The change in Fibrosis-4 index in Japanese patients with type 2 diabetes treated by a fixed-ratio combination therapy of insulin degludec and liraglutide: A retrospective observational study.

AIM: The efficacy of titratable fixed-ratio combination therapy by a combination preparation of insulin degludec and liraglutide (IDegLira) in Japanese patients with type 2 diabetes, focusing particularly on the change in Fibrosis-4 index (FIB-4), a noninvasive method for the evaluation of liver fibrosis, was investigated. METHODS: As the full analysis set, 113 patients were treated with IDegLira. The patients were categorized into two groups according to the absence (GLP-1RA-naïve group, n = 72) or presence (GLP-1RA-treated group, n = 41) of glucagon-like peptide-1 receptor agonist (GLP-1RA) use before starting IDegLira. The clinical parameters were retrospectively determined over 6 months. RESULTS: The glycated hemoglobin value was significantly reduced in both groups. The bodyweight significantly decreased from 67.4 ± 11.0 kg at baseline to 66.4 ± 11.6 kg at 6 months in the GLP-1RA-naïve group, although it slightly increased in the GLP-1RA-treated group. FIB-4 significantly decreased from 1.60 ± 0.84 at baseline to 1.49 ± 0.74 at 6 months in the GLP-1RA-naïve group. Although FIB-4 significantly increased in the GLP-1RA-treated group, it remained within the low-risk level for liver fibrosis. CONCLUSION: Fixed-ratio combination therapy using IDegLira for the treatment of type 2 diabetes is useful for glycemic control and weight management. In particular, IDegLira may be more effective for lowering FIB-4 than adding unused oral antidiabetic agents or increasing the dose of insulin in GLP-1RA-naïve patients.

[Clinical study of sigmoid volvulus at eleven core hospitals in the Kagawa Prefecture].

We analyzed the clinical features of 157 patients admitted to 11 institutions in the Kagawa Prefecture for volvulus of the sigmoid colon. The following were the background information of the patients:median age, 79.0 years;male-to-female ratio, 102:55;median body mass index, 20.0kg/m2;and the proportion of patients with performance status ≥3, 43.9%. Abdominal bloating and pain were the chief complaints. During hospitalization, endoscopy and endoscopic detorsion were performed 157 and 100 times, respectively. An accidental complication was observed in 3 cases, all of which were intestinal perforations. Surgery, which was indicated for ischemia, was performed in 62 of the 157 cases. Endoscopy is useful in the diagnosis of ischemia, which can be treated following an early diagnosis. Of the 157 patients, 19 died, whereas the rest were discharged. The risk factors for death were age ≥80 years and creatinine kinase level ≥200IU/L.

Oxytocin improves behavioural and neural deficits in inferring others' social emotions in autism.

Recent studies have suggested oxytocin's therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others' social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person's social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others' social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others' social emotions (P = 0.018) but not in inferring others' beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others' social emotions, and in the dorsomedial prefrontal cortex during inferring others' beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others' social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others' social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others' beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others' social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

Factors predicting survival and pathological subtype in patients with ampullary adenocarcinoma.

BACKGROUND: Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes. METHODS: Medical records were reviewed for 86 patients who underwent curative resection for ampullary adenocarcinoma between 2000 and 2012 at 12 principal hospitals in Kagawa, Japan. RESULTS: Resection was most common among 75-79-year-old patients. Actuarial 1-, 3-, and 5-year postoperative survival rates for ampullary adenocarcinoma were 90%, 72.3%, and 69.1%, respectively. Preoperative biliary drainage; serum CA19-9 and total bilirubin levels; pathological grade; perineural, vascular, pancreatic, and duodenal invasion; nodal metastasis; UICC-T stage; and pancreatobiliary subtype were predictors of poor survival. An elevated serum CA19-9 level; an elevated total bilirubin level; lymphatic, vascular, perineural, and pancreatic invasion; and advanced overall tumor stage were more common in patients with pancreatobiliary-type tumors than in patients with intestinal-type tumors. Additionally, pathologic subtype analysis showed that each subtype had distinct prognostic factors. CONCLUSIONS: Preoperative elevated serum CA19-9 and total bilirubin levels are prognostic factors for ampullary adenocarcinoma, and are both associated with pancreatobiliary-type tumors. Surgeons should be aware of these factors because pancreatobiliary-type adenocarcinoma is aggressively invasive and is associated with poor survival.

