RESUMO
INTRODUCTION: Axillary sentinel node biopsy for melanoma is routinely performed under general anaesthesia. Emerging evidence has shown general anaesthetics are associated with increased mortality in the context of the COVID-19 pandemic. In the interest of patient safety, we have designed a series of bespoke axillary regional blocks enabling surgeons to remove nodes up to and including level III without the need for a general anaesthetic. The aim of this study was to assess the feasibility of performing axillary sentinel node biopsy under such blocks. METHODS: Approval was granted by the Joint Study Review Committee on behalf of the Research and Ethics Department. Ten consecutive patients having axillary sentinel node biopsy for melanoma were included in this prospective study. Patients completed a Quality of Recovery-15 (QoR15) questionnaire preoperatively and 24 h postoperatively. DISCUSSION: One patient had a positive sentinel node, the remining were negative. A significant reduction in time spent in hospital post-operatively (p = 0.0008) was observed. QoR15 patient reported outcome measures demonstrated high levels of satisfaction evidenced by lack of statistical difference between pre and post-operative scores (p = 0.0118). 80% of patients were happy to have a regional block and 90% were happy to attend hospital during the pandemic. CONCLUSION: ASNB under regional block is safe, negates risks associated with performing GAs during the COVID-19 pandemic and facilitates quicker theatre turnover and discharge from hospital. Collaboration between anaesthetic and surgical teams has enabled this change in practice. There is a learning curve with both patient selection, education and development of technique.
Assuntos
Anestesia por Condução/métodos , COVID-19/epidemiologia , Linfonodos/cirurgia , Melanoma/secundário , Biópsia de Linfonodo Sentinela/métodos , Neoplasias Cutâneas/patologia , Axila , Comorbidade , Saúde Global , Humanos , Excisão de Linfonodo/métodos , Metástase Linfática , Melanoma/diagnóstico , Melanoma/epidemiologia , Pandemias , Neoplasias Cutâneas/epidemiologiaRESUMO
In several systems of the body (muscle, liver, nerves), new studies have examined the internal structure of mitochondria and brought to light striking new findings about how mitochondria are constructed and how their structure affects cell function. In the inner ear field, however, we have little structural knowledge about hair cell and supporting cell mitochondria, and virtually none about mitochondrial subtypes or how they function in health and disease. The need for such knowledge is discussed in this short review.
Assuntos
Orelha Interna , Células Ciliadas Auditivas/fisiologia , Mitocôndrias/fisiologia , Cóclea , Cabelo , HumanosRESUMO
The precise mechanism underlying the neurotoxicity of Hepatic Encephalopathy (HE) is remains unclear. The dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain. Among the various toxins proposed, the case for ammonia is most compelling. Events that lead to increased levels of blood or brain ammonia have been shown to worsen HE, whereas reducing blood ammonia levels alleviates HE. Clinical, pathological, and biochemical changes observed in HE can be reproduced by increasing blood or brain ammonia levels in experimental animals, while exposure of cultured astrocytes to ammonium salts reproduces the morphological and biochemical findings observed in HE. However, factors other than ammonia have recently been proposed to be involved in the development of HE, including cytokines and other blood and brain immune factors. Moreover, recent studies have questioned the critical role of ammonia in the pathogenesis of HE since blood ammonia levels do not always correlate with the level/severity of encephalopathy. This review summarizes the vital role of ammonia in the pathogenesis of HE in humans, as well as in experimental models of acute and chronic liver failure. It further emphasizes recent advances in the molecular mechanisms involved in the progression of neurological complications that occur in acute and chronic liver failure.
