ABSTRACT
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).
Subject(s)
Gastroesophageal Reflux , Pyrroles , Cross-Over Studies , Gastroesophageal Reflux/diagnosis , Gastroesophageal Reflux/drug therapy , Humans , Prospective Studies , Proton Pump Inhibitors/therapeutic use , Pyrroles/adverse effects , Sulfonamides , Treatment OutcomeABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Periodontitis/complications , Periodontitis/epidemiology , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Microvessels/physiopathology , Middle Aged , Risk Factors , Severity of Illness IndexABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Hodgkin Disease/diagnosis , Immunosuppressive Agents/therapeutic use , Lymphadenopathy/diagnosis , Methotrexate/adverse effects , Aged, 80 and over , Female , Humans , Infliximab/therapeutic use , Liver/pathology , Methotrexate/therapeutic use , Spleen/pathologyABSTRACT
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.
Subject(s)
Anti-Obesity Agents/therapeutic use , Brain/pathology , Galanin-Like Peptide/therapeutic use , Obesity/drug therapy , Administration, Intranasal , Animals , Autoradiography , Body Weight , Energy Metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Attitude of Health Personnel , Catheterization , Kidney Failure, Chronic/therapy , Nephrology , Patient Preference , Peritoneal Dialysis , Aged , Catheters, Indwelling , Female , Humans , Male , Middle Aged , Surveys and QuestionnairesABSTRACT
New erythropoiesis-stimulating agents with a longer half-life have been developed for the treatment of anemia in patients with end-stage renal disease. This study evaluated the efficacy of darbepoetin alfa (DA) and long-acting epoetin beta pegol (continuous erythropoietin receptor activator, CERA) in patients on peritoneal dialysis (PD). Twenty-nine patients who had undergone PD for at least 6 months and were iron replacement-naïve and negative for inflammatory parameters were enrolled. Hemoglobin (Hgb) levels and blood pressure were evaluated before and after switching from DA to CERA. Percent transferrin saturation (TSAT), serum ferritin levels and blood pressure were also assessed. Twenty-eight patients were subject to the analysis, excluding one patient with a decrease in Hgb by ≥10%. Switching from DA to CERA did not alter Hgb levels. The doses of DA and CERA after 12 month treatment of each agent were 118.48 ± 79.63 and 89.88 ± 47.50 µg/4 weeks, respectively (conversion ratio, 1:0.76). The CERA dose administered during the final 6 months was abated, compared with that given during the initial 6 months (P = 0.035). The frequency of CERA injection over a 12-month period was less than that of DA (10.0 ± 3.0 vs. 16.4 ± 5.0, P < 0.01). The conversion from DA to CERA did not alter TSAT, but decreased serum ferritin levels (from 202.69 ± 132.57 to 150.15 ± 110.07 ng/mL, P = 0.012) and systolic blood pressure (from 133.8 ± 17.3 to 129.5 ± 11.3 mm Hg, P = 0.024). In PD patients, lower doses and less frequent injection of CERA are sufficient to maintain Hgb at levels similar to those achieved by DA therapy, with improved iron utilization and reduced blood pressure.
Subject(s)
Blood Pressure/drug effects , Darbepoetin alfa/therapeutic use , Erythropoietin/therapeutic use , Hematinics/therapeutic use , Iron/metabolism , Peritoneal Dialysis , Polyethylene Glycols/therapeutic use , Darbepoetin alfa/administration & dosage , Darbepoetin alfa/pharmacology , Erythropoietin/administration & dosage , Erythropoietin/pharmacology , Female , Ferritins/blood , Hematinics/administration & dosage , Hematinics/pharmacology , Hemoglobins/analysis , Humans , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacology , Receptors, Erythropoietin , Transferrin/analysisABSTRACT
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.