A Case of Diabetic Chorea Secondary to Appetite Loss Due to COVID-19 Vaccination.

A 76-year-old woman with type 2 diabetes mellitus was admitted to our hospital with a complaint of involuntary movements of the limbs and face. Brain MRI demonstrated a bilateral high signal of putamen on the T1 weighted image, and she was diagnosed with diabetic chorea. She took a second dose of the COVID-19 vaccine 28 days before admission and lost her appetite. Consequently, her HbA1c level on admission decreased from 13.5% to 10.0% in 28 days. This case suggests that diabetic chorea could be induced by the rapid amelioration of a hyperglycemic state due to appetite loss after COVID-19 mRNA vaccination.

Relationship Between the Effect of Roxadustat and Comorbid Diabetes in Non-dialyzed Chronic Kidney Disease Patients: A Retrospective Observational Study.

Introduction The dose of roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, required to treat anemia, the hemoglobin level and the rate of hemoglobin target achievement were retrospectively investigated in non-dialyzed chronic kidney disease (CKD) patients with and without type 2 diabetes. Methods As the full analysis set, 25 subjects (10 with diabetes and 15 without diabetes) were observed over six months among 44 non-dialyzed CKD patients who received roxadustat. The target hemoglobin level was set at 110-130 g/L. Results The comorbidities of diabetes and body weight at baseline were significantly associated with each dose of roxadustat at six months and the change in each dose of roxadustat from the initiation of roxadustat treatment. There was no significant difference in the amount of increase in the hemoglobin level (14±11 g/L vs. 15±8 g/L) and the rate of hemoglobin target achievement (70% vs. 67%) between patients with and without diabetes. Each dose of roxadustat gradually decreased in patients without diabetes, whereas it increased in those with diabetes. Each dose of roxadustat was significantly higher in patients with diabetes than in those without diabetes at 3 (60±21 mg vs. 42±14 mg) and 6 (61±22 mg vs. 41±14 mg) months after the initiation of roxadustat treatment. Conclusion Roxadustat is useful for the treatment of anemia in both CKD patients with and without diabetes. However, the dose required to achieve the target hemoglobin level may be higher in patients with diabetes than in those without diabetes.

Changes in the estimated glomerular filtration rate and predictors of the renal prognosis in Japanese patients with type 2 diabetes: A retrospective study during the 12 months after the initiation of tofogliflozin.

BACKGROUND: The changes in the estimated glomerular filtration rate (eGFR) and predictors of the renal prognosis were retrospectively assessed over the 12 months after the initiation of tofogliflozin, which has the shortest half-life among sodium-glucose cotransporter 2 (SGLT2) inhibitors, in Japanese patients with type 2 diabetes and renal impairment. METHODS: In total, 158 patients treated with tofogliflozin between 2019 and 2021 were studied as the safety analysis set. One hundred and thirty subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into two groups based on the eGFR: normal- (eGFR ≥60 mL/min/1.73 m2, n = 87) and low- (eGFR <60 mL/min/1.73 m2, n = 43) eGFR groups. RESULTS: The body weight, blood pressure, urinary protein excretion, and serum uric acid concentration decreased from baseline in both eGFR groups while the hemoglobin level increased. The eGFR did not significantly differ over time, except for the initial dip (-4.3±9.6 mL/min/1.73 m2 in the normal-eGFR group and -1.5±5.3 mL/min/1.73 m2 in the low-eGFR group). The change in the eGFR at 12 months after the initiation of tofogliflozin was -1.9±9.0 mL/min/1.73 m2 and 0.2±6.0 mL/min/1.73 m2 in the normal- and low-eGFR group, respectively. In the normal-eGFR group, the change in the eGFR showed a significant negative correlation with the HbA1c and eGFR at baseline, according to a multiple regression analysis. In the low-eGFR group, the change in the eGFR showed a significant negative correlation with urate-lowering agent use. The frequencies of adverse events specific for SGLT2 inhibitors were not significantly different between the normal- and low-eGFR groups. CONCLUSIONS: Tofogliflozin may preserve renal function in the medium term in patients with type 2 diabetes and kidney impairment without an increase in specific adverse events.

