RESUMO
Upon inhalation, house dust mite (HDM) allergens are deposited at the nasal and oral mucosa, where IgA is produced abundantly. IgA subclasses have been linked to protection against respiratory allergy previously. It is currently not known whether and how the human IgA subclasses IgA1 and IgA2 contribute to the clinical status of house dust mite-allergic patients. Saliva and serum samples were collected, and HDM-specific, IgE, IgG4, IgA1 and IgA2 levels were determined. HDM-specific levels of IgA in serum were similar to levels measured in nonallergic controls, but HDM-specific levels of IgA2 in saliva were decreased in allergic subjects. HDM-allergic patients who suffered from rhinitis and eczema showed a significant decrease in IgA2-levels compared to patients who suffered from rhinitis only. Taken together, our findings indicate that HDM-specific IgA2, but not IgA1, levels in serum and saliva are reduced in HDM-allergic patients suffering from eczema.
Assuntos
Alérgenos/imunologia , Eczema/prevenção & controle , Hipersensibilidade/imunologia , Imunoglobulina A/imunologia , Pyroglyphidae/imunologia , Animais , Especificidade de Anticorpos/imunologia , Progressão da Doença , Feminino , Humanos , Imunoglobulina A/sangue , Masculino , Rinite Alérgica/imunologia , Saliva/imunologiaRESUMO
BACKGROUND: Information on the magnitude and duration of antibody levels after COVID-19 vaccination in different groups may be useful for prioritizing of additional vaccinations. METHODS: Serum samples were collected every six months in a prospective cohort study among adults in the Netherlands. Geometric mean concentrations (GMCs) of antibodies against the receptor binding domain of the SARS-CoV-2 spike protein were calculated after the primary series, first, and second booster vaccinations. Effects of age (18-59 vs 60-85 years) and medical risk conditions on GMC 2-6 weeks and 21-25 weeks after each vaccination, and on waning during 3-25 weeks after each vaccination, were estimated by linear regression. RESULTS: We included 20,640, 15,229 and 8,392 samples collected after primary, first and second booster vaccination, respectively. GMCs at 2-6 and 21-25 weeks after primary series were lower in participants with older age or medical risk conditions. After the first booster, older age was associated with lower GMC at 2-6 weeks and at 21-25 weeks. Waning after the first and second boosters (only 60-85) was not associated with age or medical risk conditions. CONCLUSIONS: Since antibody differences by age and medical risk groups have become small with increasing number of doses, other factors such as COVID-19 disease severity rather than antibody levels are useful for prioritization of additional vaccinations.
RESUMO
AIMS/HYPOTHESIS: High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function. METHODS: The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry. RESULTS: SkQ treatment reduced oxidative stress in muscle cells (-23% p < 0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p < 0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p < 0.001; HF+SkQ up 22%; p < 0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function. CONCLUSIONS/INTERPRETATION: SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.
Assuntos
Gorduras na Dieta/farmacologia , Resistência à Insulina/fisiologia , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Plastoquinona/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Animais , Sequestradores de Radicais Livres/farmacologia , Glucose/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Plastoquinona/farmacologiaRESUMO
Pertussis is a severe respiratory tract infection caused by Bordetella pertussis. This bacterium infects the ciliated epithelium of the human airways. We investigated the epithelial cell response to B. pertussis infection in primary human airway epithelium (HAE) differentiated at air-liquid interface. Infection of the HAE cells mimicked several hallmarks of B. pertussis infection such as reduced epithelial barrier integrity and abrogation of mucociliary transport. Our data suggests mild immunological activation of HAE by B. pertussis indicated by secretion of IL-6 and CXCL8 and the enrichment of genes involved in bacterial recognition and innate immune processes. We identified IL-1ß and IFNγ, present in conditioned media derived from B. pertussis-infected macrophage and NK cells, as essential immunological factors for inducing robust chemokine secretion by HAE in response to B. pertussis. In transwell migration assays, the chemokine-containing supernatants derived from this HAE induced monocyte migration. Our data suggests that the airway epithelium on its own has a limited immunological response to B. pertussis and that for a broad immune response communication with local innate immune cells is necessary. This highlights the importance of intercellular communication in the defense against B. pertussis infection and may assist in the rational design of improved pertussis vaccines.