Subject(s)
Duodenal Neoplasms/genetics , Duodenal Neoplasms/surgery , Exons/genetics , Gastrointestinal Hemorrhage/surgery , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/surgery , Pancreaticoduodenectomy , Proto-Oncogene Proteins c-kit/genetics , Duodenal Neoplasms/complications , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Stromal Tumors/complications , Humans , Middle AgedABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Helicobacter Infections/drug therapy , Helicobacter pylori , Polyps/pathology , Stomach Neoplasms/pathology , Amoxicillin/therapeutic use , Clarithromycin/therapeutic use , Endoscopy, Digestive System , Gastritis, Atrophic/complications , Gastritis, Atrophic/pathology , Helicobacter Infections/complications , Humans , Male , Middle Aged , Polyps/complications , Polyps/surgery , Proton Pump Inhibitors/therapeutic use , Rabeprazole/therapeutic use , Stomach Neoplasms/complications , Stomach Neoplasms/surgeryABSTRACT
In obese humans and animals, adiponectin production and release in adipose tissue are downregulated by feedback inhibition, resulting in decreased serum adiponectin. We investigated adiponectin production and release in ventromedial hypothalamic (VMH)-lesioned animals. VMH-lesioned mice showed significant increases in food intake and body weight gain, with hyperinsulinemia and hyperleptinemia at 1 and 4 weeks after VMH-lesioning. Serum adiponectin was elevated in VMH-lesioned mice at 1 and 4 weeks, despite adipocyte hypertrophy in subcutaneous and visceral adipose tissues and increased body fat. Adiponectin production and mRNA were also increased in both adipose tissues in VMH-lesioned mice at 1 week. These results were replicated in VMH-lesioned rats at 1 week. Daily atropine administration for 5 days or subdiaphragmatic vagotomy completely reversed the body weight gain and eliminated the increased adiponectin production and release in these rats, with reversal to a normal serum adiponectin level. Parasympathetic nerve activation by carbachol infusion for 5 days in rats increased serum adiponectin, with increased adiponectin production in visceral and subcutaneous adipose tissues without changes of body weight. These results demonstrate that activation of the parasympathetic nerve by VMH lesions stimulates production of adiponectin in visceral and subcutaneous adipose tissues and adiponectin release, resulting in elevated serum adiponectin.
Subject(s)
Adiponectin/metabolism , Adipose Tissue/physiopathology , Parasympathetic Nervous System/physiopathology , Vagus Nerve/physiopathology , Ventromedial Hypothalamic Nucleus/physiopathology , Adiponectin/blood , Adiponectin/genetics , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Atropine/pharmacology , Blood Glucose , Carbachol/pharmacology , Female , Insulin/blood , Leptin/blood , Mice , Oxidopamine/pharmacology , Parasympathetic Nervous System/drug effects , Parasympathetic Nervous System/metabolism , Rats , Rats, Sprague-Dawley , Vagus Nerve/drug effects , Vagus Nerve/metabolism , Ventromedial Hypothalamic Nucleus/drug effects , Ventromedial Hypothalamic Nucleus/metabolismABSTRACT
McKittrick-Wheelock syndrome can be successfully treated by emergent dialysis, prescription of bicarbonate, and endoscopic submucosal dissection, which allow elderly people suffering from this syndrome to maintain their activities of daily living. In patients with this syndrome, a large colonic villous adenoma secretes excessive amounts of mucus and causes severe electrolyte depletion and dehydration. An 81-year-old man who had been suffering from chronic renal failure (creatinine 256.4 µmol/L), hypertension, and arrhythmia presented with frequent mucous diarrhea for a month. He was hospitalized for appetite loss, vomiting, general fatigue, and acute renal failure. His blood tests and blood gas analysis revealed urea nitrogen 58.9 mmol/L, creatinine 954.7 µmol/L, pH 7.13, and a base excess of -20.1 mmol/L. Although his symptoms were improved by the emergent dialysis and rehydration, he suffered a relapse only 4 days after he was discharged. At the second admission, a near-circumferential tumor was found in the rectum by the colonoscopy, which was pathologically confirmed as a villous adenoma. Considering his age and complications, endoscopic submucosal dissection was selected, and internal use of sodium bicarbonate was prescribed. Diarrhea and appetite loss were improved by these treatments, and the creatinine level was also improved to 168.0 µmol/L.
