Discriminative Ability of Dynamic Chest Radiography to Identify Left Ventricular Dysfunction.

BACKGROUND: Dynamic chest radiography (DCR) produces sequential radiographs within a short examination time. It is also inexpensive and only uses a low dose of radiation. Because of the lack of reports of evaluating cardiac function using DCR in humans, we investigated its discriminative ability for left ventricular (LV) dysfunction in a study cohort.Methods and Results: We analyzed the DCR pixel values of 4 circular regions of interest (ROIs) in the hearts of 61 patients with cardiovascular disease and 10 healthy volunteers. We evaluated the relationship between changes in pixel value in the heart and the LV ejection fraction (LVEF) by echocardiography. We constructed receiver operating characteristic (ROC) curves to evaluate whether the percent change in pixel value (%∆pixel value) could be used to identify patients with reduced LVEF. A total of 21 patients had reduced LVEF (LVEF <50%), and 40 had preserved LVEF (LVEF ≥50%). The correlation between LVEF and %∆pixel value in each ROI was significant, and the area under the ROC curve of the %∆pixel values for identifying patients with reduced LVEF was satisfactory (0.808-0.827) in 3 ROIs where the entire circular area was within the cardiac shadow. CONCLUSIONS: LV dysfunction can be detected by changes in the pixel value on DCR.

Aberrant bone marrow-derived microglia in the hypothalamus may dysregulate appetite in diabetes.

Bone marrow derived cells (BMDCs) migrate into the hypothalamus, where those cells give rise to microglia to regulate food intake. Given the fact that diabetes functionally impairs BMDCs, we hypothesized that diabetic microglia would fail to exhibit physiological function, accounting for hyperphagia in diabetes. To examine the role of BMDCs, total bone marrow cells from GFP transgenic mice were transplanted into wild type mice in which diabetes was induced by streptozotocin. We first confirmed that bone marrow transplantation could be utilized to examine BMDCs in the brain parenchyma as GFP positive cells could engraft the brain parenchyma and give rise to microglia even when the BBB was intact in the recipient mice. While diabetic mice manifested hyperphagia, BMDCs were in smaller number in the hypothalamus with less response to fasting in the brain parenchyma compared to nondiabetic mice. This finding was also confirmed by examining nondiabetic chimera mice in which BMDCs were diabetic. Those mice also exhibited less response of BMDCs in response to fasting. In conclusion, diabetic BMDCs had less response of microglia to fasting, perhaps accounting for diabetic hyperphagia.

Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice.

Despite the growing epidemic worldwide, diabetes is an incurable disease. We have been focusing on why diabetes manifests refractoriness to any therapy. We recently found that abnormal bone marrow-derived cells (BMDCs), namely, Vcam-1+ST-HSCs, was a key mechanism for diabetic complications. We then hypothesize that those aberrant BMDCs sustainedly impair pancreatic ß cells. Here we show that eliminating abnormal BMDCs using bone marrow transplantation results in controlling serum glucose in diabetic mice, in which normoglycemia is sustained even after cessation of insulin therapy. Alternatively, abnormal BMDCs exhibiting epigenetic alterations are treated with an HDAC inhibitor, givinostat, in diabetic mice. As a result, those mice are normoglycemic along with restored insulin secretion even following the cessation of both insulin and givinostat. Diabetic cell fusion between abnormal BMDCs and resident cells is significantly blocked by the combination therapy in the pancreatic islets and thymus while surgical ablation of the thymus completely eliminates therapeutic protection in diabetic mice. In conclusion, diabetes is an epigenetic stem cell disorder with thymic disturbances. The combination may be applied to patients aiming at complete remission from diabetes in clinical medicine.

Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion.

Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy.

Impact of abdominal aortic calcification on 90-day mortality in sepsis patients: a pilot retrospective cohort study.

