RESUMO
Calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA-/- mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiopatias/metabolismo , Metionina/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Angiotensina II , Animais , Apoptose , Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Calmodulina/metabolismo , Metionina Sulfóxido Redutases , Camundongos , Mutagênese Sítio-Dirigida , Miócitos Cardíacos/citologia , Oxirredução , Oxirredutases/genética , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The connection between lipoprotein (a) [Lp(a)] levels and the risks of cardiovascular disease and diabetes remains poorly understood. Lp(a) is encoded by the LPA gene, and evidence suggests that the kringle IV type 2 (KIV-2) variant is particularly important to Lp(a) isoform size. A large isoform size, represented as a high number of KIV-2 repeats in LPA, is associated with low serum Lp(a) concentrations and an increased risk of type 2 diabetes. We investigated the associations among Lp(a) concentrations, LPA KIV-2 repeats, and type 2 diabetes in a Chinese population of 1,863 consecutive patients with very high cardiovascular risk, as identified by coronary angiography. Individuals with Lp(a) levels in the top tertile [67.86 (35.34-318.50) mg/dl] had a lower risk of diabetes compared with those in the bottom tertile [7.38 (0.60-12.91) mg/dl]. There was an inverse association between the number of KIV-2 repeats and serum Lp(a) concentrations. This study demonstrated that a high number of LPA KIV-2 repeats are associated with increased risk of type 2 diabetes in a Chinese population with very high cardiovascular risk, which suggests that large Lp(a) isoform size, associated with low Lp(a) concentration, has a causal effect on type 2 diabetes.
Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Lipoproteína(a)/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Genótipo , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genéticaRESUMO
Myocardial cell death is initiated by excessive mitochondrial Ca(2+) entry causing Ca(2+) overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm). However, the signalling pathways that control mitochondrial Ca(2+) entry through the inner membrane mitochondrial Ca(2+) uniporter (MCU) are not known. The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated in ischaemia reperfusion, myocardial infarction and neurohumoral injury, common causes of myocardial death and heart failure; these findings suggest that CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (I(MCU)). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia reperfusion injury, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to ischaemia reperfusion injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition have reduced I(MCU) and are resistant to ischaemia reperfusion injury, myocardial infarction and neurohumoral injury, suggesting that pathological actions of CaMKII are substantially mediated by increasing I(MCU). Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca(2+) entry in myocardial cell death, and indicate that mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure in response to common experimental forms of pathophysiological stress.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miocárdio/enzimologia , Miocárdio/patologia , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Cálcio/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Ciclosporina/farmacologia , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/enzimologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Serina/metabolismo , Estresse Fisiológico/efeitos dos fármacosRESUMO
BACKGROUND: Premedication in upper gastrointestinal endoscopy for higher lesions detection rate has not been well studied so far. This study aimed to confirm whether premedication could improve the detection rate of early cancer or precancerous lesions and mucosal visibility. METHOD: From July 2015 to December 2015, 7200 participants from 6 centers were screened by endoscopy with one of the 4 following premedications randomly: (1) water (group D); (2) pronase (group A); (3) simethicone (group B); (4) pronase and simethicone (group C). Early cancer and precancerous lesions detection rates were taken as the primary endpoints, and mucosal visibility was taken as the secondary endpoint. They were compared among four groups to determine different premedication effects in terms of different anatomical sites. Trial was registered at Chinese Clinical Trial Registry; the registration number is ChiCTR-IOR-17010985. RESULTS: The upper gastrointestinal overall precancerous lesion detection rates among four groups were 8.7, 8.4, 10.0, and 10.3%, the overall early cancer detection rates were 1.3, 1.4%, 1.5, and 1.6%, both without significant difference (p = 0.138 and 0.878). However, the visibility score distributions between control group (D) and premedication groups (A, B, and C) were all statistically significant, with all anatomical sites p values < 0.001. Subgroup analyses, from 2 centers without screening before, also showed significant difference in esophageal (3.9, 3.3, 4.5, and 8.4% with p = 0.004) and overall (7.0, 5.5, 7.3, and 12.0% with p = 0.004) precancerous lesion detection rate. CONCLUSIONS: Premedication with pronase and simethicone may not increase lesion detection rates but could significantly increase the upper gastrointestinal mucosal visibility.
