RESUMO
In this paper, we identify and describe early signs of a shift towards 3rd generation UD, of which "nonclusive design" is an essential part. The paper explores the significance of such a shift using examples of the built and designed environment and of signage. Nonclusive design means design that resists categorisations of bodies/roles and that does not come with predefined or presupposed limits in terms of who it is meant for. We outline seven themes characterising the shift towards nonclusive design: 1) from included to undefined users, 2) from person to function, 3) from adaptism to variation, 4) from separation to convergence, 5) from reactive to proactive, 6) from unaware to aware, and 7) from explicit to tacit. Nonclusive design directs attention to context instead of the individual, focusing on possibilities, functions and facilities. It has a convergent character, highlighting variation and unity rather than separation. Nonclusive design presupposes awareness, knowledge and proactive development void of adaptism. It incorporates human variation without reiterating patterns of norm-deviation. We argue that the continued growth of UD demands, is part of, and contributes to a shift in culture, with nonclusive, intersectional thinking as a key future driver. In such a culture, 3rd generation UD can contribute as a common guiding mindset, as a source for innovation, as a way to listen for diversity in all its forms, and as a way to lead towards a sustainable society.
Assuntos
Conhecimento , Desenho Universal , HumanosRESUMO
Submucosal glands (SMGs) are a prominent structure that lines human cartilaginous airways. Although it has been assumed that SMGs contribute to respiratory defense, that hypothesis has gone without a direct test. Therefore, we studied pigs, which have lungs like humans, and disrupted the gene for ectodysplasin (EDA-KO), which initiates SMG development. EDA-KO pigs lacked SMGs throughout the airways. Their airway surface liquid had a reduced ability to kill bacteria, consistent with SMG production of antimicrobials. In wild-type pigs, SMGs secrete mucus that emerges onto the airway surface as strands. Lack of SMGs and mucus strands disrupted mucociliary transport in EDA-KO pigs. Consequently, EDA-KO pigs failed to eradicate a bacterial challenge in lung regions normally populated by SMGs. These in vivo and ex vivo results indicate that SMGs are required for normal antimicrobial activity and mucociliary transport, two key host defenses that protect the lung.
Assuntos
Ectodisplasinas/genética , Glândulas Exócrinas/imunologia , Mucosa Respiratória/imunologia , Staphylococcus aureus/fisiologia , Sus scrofa/imunologia , Animais , Ectodisplasinas/imunologia , Feminino , Técnicas de Inativação de Genes , Masculino , Sus scrofa/genéticaRESUMO
Mainstay therapeutics are ineffective in some people with asthma, suggesting a need for additional agents. In the current study, we used vagal ganglia transcriptome profiling and connectivity mapping to identify compounds beneficial for alleviating airway hyperreactivity (AHR). As a comparison, we also used previously published transcriptome data from sensitized mouse lungs and human asthmatic endobronchial biopsies. All transcriptomes revealed agents beneficial for mitigating AHR; however, only the vagal ganglia transcriptome identified agents used clinically to treat asthma (flunisolide, isoetarine). We also tested one compound identified by vagal ganglia transcriptome profiling that had not previously been linked to asthma and found that it had bronchodilator effects in both mouse and pig airways. These data suggest that transcriptome profiling of the vagal ganglia might be a novel strategy to identify potential asthma therapeutics.
Assuntos
Hiper-Reatividade Brônquica/metabolismo , Gânglios Parassimpáticos/metabolismo , Transcriptoma , Nervo Vago/metabolismo , Animais , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/patologia , Hiper-Reatividade Brônquica/terapia , Gânglios Parassimpáticos/patologia , Masculino , Camundongos , Camundongos Knockout , Nervo Vago/patologiaRESUMO
Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.
