RESUMO
BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a rare disease that is believed to be mediated by dysautonomia. Gastrointestinal complaints in POTS patients are common and disturbing but not well characterized. AIMS: We hypothesized that gastrointestinal dysmotility may be contributory to these symptoms. METHODS: We studied 12 POTS patients who presented with gastrointestinal symptoms to a tertiary referral center. Gastrointestinal symptoms were quantified using a previously validated symptom questionnaire. All patients underwent gastroduodenal manometry (GDM); select patients also underwent further testing including esophageal manometry (EM), anorectal manometry (ARM), plain abdominal radiography (AXR), abdominal computed tomography (CT), gastric emptying studies (GES), and colonic transit time (CTT) studies. RESULTS: The four most common symptoms were bloating, constipation, abdominal pain, and nausea/vomiting, all experienced by greater than 70 % of patients. On GDM testing, 93 % of patients demonstrated signs of neuropathy, and the most common abnormalities observed included bursts of uncoordinated phasic activity in both fasting (59 %) and post-prandial (42 %) states, low contractility in the post-prandial state (67 %), and lack of post-prandial pattern (42 %). A total of 67 % of patients undergoing EM and 86 % of those undergoing ARM demonstrated abnormalities consistent with dysmotility. On AXR or CT, 58 % demonstrated either dilated intestinal loops or air-fluid levels. On CTT 80 % demonstrated delayed colonic transit, while on GES 60 % demonstrated delayed gastric emptying. CONCLUSIONS: In this cohort of POTS patients with gastrointestinal symptoms, there is a high prevalence of abnormal manometric and radiographic findings suggestive of dysmotility.
Assuntos
Motilidade Gastrointestinal/fisiologia , Manometria/métodos , Síndrome da Taquicardia Postural Ortostática/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The light-organ symbiosis between the squid Euprymna scolopes and the luminous bacterium Vibrio fischeri offers the opportunity to decipher the hour-by-hour events that occur during the natural colonization of an animal's epithelial surface by its microbial partners. To determine the genetic basis of these events, a glass-slide microarray was used to characterize the light-organ transcriptome of juvenile squid in response to the initiation of symbiosis. Patterns of gene expression were compared between animals not exposed to the symbiont, exposed to the wild-type symbiont, or exposed to a mutant symbiont defective in either of two key characters of this association: bacterial luminescence or autoinducer (AI) production. Hundreds of genes were differentially regulated as a result of symbiosis initiation, and a hierarchy existed in the magnitude of the host's response to three symbiont features: bacterial presence > luminescence > AI production. Putative host receptors for bacterial surface molecules known to induce squid development are up-regulated by symbiont light production, suggesting that bioluminescence plays a key role in preparing the host for bacteria-induced development. Further, because the transcriptional response of tissues exposed to AI in the natural context (i.e., with the symbionts) differed from that to AI alone, the presence of the bacteria potentiates the role of quorum signals in symbiosis. Comparison of these microarray data with those from other symbioses, such as germ-free/conventionalized mice and zebrafish, revealed a set of shared genes that may represent a core set of ancient host responses conserved throughout animal evolution.
Assuntos
Aliivibrio fischeri/fisiologia , Decapodiformes/fisiologia , Regulação Bacteriana da Expressão Gênica/fisiologia , Genes Bacterianos/fisiologia , Luminescência , Simbiose/fisiologia , Animais , Sequência de Bases , Decapodiformes/microbiologia , Epitélio/microbiologia , Epitélio/fisiologia , Camundongos , Dados de Sequência Molecular , Organismos Livres de Patógenos Específicos/fisiologia , Peixe-ZebraRESUMO
Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units. Using unbiased approaches, we sought to define acid-adaptive pathways elicited by PMN TEM. Given the significant amount of adenosine (Ado) generated during PMN TEM, we profiled the influence of Ado on IECs gene expression by microarray and identified the induction of SLC26A3, the major apical Cl-/HCO3- exchanger in IECs. Utilizing loss- and gain-of-function approaches, as well as murine and human colonoids, we demonstrate that Ado-induced SLC26A3 promotes an adaptive IECs phenotype that buffers local pH during active inflammation. Extending these studies, chronic murine colitis models were used to demonstrate that SLC26A3 expression rebounds during chronic DSS-induced inflammation. In conclusion, Ado signaling during PMN TEM induces an adaptive tissue response to inflammatory acidification through the induction of SLC26A3 expression, thereby promoting pH homeostasis.