Anemia combined with albuminuria increases the risk of cardiovascular and renal events, regardless of a reduced glomerular filtration rate, in patients with type 2 diabetes: a prospective observational study.

Aim: The incidence of cardiovascular and renal events was investigated in patients with type 2 diabetes who were classified according to anemia and the components of dialysis-independent chronic kidney disease (CKD) in a prospective observational study. Methods: A population of 778 Japanese patients with type 2 diabetes was prospectively analyzed for 4 years. The outcomes were the incidence of cardiovascular events and renal events. Results: In all subjects, the incidence of cardiovascular and renal events was found to be 5% and 11%, respectively. Even after adjusting for a reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2), the incidence of cardiovascular events was significantly higher (hazard ratio [HR]: 5.73) in patients with anemia and albuminuria than in those without anemia and albuminuria. The incidence of renal events was significantly higher in patients with no anemia and albuminuria (HR: 2.93) and further in those with anemia and albuminuria (HR: 7.56) than in those without anemia and albuminuria even after adjusting for a reduced eGFR. Conclusion: Anemia combined with albuminuria is a risk factor for vascular events in patients with type 2 diabetes, regardless of the eGFR. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00637-x.

New technique for safer endoscopic submucosal dissection using the duodenal balloon occlusion method.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) enables complete, collective removal of gastrointestinal (GI) malignant tumors, but requires a long operation time. Air insufflated during ESD is distributed throughout the entire GI tract, and thus causes an enlarged feeling of the abdomen. We aimed to reduce the incidence of an enlarged feeling of the abdomen by wedging a balloon in the bulbus duodeni to reduce air flow into the lower parts of the GI tract. METHODS: Sixteen patients who were approved by the institutional ethics committee and provided consent to participate in this single-center, prospective study were divided into two groups using a sealed-envelope randomization method: ESD with a balloon wedged in the bulbus duodeni (the balloon [+] group) or conventional ESD with no balloon (the balloon [-] group). Total air volume in the entire GI tract and its change before and after ESD were measured objectively by 3-D computed tomography. RESULTS: In the balloon (+) group, the mean intestinal gas volume (± standard deviation) was 274.3 ± 142.0 mL before ESD, and 352.5 ± 183.2 mL after, with a mean change of 78.1 ± 139.7 mL. The increase in intestinal gas volume was well controlled. No postoperative complications, such as an enlarged feeling of the abdomen, was reported in the balloon (+) group. CONCLUSIONS: Our new technique has several advantages, including reduction in the frequency of postoperative abdominal symptoms, and will be useful and safe for gastric ESD.

Efficacy of dulaglutide after switching from incretin-related drugs in patients with type 2 diabetes and inadequate glycemic control.

AIMS: The efficacy of dulaglutide was assessed according to the pretreatments administered before the initiation of dulaglutide in patients with type 2 diabetes. METHODS: In total, 89 patients treated using dulaglutide (0.75 mg, once a weekly) were investigated. The subjects were divided into the three groups based on the form in which therapy was started: additional therapy (n = 35), switched from dipeptidyl peptidase-4 (DPP-4) inhibitors (n = 32) and switched from daily glucagon-like peptide-1 receptor agonists (GLP-1 RAs, n = 30). The changes in medication adherence were determined in the daily GLP-1 RAs group using questionnaire surveys. RESULTS: The HbA1c values significantly decreased after the initiation of dulaglutide in all groups (additional therapy group, - 1.4 ± 1.6%; DPP-4 inhibitors group, - 1.2 ± 1.3%; and daily GLP-1 RAs group, - 0.5 ± 0.7%). Forty-six percent of the subjects in the daily GLP-1 RAs group reported that the incidence of forgetting injections of GLP-1 RA was decreased. The reduction of HbA1c was significantly greater in the subjects who reported a decrease in the incidence of forgetting injections (0.9 ± 0.9%) in comparison to those in which there was no change (0.1 ± 0.4%). CONCLUSIONS: Dulaglutide is considered effective in patients with type 2 diabetes and inadequate glycemic control, regardless of whether their pretreatment includes daily GLP-1 RA treatment.