RESUMO
BACKGROUND AND PURPOSE: Central nervous system (CNS) tuberculosis (TB) accounts for over 4% of all TB notifications in the UK and causes death or significant disability in over half of those affected. Tumour necrosis factor alpha is a critical cytokine involved in the neuropathogenesis of CNS TB. Thalidomide has been trialled in CNS TB due to its immunomodulatory and immune reconstitution effects through the inhibition of tumour necrosis factor alpha. Despite animal models demonstrating dramatic improvement in survival, studies in paediatric patients have been associated with higher levels of mortality. The effects of thalidomide have not yet been studied in adults with CNS TB. This narrative case series guides clinicians through a range of CNS TB clinical cases seen in a large London teaching hospital, serving a region with a high incidence of TB (32 per 100 000) with 55% of TB cases manifesting as extrapulmonary disease. We aimed to illustrate our experiences of using thalidomide to treat a range of severe CNS TB complications. METHODS: Five inpatients at The Royal London Hospital, London, UK treated with thalidomide in addition to standard TB treatment are described in detail. The rationale for treatment initiation with thalidomide is explained. RESULTS: The case examples are used to guide our reflections and lessons learnt regarding the use of thalidomide. Responses to treatment and functional outcomes suggest that thalidomide may be a useful adjunct to standard TB therapy in selected adult cases. CONCLUSIONS: The experience gained from using thalidomide in this small case series may provide evidence leading to more research into using thalidomide to treat severe CNS TB.
Assuntos
Imunossupressores/uso terapêutico , Talidomida/uso terapêutico , Tuberculose do Sistema Nervoso Central/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Brain edema and the associated increase in intracranial pressure are major consequences of traumatic brain injury (TBI) that accounts for most early deaths after TBI. We recently showed that acute severe trauma to cultured astrocytes results in cell swelling. We further examined whether trauma induces cell swelling in neurons and microglia. We found that severe trauma also caused cell swelling in cultured neurons, whereas no swelling was observed in microglia. While severe trauma caused cell swelling in both astrocytes and neurons, mild trauma to astrocytes, neurons, and microglia failed to cell swelling. Since extracellular levels of glutamate are increased in brain post-TBI and microglia are known to release cytokine, and direct exposure of astrocytes to these molecules are known to stimulate cell swelling, we examined whether glutamate or cytokines have any additive effect on trauma-induced cell swelling. Exposure of cultured astrocytes to trauma caused cell swelling, and such swelling was potentiated by the exposure of traumatized astrocytes to glutamate and cytokines. Conditioned medium (CM) from traumatized astrocytes had no effect on neuronal swelling post-trauma, while CM from traumatized neurons and microglia potentiated the effect of trauma on astrocyte swelling. Further, trauma significantly increased the Na-K-Cl co-transporter (NKCC) activity in neurons, and that inhibition of NKCC activity diminished the trauma-induced neuronal swelling. Our results indicate that a differential sensitivity to trauma-induced cell swelling exists in neural cells and that neurons and microglia are likely to be involved in the potentiation of the astrocyte swelling post-trauma.
Assuntos
Astrócitos/metabolismo , Lesões Encefálicas/complicações , Microglia/metabolismo , Neurônios/metabolismo , Animais , Animais Recém-Nascidos , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Lesões Encefálicas/metabolismo , Células Cultivadas , Citocinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , RatosRESUMO
Matricellular proteins (MCPs) are actively expressed non-structural proteins present in the extracellular matrix, which rapidly turnover and possess regulatory roles, as well as mediate cell-cell interactions. MCPs characteristically contain binding sites for other extracellular proteins, cell surface receptors, growth factors, cytokines and proteases, that provide structural support for surrounding cells. MCPs are present in most organs, including brain, and play a major role in cell-cell interactions and tissue repair. Among the MCPs found in brain include thrombospondin-1/2, secreted protein acidic and rich in cysteine family (SPARC), including Hevin/SC1, Tenascin C and CYR61/Connective Tissue Growth Factor/Nov family of proteins, glypicans, galectins, plasminogen activator inhibitor (PAI-1), autotaxin, fibulin and perisostin. This review summarizes the potential role of MCPs in the pathogenesis of major neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, ischemia, trauma, hepatic encephalopathy, Down's syndrome, autism, multiple sclerosis, brain neoplasms, Parkinson's disease and epilepsy. Potential therapeutic opportunities of MCP's for these disorders are also considered in this review.
Assuntos
Doenças do Sistema Nervoso Central/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Animais , Proteínas de Sinalização Intercelular CCN/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Glipicanas/metabolismo , Humanos , Osteonectina/metabolismo , Tenascina/metabolismo , Trombospondinas/metabolismoRESUMO
The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 µg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.