Assuntos
Antiespumantes/uso terapêutico , Detecção Precoce de Câncer/métodos , Endoscopia Gastrointestinal , Expectorantes/uso terapêutico , Neoplasias Gastrointestinais/diagnóstico por imagem , Lesões Pré-Cancerosas/diagnóstico por imagem , Pré-Medicação/métodos , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa/diagnóstico por imagem , Pronase/uso terapêutico , Simeticone/uso terapêuticoRESUMO
Myocardial mitochondrial Ca(2+) entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca(2+) are lacking. We developed a mouse model with myocardial delimited transgenic expression of a dominant negative (DN) form of the mitochondrial Ca(2+) uniporter (MCU). DN-MCU mice lack MCU-mediated mitochondrial Ca(2+) entry in myocardium, but, surprisingly, isolated perfused hearts exhibited higher O2 consumption rates (OCR) and impaired pacing induced mechanical performance compared with wild-type (WT) littermate controls. In contrast, OCR in DN-MCU-permeabilized myocardial fibers or isolated mitochondria in low Ca(2+) were not increased compared with WT, suggesting that DN-MCU expression increased OCR by enhanced energetic demands related to extramitochondrial Ca(2+) homeostasis. Consistent with this, we found that DN-MCU ventricular cardiomyocytes exhibited elevated cytoplasmic [Ca(2+)] that was partially reversed by ATP dialysis, suggesting that metabolic defects arising from loss of MCU function impaired physiological intracellular Ca(2+) homeostasis. Mitochondrial Ca(2+) overload is thought to dissipate the inner mitochondrial membrane potential (ΔΨm) and enhance formation of reactive oxygen species (ROS) as a consequence of ischemia-reperfusion injury. Our data show that DN-MCU hearts had preserved ΔΨm and reduced ROS during ischemia reperfusion but were not protected from myocardial death compared with WT. Taken together, our findings show that chronic myocardial MCU inhibition leads to previously unanticipated compensatory changes that affect cytoplasmic Ca(2+) homeostasis, reprogram transcription, increase OCR, reduce performance, and prevent anticipated therapeutic responses to ischemia-reperfusion injury.
Assuntos
Adaptação Fisiológica , Canais de Cálcio/metabolismo , Coração/fisiopatologia , Mitocôndrias Cardíacas/metabolismo , Estresse Fisiológico , Animais , Pressão Sanguínea , Cálcio/metabolismo , Estimulação Cardíaca Artificial , Reprogramação Celular , Citosol/efeitos dos fármacos , Citosol/metabolismo , Diástole , Eletrocardiografia , Genes Dominantes , Glucose/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Camundongos , Mitocôndrias Cardíacas/efeitos dos fármacos , Reperfusão Miocárdica , Miocárdio/metabolismo , Miocárdio/patologia , Consumo de Oxigênio , Prostaglandina-Endoperóxido Sintases/metabolismo , Retículo Sarcoplasmático/metabolismo , Transcrição GênicaRESUMO
INTRODUCTION: Haemoglobin Bart's hydrops fetalis syndrome was once considered a fatal condition. However, advances over the past two decades have enabled survival of affected patients. Data relating to their morbidities and outcomes will help medical specialists formulate a management plan and parental counselling. METHODS: All babies with the syndrome who survived beyond the neonatal period and were subsequently managed long-term in eight public hospitals in Hong Kong from 1 January 1996 to 31 December 2015 were included. Patient and parent characteristics, antenatal care, reasons for continuation of pregnancy, intrauterine interventions, perinatal course, presence of congenital malformations, stem-cell transplantation details, and long-term neurodevelopmental outcomes were reviewed. RESULTS: A total of nine patients were identified, of whom five were female and four male. The median follow-up duration was 7 years. All were Chinese and were homozygous for the Southeast Asian α-thalassaemia deletion. Five of the nine mothers received antenatal care at a public hospital and opted to continue the pregnancy after antenatal diagnosis and counselling. Despite intrauterine transfusions, all babies were born with respiratory depression and required intubation and mechanical ventilation during the neonatal period. Hypospadias was identified in all four male infants. Growth retardation, global developmental delay, and residual neurological deficits were noted in two-thirds of the patients. Haematopoietic stem-cell transplantation was performed in two patients, who became transfusion-independent. CONCLUSIONS: Survival of patients with Bart's hydrops fetalis syndrome is possible but not without short- and long-term complications; local epidemiology is comparable to that documented for an international registry. Detailed antenatal counselling of parents with a non-judgemental attitude and cautious optimism are imperative.