Assuntos
Bordetella pertussis , Coqueluche , Bordetella pertussis/genética , Epitélio , Humanos , Imunidade Inata , Sistema Respiratório , Coqueluche/microbiologiaRESUMO
Optimal collection and analysis of exhaled breath condensate (EBC) are prerequisites for standardisation and reproducibility of assessments. The present study aimed to assess reproducibility of EBC volume, hydrogen peroxide (H(2)O(2)), 8-isoprostane and cytokine measurements using different condensers, including a newly developed glass condenser. At four points in time, 30 healthy subjects performed sequential EBC collections randomly using the following four condensers: glass, silicone, EcoScreen (Erich Jaeger GmbH, Hoechberg, Germany) and an optimised glass condenser. In small EBC samples, H(2)O(2) was measured by spectrophotometer, 8-isoprostane by enzyme immunoassay, and cytokines by multiplexed xMAP technology (Luminex Corporation, Austin, TX, USA). The optimised glass condenser yielded significantly more EBC volume (median 2,025 microL, interquartile range 1,600-2,525). The reproducibility of EBC volume, yielded by the new glass condenser, was comparable with EcoScreen (19-20 coefficients of variation (CV)%), but was significantly better compared with silicone and glass (29-37 CV%). The new condenser was associated with significantly more detections of H(2)O(2), 8-isoprostane, interleukin-2, -4, -5 and -13, and tumour necrosis factor-alpha. Isoprostane concentrations were significantly higher using the new condenser, whereas H(2)O(2) and cytokine concentrations were not. Reproducibility of biomarkers was equally variable for all condenser types. In conclusion, significantly more exhaled breath condensate volume and biomarker detections were found using the optimised glass condenser, including higher 8-isoprostane levels. However, biomarker reproducibility in exhaled breath condensate in healthy adults was not influenced by the type of condenser.
Assuntos
Testes Respiratórios/instrumentação , Manejo de Espécimes/instrumentação , Adulto , Biomarcadores , Testes Respiratórios/métodos , Dinoprosta/análogos & derivados , Dinoprosta/análise , Expiração , Feminino , Humanos , Peróxido de Hidrogênio/análise , Interleucinas/análise , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Manejo de Espécimes/métodos , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. AIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. PATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. METHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. RESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively. CONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fígado/efeitos dos fármacos , Tioguanina/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Hiperplasia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tioguanina/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stress-mediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. EXPERIMENTAL APPROACH: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H(2)O(2)) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay. KEY RESULTS: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H(2)O(2)/Fe(2+) in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H(2)O(2)/Fe(2+). Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H(2)O(2)/Fe(2+). CONCLUSIONS AND IMPLICATIONS: We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Doxorrubicina/toxicidade , Quelantes de Ferro/farmacologia , Compostos de Ferro/metabolismo , Neoplasias Pulmonares/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Aldeídos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres/química , Humanos , Hidrazonas/farmacologia , Peróxido de Hidrogênio/química , Ferro/química , Quelantes de Ferro/química , Compostos de Ferro/química , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Piridoxal/análogos & derivados , Piridoxal/farmacologia , Razoxano/farmacologia , Fatores de TempoRESUMO
BACKGROUND: (13)Carbon urea breath testing is reliable to detect current infection with Helicobacter pylori but has been reported to be of limited value in selected patients with atrophic body gastritis or acid-lowering medication. AIM: To evaluate the accuracy of (13)carbon urea breath testing for H. pylori detection in 20 asymptomatic patients with histologically confirmed atrophic body gastritis in a primary care setting. METHODS: (13)Carbon urea breath testing and serology were compared with H. pylori culture of a corpus biopsy as reference test. RESULTS: All tests were in agreement in 12 patients, being all positive in six and all negative in six. One patient was positive for serology and culture but negative for (13)carbon urea breath testing, five patients had only positive serology and two patients had only positive (13)carbon urea breath testing. (13)Carbon urea breath testing showed an accuracy with culture of 85% and anti-H. pylori serology with culture of 75%. (13)Carbon urea breath testing carried out in patients with positive serology showed an accuracy of 92%. Receiver operating characteristic curve analysis of (13)carbon urea breath testing shows optimal discrimination at the prescribed cut-off value. CONCLUSIONS: (13)Carbon urea breath testing can be used as diagnostic H. pylori test in asymptomatic patients with atrophic body gastritis, preferably in addition to serology, to select subjects for anti-H. pylori therapy.
Assuntos
Radioisótopos de Carbono , Gastrite Atrófica/microbiologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori , Adulto , Idoso , Idoso de 80 Anos ou mais , Testes Respiratórios/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Mucosal atrophy of the gastric antrum (type B atrophic gastritis) is generally accepted as predisposing to the development of the intestinal type of gastric cancer. Since bombesin stimulates gastrin release selectively from the antral mucosa, the response can be used as a marker for antral mucosal atrophy. In this study we have investigated bombesin-stimulated plasma gastrin responses in 21 patients with the intestinal type of gastric cancer and we have compared the results with 12 patients with the diffuse type of gastric cancer, 17 patients with benign gastric ulcer, and 30 dyspeptic patients without endoscopical or histological abnormalities. Gastrin concentrations were also measured in extracts of antral biopsies. Basal plasma gastrin concentrations were not significantly different. In contrast, patients with the intestinal type of gastric cancer had a significantly lower plasma gastrin response to bombesin than did the normal subjects (P less than 0.01) and patients with the diffuse type of gastric cancer (P less than 0.05), but the result was not significantly different from that of the gastric ulcer patients. The antral gastrin content of the patients with the intestinal type of gastric cancer was significantly lower than in controls (P less than 0.005), the patients with the diffuse type of gastric cancer (P less than 0.05), and those with gastric ulcer (P less than 0.05). It is concluded that patients with the intestinal type of gastric cancer have, in contrast to those with the diffuse type of gastric cancer, an abnormally low plasma gastrin response to bombesin. This low response is due to a reduced gastrin content of the antral mucosa.
Assuntos
Bombesina/farmacologia , Gastrinas/sangue , Neoplasias Gástricas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Mucosa Gástrica/análise , Mucosa Gástrica/patologia , Humanos , Masculino , Metaplasia , Pessoa de Meia-Idade , Antro Pilórico/análiseRESUMO
Oil-soluble components can be encapsulated in an O/W1/W2 microsystem, in which they are dissolved in oil droplets dispersed in a gelled microbead (W1), which forms a barrier between the oil droplets and the aqueous continuous phase (W2). We investigated the rate and mechanism of breakdown of protein microbeads in a simulated gastric system, and studied the influence of microbead protein concentration, gelling method (cold-set, slow and fast heat-set), and further processing (freeze-drying), on the breakdown process. Breakdown rate decreased with increasing protein content of the beads, for the same method of production. Due to the porosity of the slowly-heated heat-set beads, breakdown occurred evenly throughout the entire bead. Cold-set microbeads of 10% protein broke down slightly slower than the heat-set microbeads of 15%. The denser surface of the 10% beads slowed down the diffusion of the enzymes into the bead's interior, causing the beads to be broken down from the outside inward. All these beads broke down within one hour. Increasing the rate of temperature increase during the heating step dramatically slowed breakdown. There was no significant breakdown of rapidly heated beads within 138 minutes, even though no difference in microstructure between rapidly and slowly heated beads was visible with electron microscopy. Freeze-drying of the beads also slowed their breakdown. After 132 minutes more than half the measured particle volume of were intact beads. Freeze-drying changed the microstructure of the beads irreversibly: rehydrating the dried beads did not result in a breakdown behaviour similar to that of unprocessed beads.
Assuntos
Digestão , Conteúdo Gastrointestinal/química , Microesferas , Proteínas do Soro do Leite/química , Cloreto de Cálcio/química , Sistemas de Liberação de Medicamentos , Liofilização , Mucosa Gástrica/metabolismo , Géis/química , Hidrogéis/química , Microscopia Eletrônica , Nanopartículas/química , Óleos/química , Tamanho da PartículaRESUMO
In animals establishment of the intestinal microbial ecosystem is influenced by mucosal immune functions. As mucosal immune functions dynamically change during development of juvenile layer chicken, this study focused on dynamics in the ileal microbiota composition in relation to intestinal immune development. In addition, the levels of immunoglobulin (Ig) in serum and amount of bacteria coated with IgA, a hallmark of intestinal immune maturation, were analysed. The composition of the intestinal microbiota transiently changed at the age of 14-42 days compared to the microbiota composition before and after this period. This temporal deviation in microbiota composition was associated to a temporal increase in transcriptional activity of pro-inflammatory cytokine genes. Furthermore, before week two limited amounts of faecal bacteria were bound by IgM and from week two increasing amounts of bacteria were bound by IgA, reaching a maximal level of 70% of IgA-coated bacteria at 6 weeks of age. These data could indicate that prior to achievement of intestinal homeostasis at 6-10 weeks post hatch, activation of inflammatory pathways cause a temporal disturbance of the microbiota composition. This period of imbalance may be essential for adequate immune development and establishment of intestinal homeostasis.
Assuntos
Galinhas/microbiologia , Microbioma Gastrointestinal , Animais , Galinhas/imunologia , Fezes/microbiologia , Feminino , Homeostase , Íleo/imunologia , Íleo/microbiologia , Imunoglobulinas/sangue , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/imunologia , Intestinos/microbiologiaRESUMO
BACKGROUND: No data are available on differences in complication rate and long-term functioning between polyurethane and silicone percutaneous endoscopic gastrostomy (PEG) catheters. METHODS: We randomized patients who qualified for PEG placement to receive either a polyurethane or silicone PEG catheter. Patients were prospectively monitored for 28 days after placement for the occurrence of complications. Data on long-term PEG survival were obtained retrospectively from the Hospital and general practitioner's medical records. RESULTS: One hundred and six patients were randomized (polyurethane 50, silicone 56). During the first four weeks of follow-up, major complications occurred twice with both polyurethane and silicone PEGs (relative risk 1.1, 95% confidence interval: 0.11-11). Overall complications occurred four times with polyurethane and 17 times with silicone PEGs (relative risk 3.8, 95% confidence interval: 1.37-10.5). Long-term follow-up was available in 96 patients. Seven polyurethane PEGs and 10 silicone PEGs were removed because of PEG malfunctioning, the remainder functioned well until death or the reinstitution of oral feeding. The median complication-free survival was 916 days for the polyurethane PEG and 354 days for the silicone PEG (Log rank test: P=0.24). CONCLUSION: Polyurethane PEG catheters were associated with less short-term complications than silicone catheters, but major complications and long-term function were comparable.
Assuntos
Cateterismo/efeitos adversos , Cateterismo/instrumentação , Gastroscopia , Gastrostomia/instrumentação , Poliuretanos , Silicones , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a widely used tool for the depletion of neuropeptides from sensory C-fibres. Upon capsaicin treatment tachykinins are released, resulting in a variety of responses in the airways. We showed that after capsaicin (0.3 microM; 30 min) treatment of guinea pig tracheal smooth muscle preparations, the maximal contraction of the trachea after methacholine stimulation was strongly increased (capsaicin: 1.147 +/- 0.050 g vs. control: 0.717 +/- 0.047 g). This effect was completely nullified after pretreatment with capsazepine (2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3, 4,5-tetrahydro-1H-2benzazepine; a vanilloid receptor antagonist) and YM38336 (a dual tachykinin NK1 and tachykinin NK2 receptor antagonist). Our results serve as a warning against using capsaicin as a putatively clean pharmacological tool to deplete the neuropeptides from pools on the C-fibres because we showed that capsaicin also strongly influences basal mechanisms in tracheal smooth muscle control.
Assuntos
Capsaicina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Receptores Muscarínicos/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Animais , Broncoconstrição/efeitos dos fármacos , Capsaicina/análogos & derivados , Relação Dose-Resposta a Droga , Interações Medicamentosas , Cobaias , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Músculo Liso/fisiologia , Receptores de Taquicininas/antagonistas & inibidores , Traqueia/fisiologiaRESUMO
Glutathione S-transferase is a phase II detoxification enzyme that can be inactivated by H(2)O(2). During oxidative stress various other reactive oxygen species are generated that are more reactive than the relatively stable H(2)O(2). Hypochlorous acid (HOCl) is a powerful oxidant which is highly reactive towards a range of biological substrates. We studied the influence of HOCl on the activity of GST P1-1. HOCl inhibits purified glutathione S-transferase P1-1 in a concentration dependent manner with an IC(50)-value of 0.6 microM, which is more than 1000 times as low as IC(50) reported for H(2)O(2). HOCl lowered the V(max) value, but did not affect the K(m) for CDNB. Our results show that HOCl is a potent, non-competitive inhibitor of GST P1-1. The relevance of this effect is discussed.
Assuntos
Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Ácido Hipocloroso/farmacologia , Isoenzimas/antagonistas & inibidores , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Feminino , Glutationa S-Transferase pi , Humanos , Masculino , Placenta/efeitos dos fármacos , Placenta/enzimologia , Gravidez , Ácido Tióctico/farmacologiaRESUMO
Besides inducing cardiotoxicity, doxorubicin also affects the vasculature. Recent observations in cultured endothelial cells indicated that the endothelial form of nitric oxide synthase might be inhibited by doxorubicin thereby seriously interfering with vascular function. We have investigated the effect of doxorubicin on the relaxation induced by the muscarinic agonist carbachol in the isolated rat aorta. It was found that doxorubicin at concentrations up to 50 microM does not alter the relaxant response to carbachol. Direct measurement of nitrite, the metabolite of NO*, by the Griess assay confirmed our observation that NO*)production is not inhibited by doxorubicin.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Técnicas In Vitro , Relaxamento Muscular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III , Ratos , Ratos WistarRESUMO
Epidemiological studies have shown an association between ambient levels of particulate matter (PM) and increased mortality from cardiovascular diseases. However, the underlying mechanisms are still not clear. We hypothesised that PM, when translocated after inhalation, could affect vascular smooth muscle function. Therefore, total suspended particulate matter (TSP) was sampled and investigated for its ability to affect aortic muscle contraction. Both TSP and TSP supernatant (TSP-sup) induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted aortic rings. Relaxation induced by 100 microg/ml TSP was 51.5 +/- 3.1% of total contraction. At 60 and 100 microg/ml, relaxation induced by TSP was significantly higher compared to TSP-sup. Ultrafine TiO2, used as a model to investigate the role of ultrafine particles, did not show an effect. Soluble iron, present in TSP suspensions, seems not to be involved, as chelating with deferoxamine did not affect TSP-induced relaxation. However, TSP effects were inhibited by Trolox, suggesting a role of oxidants. Nudation of aortic rings showed that effects of TSP were only partly endothelium-dependent, while preincubation with L-NAME increased TSP-induced relaxation. From these data, we conclude that both the particle core and soluble components of TSP can affect the smooth muscle function, leading to changes in the vascular contractile response.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Aorta/fisiologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Administração por Inalação , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Cromanos/administração & dosagem , Cromanos/farmacologia , Técnicas In Vitro , Masculino , Músculo Liso/fisiologia , Oxidantes , Tamanho da Partícula , Ratos , Ratos Endogâmicos Lew , SolubilidadeRESUMO
Patients with late-onset hypogammaglobulinaemia have a very high risk of developing gastric cancer. In such patients there is a high frequency of atrophy of the gastric mucosa. This is reflected in low gastrin content of the antral mucosa, low serum pepsinogen A level and pepsinogen A/C ratio, and reduced serum gastrin secretion in response to bombesin stimulation. There is no evidence to support a role of Helicobacter pylori infection in the aetiopathology of these gastric abnormalities, although prior infection cannot be excluded with certainty. Since patients with early-onset hypogammaglobulinaemia and X-linked agammaglobulinaemia do not show this increased frequency of gastric abnormalities, it is unlikely that the immunoglobulin deficiency per se is responsible for the development of the gastric abnormalities found in patients with late-onset hypogammaglobulinaemia. Because of the very high risk of gastric cancer, regular endoscopic screening is warranted in patients with late-onset hypogammaglobulinaemia.
Assuntos
Agamaglobulinemia/patologia , Mucosa Gástrica/patologia , Agamaglobulinemia/complicações , Atrofia , Humanos , Fatores de Risco , Neoplasias Gástricas/etiologiaRESUMO
The number of dyspeptic patients with upper abdominal pain that are referred for investigation is increasing and will undoubtedly continue to increase, because these days peptic ulcer disease is increasingly becoming a primary care management issue, the specialist being left to deal with the patients who cannot be helped by antibiotics and antisecretory drugs prescribed by their general practitioner. Many of these patients are referred for an upper endoscopy to rule out organic disease. Carefully taken history, however, shows that a great number of those dyspeptics, on the basis of their clinical manifestations, do have a functional gastrointestinal disorder, representing the 'irritable gut'. A probable better term reflecting the direct relation is the syndrome of 'the constipated stomach'. In our opinion these patients are an important and increasing clinical problem for general practitioners, gastroenterologists, surgeons and physicians. The aim of this article is to make the practitioner aware of advancements in understanding pathophysiologic and psychosocial processes, as well as to give an overview of the great overlap between many functional gastrointestinal disorders, the important role of history-taking and some insights into the functional rectal outlet syndrome.
Assuntos
Dor Abdominal/etiologia , Doenças Funcionais do Colo/complicações , Doenças Funcionais do Colo/diagnóstico , Constipação Intestinal/complicações , Esvaziamento Gástrico , Gastroenteropatias/diagnóstico , Dor Abdominal/fisiopatologia , Doenças Funcionais do Colo/fisiopatologia , Diagnóstico Diferencial , Gastroenteropatias/fisiopatologia , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Measurement of the serum concentration of the secretory products of the gastric mucosa, pepsinogen A (PgA), pepsinogen C (PgC) and gastrin is called the serological gastric biopsy. Additional measurement of Helicobacter pylori antibodies and antibodies to parietal cells and intrinsic factor supports the non-invasive diagnostic value of the serum markers. In many clinical studies, the diagnostic potential of the serum markers in predicting the topography and severity of gastric mucosal disorders has been established. The aim was to assess the diagnostic value of the serological gastric biopsy for primary care. METHOD: Survey of the literature. RESULTS: The cell-physiological background of the serological gastric biopsy, the interpretation of the outcome of serum markers and the relation of these parameters to various gastric mucosal disorders are described. Measurement of PgA is a reliable way to discriminate between mucosal gastritis and functional dyspepsia. PgA is raised in duodenal, gastric and pyloric ulcer even though gastrin is normal. Both PgA and gastrin are raised in renal insufficiency and the Zollinger-Ellison syndrome. A low PgA is indicative of mucosal atrophy and a good indicator for gastric hypoacidity. An additional low PgA:C ratio is indicative of atrophic gastritis or extensive intestinal metaplasia of the stomach. A hypopepsinogenaemia can also be an alarm symptom for gastric cancer. A low PgA and a high gastrin is indicative of corpus atrophy. CONCLUSION: In primary care, the serological gastric biopsy might be a feasible and appropriate diagnostic method for management of the dyspeptic patient. Further research in general practice has to be done to validate the predictive value of the serological gastric biopsy and to define a diagnostic strategy.