Assuntos
DNA Bacteriano/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/análogos & derivados , Escarro/microbiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Sensibilidade e Especificidade , Adulto JovemRESUMO
Traumatic brain injury (TBI) is a devastating neurological disorder that usually presents in acute and chronic forms. Brain edema and associated increased intracranial pressure in the early phase following TBI are major consequences of acute trauma. On the other hand, neuronal injury, leading to neurobehavioral and cognitive impairments, that usually develop months to years after single or repetitive episodes of head trauma, are major consequences of chronic TBI. The molecular mechanisms responsible for TBI-induced injury, however, are unclear. Recent studies have suggested that early mitochondrial dysfunction and subsequent energy failure play a role in the pathogenesis of TBI. We therefore examined whether oxidative metabolism of (13)C-labeled glucose, lactate or glutamine is altered early following in vitro mechanical percussion-induced trauma (5 atm) to neurons (4-24 h), and whether such events contribute to the development of neuronal injury. Cell viability was assayed using the release of the cytoplasmic enzyme lactate dehydrogenase (LDH), together with fluorescence-based cell staining (calcein and ethidium homodimer-1 for live and dead cells, respectively). Trauma had no effect on the LDH release in neurons from 1 to 18 h. However, a significant increase in LDH release was detected at 24 h after trauma. Similar findings were identified when traumatized neurons were stained with fluorescent markers. Additionally (13)C-labeling of glutamate showed a small, but statistically significant decrease at 14 h after trauma. However, trauma had no effect on the cycling ratio of the TCA cycle at any time-period examined. These findings indicate that trauma does not cause a disturbance in oxidative metabolism of any of the substrates used for neurons. Accordingly, such metabolic disturbance does not appear to contribute to the neuronal death in the early stages following trauma.
Assuntos
Morte Celular , Glucose/metabolismo , Glutamina/metabolismo , Ácido Láctico/metabolismo , Neurônios/metabolismo , Percussão , Animais , Células Cultivadas , Neurônios/citologia , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: Biomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda. METHODS: We consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C-statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age. RESULTS: All but one analyte decreased from baseline to week 8 (all p < 0.01). Individual biomarkers were not associated with 8 week culture status. Logistic models including increasing age, higher baseline soluble tumor necrosis factor receptor alpha 1 (sTNF-R1), and higher week 8 C-reactive protein (CRP) concentration classified subjects by culture status with up to 85% accuracy and acceptable discrimination (cross-validated C-statistic 0.76) and calibration (Hosmer-Lemeshow P > 0.2). CONCLUSION: Exploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy.
Assuntos
Citocinas/sangue , Mycobacterium tuberculosis/patogenicidade , Receptores de Citocinas/sangue , Tuberculose Pulmonar/diagnóstico , Adulto , Fatores Etários , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Interações Hospedeiro-Patógeno , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Valor Preditivo dos Testes , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Fatores de Tempo , Resultado do Tratamento , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Uganda , Adulto JovemRESUMO
BACKGROUND: Fear and pain are the factors producing stress and there is evidence that dental fear acquired in childhood may persist to influence adult behavior. Dental treatment is often considered as anxiety producing and stressful. AIM: To assess the levels of stress displayed by the healthy children undergoing routine dental procedures like oral examination, restoration, and extraction by analyzing salivary levels of cortisol before, during, and after the procedures. MATERIALS AND METHODS: Twenty healthy children aged between 4 and 8 years having their first dental visit and requiring at least one restoration and one extraction were selected. In each patient, three procedures were carried out: (i) Routine dental examination, (ii) restoration, and (iii) extraction. Unstimulated salivary samples were collected 10 min before, during the procedure, and 30 min after each procedure at three different visits for comparison of cortisol production in response to anxiety and stress over time. Total 180 samples were collected to determine salivary cortisol levels using UBI-MAGIWEL TM kit and the readings were noted. STATISTICAL ANALYSIS USED: Statistical Package for Social Sciences (SPSS) software with paired t-test, two independent sample t-tests, and analysis of variance (ANOVA) were used to analyze the findings. RESULTS: A correlation between salivary cortisol and stress in dental procedure was noticed. Cavity preparation is more stressful procedure in children, so alternative methods can be used in anxious children. Stress associated with extraction persists to a postoperative period. No correlation exists in between Corah's anxiety scale and salivary cortisol.