AIM: We aimed to investigate the association between aortic calcification and 90-day mortality in sepsis patients admitted to the intensive care unit. METHODS: We evaluated adult patients (≥18 years) diagnosed with sepsis based on the Sepsis-3 criteria and admitted to our intensive care unit between April 2011 and March 2015. They were classified according to the degree of abdominal aortic calcification (severe and non-severe), grouped per age (<65, 65-75, and >75 years), and matched. Survival curves were generated, and between-group differences were evaluated. RESULTS: Overall, 164 patients were included. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were not significantly different between the severity groups, whereas there were significant differences in age (P < 0.001), sex (P = 0.017), and presence of diabetes mellitus (P < 0.001), hypertension (P < 0.001), dyslipidemia (P = 0.048), and maintenance dialysis (P = 0.001). The severe abdominal aortic calcification group showed significantly poorer prognosis than the non-severe group (log-rank P = 0.009). The adjusted odds ratio of severe calcification was the highest in patients aged <65 years (7.167; 95% confidence interval, 1.042-49.28, P = 0.045). Twenty-eight patients from each group were matched. The 90-day survival rate of the severe calcification group remained significantly lower than that of the non-severe calcification group (53.6% [15/28] versus 82.1% [23/28], P = 0.022). CONCLUSIONS: Severe abdominal aortic calcification is associated with the 90-day mortality of sepsis patients, particularly among those aged <65 years. Thus, caution is necessary in patients younger than 65 years; they may need to be treated with as much care as the elderly.

Detection of Pulmonary Embolism Using a Novel Dynamic Flat-Panel Detector System in Monkeys.

BACKGROUND: Recently, dynamic chest radiography (DCR) was developed to evaluate pulmonary function using a flat-panel detector (FPD), which can evaluate blood flow in the pulmonary artery without injection of contrast agents. This study investigated the ability of a FPD to measure physiological changes in blood flow and to detect pulmonary embolism (PE) in monkeys.Methods and Results:DCR was performed in 5 monkeys using a FPD. Regions of interest (ROI) were placed in both lung fields of the image, and maximum changes in pixel value (∆pixel value) in the ROI were measured during 1 electrocardiogram cardiac cycle. Next, a PE model was induced using a Swan-Ganz catheter and additional images were taken. The ∆pixel value of the lungs in normal and PE models were compared in both supine and standing positions. The lung ∆pixel value followed the same cycle as the monkey electrocardiogram. ∆pixel values in the upper lung field decreased in the standing as compared to the supine position. In the PE model, the ∆pixel value decreased in the area of pulmonary blood flow occlusion and increased in the contralateral lung as compared to the normal model (normal model 1.287±0.385, PE model occluded side 0.428±0.128, PE model non-occluded side 1.900±0.431). CONCLUSIONS: A FPD could detect postural changes in pulmonary blood flow and its reduction caused by pulmonary artery occlusion in a monkey model.

Association between plasma complement factor H concentration and clinical outcomes in patients with sepsis.

AIM: The complement system is important for defending against pathogens, however, excessive complement activation is associated with a poor prognosis and organ dysfunction in sepsis. Complement factor H (CFH) acts to prevent excessive complement activation and damage to the self through the regulation of the complement alternative pathway. We investigated the association between plasma CFH levels on admission to the intensive care unit (ICU) and 90-day mortality, severity scores, and organ dysfunction in patients with sepsis. METHODS: We assessed the relationship between the plasma CFH on admission to the ICU and 90-day mortality, severity scores such as the Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, and Simplified Acute Physiology Score 2, and organ dysfunction. RESULTS: This analysis included 62 patients. The plasma CFH levels were significantly lower in 90-day non-survivors than in survivors (70.0 µg/mL [interquartile range, 51.2-97.6] versus 104.8 µg/mL [interquartile range, 66.8-124.2]; P = 0.006) . The plasma CFH levels were associated with 90-day mortality (odds ratio 0.977; 95% confidence interval, 0.957-0.994; P = 0.01). The plasma CFH levels were negatively correlated with severity scores. The Sequential Organ Failure Assessment scores for the coagulation and neurological components were negatively correlated with the CFH concentration. CONCLUSION: Lower plasma levels of CFH were associated with increased severity and mortality in patients with sepsis on admission to the ICU and were correlated with central nervous system dysfunction and coagulopathy.