Assuntos
Acidose/imunologia , Antiporters/metabolismo , Colite/imunologia , Inflamação/imunologia , Mucosa Intestinal/fisiologia , Intestinos/imunologia , Neutrófilos/imunologia , Transportadores de Sulfato/metabolismo , Acidose/induzido quimicamente , Adaptação Fisiológica , Adenosina/metabolismo , Animais , Antiporters/genética , Células Cultivadas , Colite/induzido quimicamente , Modelos Animais de Doenças , Humanos , Doenças do Sistema Imunitário , Inflamação/induzido quimicamente , Transtornos Leucocíticos , Camundongos , Ativação de Neutrófilo , Dodecilsulfato de Sódio , Transportadores de Sulfato/genética , Migração Transendotelial e Transepitelial , Regulação para CimaAssuntos
Angioplastia , Isquemia/etiologia , Oclusão Vascular Mesentérica/etiologia , Lesões por Radiação/diagnóstico por imagem , Stents , Neoplasias Testiculares/radioterapia , Dor Abdominal/diagnóstico por imagem , Dor Abdominal/etiologia , Dor Abdominal/terapia , Idoso , Artéria Celíaca/diagnóstico por imagem , Humanos , Isquemia/diagnóstico por imagem , Isquemia/terapia , Masculino , Artérias Mesentéricas/diagnóstico por imagem , Oclusão Vascular Mesentérica/diagnóstico por imagem , Oclusão Vascular Mesentérica/terapia , Lesões por Radiação/terapia , Radiografia , Neoplasias Testiculares/secundário , Fatores de TempoAssuntos
Colite Ulcerativa/complicações , Infecções por Citomegalovirus/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/etiologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etiologia , Infecções por Citomegalovirus/complicações , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
In recent years, studies in the gastrointestinal (GI) mucosa have taught us a number of important lessons related to tissue oxygenation and metabolism in health and disease. The highly vascularized mucosa lies immediately adjacent to an anaerobic lumen containing trillions of metabolically active microbes (i.e. the microbiome) that results in one of the more austere tissue microenvironments in the body. These studies have also implicated a prominent role for oxygen metabolism and hypoxia in inflammation, so called "inflammatory hypoxia", that results from the activation of multiple oxygen consuming enzymes. Inflammation-associated shifts in the composition of the microbiome and microbial-derived metabolites have revealed a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of key target genes that promote inflammatory resolution. Analyses of these pathways have provided a multitude of opportunities for understanding basic mechanisms of both homeostasis and disease and have defined new targets for intervention. Here, we review recent advances in our understanding of metabolic influences on host-microbe interactions in the GI mucosa.
Assuntos
Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Mucosa Intestinal/microbiologia , Animais , Hipóxia Celular , Colite/microbiologia , Trato Gastrointestinal/microbiologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , OxirreduçãoRESUMO
BACKGROUND: Biologists are becoming increasingly aware that the interaction of animals, including humans, with their coevolved bacterial partners is essential for health. This growing awareness has been a driving force for the development of models for the study of beneficial animal-bacterial interactions. In the squid-vibrio model, symbiotic Vibrio fischeri induce dramatic developmental changes in the light organ of host Euprymna scolopes over the first hours to days of their partnership. We report here the creation of a juvenile light-organ specific EST database. RESULTS: We generated eleven cDNA libraries from the light organ of E. scolopes at developmentally significant time points with and without colonization by V. fischeri. Single pass 3' sequencing efforts generated 42,564 expressed sequence tags (ESTs) of which 35,421 passed our quality criteria and were then clustered via the UIcluster program into 13,962 nonredundant sequences. The cDNA clones representing these nonredundant sequences were sequenced from the 5' end of the vector and 58% of these resulting sequences overlapped significantly with the associated 3' sequence to generate 8,067 contigs with an average sequence length of 1,065 bp. All sequences were annotated with BLASTX (E-value < -03) and Gene Ontology (GO). CONCLUSION: Both the number of ESTs generated from each library and GO categorizations are reflective of the activity state of the light organ during these early stages of symbiosis. Future analyses of the sequences identified in these libraries promise to provide valuable information not only about pathways involved in colonization and early development of the squid light organ, but also about pathways conserved in response to bacterial colonization across the animal kingdom.