ABSTRACT
OBJECTIVES: Chronic inflammation of periodontitis aggravates glycemic control in type 2 diabetic patients through aggravation of insulin resistance. Increased or decreased release of various inflammatory mediators, such as high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and adipokines, such as adiponectin, leptin, and resistin, are presumed to be responsible for developing and progressing insulin resistance. The purpose of this study was to examine the effects of periodontal treatment on glycemic control, serum inflammatory mediators and adipokines in type 2 diabetes patients with periodontitis. METHODS: Twenty-one type 2 diabetic patients with periodontitis received periodontal treatment with topical antibiotics (intervention group) and 8 patients did not receive periodontal treatment (control group). Periodontal examination, including probing pocket depth (PPD) and bleeding on probing (BOP), and blood sampling were performed at baseline, 2 and 6 months after periodontal treatments. Glycated hemoglobin (HbA1c), hs-CRP, TNF-α, IL-6, adiponectin, leptin, and resistin were analyzed. RESULTS: In the intervention group, improvements of PPD and BOP, decrease in HbA1c and elevation of serum adiponectin were observed, while in the control group, all parameters were not changed. Generalized linear model revealed that changes of serum adiponectin and TNF-α and change of BOP correlated significantly with the reduction of HbA1c at 6 months after periodontal treatments. CONCLUSION: The results demonstrated that periodontal treatment improves periodontal status and glycemic control with elevation of serum adiponectin in type 2 diabetic patients. The results suggest that HbA1c is reduced by amelioration of insulin resistance due to elevated serum adiponectin after periodontal treatments.
Subject(s)
Adiponectin/blood , Anti-Bacterial Agents/therapeutic use , Blood Glucose/metabolism , Chronic Periodontitis , Diabetes Mellitus, Type 2 , Glycated Hemoglobin/metabolism , Inflammation Mediators/blood , Administration, Topical , Aged , Chronic Periodontitis/blood , Chronic Periodontitis/complications , Chronic Periodontitis/drug therapy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Male , Middle Aged , Periodontal Index , Periodontal Pocket/drug therapyABSTRACT
AIMS/INTRODUCTION: Diabetes mellitus and periodontitis are closely related. A huge number of reports has addressed the effect of periodontal intervention therapy on glycemic control, but no reports have addressed the effect of glycemic intervention therapy on periodontal disease in type 2 diabetic patients. The aim of this study was to examine the effect of improved glycemic control by glycemic intervention therapy on periodontitis in type 2 diabetic patients. MATERIALS AND METHODS: A total of 35 patients underwent intervention therapy to improve glycemic control without periodontal treatment. Glycohemoglobin (HbA1c), high-sensitivity C-reactive protein (hs-CRP), bleeding on probing (BOP), probing pocket depth (PPD) and intraoral community periodontal index (CPI) codes of the World health Organization (WHO) were examined at baseline, and 2 and 6 months after the intervention therapy to improve glycemic control. RESULTS: After the improvement of glycemic control, BOP lesions improved, but deep PPD lesions and WHO CPI codes did not improve. Subanalyses showed that effective glycemic control (average HbA1c reduction 1.8%) improved BOP lesions, but did not affect deep PPD lesions and WHO CPI codes. In addition, high BOP lesions at baseline responded more effectively to glycemic intervention. Further analysis of CPI codes in all individual periodontal sites independent of WHO CPI codes in 35 patients showed that only gingival inflammation without a deep periodontal pocket improved after glycemic intervention. CONCLUSIONS: Effective glycemic control improves BOP lesions in type 2 diabetic patients with periodontitis through ameliorating inflammation at the gingival sites of periodontal tissue. This trial was registered with the University Hospital Medical Information Network (no. UMIN000007670).
ABSTRACT
Neuropeptide Y (NPY) is a 36-amino-acid neuropeptide that was first discovered in porcine brain extracts and later in the porcine intestine. It is widely distributed in both the central and peripheral nervous systems and exerts a powerful orexigenic effect. NPY-producing neuronal cell bodies are abundantly localized in the medial arcuate nucleus of the hypothalamus, this being a brain center that integrates signals for energy homeostasis. Accumulated evidence shows that hypothalamic neuropeptides such as ghrelin, orexin, melanin-concentrating hormone (MCH), galanin-like peptide (GALP) and proopiomelanocortin (POMC) are involved in the regulation of feeding behavior and energy homeostasis via neuronal circuits in the hypothalamus. NPY also forms part of the feeding-regulating neuronal circuitry in conjunction with other feeding-regulating peptide-containing neurons within the hypothalamus. We summarize here current knowledge of the neuronal interactions between NPY and the different types of feeding-regulating peptide-containing neurons in the hypothalamus based on evidence at the immunohistochemicl level and with calcium imaging techniques.