"Impact of timing of polymyxin B-immobilized fiber column direct hemoperfusion on outcome in patients with septic shock: a single-center observational study".

AIM: The effect of polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) is controversial. The present study investigates whether outcome in septic shock patients is affected by the time until PMX-DHP initiation and the location of the infection site (intra- or extra-abdominal infection (IAI/EAI)]. METHODS: This retrospective observational study included patients receiving PMX-DHP for septic shock but excluded those treated after cardiac surgery or cardiac arrest. Based on the median and/or quartile time from catecholamine treatment to PMX-DHP initiation, the patient cohort was divided into four groups and the IAI and EAI groups into two subgroups. RESULTS: Among the 49 eligible patients, overall 90-day mortality in group 1 (PMX-DHP within 6 h) at 8.3% was significantly lower than in groups 2 (6-9 h; 46.1%), 3 (9-29 h; 58.3%) and 4 (>29 h; 75.0%) (P = 0.021). Multivariate logistic regression analysis showed that the duration from catecholamine treatment to PMX-DHP initiation correlated with 90-day mortality (odds ratio 1.060; 95% confidence interval, 1.004-1.117; P = 0.028). Among the 29 IAI patients, 90-day mortality was significantly lower in the early (within 9 h) than the late group (>9 h) (13.3% versus 64.2%; P = 0.003), but no significant intergroup difference was noted among the 20 EAI patients. CONCLUSION: Our results suggest that early PMX-DHP initiation (within 9 h after catecholamine treatment) reduces mortality from septic shock, especially in IAI patients.

Association between physician-staffed ambulances and patient prognoses after out-of-hospital cardiac arrests with respect to shockable and non-shockable rhythms: a retrospective observational study in a southern area of Shiga Prefecture Japan.

AIM: Out-of-hospital cardiac arrests (OHCA) are a significant public health problem; to improve patients' prognoses, various interventions, such as providing physician-staffed ambulances, have been implemented. We aimed to examine whether physician-staffed ambulances were associated with patients' prognoses after OHCA with respect to first-monitored rhythms. METHODS: This retrospective observational study was undertaken between 1 September 2011 and 31 December 2015, using data based on Utstein-style guidelines. We extracted data on age, sex, first-monitored rhythm (shockable or non-shockable), presence of a witness, bystander cardiopulmonary resuscitation, time from call to arrival at the scene, out-of-hospital adrenaline administration, out-of-hospital intubation, return of spontaneous circulation before arrival at the hospital, and survival and neurological outcomes 30 days after OHCA, according to cerebral performance categories. We undertook logistic regression analyses to assess the association between physician-staffed ambulances and patients' prognoses. RESULTS: A total of 882 OHCA patients were eligible for this study. Physician-staffed ambulances attended to 164 OHCA patients. Multivariable analysis found that in non-shockable rhythm patients, physician-staffed ambulances significantly improved good neurological outcome (odds ratio, 3.65; 95% confidence interval [CI], 1.28-10.50; P = 0.02), return of spontaneous circulation before arrival at the hospital (odds ratio, 2.68; 95% CI, 1.62-4.42; P < 0.001), and 30-day survival (odds ratio, 2.90; 95% CI, 1.30-6.45; P = 0.009). However, physician-staffed ambulances were not associated with patient prognoses in shockable rhythm patients. CONCLUSION: Despite our study's limitations, physician-staffed ambulances might be associated with good neurological outcomes in non-shockable rhythm patients. Our observations could provide more appropriate prehospital treatment options for OHCA patients.

Effects of Serum Albumin Levels on Antithrombin Supplementation Outcomes Among Patients With Sepsis-Associated Coagulopathy: A Retrospective Study.