Assuntos
Hemoglobinas Anormais , Hidropisia Fetal/mortalidade , Talassemia alfa/mortalidade , Feminino , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Recém-Nascido , Masculino , Morbidade , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Talassemia alfa/diagnóstico , Talassemia alfa/genéticaRESUMO
In this paper we present a general method for estimating rates of accidental coincidence between a pair of single photon detectors operated within their saturation regimes. By folding the effects of recovery time of both detectors and the detection circuit into an "effective duty cycle" we are able to accomodate complex recovery behaviour at high event rates. As an example, we provide a detailed high-level model for the behaviour of passively quenched avalanche photodiodes, and demonstrate effective background subtraction at rates commonly associated with detector saturation. We show that by post-processing using the updated model, we observe an improvement in polarization correlation visibility from 88.7% to 96.9% in our experimental dataset. This technique will be useful in improving the signal-to-noise ratio in applications which depend on coincidence measurements, especially in situations where rapid changes in flux may cause detector saturation.
RESUMO
RATIONALE: The sodium-calcium exchanger 1 (NCX1) is predominantly expressed in the heart and is implicated in controlling automaticity in isolated sinoatrial node (SAN) pacemaker cells, but the potential role of NCX1 in determining heart rate in vivo is unknown. OBJECTIVE: To determine the role of Ncx1 in heart rate. METHODS AND RESULTS: We used global myocardial and SAN-targeted conditional Ncx1 knockout (Ncx1(-/-)) mice to measure the effect of the NCX current on pacemaking activity in vivo, ex vivo, and in isolated SAN cells. We induced conditional Ncx1(-/-) using a Cre/loxP system. Unexpectedly, in vivo and ex vivo hearts and isolated SAN cells showed that basal rates in Ncx1(-/-) (retaining ≈20% of control level NCX current) and control mice were similar, suggesting that physiological NCX1 expression is not required for determining resting heart rate. However, increases in heart rate and SAN cell automaticity in response to isoproterenol or the dihydropyridine Ca(2+) channel agonist BayK8644 were significantly blunted or eliminated in Ncx1(-/-) mice, indicating that NCX1 is important for fight or flight heart rate responses. In contrast, the pacemaker current and L-type Ca(2+) currents were equivalent in control and Ncx1(-/-) SAN cells under resting and isoproterenol-stimulated conditions. Ivabradine, a pacemaker current antagonist with clinical efficacy, reduced basal SAN cell automaticity similarly in control and Ncx1(-/-) mice. However, ivabradine decreased automaticity in SAN cells isolated from Ncx1(-/-) mice more effectively than in control SAN cells after isoproterenol, suggesting that the importance of NCX current in fight or flight rate increases is enhanced after pacemaker current inhibition. CONCLUSIONS: Physiological Ncx1 expression is required for increasing sinus rates in vivo, ex vivo, and in isolated SAN cells, but not for maintaining resting heart rate.
Assuntos
Frequência Cardíaca/fisiologia , Descanso/fisiologia , Nó Sinoatrial/fisiologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Trocador de Sódio e Cálcio/genética , Agonistas Adrenérgicos beta/farmacologia , Animais , Frequência Cardíaca/efeitos dos fármacos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Nó Sinoatrial/citologia , Nó Sinoatrial/efeitos dos fármacos , Trocador de Sódio e Cálcio/metabolismo , Trocador de Sódio e Cálcio/fisiologiaRESUMO
BACKGROUND: To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status). METHODS: CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial). RESULTS: We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P<0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P<0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis. CONCLUSIONS: Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer.