Assuntos
Ansiedade ao Tratamento Odontológico/psicologia , Assistência Odontológica para Crianças/psicologia , Hidrocortisona/metabolismo , Saliva/química , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
PURPOSE: To assess the levels of dental anxiety among patients anticipating dental treatments in dental clinics/hospitals of Ranga Reddy district. MATERIALS AND METHODS: A cross-sectional study was conducted among a representative sample of 1200 subjects (at least 18 years old) in dental clinics/hospitals which were selected from a list obtained through systematic random sampling. The data were collected using a pre-tested and calibrated questionnaire consisting of the Modified Corah Dental Anxiety Scale (MDAS) to assess anxiety levels. RESULTS: The majority (52.4%) of subjects showed a low level of anxiety. Females (11.44 ± 4.41) were found to have higher mean MDAS scores than males, and the highest mean MDAS scores were found among 18- to 34-year-olds (11.28 ± 4.67) (P < 0.05). Significant differences were found among subjects anticipating different treatments, with higher MDAS scores for extraction (11.25 ± 5.4), followed by examination, root canal treatment, gum surgery, scaling, restoration and others, e.g. orthodontic treatment, restoration with crowns, bridges and dentures (7.79 ± 3.80). The highest mean MDAS scores were found among subjects who were apprehensive due to 'past difficult experience in dental treatments', followed by 'drill' and 'injection', with the lowest scores among subjects indicating 'other reasons' (7.82 ± 3.84). CONCLUSION: The present data show that anxiety levels are higher in patients who have to undergo extractions than those who must be fitted with dentures. Thus, dental health care providers should pay more attention to patients' anxiety levels associated with different types of treatment.
Assuntos
Ansiedade ao Tratamento Odontológico/diagnóstico , Assistência Odontológica/psicologia , Adolescente , Adulto , Fatores Etários , Estudos Transversais , Ansiedade ao Tratamento Odontológico/classificação , Clínicas Odontológicas , Prótese Dentária/psicologia , Restauração Dentária Permanente/psicologia , Raspagem Dentária/psicologia , Unidade Hospitalar de Odontologia , Feminino , Humanos , Índia , Injeções/psicologia , Masculino , Pessoa de Meia-Idade , Doenças Periodontais/cirurgia , Tratamento do Canal Radicular/psicologia , Fatores Sexuais , Inquéritos e Questionários , Extração Dentária/psicologia , Preparo do Dente/instrumentação , Adulto JovemRESUMO
Astrocyte swelling (cytotoxic brain edema) is the major neurological complication of acute liver failure (ALF), a condition in which ammonia has been strongly implicated in its etiology. Ion channels and transporters are known to be involved in cell volume regulation, and a disturbance in these systems may result in cell swelling. One ion channel known to contribute to astrocyte swelling/brain edema in other neurological disorders is the ATP-dependent, nonselective cation (NCCa-ATP) channel. We therefore examined its potential role in the astrocyte swelling/brain edema associated with ALF. Cultured astrocytes treated with 5 mM ammonia showed a threefold increase in the sulfonylurea receptor type 1 (SUR1) protein expression, a marker of NCCa-ATP channel activity. Blocking SUR1 with glibenclamide significantly reduced the ammonia-induced cell swelling in cultured astrocytes. Additionally, overexpression of SUR1 in ammonia-treated cultured astrocytes was significantly reduced by cotreatment of cells with BAY 11-7082, an inhibitor of NF-κB, indicating the involvement of an NF-κB-mediated SUR1 upregulation in the mechanism of ammonia-induced astrocyte swelling. Brain SUR1 mRNA level was also found to be increased in the thioacetamide (TAA) rat model of ALF. Additionally, we found a significant increase in SUR1 protein expression in rat brain cortical astrocytes in TAA-treated rats. Treatment with glibenclamide significantly reduced the brain edema in this model of ALF. These findings strongly suggest the involvement of NCCa-ATP channel in the astrocyte swelling/brain edema in ALF and that targeting this channel may represent a useful approach for the treatment of the brain edema associated with ALF.