BACKGROUND: Severe sepsis is commonly associated with mortality among critically ill patients and is known to cause coagulopathy. While antithrombin is an anticoagulant used in this setting, serum albumin levels are known to influence serum antithrombin levels. Therefore, this study aimed to evaluate the outcomes of antithrombin supplementation in patients with sepsis-associated coagulopathy, as well as the relationship between serum albumin levels and the effects of antithrombin supplementation. METHODS: This retrospective study evaluated patients who were >18 years of age and had been admitted to either of two intensive care units for sepsis-associated coagulopathy. The groups that did and did not receive antithrombin supplementation were compared for outcomes up to 1 year after admission. Subgroup analyses were performed for patients with serum albumin levels of <2.5 g/dL or ⩾2.5 g/dL. RESULTS: Fifty-one patients received antithrombin supplementation and 163 patients did not. The Cox proportional hazards model revealed that antithrombin supplementation was independently associated with 28-day survival (hazard ratio [HR]: 0.374, P = 0.025) but not with 1 year survival (HR: 0.915, P = 0.752). In addition, among patients with serum albumin levels of <2.5 g/dL, antithrombin supplementation was associated with a significantly lower 28-day mortality rate (9.4% vs 36.8%, P = .009). CONCLUSION: Antithrombin supplementation may improve short-term survival, but not long-term survival, among patients with sepsis-associated coagulopathy.

An evaluation of clinical inflammatory and coagulation markers in patients with sepsis: a pilot study.

AIM: Presepsin values could assist early diagnosis and prognosis of sepsis. In sepsis, prognosis is determined according to multiple organ dysfunction, where coagulopathy is common and associated with prognosis. This study aimed to determine the correlation between presepsin value trend and prognosis, and investigate coagulation abnormality in sepsis. METHODS: We retrospectively examined 18 intensive care unit patients diagnosed with sepsis whose presepsin values at admission were ≥500 ng/mL. If presepsin values had decreased ≥50% on hospital day 6, compared to admission values, the patient was allocated into a decreased presepsin group. RESULTS: Presepsin values in non-survivors with sepsis were significantly higher than in survivors on day 6 (P = 0.022). No significant differences in procalcitonin or C-reactive protein were identified between survivors and non-survivors, and platelet counts were significantly lower in non-survivors on days 0, 3, and 6 (P = 0.001, P < 0.001, and P = 0.001, respectively). The 90-day mortality rate in a decreased presepsin group significantly improved, even when presepsin values were high on admission (P = 0.012). Platelet counts were significantly lower on all hospital days in the non-decreased presepsin group. CONCLUSION: Fifty percent decrease in presepsin levels could be a useful prognostic predictor of sepsis. Larger studies are required to confirm our findings.

Association between lymphocyte count and neurological outcomes in post-cardiac arrest patients treated with mild therapeutic hypothermia.

AIM: To examine lymphocyte counts as a predictive prognostic marker in patients with coma after cardiac arrest. METHODS: We retrospectively evaluated patients with coma after cardiac arrest admitted to the intensive care unit of Shiga University of Medical Science (Otsu, Japan). Lymphocyte counts were measured for 6 days from admission. Neurological outcome was assessed as favorable or unfavorable using cerebral performance categories. Associations between lymphocyte count and prognosis were investigated using multivariate logistic regression analysis and receiver operating characteristic curves. RESULTS: Forty-six patients were assessed from February 2012 to December 2016. Survivors had significantly higher lymphocyte counts than non-survivors on days 2 and 5. Multivariate analysis showed that lymphocyte count was not associated with 90-day mortality. Patients with favorable neurological outcome at discharge had significantly higher lymphocyte counts on days 2-6 than patients with unfavorable outcomes. Multivariate logistic regression analysis, including possible confounders, showed that lymphocyte counts on days 2-4 and 6 were associated with neurological outcome (day 2: odds ratio [OR] = 0.75, 95% confidence interval [CI] = 0.58-0.97, P = 0.029; day 3: OR = 0.68, 95% CI = 0.47-0.98, P = 0.04; day 4: OR = 0.4, 95% CI = 0.16-1.00, P = 0.05; day 6: OR = 0.69, 95% CI = 0.48-0.99, P = 0.046). Receiver operating characteristic curve analysis indicated high accuracy for predicting neurological outcome for each lymphocyte count on days 2-6 using the area under the curve, day 4 values being most accurate (day 2: 0.776, day 3: 0.787, day 4: 0.909, day 5: 0.774, day 6: 0.839). CONCLUSION: Lymphocyte counts on days 2-4 and 6 after cardiac arrest are associated with neurological outcome; counts on day 4 most accurately predict neurological outcome.