Assuntos
Acidose , Medo , Memória , Tonsila do Cerebelo/fisiologia , Animais , Dióxido de Carbono/metabolismo , Condicionamento Clássico , Camundongos , Receptores de AMPA/metabolismoRESUMO
Neurons innervating the airways contribute to airway hyperreactivity (AHR), a hallmark feature of asthma. Several observations suggested that acid-sensing ion channels (ASICs), neuronal cation channels activated by protons, might contribute to AHR. For example, ASICs are found in vagal sensory neurons that innervate airways, and asthmatic airways can become acidic. Moreover, airway acidification activates ASIC currents and depolarizes neurons innervating airways. We found ASIC1a protein in vagal ganglia neurons, but not airway epithelium or smooth muscle. We induced AHR by sensitizing mice to ovalbumin and found that ASIC1a-/- mice failed to exhibit AHR despite a robust inflammatory response. Loss of ASIC1a also decreased bronchoalveolar lavage fluid levels of substance P, a sensory neuropeptide secreted from vagal sensory neurons that contributes to AHR. These findings suggest that ASIC1a is an important mediator of AHR and raise the possibility that inhibiting ASIC channels might be beneficial in asthma.
Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Hipersensibilidade Respiratória/metabolismo , Sistema Respiratório/metabolismo , Animais , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/química , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Células Receptoras Sensoriais/metabolismo , Substância P/metabolismo , Nervo Vago/metabolismoRESUMO
Stimulating presynaptic terminals can increase the proton concentration in synapses. Potential receptors for protons are acid-sensing ion channels (ASICs), Na(+)- and Ca(2+)-permeable channels that are activated by extracellular acidosis. Those observations suggest that protons might be a neurotransmitter. We found that presynaptic stimulation transiently reduced extracellular pH in the amygdala. The protons activated ASICs in lateral amygdala pyramidal neurons, generating excitatory postsynaptic currents. Moreover, both protons and ASICs were required for synaptic plasticity in lateral amygdala neurons. The results identify protons as a neurotransmitter, and they establish ASICs as the postsynaptic receptor. They also indicate that protons and ASICs are a neurotransmitter/receptor pair critical for amygdala-dependent learning and memory.
Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Tonsila do Cerebelo/fisiologia , Plasticidade Neuronal , Neurotransmissores/metabolismo , Prótons , Sinapses/fisiologia , Bloqueadores do Canal Iônico Sensível a Ácido/química , Acidose , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/metabolismo , Eletrodos , Potenciais Pós-Sinápticos Excitadores , Concentração de Íons de Hidrogênio , Canais Iônicos/química , Aprendizagem , Potenciação de Longa Duração , Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Peptídeos/química , Venenos de Aranha/químicaRESUMO
Three observations have suggested that acid-sensing ion channels (ASICs) might be mammalian cutaneous mechanoreceptors; they are structurally related to Caenorhabditis elegans mechanoreceptors, they are localized in specialized cutaneous mechanosensory structures, and mechanical displacement generates an ASIC-dependent depolarization in some neurons. However, previous studies of mice bearing a single disrupted ASIC gene showed only subtle or no alterations in cutaneous mechanosensitivity. Because functional redundancy of ASIC subunits might explain limited phenotypic alterations, we hypothesized that disrupting multiple ASIC genes would markedly impair cutaneous mechanosensation. We found the opposite. In behavioral studies, mice with simultaneous disruptions of ASIC1a, -2 and -3 genes (triple-knockouts, TKOs) showed increased paw withdrawal frequencies when mechanically stimulated with von Frey filaments. Moreover, in single-fiber nerve recordings of cutaneous afferents, mechanical stimulation generated enhanced activity in A-mechanonociceptors of ASIC TKOs compared to wild-type mice. Responses of all other fiber types did not differ between the two genotypes. These data indicate that ASIC subunits influence cutaneous mechanosensitivity. However, it is unlikely that ASICs directly transduce mechanical stimuli. We speculate that physical and/or functional association of ASICs with other components of the mechanosensory transduction apparatus contributes to normal cutaneous mechanosensation.
Assuntos
Comportamento Animal/fisiologia , Mecanorreceptores/fisiologia , Mecanotransdução Celular/fisiologia , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Canais Iônicos Sensíveis a Ácido , Ácidos/metabolismo , Animais , Feminino , Masculino , Mecanorreceptores/metabolismo , Mecanotransdução Celular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse MecânicoRESUMO
After ending inpatient care, a hospital recommits to its community.