Assuntos
Adenocarcinoma/patologia , Antígenos CD8/análise , Linfócitos T CD8-Positivos/patologia , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/análise , Linfócitos do Interstício Tumoral/patologia , Subpopulações de Linfócitos T/patologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/química , Colectomia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Ilhas de CpG , Epitélio/imunologia , Epitélio/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/química , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Invasividade Neoplásica , Especificidade de Órgãos , Prognóstico , Subpopulações de Linfócitos T/química , Linfócitos T Citotóxicos/química , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/química , Linfócitos T Reguladores/patologiaRESUMO
Central noradrenergic signalling mediates arousal and facilitates learning through unknown molecular mechanisms. Here, we show that the beta(2)-adrenergic receptor (beta(2)AR), the trimeric G(s) protein, adenylyl cyclase, and PKA form a signalling complex with the AMPA-type glutamate receptor subunit GluR1, which is linked to the beta(2)AR through stargazin and PSD-95 and their homologues. Only GluR1 associated with the beta(2)AR is phosphorylated by PKA on beta(2)AR stimulation. Peptides that interfere with the beta(2)AR-GluR1 association prevent this phosphorylation of GluR1. This phosphorylation increases GluR1 surface expression at postsynaptic sites and amplitudes of EPSCs and mEPSCs in prefrontal cortex slices. Assembly of all proteins involved in the classic beta(2)AR-cAMP cascade into a supramolecular signalling complex and thus allows highly localized and selective regulation of one of its major target proteins.
Assuntos
Adenilil Ciclases/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Receptores de AMPA/análise , Receptores de AMPA/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Adenilil Ciclases/análise , Animais , Canais de Cálcio/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/análise , Proteína 4 Homóloga a Disks-Large , Eletrofisiologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/análise , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/genética , Receptores Adrenérgicos beta 2/análiseRESUMO
BACKGROUND: Adverse drug events (ADE) contribute significantly to hospital admissions. Prospective New Zealand data are scant, and the ability of clinical coding to identify ADE associated admissions is uncertain. Outcomes after cessation of causative medications are unknown. AIMS: To assess the frequency, nature and causality of ADE associated with acute admissions to General Medicine at Christchurch Hospital. METHODS: Prospective observational study of patients admitted to our medical team over 20 weeks. RESULTS: Of 336 admissions, 96 (28.6%) were ADE related. Sixty-five (19.3%) were caused by an ADE, and 31 (9.2%) were contributed to by an ADE. The mean age of non-ADE patients was 64.3 years (range 16-91), which was similar to the mean age of ADE patients (65.9 years; 21-92). However, if intentional overdoses and recreational drug use were excluded, ADE patients were significantly older at 72.4 years (21-92) (P = 0.0007). ADE patients took more regular medications on admission (mean 6.6, range 0-22) than non-ADE patients (mean 5.0, 0-18), (P = 0.003). The average length of stay was similar. The commonest medications implicated were vasodilators, psychotropics and diuretics. The most common adverse effects were postural hypotension and/or vasovagal syncope (29% of ADE), intentional overdoses and recreational drug use (15%) and acute renal failure and/or clinical dehydration (10%). Seventy-six patients had culprit medications stopped or reduced, and this potentially contributed to six readmissions. Coding identified 61% of ADE associated admissions. CONCLUSION: ADE are a common cause of hospital admission. The most frequent problems are postural hypotension and vasovagal syncope, intentional drug misuse and dehydration.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Serviço Hospitalar de Emergência , Admissão do Paciente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Serviço Hospitalar de Emergência/tendências , Feminino , Seguimentos , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/epidemiologia , Hipotensão Ortostática/terapia , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Admissão do Paciente/tendências , Estudos Prospectivos , Síncope Vasovagal/diagnóstico , Síncope Vasovagal/epidemiologia , Síncope Vasovagal/terapia , Adulto JovemRESUMO
The Lim1 transcription factor is required in Drosophila for patterning the eye-antennal disk. At the adult stage, Lim1 is strongly expressed in Johnston's Organ (JO) neurons, the antennal auditory organ. Using RNAi-mediated knockdown of Lim1 using a strong neuronal driver, we find a significant reduction in electrophysiological responses to auditory stimuli, recorded from the antennal nerve. This reduction can be accounted for by Lim1 knockdown in the auditory subset of JO neurons, with no effect of knockdown in JO neuron subsets associated with wind or gravity detection. Conversely, Lim1 knockdown in JO sense organ precursors had no effect on hearing. Mosaic animals with antennal clones of the Lim1 E9 null mutation showed morphological defects in the antenna, and significant auditory electrophysiological defects. Our results are consistent with two distinct functions for Lim1 in the antenna, including an early patterning function in the eye-antennal disk, and a later neural differentiation function in the JO neurons.