Constipation Is a Frequent Problem Associated with Vascular Complications in Patients with Type 2 Diabetes: A Cross-sectional Study.

Objective Diabetes is recognized as an underlying disease of constipation. However, the prevalence of constipation varies according to the diagnostic criteria applied. We investigated the prevalence of constipation based on the new guideline for constipation in Japanese patients with type 2 diabetes and examined the relationship with the clinical background, including diabetic vascular complications. Methods Questionnaire surveys including items concerning the diagnosis and treatment status of constipation were administered to 410 patients with type 2 diabetes. Results Although 29% of the patients considered that they had experienced constipation (self-judged), only 14% had consulted a physician about constipation. The prevalence of chronic constipation based on the guideline was 26%. After including laxative users, constipation was finally found in 36%. Despite the use of laxatives (n=81), 51% of the patients were still diagnosed with chronic constipation. Patients with constipation (chronic constipation or laxative use) were significantly older and had a longer duration of diabetes than those without constipation. The body mass index (BMI) of patients with constipation (24.9±3.8 kg/m2) was significantly lower than that of those without constipation (26.3±4.6 kg/m2). Diabetic neuropathy (49% vs. 32%) and coronary heart disease (CHD) (27% vs. 13%) were significantly more frequent in the patients with constipation than in those without constipation. A multivariate logistic regression analysis revealed that gender, BMI, diabetic neuropathy, insulin use, and CHD were significantly associated with constipation. Conclusion An accurate diagnosis of constipation is desirable in patients with type 2 diabetes because constipation is independently associated with CHD.

Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: A retrospective study during 12 months before and after initiation.

AIMS: The safety and efficacy, particularly, the factors associated with the renal prognosis, were assessed over 12 months after the initiation of luseogliflozin therapy in Japanese patients with type 2 diabetes and renal impairment. METHODS: In total, 238 patients treated with luseogliflozin (2.5 mg, once daily) were studied as the safety analysis set. Two hundred and two subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into 3 groups based on the estimated glomerular filtration rate (eGFR): high eGFR (n = 49), normal eGFR (n = 116) and low eGFR (n = 37) groups. RESULTS: The body weight, systolic blood pressure, HbA1c and urinary protein excretion gradually decreased from baseline in all eGFR groups. While the eGFR was significantly reduced from baseline in the high and normal eGFR groups, the eGFR did not significantly differ over time in the low eGFR group. There was no marked difference in the frequency of adverse events that were specific for SGLT2 inhibitors among the 3 groups in the safety analysis set. CONCLUSIONS: Luseogliflozin can preserve the renal function in the medium term in patients with type 2 diabetes and renal impairment without an increase in specific adverse events.

A case of adult-onset type II citrullinemia with comorbid epilepsy even after liver transplantation.

The current study using single case voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) and ¹H-MR-spectroscopy (¹H-MRS) explores the neural background of unexplained seizure attacks and electroencephalography (EEG) abnormalities persisting even after liver transplantation in a patient with adult-onset type II citrullinemia (CTLN2). Although the MRI had shown no gross abnormality, the VBM revealed significantly smaller-than-normal regional volume in the left hippocampus of the patient as compared with 111 age-matched controls. ¹H-MRS further indicated reduction of all metabolite concentrations in the left hippocampus compared with those in the right homolog region, with the single exception of elevated glutamate concentration. These results are similar to those of patients with mesial temporal lobe epilepsy (TLE), although CTLN2-complicated mesial TLE has rarely been reported. In contrast to TLE, periictal asterixis and interictal slow activities on EEG support another possibility that the patient might have slight metabolic encephalopathy even after the liver transplantation.

Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression.