Assuntos
Astrócitos/metabolismo , Edema Encefálico/metabolismo , Falência Hepática Aguda/metabolismo , Receptores de Sulfonilureias/metabolismo , Amônia/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Canais Iônicos/metabolismo , RatosRESUMO
Brain edema is a major neurological complication of acute liver failure (ALF) and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in this condition. Elevated brain ammonia level has been strongly implicated as an important factor in the mechanism of astrocyte swelling/brain edema in ALF. Recent studies, however, have suggested the possibility of a vasogenic component in the mechanism in ALF. We therefore examined the effect of ammonia on blood-brain barrier (BBB) integrity in an in vitro co-culture model of the BBB (consisting of primary cultures of rat brain endothelial cells and astrocytes). We found a minor degree of endothelial permeability to dextran fluorescein (16.2%) when the co-culture BBB model was exposed to a pathophysiological concentration of ammonia (5mM). By contrast, lipopolysaccharide (LPS), a molecule well-known to disrupt the BBB, resulted in an 87% increase in permeability. Since increased neurosteroid biosynthesis has been reported to occur in brain in ALF, and since neurosteroids are known to protect against BBB breakdown, we examined whether neurosteroids exerted any protective effect on the slight permeability of the BBB after exposure to ammonia. We found that a nanomolar concentration (10nM) of the neurosteroids allopregnanolone (THP) and tetrahydrodeoxycorticosterone (THDOC) significantly reduced the ammonia-induced increase in BBB permeability (69.13 and 58.64%, respectively). On the other hand, we found a marked disruption of the BBB when the co-culture model was exposed to the hepatotoxin azoxymethane (218.4%), but not with other liver toxins commonly used as models of ALF (thioacetamide and galactosamine, showed a 29.3 and 30.67% increase in permeability, respectively). Additionally, THP and THDOC reduced the effect of TAA and galactosamine on BBB permeability, while no BBB protective effect was observed following treatment with azoxymethane. These findings suggest that ammonia does not cause a significant BBB disruption, and that the BBB is intact in the TAA or galactosamine-induced animal models of ALF, likely due to the protective effect of neurosteroids that are synthesized in brain in the setting of ALF. However, caution should be exercised when using azoxymethane as an experimental model of ALF as it caused a severe breakdown of the BBB, and neurosteriods failed to protect against this breakdown.
Assuntos
Amônia/metabolismo , Edema Encefálico/complicações , Encéfalo/fisiopatologia , Falência Hepática Aguda/complicações , Neurotransmissores/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fígado/metabolismo , Fígado/fisiopatologia , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/fisiopatologia , Permeabilidade , RatosAssuntos
Artroplastia do Joelho/métodos , Joelho/diagnóstico por imagem , Bloqueio Nervoso/métodos , Período de Recuperação da Anestesia , Deambulação Precoce , Humanos , Joelho/inervação , Debilidade Muscular/etiologia , Bloqueio Nervoso/efeitos adversos , Medição da Dor/efeitos dos fármacos , Coxa da Perna/inervação , Ultrassonografia de IntervençãoRESUMO
Brain edema and the subsequent increase in intracranial pressure are major neurological complications of acute liver failure (ALF), and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in ALF. Recent studies, however, have suggested the co-existence of cytotoxic and vasogenic mechanisms in the brain edema associated with ALF. This review 1) summarizes the nature of the brain edema in humans and experimental animals with ALF; 2) reviews in vitro studies supporting the presence of cytotoxic brain edema (cell swelling in cultured astrocytes); and 3) documents the role of brain endothelial cells in the development of astrocyte swelling/brain edema in ALF.
Assuntos
Astrócitos/patologia , Endotélio/patologia , Falência Hepática Aguda/patologia , Animais , Barreira Hematoencefálica/patologia , Edema Encefálico/patologia , Encefalopatia Hepática/patologia , HumanosRESUMO
Brain edema is an important complication of acute hepatic encephalopathy (AHE), and astrocyte swelling is largely responsible for its development. Elevated blood and brain ammonia levels have been considered as major etiological factors in this edema. In addition to ammonia, recent studies have suggested that systemic infection, inflammation (and associated cytokines (CKs)), as well as endotoxin (lipopolysaccharide (LPS)) are also involved in AHE-associated brain edema. As endothelial cells (ECs) are the first resident brain cells exposed to blood-borne "noxious agents" (i.e., ammonia, CKs, LPS) that are present in AHE, these cells may be in a critical position to react to these agents and trigger a process resulting in astrocyte swelling/brain edema. We therefore examined the effect of conditioned media (CM) from ammonia, LPS and cytokine-treated cultured brain ECs on cell swelling in cultured astrocytes. CM from ammonia-treated ECs when added to astrocytes caused significant cell swelling, and such swelling was potentiated when astrocytes were exposed to CM from ECs treated with a combination of ammonia, LPS and CKs. We also found an additive effect when astrocytes were exposed to ammonia along with CM from ammonia-treated ECs. Additionally, ECs treated with ammonia showed a significant increase in the production of oxy-radicals, nitric oxide (NO), as well as evidence of oxidative/nitrative stress and activation of the transcription factor nuclear factor kappa B (NF-κB). CM derived from ECs treated with ammonia, along with antioxidants (AOs) or the NF-κB inhibitor BAY 11-7082, when added to astrocytes resulted in a significant reduction in cell swelling, as compared to the effect of CM from ECs-treated only with ammonia. We also identified increased nuclear NF-κB expression in rat brain cortical ECs in the thioacetamide (TAA) model of AHE. These studies suggest that ECs significantly contribute to the astrocyte swelling/brain edema in AHE, likely as a consequence of oxidative/nitrative stress and activation of NF-κB.