Assuntos
Aliivibrio fischeri/crescimento & desenvolvimento , Decapodiformes/genética , Biblioteca Gênica , Simbiose/fisiologia , Animais , Sequência de Bases , Decapodiformes/crescimento & desenvolvimento , Decapodiformes/microbiologia , Etiquetas de Sequências Expressas , Regulação da Expressão Gênica no Desenvolvimento , Dados de Sequência Molecular , Análise de Sequência de DNAAssuntos
Doenças do Esôfago/diagnóstico , Fundoplicatura/métodos , Hérnia Hiatal/diagnóstico , Laparoscopia , Inibidores da Bomba de Prótons/uso terapêutico , Úlcera/diagnóstico , Idoso , Diagnóstico Diferencial , Doenças do Esôfago/complicações , Doenças do Esôfago/terapia , Esofagoscopia , Feminino , Seguimentos , Hérnia Hiatal/complicações , Hérnia Hiatal/cirurgia , Humanos , Úlcera/complicações , Úlcera/terapiaAssuntos
Adenocarcinoma/secundário , Acalasia Esofágica/patologia , Neoplasias Esofágicas/patologia , Adenocarcinoma/terapia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antieméticos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos Antineoplásicos , Cisplatino/uso terapêutico , Terapia Combinada , Docetaxel , Epirubicina/uso terapêutico , Acalasia Esofágica/terapia , Neoplasias Esofágicas/terapia , Evolução Fatal , Fluoruracila/uso terapêutico , Humanos , Polipose Intestinal/congênito , Polipose Intestinal/patologia , Polipose Intestinal/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Síndromes Neoplásicas Hereditárias , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Inibidores da Bomba de Prótons/uso terapêutico , Taxoides/uso terapêutico , TrastuzumabRESUMO
Pityriasis rosea (PR) is an acute exanthematous skin disease that is likely due to reactivation of human herpesviruses (HHVs) 6b and 7. In contrast to herpes simplex and zoster (alphaherpesviruses), HHV-6b and -7 (betaherpesviruses) are not found predominantly in skin lesions. This difference in virion location may decrease the possibility of causing central nervous system infection through skin contamination, but the risk for hematogenous spread likely remains the same. This article uses the first-known epidural placement through active PR to illustrate risk-benefit considerations when deciding between neuraxial and general anesthesia for obstetric patients with PR.
Assuntos
Anestesia Epidural/métodos , Anestesia Obstétrica/métodos , Recesariana/métodos , Vértebras Lombares , Pitiríase Rósea/diagnóstico , Complicações na Gravidez/diagnóstico , Adulto , Feminino , Humanos , Pitiríase Rósea/complicações , Pitiríase Rósea/cirurgia , Gravidez , Complicações na Gravidez/cirurgiaRESUMO
The pathogenic bacterium Pseudomonas aeruginosa uses acyl-HSL quorum-sensing signals to regulate genes controlling virulence and biofilm formation. We found that paraoxonase 1 (PON1), a mammalian lactonase with an unknown natural substrate, hydrolyzed the P. aeruginosa acyl-HSL 3OC12-HSL. In in vitro assays, mouse serum-PON1 was required and sufficient to degrade 3OC12-HSL. Furthermore, PON2 and PON3 also degraded 3OC12-HSL effectively. Serum-PON1 prevented P. aeruginosa quorum-sensing and biofilm formation in vitro by inactivating the quorum-sensing signal. Although 3OC12-HSL production by P. aeruginosa was important for virulence in a mouse sepsis model, Pon1-knock-out mice were paradoxically protected. These mice showed increased levels of PON2 and PON3 mRNA in epithelial tissues suggesting a possible compensatory mechanism. Thus, paraoxonase interruption of bacterial communication represents a novel mechanism to modulate quorum-sensing by bacteria. The consequences for host immunity are yet to be determined.
Assuntos
4-Butirolactona/análogos & derivados , Arildialquilfosfatase/metabolismo , Pseudomonas aeruginosa/metabolismo , 4-Butirolactona/metabolismo , Animais , Arildialquilfosfatase/deficiência , Arildialquilfosfatase/genética , Biofilmes/crescimento & desenvolvimento , Genes Bacterianos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peritonite/enzimologia , Peritonite/genética , Peritonite/microbiologia , Infecções por Pseudomonas/enzimologia , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidade , Pseudomonas aeruginosa/fisiologia , Sepse/enzimologia , Sepse/genética , Sepse/microbiologia , Transdução de SinaisRESUMO
PURPOSE: This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS: All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year. CONCLUSION: Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Radiocirurgia/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada/métodos , Terapia Combinada/mortalidade , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Dosagem Radioterapêutica , GencitabinaRESUMO
Mammalian airways protect themselves from bacterial infection by using multiple defense mechanisms including antimicrobial peptides, mucociliary clearance, and phagocytic cells. We asked whether airways might also target a key bacterial cell-cell communication system, quorum-sensing. The opportunistic pathogen Pseudomonas aeruginosa uses two quorum-sensing molecules, N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) and N-butanoyl-l-homoserine lactone (C4-HSL), to control production of extracellular virulence factors and biofilm formation. We found that differentiated human airway epithelia inactivated 3OC12-HSL. Inactivation was selective for acyl-HSLs with certain acyl side chains, and C4-HSL was not inactivated. In addition, the capacity for inactivation varied widely in different cell types. 3OC12-HSL was inactivated by a cell-associated activity rather than a secreted factor. These data suggest that the ability of human airway epithelia to inactivate quorum-sensing signal molecules could play a role in the innate defense against bacterial infection.