The purpose of this study is to use voxel-based analysis to simultaneously elucidate regional changes in gray/white matter volume, mean diffusivity (MD), and fractional anisotropy (FA) in patients with unipolar major depressive disorder. We studied 21 right-handed patients and 42 age- and gender-matched right-handed normal subjects. Local areas showing significant gray matter volume reduction in depressive patients compared with controls were observed in the right parahippocampal gyrus, hippocampus, bilateral middle frontal gyri, bilateral anterior cingulate cortices, left parietal and occipital lobes, and right superior temporal gyrus. Local areas showing an increase of MD in depressive patients were observed in the bilateral parahippocampal gyri, hippocampus, pons, cerebellum, left frontal and temporal lobes, and right frontal lobe. There was no significant difference between the two groups for FA and white matter volume in the entire brain. Although there was no local area where brain volume and MD were significantly correlated with disease severity, FA tended to correlate negatively with total days depressed in the right anterior cingulate and the left frontal white matter. These results suggest that the frontolimbic neural circuit might play an important role in the neuropathology of patients with major depressive disorder.

Reduced gray matter volume of Brodmann's Area 45 is associated with severe psychotic symptoms in patients with schizophrenia.

Previous literature has suggested an important role of inferior frontal gyrus, which mainly consists of Brodmann's Area (BA) 44 and 45, in the pathophysiology of schizophrenia. While recent neuroimaging techniques have revealed differential functional correlates of BA 44 and 45 in healthy individuals, previous studies have not yet separately evaluated the gray matter volume reduction of BA 44 and 45 and their relationships to psychotic symptoms in patients with schizophrenia. In the present study, magnetic resonance images were obtained from 29 right-handed male patients with schizophrenia and from 29 age- and handedness-matched healthy male controls. The reliable manual tracing methodology was employed to measure the gray matter volume of BA 44 and BA 45. The severities of psychotic symptoms were evaluated using the five-factor model of positive and negative syndrome scale in the patient group. A significant gray matter volume reduction of both the BA 44 and BA 45 was found bilaterally in the patients with schizophrenia compared with the healthy controls. Among these inferior frontal sub-regions, reduced volume of right BA 45 revealed the largest effect size. In addition, the reduced volume of BA 45 in left hemisphere showed a significant association with the increased severity of delusional behavior, while the severity of disorganized and positive symptoms were correlated with the bilateral BA 45 volumes in the patient group. The findings support an important role of inferior frontal gyrus in the pathophysiology of schizophrenia. The present study further demonstrated that BA 45 might especially contribute to the production of psychotic symptoms in the patients with schizophrenia.

Gender-common and -specific neuroanatomical basis of human anxiety-related personality traits.

Exploration of the relationships between regional brain volume and anxiety-related personality traits is important for understanding preexisting vulnerability to depressive and anxiety disorders. However, previous studies on this topic have employed relatively limited sample sizes and/or image processing methodology, and they have not clarified possible gender differences. In the present study, 183 (male/female: 117/66) right-handed healthy individuals in the third and fourth decades of life underwent structural magnetic resonance imaging scans and Temperament and Character Inventory. Neuroanatomical correlates of individual differences in the score of harm avoidance (HA) were examined throughout the entire brain using voxel-based morphometry. We found that higher scores on HA were associated with smaller regional gray matter volume in the right hippocampus, which was common to both genders. In contrast, female-specific correlation was found between higher anxiety-related personality traits and smaller regional brain volume in the left anterior prefrontal cortex. The present findings suggest that smaller right hippocampal volume underlies the basis for higher anxiety-related traits common to both genders, whereas anterior prefrontal volume contributes only in females. The results may have implications for why susceptibility to stress-related disorders such as anxiety disorders and depression shows gender and/or individual differences.

Disrupted integrity of the fornix is associated with impaired memory organization in schizophrenia.