RESUMO
AIMS: To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. METHODS: Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. RESULTS: All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. CONCLUSIONS: Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE.
Assuntos
Antígenos Virais/análise , Sistema Nervoso Central/patologia , Encefalite Japonesa/patologia , Enterovirus Humano A , Infecções por Enterovirus/patologia , RNA Viral/análise , Adolescente , Ásia , Sistema Nervoso Central/virologia , Criança , Pré-Escolar , Encefalite Japonesa/virologia , Enterovirus Humano A/genética , Enterovirus Humano A/isolamento & purificação , Enterovirus Humano A/metabolismo , Infecções por Enterovirus/virologia , Feminino , França , Humanos , Imuno-Histoquímica , Masculino , Adulto JovemAssuntos
Enteropatias/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Anormalidade Torcional/diagnóstico por imagem , Feminino , Humanos , Enteropatias/complicações , Enteropatias/cirurgia , Valor Preditivo dos Testes , Anormalidade Torcional/complicações , Anormalidade Torcional/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To provide a synopsis of current thalassaemia major patient care in Hong Kong. DESIGN: Retrospective study. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with thalassaemia major with regular transfusion. RESULTS: To date, there were 363 thalassaemia major patients under the care of the Hospital Authority. Prenatal diagnosis has helped to reduce the number of indigenous new cases, but in recent years immigrant cases are appearing. The patients have a mean age of 23 (range, 1-52) years, and 78% of them are adults. In 2009, they received 18 782 units of blood. This accounted for 9.5% of all blood consumption from the Hong Kong Red Cross. In the past, cardiac iron overload was the major cause of death (65%) and few patients survived beyond the age of 45 years. The availability of cardiac iron assessment by magnetic resonance imaging (T2 MRI) to direct the use of oral deferiprone chelation has reduced the prevalence of heart failure and cardiac haemosiderosis, which should reduce mortality and improve life expectancy. CONCLUSION: The future for thalassaemia care in Hong Kong is bright. With better transfusion and chelation, it should be possible to avoid growth and endocrine deficiencies in younger patients.
Assuntos
Talassemia/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Transfusão de Eritrócitos , Hong Kong , Humanos , Lactente , Sobrecarga de Ferro/etiologia , Pessoa de Meia-Idade , Osteoporose/etiologia , Estudos Retrospectivos , Talassemia/complicações , Talassemia/mortalidadeRESUMO
Ever since the first reported case series on SARS-CoV-2-induced neurological manifestation in Wuhan, China in April 2020, various studies reporting similar as well as diverse symptoms of COVID-19 infection relating to the nervous system were published. Since then, scientists started to uncover the mechanism as well as pathophysiological impacts it has on the current understanding of the disease. SARS-CoV-2 binds to the ACE2 receptor which is present in certain parts of the body which are responsible for regulating blood pressure and inflammation in a healthy system. Presence of the receptor in the nasal and oral cavity, brain, and blood allows entry of the virus into the body and cause neurological complications. The peripheral and central nervous system could also be invaded directly in the neurogenic or hematogenous pathways, or indirectly through overstimulation of the immune system by cytokines which may lead to autoimmune diseases. Other neurological implications such as hypoxia, anosmia, dysgeusia, meningitis, encephalitis, and seizures are important symptoms presented clinically in COVID-19 patients with or without the common symptoms of the disease. Further, patients with higher severity of the SARS-CoV-2 infection are also at risk of retaining some neurological complications in the long-run. Treatment of such severe hyperinflammatory conditions will also be discussed, as well as the risks they may pose to the progression of the disease. For this review, articles pertaining information on the neurological manifestation of SARS-CoV-2 infection were gathered from PubMed and Google Scholar using the search keywords "SARS-CoV-2", "COVID-19", and "neurological dysfunction". The findings of the search were filtered, and relevant information were included.