Assuntos
Relações Comunidade-Instituição , Fechamento de Instituições de Saúde , Acessibilidade aos Serviços de Saúde , Kansas , Estudos de Casos Organizacionais , Papel Profissional , CuradoresRESUMO
RATIONALE: Acid-sensing ion channels (ASICs) are Na+ channels that are activated by acidic pH. Their expression in cardiac afferents and remarkable sensitivity to small pH changes has made them leading candidates to sense cardiac ischemia. OBJECTIVE: Four genes encode six different ASIC subunits, however it is not yet clear which of the ASIC subunits contribute to the composition of ASICs in cardiac afferents. METHODS AND RESULTS: Here, we labeled cardiac afferents using a retrograde tracer dye in mice, which allowed for patch-clamp studies of murine cardiac afferents. We found that a higher percentage of cardiac sensory neurons from the dorsal root ganglia respond to acidic pH and generated larger currents compared to those from the nodose ganglia. The ASIC-like current properties of the cardiac dorsal root ganglia neurons from wild-type mice most closely matched the properties of ASIC2a/3 heteromeric channels. This was supported by studies in ASIC-null mice: acid-evoked currents from ASIC3(-/-) cardiac afferents matched the properties of ASIC2a channels, and currents from ASIC2(-/-) cardiac afferents matched the properties of ASIC3 channels. CONCLUSIONS: We conclude that ASIC2a and -3 are the major ASIC subunits in cardiac dorsal root ganglia neurons and provide potential molecular targets to attenuate chest pain and deleterious reflexes associated with cardiac disease.
Assuntos
Gânglios Espinais/metabolismo , Coração/inervação , Proteínas do Tecido Nervoso/metabolismo , Multimerização Proteica/fisiologia , Canais de Sódio/metabolismo , Canais Iônicos Sensíveis a Ácido , Trifosfato de Adenosina/farmacologia , Animais , Capsaicina/farmacologia , Células Cultivadas , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Prótons , Canais de Sódio/genéticaRESUMO
No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a(-/-) mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression.
Assuntos
Tonsila do Cerebelo/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Canais de Sódio/metabolismo , Canais Iônicos Sensíveis a Ácido , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Transtorno Depressivo/psicologia , Feminino , Isoquinolinas/administração & dosagem , Masculino , Camundongos , Camundongos Transgênicos , Naftalenos/administração & dosagem , Proteínas do Tecido Nervoso/deficiência , Canais de Sódio/deficiência , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologiaRESUMO
Arterial baroreceptors provide a neural sensory input that reflexly regulates the autonomic drive of circulation. Our goal was to test the hypothesis that a member of the acid-sensing ion channel (ASIC) subfamily of the DEG/ENaC superfamily is an important determinant of the arterial baroreceptor reflex. We found that aortic baroreceptor neurons in the nodose ganglia and their terminals express ASIC2. Conscious ASIC2 null mice developed hypertension, had exaggerated sympathetic and depressed parasympathetic control of the circulation, and a decreased gain of the baroreflex, all indicative of an impaired baroreceptor reflex. Multiple measures of baroreceptor activity each suggest that mechanosensitivity is diminished in ASIC2 null mice. The results define ASIC2 as an important determinant of autonomic circulatory control and of baroreceptor sensitivity. The genetic disruption of ASIC2 recapitulates the pathological dysautonomia seen in heart failure and hypertension and defines a molecular defect that may be relevant to its development.