Subject(s)
Arcuate Nucleus of Hypothalamus/physiology , Eating/physiology , Neurons/physiology , Neuropeptide Y/physiology , Animals , Galanin/physiology , Ghrelin/physiology , Humans , Hypothalamic Hormones/physiology , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/physiology , Leptin/physiology , Melanins/physiology , Neuropeptides/physiology , Orexins , Pituitary Hormones/physiology , Signal Transduction/physiologyABSTRACT
Nesfatin-1, an anorexigenic protein, is ubiquitously expressed in the body. However, the exact mechanism underlying the in vivo regulation of production of nesfatin/nucleobindin-2 (NUCB2), a precursor protein of nesfatin-1, is unknown. We investigated the influence of modulation of autonomic nerve activity by a ventromedial hypothalamus (VMH) lesion and the subsequent effect on nesfatin/NUCB2 production in rat tissues innervated by the peripheral nervous system. Nesfatin/NUCB2 is strongly expressed in the pancreas and liver, moderately expressed in subcutaneous and visceral fat tissues and interscapular brown adipose tissue (iBAT), but is weakly expressed in the skeletal muscles. Our study results showed that the VMH lesion in VMH-lesioned rats did not affect nesfatin/NUCB2 expression in the pancreas, liver, skeletal muscle, and iBAT; however, the protein expression was significantly high in both subcutaneous and visceral fat tissues. In addition, continuous peripheral administration of carbachol for 5 days did not affect nesfatin/NUCB2 expression, but chemical sympathectomy using 6-hydroxydopamine mimicked the effect of VMH lesion by showing significantly high nesfatin/NUCB2 expression in the subcutaneous fat tissues. These results show that VMH lesion can modulate the autonomic nervous system activity and balance and increase nesfatin/NUCB2 expression in white adipose tissues of rats. Further, this action may be mediated via inhibition of the sympathetic nerve activity.
Subject(s)
Adipose Tissue, White/metabolism , Calcium-Binding Proteins/biosynthesis , DNA-Binding Proteins/biosynthesis , Hypothalamus/metabolism , Nerve Tissue Proteins/biosynthesis , Adipose Tissue, White/innervation , Animals , Autonomic Nervous System/metabolism , Carbachol/pharmacology , Female , Hypothalamus/injuries , Muscarinic Agonists/pharmacology , Nucleobindins , Organ Specificity , Oxidopamine , Rats , Rats, Sprague-Dawley , Sympathectomy, ChemicalABSTRACT
SUMMARY: In neural regulation of the endocrine pancreas, there is much evidence to suggest that vagal efferents alter insulin and glucagon secretion, but less information on the effects of vagal afferents. In this study, we investigated the role and function of afferent fibers of the vagus nerve in normal and ventromedial hypothalamic (VMH) lesioned rats with marked hyperinsulinemia. In normal rats, hepatic vagotomy was associated with intraperitoneal (ip) arginine-induced enhancement of insulin and glucagon secretion without an accompanying change in blood glucose levels, ip leucine induced enhancement of insulin secretion accompanied by a decrease in blood glucose levels, and ip alanine-induced enhancement of glucagon secretion accompanied by an increase in blood glucose levels. In VMH lesioned rats with marked hyperinsulinemia, none of these amino acids caused significant changes in insulin and glucagon secretion. We conclude that amino acid sensors in normal rats inhibit excess release of pancreatic hormones induced directly by intake of amino acids, such as that in excess protein ingestion, and maintain blood glucose levels within the normal range. In contrast, in VMH lesioned rats with marked hyperinsulinemia, the function of the amino acid sensors is masked due to the marked hyperinsulinemia in these rats.:
ABSTRACT
BACKGROUND: We have found previously that ventromedial hypothalamic lesions (VMH) enhance cell proliferation in the visceral organs through vagal hyperactivity in rats. The goal of the current study was to determine the characteristics and nature of cell proliferation in the small intestine in VMH-lesioned mice. METHODS: The weight and length of the small intestine, thickness of the mucosal and muscle layers, number of proliferating cell nuclear antigen (PCNA)-positive cells, and mitotic cell count in the mucosal layer in VMH-lesioned and Sham VMH-lesioned mice were determined at 7 days after the operation. RESULTS: The weight and length of the small intestine in VMH-lesioned mice were significantly greater than those in Sham VMH-lesioned mice, by 11.6% and 15.0%, respectively. The thicknesses of the mucosal and muscle layers of the small intestine in VMH-lesioned mice were also significantly greater than those in Sham VMH-lesioned mice, by 12.7% and 12.5%, respectively. PCNA-positive cells and mitotic cells in the mucosal layer were densely present in crypts in VMH-lesioned mice, and were significantly increased by 31.9% and 71.7%, respectively, compared to Sham VMH-lesioned mice. CONCLUSIONS: These results demonstrate that VMH lesions in mice enhance cell proliferation in the mucosal layers and cause cell hypertrophy or cell proliferation in the muscle layers of the small intestine, which increases the weight and length of the small intestine. VMH lesions in mice may be a new tool for identifying growth factors and related genes involved in enlarging the small intestine mainly through cell proliferation.