Assuntos
Astrócitos/patologia , Edema Encefálico/patologia , Células Endoteliais/metabolismo , Encefalopatia Hepática/complicações , Amônia/farmacologia , Animais , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Meios de Cultivo Condicionados , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/patologia , Imuno-Histoquímica , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos WistarRESUMO
Astrocyte swelling and brain edema are major complications of the acute form of hepatic encephalopathy (acute liver failure, ALF). While elevated brain ammonia level is a well-known etiological factor in ALF, the mechanism by which ammonia brings about astrocyte swelling is not well understood. We recently found that astrocyte cultures exposed to ammonia activated nuclear factor-κB (NF-κB), and that pharmacological inhibition of such activation led to a reduction in astrocyte swelling. Although these findings suggest the involvement of NF-κB in astrocyte swelling in vitro, it is not known whether NF-κB contributes to the development of brain edema in ALF in vivo. Furthermore, pharmacological agents used to inhibit NF-κB may have non-specific effects. Accordingly, we used transgenic (Tg) mice that have a functional inactivation of astrocytic NF-κB and examined whether these mice are resistant to ALF-associated brain edema. ALF was induced in mice by treatment with the hepatotoxin thioacetamide (TAA). Wild type (WT) mice treated with TAA showed a significant increase in brain water content (1.65%) along with prominent astrocyte swelling and spongiosis of the neuropil, consistent with the presence of cytotoxic edema. These changes were not observed in Tg mice treated with TAA. Additionally, WT mice with ALF showed an increase in inducible nitric oxide synthase (iNOS) immunoreactivity in astrocytes from WT mice treated with TAA (iNOS is known to be activated by NF-κB and to contribute to cell swelling). By contrast, Tg mice treated with TAA did not exhibit brain edema, histological changes nor an increase in iNOS immunoreactivity. We also examined astrocytes cultures derived from Tg mice to determine whether these cells exhibit a lesser degree of swelling and cytopathological changes following exposure to ammonia. Astrocyte cultures derived from Tg mice showed no cell swelling nor morphological abnormalities when exposed to ammonia for 24h. By contrast, ammonia significantly increased cell swelling (31.7%) in cultured astrocytes from WT mice and displayed cytological abnormalities. Moreover, we observed a lesser increment in iNOS and NADPH oxidase activity (the latter is also known to be activated by NF-κB and to contribute to astrocyte swelling) in astrocyte cultures from Tg mice treated with ammonia, as compared to ammonia-treated WT mice astrocytes. These findings strongly suggest that activation of NF-κB is a critical factor in the development of astrocyte swelling/brain edema in ALF.