Variation of Risk Factors for Cause-Specific Reintubation: A Preliminary Study.

Unexpected reintubation may occur, even if the risk factors are considered and a spontaneous breathing trial is successful. Reintubation is thought to be caused by various factors. Several studies have investigated the risk factors of reintubation, but most did not classify reintubation by cause. We retrospectively classified patients undergoing reintubation at intensive care unit by cause (respiratory insufficiency vs. nonrespiratory insufficiency) to examine the cause-specific risk factors of reintubation. A total of 262 patients were included; reintubation within 48 hours after extubation was performed in 12 patients (reintubation rate, 4.5%). After classification by cause of reintubation, the pressure of arterial oxygen to fractional inspired oxygen concentration (P/F) ratio exhibited a significant association with reintubation only in the respiratory insufficiency group (odds ratio (OR) 0.989, 95% confidence interval (CI) 0.980 to 0.999, p=0.036, and OR 0.989, 95% CI 0.979 to 0.999, p=0.026, in the univariate and multivariate analyses, respectively). In the propensity score analysis, a P/F ratio ≤ 200 may be a risk factor for reintubation in the respiratory insufficiency group (OR 7.811, 95% CI 1.345 to 45.367, p=0.022). In the nonrespiratory insufficiency group, intubation duration was significantly related to reintubation (OR 1.165, 95% CI 1.012 to 1.342, p=0.033, and OR 1.163, 95% CI 1.004 to 1.348, p=0.044, in the univariate and multivariate analyses, respectively). In conclusion, a low P/F ratio at extubation may be a risk factor for reintubation due to respiratory insufficiency. In the nonrespiratory insufficiency group, intubation duration may be significantly related to reintubation. The risk factors for reintubation may differ by the cause of reintubation. Further large-scale randomized controlled trials are required.

Dexmedetomidine attenuates the positive chronotropic effects of intravenous atropine in patients with bradycardia during spinal anaesthesia: a retrospective study.

INTRODUCTION: Dexmedetomidine is a sedative used during spinal anaesthesia. However, it frequently induces bradycardia. Although intravenous atropine is often used for treating bradycardia during regional anaesthesia, the response to atropine might be attenuated by concomitantly administering sedatives. METHODS: We examined the effects of atropine used for treating bradycardia during spinal anaesthesia among patients receiving dexmedetomidine (D group), propofol (P group), or neither (nonDnonP group) for sedation, retrospectively. RESULTS: A total of 108 patients were included. Heart rate was significantly slower at all time points in the D group (n = 69) than in the nonDnonP group (n = 14) (p <  0.025 for all). On the other hand, heart rate was significantly slower only 60 min after administration of atropine in the P group (n = 25) than in the nonDnonP group (p = 0.002). There were differences in the overall values of heart rate (including all the values from time 0 to 60 min) among the three groups (p = 0.026). CONCLUSIONS: The positive chronotropic effects of atropine might be attenuated with the use of dexmedetomidine or propofol during spinal anaesthesia. Although atropine may be administered when bradycardia occurs, a dose of atropine might result in an insufficient effect against the bradycardia. The sufficient number of subjects may change the results of the investigation, and large-scale randomised controlled trials will be necessary.

Analysis of seasonal differences in emergency department attendance in Shiga Prefecture, Japan between 2007 and 2010.