Assuntos
Barorreflexo/genética , Fenômenos Fisiológicos Cardiovasculares/genética , Proteínas do Tecido Nervoso/genética , Gânglio Nodoso/metabolismo , Pressorreceptores/metabolismo , Células Receptoras Sensoriais/metabolismo , Canais de Sódio/genética , Canais Iônicos Sensíveis a Ácido , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Mecanotransdução Celular/genética , Camundongos , Camundongos Knockout , Gânglio Nodoso/citologia , Sistema Nervoso Parassimpático/metabolismo , Sistema Nervoso Parassimpático/fisiopatologia , Limiar Sensorial/fisiologia , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Acid-sensing ion channels (ASICs) are neuronal non-voltage-gated cation channels that are activated when extracellular pH falls. They contribute to sensory function and nociception in the peripheral nervous system, and in the brain they contribute to synaptic plasticity and fear responses. Some of the physiologic consequences of disrupting ASIC genes in mice suggested that ASIC channels might modulate neuronal function by mechanisms in addition to their H(+)-evoked opening. Within ASIC channel's large extracellular domain, we identified sequence resembling that in scorpion toxins that inhibit K(+) channels. Therefore, we tested the hypothesis that ASIC channels might inhibit K(+) channel function by coexpressing ASIC1a and the high-conductance Ca(2+)- and voltage-activated K(+) (BK) channel. We found that ASIC1a associated with BK channels and inhibited their current. Reducing extracellular pH disrupted the association and relieved the inhibition. BK channels, in turn, altered the kinetics of ASIC1a current. In addition to BK, ASIC1a inhibited voltage-gated Kv1.3 channels. Other ASIC channels also inhibited BK, although acidosis-dependent relief of inhibition varied. These results reveal a mechanism of ion channel interaction and reciprocal regulation. Finding that a reduced pH activated ASIC1a and relieved BK inhibition suggests that extracellular protons may enhance the activity of channels with opposing effects on membrane voltage. The wide and varied expression patterns of ASICs, BK, and related K(+) channels suggest broad opportunities for this signaling system to alter neuronal function.
Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Transdução de Sinais/fisiologia , Canais de Sódio/genética , Canais de Sódio/metabolismo , Canais Iônicos Sensíveis a Ácido , Sequência de Aminoácidos , Linhagem Celular , DNA Complementar/genética , Eletrofisiologia , Humanos , Concentração de Íons de Hidrogênio , Cinética , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Dados de Sequência Molecular , Neurônios/metabolismo , Estrutura Terciária de Proteína , Venenos de Escorpião/genéticaRESUMO
BACKGROUND: The molecular mechanisms underlying innate fear are poorly understood. Previous studies indicated that the acid sensing ion channel ASIC1a influences fear behavior in conditioning paradigms. However, these differences may have resulted from an ASIC1a effect on learning, memory, or the expression of fear. METHODS: To test the hypothesis that ASIC1a influences the expression of fear or anxiety independent of classical conditioning, we examined the effects of disrupting the mouse ASIC1a gene on unconditioned fear in the open field test, unconditioned acoustic startle, and fear evoked by the predator odor trimethylthiazoline (TMT). In addition, we tested the effects of acutely inhibiting ASIC1a with PcTx, an ASIC1a antagonist in tarantula venom. Our immunohistochemistry suggested ASIC1a is expressed in the bed nucleus of the stria terminalis, medial amygdala, and periaqueductal gray, which are thought to play important roles in the generation and expression of innate fear. Therefore, we also tested whether ASIC1a disruption altered c-fos expression in these structures following TMT exposure. RESULTS: We found that the loss of ASIC1a reduced fear in the open field test, reduced acoustic startle, and inhibited the fear response to TMT. Similarly, intracerebroventricular administration of PcTx reduced TMT-evoked freezing in ASIC1a(+/+) mice but not ASIC1a(-/-) mice. In addition, loss of ASIC1a altered TMT-evoked c-fos expression in the medial amydala and dorsal periaqueductal gray. CONCLUSIONS: These findings suggest that ASIC1a modulates activity in the circuits underlying innate fear. Furthermore, the data indicate that targeting the ASIC1a gene or acutely inhibiting ASIC1a suppresses fear and anxiety independent of conditioning.