Assuntos
Edema Encefálico/metabolismo , Encefalopatia Hepática/metabolismo , NF-kappa B/fisiologia , Doença Aguda , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Edema Encefálico/diagnóstico , Edema Encefálico/genética , Modelos Animais de Doenças , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/genética , Camundongos , Camundongos Transgênicos , NF-kappa B/genéticaRESUMO
Cytotoxic brain edema, usually a consequence of astrocyte swelling, is an important complication of stroke, traumatic brain injury, hepatic encephalopathy, and other neurological disorders. Although mechanisms underlying astrocyte swelling are not fully understood, oxidative stress (OS) has generally been considered an important factor in its pathogenesis. To better understand the mechanism(s) by which OS causes cell swelling, we examined the potential involvement of mitogen-activated protein kinases (MAPKs) in this process. Cultures exposed to theoxidant H(2)O(2) (10, 25, 50 microM) for different time periods (1-24 hr) significantly increased cell swelling in a triphasic manner. Swelling was initially observed at 10 min (peaking at 30 min), which was followed by cell shrinkage at 1 hr. A subsequent increase in cell volume occurred at approximately 6 hr, and the rise lasted for at least 24 hr. Cultures exposed to H(2)O(2) caused the activation of MAPKs (ERK1/2, JNK and p38-MAPK), whereas inhibition of MAPKs diminished cell swelling induced by 10 and 25 microM H(2)O(2). These findings suggest that activation of MAPKs is an important factor in the mediation of astrocyte swelling following oxidative stress.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Oxidantes/farmacologia , Animais , Western Blotting , Tamanho Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Radicais Livres/metabolismo , Peróxido de Hidrogênio/farmacologia , Imuno-Histoquímica , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo , Fosforilação , Carbonilação Proteica/efeitos dos fármacos , RatosRESUMO
BACKGROUND: The precise role of dentifrice in plaque removal has been debatable. While a considerable volume of literature attributes several beneficial properties and glorifies the role of dentifrice, a small body of researchers questions its efficacy. Lingering doubts are emerging about the plaque removal efficacy of toothpastes and probably a time has come to reassess its role in plaque removal. AIM: The present study is used to evaluate the plaque removal efficacy of dentifrice alone during the manual brushing of teeth. MATERIALS AND METHODS: In a double blinded 2 Chi 2 crossover study design, 42 subjects had brushed randomly with or without dentifrice under supervision, with a standard dentifrice and toothbrush, after 48 hours of plaque accumulation, for two minutes. RESULTS: Plaque reduction with dentifrice was 57.35% and without dentifrice was 66.19%. This 9% difference was statistically significant ( P < or = 0.001). CONCLUSION: Dentifrice use does not enhance plaque removal when used in conjunction with a toothbrush, and instead, may marginally lessen the brushing effect. The role of a toothbrush appears to be more crucial in the maintenance of oral hygiene.
Assuntos
Placa Dentária/tratamento farmacológico , Dentifrícios/uso terapêutico , Escovação Dentária , Adulto , Estudos Cross-Over , Método Duplo-Cego , HumanosRESUMO
BACKGROUND: Attempts to successfully regenerate lost alveolar bone have always been a clinician's dream. Angular defects, at least, have a fairer chance, but the same cannot be said about horizontal bone loss. The purpose of the present study was to evaluate the prevalence of horizontal alveolar bone loss and vertical bone defects in periodontal patients; and later, to correlate it with the treatment modalities available in the literature for horizontal and vertical bone defects. MATERIALS AND METHODS: The study was conducted in two parts. Part I was the radiographic evaluation of 150 orthopantomographs (OPGs) (of patients diagnosed with chronic periodontitis and seeking periodontal care), which were digitized and read using the AutoCAD 2006 software. All the periodontitis-affected teeth were categorized as teeth with vertical defects (if the defect angle was ≤45° and defect depth was ≥3 mm) or as having horizontal bone loss. Part II of the study comprised search of the literature on treatment modalities for horizontal and vertical bone loss in four selected periodontal journals. RESULTS: Out of the 150 OPGs studied, 54 (36%) OPGs showed one or more vertical defects. Totally, 3,371 teeth were studied, out of which horizontal bone loss was found in 3,107 (92.2%) teeth, and vertical defects were found only in 264 (7.8%) of the teeth, which was statistically significant (P<.001). Search of the selected journals revealed 477 papers have addressed the treatment modalities for vertical and horizontal types of bone loss specifically. Out of the 477 papers, 461 (96.3%) have addressed vertical bone loss, and 18 (3.7%) have addressed treatment options for horizontal bone loss. Two papers have addressed both types of bone loss and are included in both categories. CONCLUSION: Horizontal bone loss is more prevalent than vertical bone loss but has been sidelined by researchers as very few papers have been published on the subject of regenerative treatment modalities for this type of bone loss. This study should be an impetus for greater attention to an otherwise ubiquitous periodontal challenge.