Aim: Emergency department overcrowding is problematic. Some emergency departments have established a triage system to prevent overcrowding; however, effective management of a triage system requires knowledge of factors that influence emergency department attendance. Therefore, we investigated the effect of ambient temperature on emergency department attendance, as well as the types of patients that may have been affected. Methods: Data on emergency department attendance at Shiga University of Medical Science Hospital (Otsu, Japan) were retrospectively collected from 1 April, 2007 to 31 March, 2010. Attendance was classified into eight categories based on a combination of symptoms (trauma or non-trauma), transport (by ambulance or walk-in), and severity (serious or non-serious). Results: A total of 7,755 patients (4,120 [53.1%] men and 3,635 [46.9%] women) attended the emergency department during the study period. Statistically significant seasonal differences were observed in emergency department attendance in walk-in and non-serious groups of both trauma and non-trauma patients (P < 0.01), with the smallest differences occurring during winter. In a linear regression model, the mean ambient temperature had a positive correlation with emergency department attendance only in the walk-in and non-serious group of non-trauma patients during the summer (y = 0.092 × [mean ambient temperature] - 0.565). Conclusion: In the walk-in and non-serious group of non-trauma patients, emergency department attendance significantly increased with the increase in mean ambient temperature during summer. In emergency department triage systems, it may be more effective to evaluate non-trauma and walk-in patients during summer, especially on hot days.

Association of the Plasma Platelet-Derived Microparticles to Platelet Count Ratio with Hospital Mortality and Disseminated Intravascular Coagulopathy in Critically Ill Patients.

AIM: The role of platelet-derived microparticles (PDMPs) in the crosstalk between coagulopathy and inflammation in critically ill patients remains unclear. The aim of this cohort observational study was to investigate the associations between the PDMP levels and hospital mortality or disseminated intravascular coagulopathy (DIC). METHODS: This study included 119 patients who were admitted to the ICU. The PDMP levels were measured using an enzyme-linked immunosorbent assay three times a week, for a total of 372 samples. We calculated the maximum (max) PDMP value, max PDMP/platelet (PDMP/Plts) ratio (converted to the PDMP levels per 10(4) platelets) and nadir platelet count during the ICU stay. Baseline patient data and scores, including the Japanese Association for Acute Medicine (JAAM) DIC score, were collected, and potential predictors were analyzed for possible associations with hospital mortality. RESULTS: The max PDMP/Plts ratio was significantly different comparing the survivors (n=98: median, 2.54) and non-survivors (n=21: median 17.59; p＜0.001). There was a weak but statistically significant negative correlation between the max PDMP level and nadir platelet count (r=-0.332, p＜0.001). The max PDMP level and max PDMP/Plts ratio were higher in the DIC group (81.48 and 9.27, respectively) than in the non-DIC group (34.88 and 2.35, p=0.001 and p＜0.001, respectively). The max PDMP/Plts ratio was the only variable found to be independently associated with hospital mortality according to a multivariate logistic regression analysis. CONCLUSIONS: PDMPs are involved in the development of DIC but are not related to hospital mortality. There is a good association between the PDMP/Plts ratio and hospital mortality and/or DIC in critically ill patients.

Pre-synaptic localization of the γ-secretase-inhibiting protein p24α2 in the mammalian brain.

Dysregulated metabolism and consequent extracellular accumulation of amyloid-ß (Aß) peptides in the brain underlie the pathogenesis of Alzheimer's disease. Extracellular Aß in the brain parenchyma is mainly secreted from the pre-synaptic terminals of neuronal cells in a synaptic activity-dependent manner. The p24 family member p24α2 reportedly attenuates Aß generation by inhibiting γ-secretase processing of amyloid precursor protein; however, the pattern of expression and localization of p24α2 in the brain remains unknown. We performed immunohistochemical staining and subcellular fractionation for p24α2 in the mouse brain. Immunostaining showed that p24α2 is broadly distributed in the gray matter of the central nervous system and is predominantly localized to synapses. Subcellular fractionation revealed prominent localization of p24α2 in the pre-synaptic terminals. Immunoisolation of synaptic vesicles (SV) indicated that p24α2 is condensed at active zone-docked SV. During development, p24α2 expression is highest in the post-natal period and gradually decreases with age. We also confirmed that amyloid precursor protein and γ-secretase components are localized at active zone-docked SV. Our results suggest a novel functional role for p24α2 in the regulation of synaptic transmission and synaptogenesis, and provide evidence for the participation of p24α2 in the regulation of Aß generation and secretion in the brain. The p24 family member p24α2 attenuates amyloid-ß (Aß) generation by inhibiting the γ-secretase processing. We report that p24α2 is condensed at active zone-docked synaptic vesicles in the brain. p24α2 expression is highest in the post-natal period and gradually decreases with age. Our results suggest a novel function for p24α2 at the synapse, including the regulation of brain Aß generation.

