudden death through arrhythmogenic effects of efferent sympathetic drive. Patients with preexisting heart disease are particularly at risk. Moreover, generation of proarrhythmic activity patterns within cerebral autonomic centers may be amplified by afferent feedback from a dysfunctional myocardium. An electrocortical potential reflecting afferent cardiac information has been described, reflecting individual differences in interoceptive sensitivity (awareness of one's own heartbeats). To inform our understanding of mechanisms underlying arrhythmogenesis, we extended this approach, identifying electrocortical potentials corresponding to the cortical expression of afferent information about the integrity of myocardial function during stress. We measured changes in cardiac response simultaneously with electroencephalography in patients with established ventricular dysfunction. Experimentally induced mental stress enhanced cardiovascular indices of sympathetic activity (systolic blood pressure, heart rate, ventricular ejection fraction, and skin conductance) across all patients. However, the functional response of the myocardium varied; some patients increased, whereas others decreased, cardiac output during stress. Across patients, heartbeat-evoked potential amplitude at left temporal and lateral frontal electrode locations correlated with stress-induced changes in cardiac output, consistent with an afferent cortical representation of myocardial function during stress. Moreover, the amplitude of the heartbeat-evoked potential in the left temporal region reflected the proarrhythmic status of the heart (inhomogeneity of left ventricular repolarization). These observations delineate a cortical representation of cardiac function predictive of proarrhythmic abnormalities in cardiac repolarization. Our findings highlight the dynamic interaction of heart and brain in stress-induced cardiovascular morbidity

Low survival rate and muscle fiber-dependent aging effects in the McArdle disease mouse model

Altres ajuts: The present study was funded by grants received from the Fondo de Investigaciones Sanitarias (FIS, grant PI16/01492 and PI15/00558) and cofunded by 'Fondos FEDER'. Gisela Nogales-Gadea is supported by a Trampoline Grant #21108 from AMF Telethon.McArdle disease is an autosomal recessive disorder caused by the absence of the muscle glycogen phosphorylase, which leads to impairment of glycogen breakdown. The McArdle mouse, a model heavily affected by glycogen accumulation and exercise intolerance, was used to characterize disease progression at three different ages. The molecular and histopathological consequences of the disease were analyzed in five different hind-limb muscles (soleus, extensor digitorum longus, tibialis anterior, gastrocnemius and quadriceps) of young (8-week-old), adult (35-week-old) and old (70-week-old) mice. We found that McArdle mice have a high perinatal and post-weaning mortality. We also observed a progressive muscle degeneration, fibrosis and inflammation process that was not associated with an increase in muscle glycogen content during aging. Additionally, this progressive degeneration varied among muscle and fiber types. Finally, the lack of glycogen content increase was associated with the inactivation of glycogen synthase and not with compensatory expression of the Pygl and/or Pygb genes in mature muscle

Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G &gt; A; CRP + 1444T &gt; C; CRP + 4899T &gt; G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP