RESUMO
Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein-Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Doença de Hodgkin/diagnóstico , Imunossupressores/uso terapêutico , Linfadenopatia/diagnóstico , Metotrexato/efeitos adversos , Idoso de 80 Anos ou mais , Feminino , Humanos , Infliximab/uso terapêutico , Fígado/patologia , Metotrexato/uso terapêutico , Baço/patologiaRESUMO
Peritoneal dialysis (PD) is an excellent dialysis mo- dality, but it is underutilized in the United States and Japan. In the present study, we evaluated the impact of interventional nephrology in PD on the impres- sions held by patients and nurses about selection of a renal replacement therapy and the complications associated with PD therapy. Over aperiod of 7 years, PD catheter insertion in 120 patients with end-stage renal disease (age: 63.0 ± 13.3 years) was performed by nephrologists at Keio University Hospital or Saitama Medical Center. A questionnaire survey evaluating the advantages and disadvantages of this interventional nephrology approach in PD was distributed to 72 PD patients and to 53 nurses in charge of those patients. After interventional nephrology in PD was adopted, the number of patients selecting PD therapy increased. The incidence of peritonitis was relatively low (1 episode in 101.1 patient-months). Responses to the questionnaire survey showed that neither patients nor nurses were concerned about catheter insertion by physicians, and no communication problems between the patients, nurses, and physicians were reported. Approximately 60% of the nurses specializing in PD therapy showed higher motivation with interventional nephrology, which might have a favorable effect on the selection of PD therapy, on the incidence of peritonitis, and on the tripartite communication between patients, nurses, and physicians.
Assuntos
Atitude do Pessoal de Saúde , Cateterismo , Falência Renal Crônica/terapia , Nefrologia , Preferência do Paciente , Diálise Peritoneal , Idoso , Cateteres de Demora , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
A Japanese woman in her 50s presented with coffee-ground vomiting at a local clinic and was referred to our hospital for further investigation. Esophagogastroduodenoscopy demonstrated a submucosal tumor in the descending part of the duodenum, and she was diagnosed with a gastrointestinal stromal tumor (GIST) by other imaging studies. Elective surgery of the tumor was initially planned. However, on the 13th day of hospitalization, emergency pancreaticoduodenectomy was performed because of massive hematemesis with hemorrhagic shock. Genetic analysis demonstrated a deletion in exon 11 of the c-kit gene, which could dramatically alter the clinical course. Although duodenal GIST with active bleeding is comparatively rare, we have to assume that it is the cause of gastrointestinal bleeding and treat such cases with a minimally invasive surgical procedure and neoadjuvant/adjuvant chemotherapy. It is necessary to accumulate more cases with duodenal GIST to establish an evidence-based therapeutic strategy.
Assuntos
Neoplasias Duodenais/genética , Neoplasias Duodenais/cirurgia , Éxons/genética , Hemorragia Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/cirurgia , Pancreaticoduodenectomia , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Duodenais/complicações , Feminino , Hemorragia Gastrointestinal/etiologia , Tumores do Estroma Gastrointestinal/complicações , Humanos , Pessoa de Meia-IdadeRESUMO
The kidney develops through reciprocal interactions between two precursor tissues: the metanephric mesenchyme and the ureteric bud. We previously demonstrated that the zinc finger protein Sall1 is essential for ureteric bud attraction toward the mesenchyme. Here, we show that Kif26b, a kinesin family gene, is a downstream target of Sall1 and that disruption of this gene causes kidney agenesis because of impaired ureteric bud attraction. In the Kif26b-null metanephros, compact adhesion between mesenchymal cells adjacent to the ureteric buds and the polarized distribution of integrin alpha8 were impaired, resulting in failed maintenance of Gdnf, a critical ureteric bud attractant. Overexpression of Kif26b in vitro caused increased cell adhesion through interactions with nonmuscle myosin. Thus, Kif26b is essential for kidney development because it regulates the adhesion of mesenchymal cells in contact with ureteric buds.
Assuntos
Adesão Celular/fisiologia , Rim/embriologia , Cinesinas/metabolismo , Mesoderma/fisiologia , Animais , Southern Blotting , Clonagem Molecular , Primers do DNA/genética , Feminino , Imuno-Histoquímica , Hibridização In Situ , Rim/citologia , Cinesinas/genética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , TransfecçãoRESUMO
BACKGROUND: Vonoprazan is a potassium competitive acid blocker used to treat erosive gastroesophageal reflux disease (GERD) with stronger, more stable acid-suppressing effects than proton pump inhibitors (PPIs). This study clarified the usefulness and superiority of vonoprazan administered every second day over PPIs in the maintenance therapy of erosive GERD. METHODS: This is a prospective, multicenter, open-label, two-period randomized cross-over study. Patients were randomized to either the vonoprazan-lansoprazole (VP-LZ) group, who were given vonoprazan 10 mg for the first 4 weeks and then lansoprazole 15 mg for the next 4 weeks both administered once every second day, or the lansoprazole-vonoprazan (LZ-VP) group, who were treated in reverse. GERD symptoms were compared using symptom diaries, the frequency scale for symptoms of GERD (FSSG), and the gastrointestinal symptom rating scale (GSRS). RESULTS: We enrolled 122 patients between December 2017 and May 2019. Symptoms were well controlled in vonoprazan administration and lansoprazole administration were 93.6% and 82.1%, respectively, with a significant difference on McNemar's test (P = 0.003). During the second 4 weeks, 94.4% and 76.7% of patients in the VP-LZ and LZ-VP groups, respectively, were well controlled following for ≥ 6 consecutive days a week (P = 0.009). During the first 4 weeks, 96.7% and 80.0% of patients were well controlled with < 1 weekly in the VP-LZ and LZ-VP groups, respectively, during the first 4 weeks (P = 0.007). GERD symptoms, assessed via FSSG and GSRS, significantly decreased with vonoprazan administration once every second day. CONCLUSIONS: Vonoprazan administered once every second day could be an effective alternative to PPIs in the maintenance treatment of erosive GERD (UMIN000030393).
Assuntos
Refluxo Gastroesofágico , Pirróis , Estudos Cross-Over , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/efeitos adversos , Sulfonamidas , Resultado do TratamentoRESUMO
We have found that ventromedial hypothalamic (VMH) lesions produced by electrocoagulation induce cell proliferation in visceral organs through vagal hyperactivity, and also stimulate regeneration of partially resected liver in rats. To facilitate identification of proliferative and/or regenerative factors at the gene level, we developed electrical production of VMH lesions in mice, for which more genetic information is available compared to rats, and examined the pathophysiological profiles in these mice. Using ddy mice, we produced VMH lesions with reference to the previously reported method in rats. We then examined the pathophysiological profiles of the VMH-lesioned mice. Electrical VMH lesions in mice were produced using the following coordinates: 1.6 mm posterior to the bregma, anteriorly; 0.5 mm lateral to the midsagittal line, transversely; and 0.2 mm above the base of the skull, vertically, with 1 mA of current intensity and 10 s duration. The VMH-lesioned mice showed similar metabolic characteristics to those of VMH-lesioned rats, including body weight gain, increased food intake, increased percentage body fat, and elevated serum insulin and leptin. However, there were some differences in short period of hyperphagia, and in normal serum lipids compared to those of VMH-lesioned rats. The mice showed a similar cell proliferation in visceral organs, including stomach, small intestine, liver, and, exocrine and endocrine pancreas. In conclusion, procedures for development of VMH lesions in mice by electrocoagulation were developed and the VMH-lesioned mice showed pathophysiological profiles similar to those of VMH-lesioned rats, particularly in cell proliferation in visceral organs. These findings have not been observed previously in gold thioglucose-induced VMH-lesioned mice. This model may be a new tool for identifying factors involved in cell proliferation or regeneration in visceral organs.
Assuntos
Eletrocoagulação/métodos , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Insulina/sangue , Intestino Delgado/citologia , Leptina/sangue , Lipídeos/sangue , Fígado/citologia , Camundongos , Obesidade/etiologia , Pâncreas/citologia , Ratos , Regeneração/fisiologia , Estômago/citologiaRESUMO
Sall1 is expressed in the metanephric mesenchyme in the developing kidney, and mice deficient in Sall1 show kidney agenesis or dysgenesis. Sall1 is also expressed elsewhere, including in the limb buds, anus, heart, and central nervous system. Dominant-negative mutations of Sall1 in mice and humans lead to developmental defects in these organs. Here, we generated a mouse line expressing tamoxifen-inducible Cre recombinase (CreER(T2)) under the control of the endogenous Sall1 promoter. Upon tamoxifen treatment, these mice showed genomic recombination in the tissues where endogenous Sall1 is expressed. When CreER(T2) mice were crossed with the floxed Sall1 allele, tamoxifen administration during gestation led to a significant decrease in Sall1 expression and small kidneys at birth, suggesting that Sall1 functions were disrupted. Furthermore, Sall1 expression in the kidney was significantly reduced by neonatal tamoxifen treatment. The Sall1CreER(T2) mouse is a valuable tool for in vivo time-dependent and region-specific knockout and overexpression studies.
Assuntos
Integrases/genética , Rim/metabolismo , Mesoderma/metabolismo , Fatores de Transcrição/genética , Animais , Animais Recém-Nascidos , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Antagonistas de Estrogênios/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Marcação de Genes/métodos , Humanos , Imuno-Histoquímica , Hibridização In Situ , Integrases/metabolismo , Rim/embriologia , Rim/crescimento & desenvolvimento , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Mesoderma/embriologia , Mesoderma/crescimento & desenvolvimento , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Genéticos , Regiões Promotoras Genéticas/genética , Tamoxifeno/farmacologiaRESUMO
In rats, ventromedial hypothalamic (VMH) lesions induce cell proliferation in the visceral organs (stomach, small intestine, liver, and pancreas) due to hyperactivity of the vagus nerve. To investigate the effects of selective gastric vagotomy on VMH lesion-induced cell proliferation and secretion of gastric acid, we assessed the mitotic index (the number of proliferating cell nuclear antigen (PCNA)-immunopositive cells per 1,000 cells in the gastric mucosal cell layer) and measured the volume of secreted basal gastric acid. Furthermore, to explore whether or not ethanol-induced acute gastric mucosal lesions (AGML) lead to ulcer formation in VMH-lesioned rats, we assessed the ulcer index of both sham-operated and VMH-lesioned rats after administration of ethanol. VMH lesions resulted in an increased mitotic index and thickness of the gastric mucosal cell layer and gave rise to the hypersecretion of gastric acid. Selective gastric vagotomy restored these parameters to normal without affecting cell proliferation in other visceral organs. Ethanol-induced AGML caused ulcers in sham VMH-lesioned rats, whereas VMH-lesioned rats were less likely to exhibit such ulcers. These results suggest that VMH lesion-induced vagally mediated cell proliferation in the visceral organs is associated with hyperfunction in these organs, and VMH lesion-induced resistance to ethanol may be due to thickening of the gastric mucosal cell layer resulting from cell proliferation in the gastric mucosa-this in turn is due to hyperactivity of the vagus nerve.
Assuntos
Proliferação de Células , Mucosa Gástrica , Vagotomia , Nervo Vago/fisiologia , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Ácido Gástrico/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/inervação , Mucosa Gástrica/metabolismo , Intestino Delgado/citologia , Intestino Delgado/inervação , Fígado/citologia , Fígado/inervação , Masculino , Pâncreas/citologia , Pâncreas/inervação , Ratos , Ratos Sprague-DawleyRESUMO
It has been reported that ventromedial hypothalamic (VMH) lesions induce hepatic cell proliferation and apoptosis and metabolic changes in the body. In the present study, we identified genes of which expression profiles showed significant modulation in rat liver after VMH lesions. Total RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH lesioned rats were investigated using DNA microarray analysis. The results revealed that VMH lesions regulated the genes that were involved in various types of metabolisms and cell proliferations in the liver. Real-time PCR also confirmed that gene expressions of ELOVL6 and SPC24 were upregulated, and that of SERPINA7 was downregulated. VMH lesions may change the expressions of multiple metabolism genes and cell proliferation-related genes in rat liver.
Assuntos
Perfilação da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Núcleo Hipotalâmico Ventromedial/patologia , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Apoptose , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Elongases de Ácidos Graxos , Feminino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Globulina de Ligação a Tiroxina , Proteínas de Ligação a Tiroxina/genética , Proteínas de Ligação a Tiroxina/metabolismo , Regulação para Cima , Núcleo Hipotalâmico Ventromedial/cirurgiaRESUMO
Amylin is a peptide hormone that is co-released with insulin from pancreatic beta-cells following a meal. Intracerebroventricular (icv) administration of amylin (1-100 pmol), or an amylin agonist, salmon calcitonin, elicited dose-dependent thermogenic, tachycardic, and hyperthermic responses in urethane-anesthetized rats. Intravenous (iv) administration of higher doses of amylin (100 pmol-20 nmol) also induced similar responses, although the amplitudes of these responses were significantly smaller than those elicited by icv administration, suggesting the primary action of amylin to be in the brain. However, the iv administration of amylin induced the responses slightly faster than the icv injection, the former responses occurring<4 min and the latter, at 8-10 min, after the administration. The iv but not the icv injection of amylin increased the respiratory exchange ratio transiently (<20 min), though the thermogenic response lasted for a longer period after both injections, indicating a shift from mixed fuel to predominantly carbohydrate utilization in the initial phase of thermogenesis induced by the iv injection of amylin. The differences in substrate utilization and latency of the responses suggest that the actions of amylin include partly different targets when administered centrally and peripherally. Moreover, pretreatment with a beta-adrenergic blocker, propranolol (5 mg kg(-1), iv), blocked all responses elicited by either icv or iv administration of amylin, whereas ablation of the area postrema in the hindbrain did not influence the effects of icv-administered amylin. These results suggest the involvement of amylin in postprandial energy expenditure, mediated by peripheral beta-adrenoceptors.
Assuntos
Amiloide/farmacologia , Metabolismo Energético/efeitos dos fármacos , Amiloide/administração & dosagem , Amiloide/agonistas , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Calcitonina/administração & dosagem , Calcitonina/farmacologia , Relação Dose-Resposta a Droga , Metabolismo Energético/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Injeções Intravenosas , Injeções Intraventriculares , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Propranolol/farmacologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Neuropeptide W (NPW) is an endogenous ligand for GPR7, a member of the G-protein-coupled receptor family. NPW plays an important role in the regulation of both feeding and energy metabolism, and is also implicated in modulating responses to an acute inflammatory pain through activation of the hypothalamus-pituitary-adrenal axis. GPR7 mRNA has been shown to be expressed in the hypothalamus, pituitary gland and adrenal cortex. Similarly, NPW expression has been demonstrated in the brain and pituitary gland. However, the precise distribution of NPW-producing cells in the adrenal gland remains unknown. The aim of this study was to explore the distribution and localization of NPW immunoreactivity in the rat adrenal gland. Total RNA was prepared from the hypothalamus, pituitary gland and adrenal gland. RT-PCR revealed the expression of NPW mRNA in these tissues, while in situ hybridization demonstrated the presence of NPW mRNA in the adrenal medulla. When immunohistochemistry was performed on sections of adrenal gland, NPW-like immunoreactivity (NPW-LI) was observed in the medulla but not in the cortex. Moreover, NPW-LI was found to be co-localized in cells which expressed dopamine beta hydroxylase but not phenylethanolamine-N-methyltransferase. The finding that NPW is expressed in noradrenalin-containing cells in the adrenal medulla suggests that it may play an important role in endocrine function in the adrenal gland.
Assuntos
Medula Suprarrenal/metabolismo , Regulação da Expressão Gênica , Neuropeptídeos/genética , Norepinefrina/metabolismo , Animais , Imuno-Histoquímica , Hibridização In Situ , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-DawleyRESUMO
The intestinal epithelium is continuously renewed through a balance between cell proliferation and apoptosis. We identified genes of which expression profiles showed significant modulation, and we investigated the cellular mechanisms of this gene regulation in rat intestine after ventromedial hypothalamic (VMH) lesions. Total RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and in sham-VMH lesioned rats were investigated using DNA microarray analysis and real-time polymerase chain reaction (PCR) methods. DNA microarray analysis revealed that VMH lesions regulated the genes that were involved in functions predominantly related to neuronal development, cell proliferation and apoptosis. Real-time PCR also confirmed that gene expressions of Efnb1 were downregulated. Meanwhile, expression of Casp3 was similar. It is noted that the signaling networks of many gene families, including neuron-specific genes and apoptosis genes in the intestine were changed after VMH lesioning. VMH lesions may suppress mainly the caspase independent type II pathway for apoptosis and induce cell proliferation in the intestine.
Assuntos
Apoptose/genética , Expressão Gênica , Mucosa Intestinal/metabolismo , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Núcleo Hipotalâmico Ventromedial/metabolismoRESUMO
AIMS/INTRODUCTION: To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. MATERIALS AND METHODS: This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. RESULTS: After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1-1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1-2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1-2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). CONCLUSIONS: The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Periodontite/complicações , Periodontite/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: To evaluate the pharmacodynamic effect, efficacy, and safety of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease (NERD) in Japan. METHODS: A total of 37 patients were randomized to omeprazole 10 mg or omeprazole 20 mg once daily for 4 weeks. Eligible patients had a history of moderate-to-severe heartburn for 2 days or more per week during the last 1 month or longer prior to the study screening, grade M or grade N on Hoshihara's modification of the Los Angeles classification (i.e., no sign of mucosal break on esophagogastroduodenoscopy), and heartburn episodes for 2 days or more per week during the last week of the observation period while taking antacids. Ambulatory 24-h intraesophageal pH was monitored on the day before treatment and on the last day of treatment. The occurrence of a heartburn episode was recorded during pH monitoring. The primary endpoint was the change in the percentage of time with intraesophageal pH < 4 during the 24-h period before and after omeprazole treatment. RESULTS: Both omeprazole 10 mg and omeprazole 20 mg once daily reduced the percentage of time with intraesophageal pH < 4. The percentage reduction in time with intraesophageal pH < 4 after treatment with omeprazole was associated with a reduced number of heartburn episodes. Patients with grade M or grade N esophagus had similar pH profiles and NERD characteristics (e.g., pH holding time, symptom index) and comparable responses to omeprazole. No serious, drug-related adverse events were reported. CONCLUSIONS: Omeprazole 10 mg or 20 mg reduces the percentage of time with intraesophageal pH < 4, is efficacious, and is well tolerated in patients with NERD in Japan, regardless of the patient's endoscopic classification.
Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Inibidores da Bomba de Prótons , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
Lesions of the ventromedial hypothalamus (VMH) result in obesity and enhanced cellular proliferation in various organs, including the pancreas, gastrointestinal tract, and liver. Previous studies have suggested that vagal hyperactivity, rather than overeating, induces the peripheral cell proliferation in VMH-lesioned rats. The goal of the present study was to investigate the mechanism of peripheral cell proliferation in VMH-lesion-induced obesity by infusing rats with the acetylcholine agonist, carbachol, and then measuring cellular proliferation in the pancreas and duodenum using immunohistochemistry. The ventromedial hypothalamus was bilaterally lesioned in five rats. In other rats, the bilateral vagus nerves were ligated (vagotomized), and saline or carbachol was continuously administered by an osmotic minipump (n = 5 in each group). Three days later, rats were killed, and cell proliferation was assessed in the pancreas and the duodenum using immunohistochemistry for proliferating cell nuclear antigen (PCNA). Additionally, cellular proliferation in the duodenum was more precisely examined by assessing incorporation of 5-bromo-2'-deoxyuridine (BrdU). Cellular proliferation was higher in rats that received carbachol infusions and in rats with VMH-lesions when compared with control rats (P < 0.05, respectively). The pancreatic PCNA-expressing cells were predominantly identified as the B-cells of the islets of Langerhans. These data demonstrate that carbachol infusion can induce pancreatic and duodenal cell proliferation to a degree that was comparable to that in vagal hyperactivity induced by VMH lesions.
Assuntos
Carbacol , Proliferação de Células/efeitos dos fármacos , Agonistas Colinérgicos , Hipotálamo , Obesidade/metabolismo , Nervo Vago , Animais , Peso Corporal , Carbacol/administração & dosagem , Carbacol/farmacologia , Agonistas Colinérgicos/administração & dosagem , Agonistas Colinérgicos/farmacologia , Modelos Animais de Doenças , Duodeno/citologia , Duodeno/metabolismo , Ingestão de Alimentos , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Vagotomia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologiaRESUMO
Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of (125)I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Encéfalo/patologia , Peptídeo Semelhante a Galanina/uso terapêutico , Obesidade/tratamento farmacológico , Administração Intranasal , Animais , Autorradiografia , Peso Corporal , Metabolismo Energético , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Ratos , Ratos Sprague-DawleyRESUMO
Glucagon-like peptide-1 (GLP-1) is released from the gut in response to nutrient ingestion. Intravenous (iv) administration of GLP-1 (50 pmol-20 nmol) elicited dose-dependent increases in the rate of whole-body O2 consumption (VO2), an index of energy expenditure, and heart rate of urethane-anesthetized rats. The body core (colonic) temperature increased up to 0.3 degrees C without accompanying alteration of tail skin temperature. Intracerebroventricular (icv) administration of GLP-1 induced a slower and smaller increase in VO2 than the intravenous administration. The injection of glucagon-like peptide-2 (iv or icv) had no effect on VO2, body temperatures, or heart rate. Decerebration had no effect on the thermogenic responses induced by the iv administration of GLP-1, suggesting that the forebrain is not essential for these responses. However, cervical spinal transection greatly attenuated the responses, suggesting the critical involvement of the lower brainstem. Adrenalectomy or pretreatment with an autonomic ganglion blocker, hexamethonium, or a beta-adrenergic blocker, propranolol, also significantly attenuated the thermogenic response. However, subdiaphragmatic vagotomy or celiac-superior mesenteric ganglionectomy had no effect. Rats made insulin-deficient by pretreatment with streptozotocin also exhibited the normal thermogenic response to GLP-1. These results suggest the involvement of the GLP-1 in postprandial energy expenditure, mediated by the lower brainstem and sympathoadrenal system.
Assuntos
Glândulas Suprarrenais/fisiologia , Tronco Encefálico/fisiologia , Metabolismo Energético/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Sistema Nervoso Simpático/fisiologia , Adrenalectomia , Animais , Área Postrema/lesões , Área Postrema/patologia , Área Postrema/fisiopatologia , Temperatura Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Metabolismo Energético/fisiologia , Ganglionectomia , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 2 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hexametônio/farmacologia , Injeções Intravenosas , Injeções Intraventriculares , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Propranolol/farmacologia , Prosencéfalo/lesões , Prosencéfalo/cirurgia , Troca Gasosa Pulmonar/efeitos dos fármacos , Ratos , Ratos Wistar , Medula Espinal/cirurgia , Traumatismos da Medula Espinal/fisiopatologia , VagotomiaRESUMO
Cholecystokinin (CCK) plays a major role in the regulation of pancreatic enzyme secretion based on its binding to the CCK-A receptor (CCK-AR). While CCK-AR is known to be expressed in rat islet B cells, the localization of CCK-AR in rat pancreatic A and D cells remains poorly understood. The aim of this study was to identify the localization of CCK-AR in rat pancreatic islets by means of double immunofluorescence straining with antibodies against CCK-AR, glucagon, insulin and somatostatin and with in situ hybridization to detect its transcript. CCK-AR-like immunoreactive cells were found to overlap both with glucagon-like immunoreactive cells and insulin-like immunoreactive cells but not with somatostatin-like immunoreactive cells. An in situ hybridization study using a cRNA probe for CCK-AR revealed that CCK-AR mRNA was expressed in the center and periphery of the pancreatic islets. Further to this, immunofluorecsence staining using anti-glucagon antibody was carried out after in situ hybridization using the CCK-AR cRNA probe in order to identify CCK-AR mRNA expressing cells. CCK-AR mRNA exhibited a distribution pattern almost identical to that of glucagon-like immunoreactive cells. These results show clearly that CCK-AR exists not only in B but also in A cells of the rat pancreas, suggesting that CCK regulates the secretion of insulin and glucagon at least partly via CCK-AR.
Assuntos
Ilhotas Pancreáticas/fisiologia , Receptor de Colecistocinina A/biossíntese , Animais , Colecistocinina/metabolismo , Glucagon/metabolismo , Imuno-Histoquímica , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Ghrelin, a novel peptide isolated from stomach tissue of rats and humans, has been identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). In addition to its secretion from the stomach, ghrelin is also expressed in the hypothalamic arcuate nucleus, intestine, kidney, placenta, and pancreas. GHS-R mRNA, on the other hand, is expressed in the hypothalamus, pituitary, heart, lung, liver, pancreas, stomach, intestine, and adipose tissue. Ghrelin is considered to have important roles in feeding regulation and energy metabolism as well as in the release of growth hormone (GH). Recent physiological experiments on the pancreas have shown that ghrelin regulates insulin secretion. However, sites of action of ghrelin in the pancreas are yet to be identified. In this study, to gain insight into the role of ghrelin in rat pancreatic islets, we used immunohistochemistry to determine the localization of ghrelin and GHS-R in islet cells. Double fluorescence immunohistochemistry revealed that weak GHS-R-like immunoreactivity was found in B cells containing insulin. GHS-R immunoreactivity overlapped that of glucagon-like immunoreactive cells. Moreover, both ghrelin and GHS-R-like immunoreactivities were detected mostly in the same cells in the periphery of the islets of Langerhans. These observations suggest that ghrelin is synthesized and secreted from A cells, and acts back on A cells in an autocrine and/or paracrine manner. In addition, ghrelin may act on B cells via GHS-R to regulate insulin secretion.
Assuntos
Ilhotas Pancreáticas/metabolismo , Hormônios Peptídicos/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Animais , Grelina , Hormônio do Crescimento/metabolismo , Imuno-Histoquímica , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de GrelinaRESUMO
A 60-year-old male presented to our hospital for further investigation of abnormal findings on an upper gastrointestinal series. Esophagogastroduodenoscopy demonstrated atrophic gastritis and a submucosal tumor (SMT) at the anterior wall of the antrum. The patient was positive for serum anti-Helicobacter pylori (H. pylori) antibody and H. pylori eradication therapy was performed. Five months later, the SMT showed a remarkable morphological change in that an ulcer had developed on its apex, and partial gastrectomy was performed. Pathological examination suggested an inflammatory fibroid polyp (IFP), and genetic analysis revealed no mutation in the platelet-derived growth factor receptor alpha gene. This case suggests that H. pylori infection plays an important role in the etiology of IFPs.