Assuntos
COVID-19/patologia , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso/virologia , Sistema Nervoso Periférico/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , Anosmia/virologia , Sistema Nervoso Central/virologia , Disgeusia/virologia , Encefalite Viral/virologia , Humanos , Meningite Viral/virologia , Doenças do Sistema Nervoso/patologia , Sistema Nervoso Periférico/virologia , SARS-CoV-2 , Convulsões/virologiaRESUMO
Activation of Ca2+/calmodulin kinase II (CaMKII) and the N-Methyl D-aspartate receptor (NMDAR), particularly its GluN2B subunit, contribute to the central sensitization of nociceptive pathways and persistent pain. Using mutant mice wherein the activity-driven binding of CaMKII to S1303 in GluN2B is abrogated (GluN2BKI), this study investigated the importance of this interaction for acute and persistent inflammatory nociception. GluN2BKI, wild type and heterozygote mice did not differ in responses to acute noxious heat stimuli as measured with tail flick, paw flick, or hot plate assays, nor did they differ in their responses to mechanical stimulation with von Frey filaments. Surprisingly, the three genotypes exhibited similar spontaneous pain behaviors and hypersensitivity to heat or mechanical stimuli induced by intraplantar injection of capsaicin; however, GluN2BKI mice did not immediately attend to the paw. WT and GluN2BKI mice also did not differ in the nociceptive behaviors elicited by intraplantar injection of formalin, even though MK801 greatly reduced these behaviors in both genotypes concordant with NMDAR dependence. CaMKII binding to GluN2B at S1303 therefore does not appear to be critical for the development of inflammatory nociception. Finally, intrathecal KN93 reduced formalin-induced nociceptive behaviors in GluN2BKI mice. KN93 does not inhibit CaKMII, but rather binds Ca2+/calmodulin. It has multiple other targets including Ca2+-, Na+- and K+-channels, as well as various kinases. Therefore, the use of GluN2BKI mice provided genetic specificity in assessing the role of CaMKII in inflammatory pain signaling cascades. These results challenge current thinking on the involvement of the CaMKII-NMDAR interaction in inflammatory pain.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Calmodulina/metabolismo , Capsaicina/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade/fisiologia , Dor/fisiopatologia , Ligação Proteica , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
Increasing evidence suggests that cardiac pacemaking is the result of two sinoatrial node (SAN) cell mechanisms: a 'voltage clock' and a Ca(2+) dependent process, or 'Ca(2+) clock.' The voltage clock initiates action potentials (APs) by SAN cell membrane potential depolarization from inward currents, of which the pacemaker current (I(f)) is thought to be particularly important. A Ca(2+) dependent process triggers APs when sarcoplasmic reticulum (SR) Ca(2+) release activates inward current carried by the forward mode of the electrogenic Na(+)/Ca(2+) exchanger (NCX). However, these mechanisms have mostly been defined in rodents or rabbits, but are unexplored in single SAN cells from larger animals. Here, we used patch-clamp and confocal microscope techniques to explore the roles of the voltage and Ca(2+) clock mechanisms in canine SAN pacemaker cells. We found that ZD7288, a selective I(f) antagonist, significantly reduced basal automaticity and induced irregular, arrhythmia-like activity in canine SAN cells. In addition, ZD7288 impaired but did not eliminate the SAN cell rate acceleration by isoproterenol. In contrast, ryanodine significantly reduced the SAN cell acceleration by isoproterenol, while ryanodine reduction of basal automaticity was modest ( approximately 14%) and did not reach statistical significance. Importantly, pretreatment with ryanodine eliminated SR Ca(2+) release, but did not affect basal or isoproterenol-enhanced I(f). Taken together, these results indicate that voltage and Ca(2+) dependent automaticity mechanisms coexist in canine SAN cells, and suggest that I(f) and SR Ca(2+) release cooperate to determine baseline and catecholamine-dependent automaticity in isolated dog SAN cells.
Assuntos
Cálcio/metabolismo , Cálcio/fisiologia , Nó Sinoatrial , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cães , Feminino , Coração , Isoproterenol/metabolismo , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Marca-Passo Artificial , Rianodina/metabolismo , Rianodina/farmacologia , Retículo Sarcoplasmático/metabolismo , Nó Sinoatrial/citologia , Nó Sinoatrial/metabolismo , Nó Sinoatrial/fisiologiaRESUMO
We analyze the generation of single spatial mode, spectrally uncorrelated photon pairs via type II spontaneous parametric down-conversion in a Potassium Titanyl Phosphate (KTP) waveguide using real experimental parameters. We show that this source can be used as an efficient, heralded, pure-state single-photon source.