BACKGROUND: The fornix is a major projection of the hippocampus to and from other brain regions. A previous diffusion tensor imaging (DTI) study has reported disrupted integrity of the fornix in patients with schizophrenia. However, functional significance of the DTI abnormalities of the fornix in schizophrenia has not been fully studied yet. We investigated an association between DTI abnormalities of the fornix and impairment of memory organization in schizophrenia. METHODS: Thirty-one patients with schizophrenia and 65 age- and gender-matched healthy controls underwent DTI, and fractional anisotropy (FA) and mean diffusivity (MD) were measured in cross-sections of fornix tractography. In addition, all of the patients and 32 controls performed a verbal learning task specialized for evaluating memory organization, the verbal memory subscale of the Wechsler Memory Scale-Revised, the category- and letter fluency tests, and the Japanese version of National Adult Reading Test. RESULTS: Statistically significant reduction of FA and increase of MD were found in the fornix of patients with schizophrenia compared with controls with no significant lateralization. A significant patients-specific correlation was found between increased MD in the left fornix and lower scores on utilization of semantic organization in the verbal learning task. In addition, increased MD in the right fornix showed a patients-specific association with poorer performance on the category fluency test, which indexes organization of long-term semantic memory. These patients-specific correlations, however, were not statistically lateralized to either hemisphere. CONCLUSIONS: These results indicate that disrupted integrity of the fornix contributes to impaired memory organization in schizophrenia.

Esophageal function worsens with long duration of diabetes.

BACKGROUND: The aim of this study was to assess the relationship between the duration of diabetes and esophageal dysfunction. METHODS: We examined 66 patients with type 2 diabetes. Duration of diabetes was determined by asking patients and from their medical records. The patients were divided into three groups according to the duration of their diabetes: group A, 1-4 years, n=26; group B, 5-9 years, n=20; and group C, 10+ years, n=20. Ambulatory esophageal 24-h pH and motility were monitored, and gastroesophageal reflux and esophageal motility disorders were estimated in detail. RESULTS: When the duration of diabetes was long, the percentage of time with pH<4 tended to increase. The amplitude of esophageal peristaltic waves and the frequency of effective peristalsis were reduced when the duration of diabetes was long. A significant correlation was observed between the duration of diabetes and the frequency of effective peristalsis. The number of esophageal peristaltic waves per minute and the percentage of multipeaked peristaltic waves increased significantly in group B, and decreased when the duration of diabetes became longer. CONCLUSIONS: Gastroesophageal reflux and esophageal motility disorders worsened with long duration of diabetes. These esophageal dysfunctions should be considered in patients with long-standing diabetes.

Sequential assessment of the intrahepatic expression of epidermal growth factor and transforming growth factor-beta1 in hepatofibrogenesis of a rat cirrhosis model.

Responses of the liver to chronic injury include inflammation, regeneration and fibrosis, which finally lead to cirrhosis. The cause of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage, and subsequent accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). Epidermal growth factor (EGF) and transforming growth factor-beta1 (TGF-beta1) play a crucial role in hepatocyte proliferation and hepatofibrogenesis, respectively. However, sequential analyses of the intrahepatic expression of EGF and TGF-beta1 in the course of cirrhosis development have not been examined fully. In the present study, liver cirrhosis was produced in rats by intraperitoneal administration of dimethylnitrosamine (DMN), and intrahepatic mRNA expression levels of proliferating cell nuclear antigen (PCNA), EGF and TGF-beta1 were quantitatively estimated by a real-time reverse transcription-polymerase chain reaction method. Histological and semiquantitative densitometric examination of liver sections revealed that the accumulation of extracellular matrix components was increased according to the period of DMN treatment. Histological examination of liver sections of rats treated with DMN for 4 and 6 weeks revealed pre-cirrhosis and cirrhosis, respectively. Intrahepatic mRNA expression levels of PCNA and EGF correlated well. Expression levels of both molecules were increased significantly during the course of cirrhosis development, but decreased significantly at the time of complete cirrhosis manifestation. In contrast, intrahepatic TGF-beta1 expression was increased significantly according to the period of DMN treatment, and reached a peak at the time of cirrhosis manifestation. These results suggest that proliferative capability of hepatocytes was impaired by continuous liver damage due, in part, to the decrease of a hepatocyte mitogen EGF, and that increased intrahepatic TGF-beta1 activated HSCs to retrieve space lost by hepatocyte destruction, resulting in complete cirrhosis manifestation.