Assuntos
Comportamento Animal/fisiologia , Medo/fisiologia , Proteínas de Membrana/deficiência , Proteínas do Tecido Nervoso/deficiência , Vias Neurais/fisiologia , Neurônios/fisiologia , Canais de Sódio/deficiência , Canais Iônicos Sensíveis a Ácido , Estimulação Acústica/efeitos adversos , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Encéfalo/fisiologia , Células Cultivadas , Estimulantes do Sistema Nervoso Central/farmacologia , Potenciais Evocados Auditivos do Tronco Encefálico/genética , Comportamento Exploratório/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Odorantes , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reflexo de Sobressalto/genética , Reflexo de Sobressalto/fisiologia , Tiazóis/farmacologiaRESUMO
BACKGROUND & AIMS: Previous studies have shown that failure to produce serum antibodies to C. difficile (CD) toxin A is associated with more severe and recurrent C. difficile-associated diarrhea (CDAD); and that presence of AA genotype in the interleukin (IL)-8 gene promoter -251 position is associated with increased susceptibility to CDAD. This study examined the relationship between serum immunoglobulin G antibodies to CD toxin A and the presence of IL-8 AA genotype in hospitalized patients with CDAD. METHODS: At enrollment, blood for host IL-8 genotype, serum for CD anti-toxin A antibody, and stool for IL-8 by enzyme-linked immunosorbent assay were obtained in CDAD patients and in CD-toxin-negative asymptomatic controls. RESULTS: Nine of 24 (37.5%) CDAD and 3 of 20 (15%) controls were CD anti-toxin A positive (P = .095). Eleven of 24 (45.8%) CDAD subjects were positive for AA genotype compared with 5 of 20 (25.0%) controls (P = .0019). One of 11 (9.1%) CDAD with AA genotype were positive for anti-toxin A antibodies compared with 8 of 13 (61.5%) non-AA genotype CDAD (P < .0001). Fecal IL-8 concentration for the single antibody-positive CDAD subject with AA genotype was lower than the median level of 822 microg/mL seen in 10 anti-toxin A antibody-negative subjects with CDAD. CONCLUSIONS: This study provided evidence that host susceptibility to C. difficile diarrhea is related both to a defective humoral immune response to CD toxin A and host IL-8 AA genotype.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Toxinas Bacterianas/imunologia , DNA/genética , Diarreia/genética , Enterotoxinas/imunologia , Imunoglobulina G/imunologia , Interleucina-8/genética , Polimorfismo Genético , Idoso , Clostridioides difficile/isolamento & purificação , Diarreia/etiologia , Diarreia/imunologia , Enterocolite Pseudomembranosa/complicações , Enterocolite Pseudomembranosa/genética , Enterocolite Pseudomembranosa/imunologia , Ensaio de Imunoadsorção Enzimática , Seguimentos , Glucosiltransferases , Humanos , Interleucina-8/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: Using a mouse model that reproduces major features of irritable bowel syndrome (long-lasting colon hypersensitivity without inflammation), we examined the contributions of 2 proteins, transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3 (ASIC3), on development of behavioral hypersensitivity and assessed the function of colon mechanoreceptors of hypersensitive mice. METHODS: Visceral nociceptive behavior was measured as the visceromotor response (VMR) to colorectal distention (CRD) before and after intracolonic treatment with zymosan or saline. Colon pathology was assessed in parallel experiments by quantifying myeloperoxidase activity, intralumenal pH, and tissue histology. Electrophysiologic experiments were performed on naïve and zymosan-treated hypersensitive mice using an in vitro colon-pelvic nerve preparation. RESULTS: Zymosan, but not saline, produced significant and persistent increases in the VMRs of control mice; zymosan produced nonsignificant increases in the VMRs in TRPV1 and ASIC3 knockout mice. Colon myeloperoxidase activity and pH were unaffected by either CRD or intracolonic treatments. Pelvic nerve mechanoreceptors recorded from zymosan-treated or naïve mice had similar sensitivity to stretch of the colon. When applied acutely, zymosan sensitized muscular/mucosal mechanoreceptors in both naïve and hypersensitive mice. CONCLUSIONS: Zymosan produced sensitization of colon mechanoreceptors acutely in vitro and chronic (>or=7 weeks) behavioral hypersensitivity in the absence of inflammation. The behavioral hypersensitivity was partially dependent on both TRPV1 and ASIC3 because deletions of either of these genes blunted zymosan's effect, suggesting that these proteins may be important peripheral mediators for development of functional (ie, noninflammatory) visceral hypersensitivity.