Haematopoietic cells produce BDNF and regulate appetite upon migration to the hypothalamus.

Brain-derived neurotrophic factor (BDNF) suppresses food intake by acting on neurons in the hypothalamus. Here we show that BDNF-producing haematopoietic cells control appetite and energy balance by migrating to the hypothalamic paraventricular nucleus. These haematopoietic-derived paraventricular nucleus cells produce microglial markers and make direct contacts with neurons in response to feeding status. Mice with congenital BDNF deficiency, specifically in haematopoietic cells, develop hyperphagia, obesity and insulin resistance. These abnormalities are ameliorated by bone marrow transplantation with wild-type bone marrow cells. Furthermore, when injected into the third ventricle, wild-type bone marrow mononuclear cells home to the paraventricular nucleus and reverse the hyperphagia of BDNF-deficient mice. Our results suggest a novel mechanism of feeding control based on the production of BDNF by haematopoietic cells and highlight a potential new therapeutic route for the treatment of obesity.

Ghrelin family of peptides and gut motility.

Acyl ghrelin, des-acyl ghrelin, and obestatin are three peptides isolated from the gastrointestinal tract and encoded by the same preproghrelin gene. Three ghrelin gene products participate in modulating appetite, adipogenesis, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. We have investigated the effects of ghrelin family of peptides on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats by manometric method. Intracerebroventricular (ICV) and intravenous (IV) administration of acyl ghrelin induced fasted motor activity in the duodenum in fed rats. ICV and IV administration of des-acyl ghrelin disrupted fasted motor activity in the antrum. Changes in gastric motility induced by IV administration of des-acyl ghrelin were antagonized by ICV administration of a corticotropin-releasing factor (CRF) 2 receptor antagonist. IV administration of obestatin decreased the percentage motor index in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats. ICV administration of CRF 1 and 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Ghrelin gene products regulate feeding-associated gastroduodenal motility. Stomach may regulate various functions including gastrointestinal motility via acyl ghrelin, des-acyl ghrelin and obestatin as an endocrine organ. Increasing knowledge of the effects of ghrelin family of peptides on gastrointestinal motility could lead to innovative new therapies for functional gastrointestinal disorders.

Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine.

BACKGROUND: Interstitial cells of Cajal (ICCs), which express c-Kit receptor tyrosine kinase (KIT), play an important role in gastrointestinal motility. Loss of ICCs likely contributes to diabetic gastrointestinal motility disorder, however, the mechanism of attrition remains unknown. Here, we test the hypothesis that the bone marrow-derived progenitors are an important source of intestinal ICCs and that decreased homing of these progenitors in diabetes contributes to ICC diminution. METHODS: Wild type mice were X-ray irradiated, transplanted with bone marrow (BMT) from green fluorescence protein (GFP)-transgenic (TG)-mice and subsequently made diabetic by streptozotocin (STZ) injection. Intestinal homing of GFP-positive bone marrow-derived cells was examined 2 or 5 months after STZ treatment. RESULTS: In the BMT-mice, we found many GFP-positive bone marrow-derived cells (BMDCs) in most parts of the intestinal area, the number of BMDCs was significantly decreased in diabetic mice compared with nondiabetic controls. As a representative area, we further examined the myenteric plexus of the proximal small intestine, and found that the cell numbers of ICCs marked by c-Kit-positive immunoreactivity were decreased by more than 40% in diabetic versus nondiabetic mice. Furthermore, numbers of c-Kit+/GFP+ and c-Kit+/GFP- cells were similar in nondiabetic mice, and decreased by 45.8% and 42.0%, respectively, in diabetic mice. CONCLUSION: These results suggest that the decreased homing from the bone marrow is a major cause of ICC loss in the intestine in diabetes mellitus.