ABSTRACT
AIM: The role of mucosal layer thickness on prevention of acute gastric mucosal lesions (AGMLs) was examined in ventromedial hypothalamic (VMH)-lesioned rats. MATERIALS AND METHODS: The incidence of AGMLs after 48-h fasting and 60% ethanol injection into the stomach after 24-h fasting, aggressive factors (gastric acid and serum gastrin) and defensive factors [hexosamine, gastric mucosal blood flow (GMBF), serum thiobarbituric acid reacting substances (TBARS), and thickness of the gastric mucosal layer] were evaluated in VMH-lesioned rats. The effects of cell proliferation on the gastric mucosal layer of these rats were evaluated by H-E staining and immunostaining with proliferating cell nuclear antigen (PCNA). RESULTS: After 48-h fasting, no AGMLs were observed in VMH-lesioned and sham VMH-lesioned rats (controls). With 60% ethanol administration after 24-h fasting, the numbers of AGMLs were similar in the two groups, but the ulcer index, a marker of ulcer formation, was lower in VMH-lesioned rats compared to that in sham VMH-lesioned rats. VMH-lesioned rats showed increased gastric acid secretion and serum gastrin compared to sham VMH-lesioned rats, indicating an increase in aggressive factors in VMH-lesioned rats. The two groups had similar levels of gastric mucosal hexosamine, GMBF, and gastric mucosal TBARS, but VMH-lesioned rats had an increased thickness of the mucosal cell layer, indicating an increase in defensive factors in these rats. Histologically, VMH-lesioned rats had an increased total mucosal cell layer, especially for the surface epithelial cell layer, and an increased PCNA-labeling index, a marker of cell proliferation, especially in the proliferative zones of gastric mucosa, indicating increased cell proliferation in the proliferative zone of the gastric mucosa. CONCLUSION: VMH-lesioned rats are resistant to AGML formation due to increased cell proliferation in gastric mucosa through elevating the levels of defensive factors over those of aggressive factors.
ABSTRACT
Liver has a high regenerative capacity and restores its mass and function shortly after partial hepatectomy through increased proliferation and metabolic modification of hepatocytes. The proliferation of hepatocytes can be triggered by its mass reduction after hepatectomy or by the neural factors including lesioning of the ventromedial hypothalamus (VMH). In the present study, we examined the effect of VMH lesioning on liver regeneration in hepatectomized rats by evaluating liver function and morphology. We found that functional deficits caused by partial hepatectomy [prolonged prothrombin time (PT), increased indocyanine green (ICG) retention, and decrease in PAS (periodic Acid-Schiff staining)-positive hepatocytes] were restored by VMH lesioning at 1 week after the surgery, whereas these alterations disappeared at 4 weeks. Morphologically, lipid microdroplets, which are considered to be important for maintaining contiguous liver function via supplying fuel for cell proliferation, were found to accumulate in hepatocytes of the hepatectomized rats at early period (1 day) after partial hepatectomy. Interestingly, such lipid microdroplets were also detected in the VMH lesioned rats and the more abundantly in the VMH lesioned, hepatectomized rats up to 1 week after the surgery. In conclusion, our results suggest that VMH lesioning in rats promotes recovery of liver anatomically and functionally after partial hepatectomy by promoting cell proliferation process.
Subject(s)
Hepatocytes/cytology , Hypothalamus/physiology , Liver Regeneration/physiology , Animals , Cell Proliferation , Female , Hepatectomy , Hypothalamus/injuries , Lipids/physiology , Rats , Rats, Sprague-DawleyABSTRACT
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.