Assuntos
Síndrome do Intestino Irritável/fisiopatologia , Mecanorreceptores/fisiopatologia , Canais de Sódio/genética , Canais de Cátion TRPV/genética , Canais Iônicos Sensíveis a Ácido , Animais , Colo/inervação , Colo/fisiopatologia , Modelos Animais de Doenças , Eletromiografia , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Síndrome do Intestino Irritável/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nociceptores/fisiologia , Canais de Sódio/metabolismo , Canais de Cátion TRPV/metabolismo , Zimosan/farmacologiaRESUMO
Peripheral initiators of muscle pain are virtually unknown, but likely key to development of chronic pain after muscle insult. The current study tested the hypothesis that ASIC3 in muscle is necessary for development of cutaneous mechanical, but not heat, hyperalgesia induced by muscle inflammation. Using mechanical and heat stimuli, we assessed behavioral responses in ASIC3-/- and ASIC3+/+ mice after induction of carrageenan muscle inflammation. ASIC3-/- mice did not develop cutaneous mechanical hyperalgesia after muscle inflammation when compared to ASIC3+/+ mice; heat hyperalgesia developed similarly between groups. We then tested if the phenotype could be rescued in ASIC3-/- mice by using a recombinant herpes virus vector to express ASIC3 in skin (where testing occurred) or muscle (where inflammation occurred). Infection of mouse DRG neurons with ASIC3-encoding virus resulted in functional expression of ASICs. Injection of ASIC3-encoding virus into muscle or skin of ASIC3-/- mice resulted in ASIC3 mRNA in DRG and protein expression in DRG and the peripheral injection site. Injection of ASIC3-encoding virus into muscle, but not skin, resulted in development of mechanical hyperalgesia similar to that observed in ASIC3+/+ mice. Thus, ASIC3 in primary afferent fibers innervating muscle is critical to development of hyperalgesia that results from muscle insult.
Assuntos
Hiperalgesia/etiologia , Hiperalgesia/patologia , Inflamação/complicações , Músculo Esquelético/metabolismo , Canais de Sódio/metabolismo , Canais Iônicos Sensíveis a Ácido , Animais , Comportamento Animal , Células Cultivadas , Ensaio de Imunoadsorção Enzimática/métodos , Gânglios Espinais/citologia , Imuno-Histoquímica/métodos , Inflamação/etiologia , Inflamação/patologia , Potenciais da Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/fisiopatologia , Músculo Esquelético/virologia , Neurônios/fisiologia , Limiar da Dor , Técnicas de Patch-Clamp/métodos , Estimulação Física , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Simplexvirus , Pele/metabolismo , Pele/fisiopatologia , Canais de Sódio/deficiênciaRESUMO
Extracellular acid can have important effects on neuron function. In central and peripheral neurons, acid-sensing ion channels (ASICs) have emerged as key receptors for extracellular protons, and recent studies suggest diverse roles for these channels in the pathophysiology of pain, ischemic stroke and psychiatric disease. ASICs have also been implicated in mechanosensation in the peripheral nervous system and in neurotransmission in the central nervous system. Here, we briefly review advances in our understanding of ASICs, their potential contributions to disease, and the possibility for their therapeutic modification.
Assuntos
Sistema Nervoso Central/fisiologia , Mecanotransdução Celular/fisiologia , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/fisiologia , Sistema Nervoso Periférico/fisiologia , Canais de Sódio/fisiologia , Canais Iônicos Sensíveis a Ácido , Animais , Líquido Extracelular/química , Humanos , Proteínas de Membrana/química , Transtornos Mentais/fisiopatologia , Proteínas do Tecido Nervoso/química , Dor/fisiopatologia , Canais de Sódio/química , Acidente Vascular Cerebral/fisiopatologiaRESUMO
OBJECTIVE: To assess the prevalence of diarrhea at a university-affiliated medical center and the presence of modifiable risk factors. METHODS: A point prevalence survey was conducted. All patients hospitalized for more than 24 hours were asked if they were experiencing diarrhea. Stools of patients not previously tested were assessed for Clostridium difficile (CD) toxins A and B. Univariate analysis and multivariate logistic regression analyses were used to identify modifiable variables associated with diarrhea (significance defined as p < 0.05). RESULTS: Four hundred eighty-five hospitalized patients were interviewed, of whom 60 (12.4%) reported 2 or more loose, unformed stools in the last 24 hours. Six of 81 (7.4%) patients tested positive for CD toxin. Three (50%) of the CD toxin-positive patients had not previously been tested during the current admission. Patients with diarrhea were more likely to have tested CD toxin-positive (OR 10.6; p = 0.01), received antibiotics (OR 1.79; p = 0.04), or been hospitalized for a longer period of time (p = 0.04). CONCLUSIONS: Diarrhea was prevalent in 12.4% of hospitalized patients at a large university hospital at one point in time. Patients with diarrhea were more likely to have CD infection, receive antibiotics, or experience a longer hospitalization. Half of the CD diarrhea cases occurring in the hospital had been previously unidentified. Hospitalized patients should be evaluated for diarrhea on an ongoing basis with appropriate interventions instituted.
Assuntos
Diarreia/epidemiologia , Adulto , Proteínas de Bactérias/análise , Toxinas Bacterianas/análise , Clostridioides difficile , Diarreia/diagnóstico , Diarreia/microbiologia , Nutrição Enteral/efeitos adversos , Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/epidemiologia , Enterocolite Pseudomembranosa/microbiologia , Enterotoxinas/análise , Etnicidade , Feminino , Departamentos Hospitalares , Hospitais Universitários , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Diálise Renal/estatística & dados numéricos , Fatores de RiscoRESUMO
OBJECTIVE: Mucosal interleukin 8 (IL-8) and neutrophil recruitment are central to the pathogenesis of Clostridium difficile (CD) toxin-induced diarrhea (CDD). We hypothesized that like other inflammatory mucosal infections, susceptibility to CDD would relate to genetically determined variations in the production of IL-8. METHODS: Fecal IL-8 production and single nucleotide polymorphism (SNP) frequency in the -251 region of the IL-8 gene were determined in hospitalized patients: 42 with CDD, 42 with CD-negative diarrhea, and 41 without diarrhea. Cases and controls were matched by age, length of hospital stay, comorbidity, and receipt of antibiotics. RESULTS: An association was found between the IL-8 -251 A/A allele and occurrence of CDD, 39%versus 16% (OR = 3.26, 95% CI 1.09-9.17) and 17% (OR = 5.50, 95% CI 1.22-24.8) for the two control groups. Comparing results by IL-8 genotype for the CDD cases, median and mean fecal IL-8 levels were significantly higher for the -251 A/A genotype (p = 0.03 for median and 0.001 for mean). CONCLUSIONS: These studies indicate a common SNP in the IL-8 gene is associated with increased susceptibility to CDD and with increased fecal IL-8 in diarrheal stools.
Assuntos
Clostridioides difficile , Diarreia/genética , Interleucina-8/genética , Regiões Promotoras Genéticas/genética , Diarreia/microbiologia , Enterocolite Pseudomembranosa/genética , Fezes/química , Feminino , Humanos , Interleucina-8/análise , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Ion channels in the degenerin-epithelial sodium channel (DEG-ENaC) family perform diverse functions, including mechanosensation. Here we explored the role of the vertebrate DEG-ENaC protein, acid-sensing ion channel 2 (ASIC2), in auditory transduction. Contributions of ASIC2 to hearing were examined by comparing hearing threshold and noise sensitivity of wild-type and ASIC2 null mice. ASIC2 null mice showed no significant hearing loss, indicating that the ASIC2 was not directly involved in the mechanotransduction of the mammalian cochlea. However, we found that (1) ASIC2 was present in the spiral ganglion (SG) neurons in the adult cochlea and that externally applied protons induced amiloride-sensitive sodium currents and action potentials in SG neurons in vitro, (2) proton-induced responses were greatly reduced in SG neurons obtained from ASIC2 null mice, indicating that activations of ASIC2 contributed a major portion of the proton-induced excitatory response in SG neurons, and (3) ASIC2 null mice were considerably more resistant to noise-induced temporary, but not permanent, threshold shifts. Together, these data suggest that ASIC2 contributes to suprathreshold functions of the cochlea. The presence of ASIC2 in SG neurons could provide sensors to directly convert local acidosis to excitatory responses, therefore offering a cellular mechanism linking hearing losses caused by many enigmatic causes (e.g., ischemia or inflammation of the inner ear) to excitotoxicity.