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Purpose: This study was performed to determine the relationship between oral-mucosal pressure ulcer (PU) stage and mechanical conditions and individual susceptibility in intubated patients. Methods: We collected 80 patient-days data from an intensive care unit of a 700-bed hospital in Korea. We analyzed oral-mucosal PUs, medical records, amount of saliva, and oral mucosal swabs. Bacterial abundance was enumerated by real-time polymerase chain reaction. The χ2 or Fisher’s exact test, t-test or Mann-Whitney U test, and Spearman’s rho correlation analysis were performed. Results: The incidence of overall oral-mucosal PUs was 31.3%, and in the maxillary and mandibular sites were 16.3% and 26.3%, respectively. There were significant correlations between the maxillary site PU stage and restraint use (r = .43, p < .001), albumin level (r = −.22, p = .046), and relative abundance of P. aeruginosa (r = .45, p < .001) and S. aureus (r = −.24, p = .033). In the mandibular sites, there were significant correlations between PU stage and restraint use (r = .30, p = .008), level of consciousness (r = .31, p = .005), and relative abundance of P. aeruginosa (r = .25, p = .028) and S. pneumoniae (r = .22, p = .046). Conclusions: Frequent monitoring and repositioning the mechanical pressure on the oral-mucosa could be an effective preventive strategy against the development and advancement of oral-mucosal PUs. Additionally, monitoring the oral microorganisms can prevent advanced stage oral-mucosal PUs in intubated patients.

Highlights • The pathogenesis of MRONJ is related to repression of osteoclast mediated bone remodeling. • rhBMP-2 can stimulate not only osteoblasts but also osteoclasts and induce new bone formation. • ACS has been proved to be a good carrier of rhBMP-2 with maximal efficacy. • Application of rhBMP-2/ACS can be a new approach to surgical treatment for MRONJ patients., Introduction The purpose of this study was to pursue, and to report the results of, mandibular reconstruction and rehabilitation of medication-related osteonecrosis of the jaw (MRONJ) patients having large critical-sized defects of the mandible using a combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) and absorbable collagen sponge (ACS) with surgical miniplate without any grafting materials. Case presentation Three (3) patients aged 67 and 86 (2 patients) presented due to discomfort on the mandible. They all had a medical history of bisphosphonate and steroids treatment orally or intravenously, and all had been diagnosed as MRONJ stage 3. Sequestrectomy and saucerization were performed, and then a surgical miniplate (Hansolmedical, Korea) was adapted and fixed on the sound portion of the mandible. rhBMP-2 was loaded onto an ACS at a dose of 1.5 mg/cc. Several rhBMP-2 (Cowellmedi, Korea)/ACS (Ateloplug, TRMkorea, Korea) were placed into the bony defect with a surgical miniplate. All 3 patients recovered without complications. They all exhibited radiographic evidence of bone formation by 3 months postoperatively in every case. Conclusions All 3 patients were treated successfully with rhBMP-2/ACS and miniplate without any complications. This protocol reported herein represents a new approach to the surgical treatment of maxillofacial bone defects and deficiencies, especially in MRONJ patients.

Purpose To investigate the relationship between carotid arterial calcium score (CarACS) and silent cerebrovascular lesions in patients with obstructive sleep apnea (OSA). Materials and Methods This study involved retrospective evaluation of 60 OSA patients who underwent both upper airway CT and brain MRI. Using polysomnography, several indicators, including apnea index (AI), were used to evaluate the relationship between OSA and silent cerebrovascular lesions. The CarACS was quantified on CT imaging using the modified Agatston method. Silent cerebrovascular lesions were evaluated on brain MRI by grading periventricular hyperintensity (PVH). Various clinical characteristics, including age, were analyzed in each patient. Results The number of patients per PVH grade 0, 1, 2, 3, and 4 was 26 (43.3%), 14 (23.3%), 14 (23.3%), 4 (6.7%), and 2 (3.3%), respectively. The mean age, hypertension, smoking status, AI, and CarACS were significantly different among PVH groups (Ps < 0.05). In univariate analysis, the presence of carotid arterial calcification (β = 0.483, p < 0.01), CarACS (β = 0.482, p < 0.01), and age (β = 0.360, p < 0.01) showed a significant association with PVH grade. The mean AI and lowest O2 saturation had statistically weak associations with PVH grade (β = 0.267, p < 0.01; β = -0.219, p < 0.14, respectively). In multivariate analysis, CarACS was the only factor affecting PVH grade (p < 0.04). Conclusion CarACS is associated with the severity of silent cerebrovascular lesions. Therefore, additional analysis of CarACS in OSA patients may provide more information on their cerebrovascular status.

Background The purpose of this retrospective study was to evaluate the postoperative change in the position and stability of the mandibular condyle after bilateral sagittal split ramus osteotomy (BSSRO) and BSSRO with distal segmental ostectomy (DSO) in patients with facial asymmetry using 3D computed tomography. Methods The condyles of the patient diagnosed with facial asymmetry were divided into the deviated side (DS) and the non-deviated side (NDS). Group I, which was treated with BSSRO only, and Group II, which additionally received DSO along with BSSRO, were superimposed on the condyle using the pre-and postoperative 3D CT. The amount of condylar change in anteroposterior displacement, mediolateral displacement, and rotation was measured. The clinical symptoms of temporomandibular joint were also evaluated before and after surgery for each patient. Results Between Groups I and II, there was no statistically significant difference in the anteroposterior condylar position on both DS and NDS. And also, there was no statistical difference between the two groups in the mediolateral change on DS but, statistically significant difference on NDS. The change in the rotation of the condyle was observed to rotate inward from both condylar heads of Groups I and II, and a statistically significant difference was observed between the two groups on both DS and NDS. Moreover, no difference in clinical temporomandibular joint symptoms was observed after surgery in each DS and NDS condyle of the two groups. Conclusions As a result of analyzing the condylar position change of the group treated with BSSRO alone and the group treated with BSSRO and DSO in patients with facial asymmetry, there were statistically significant differences in the mediolateral displacement of NDS and the condyle rotation of NDS and DS. However, the anteroposterior condylar position did not show any difference in the bilateral condyles. In addition, since worsening clinical symptoms of bilateral temporomandibular joint were not observed before and after surgery in both groups, it is concluded that it is not necessary to accompany DSO in patients with facial asymmetry (minimum 3 mm, maximum 7 mm).

Objective To evaluate the value of airway computed tomography (CT) in patients with obstructive sleep apnea (OSA) as a predictor of cerebrocardiovascular disease (CCVD) clinically, by quantitatively analyzing carotid arterial calcification (CarAC). Materials and methods This study included 287 patients aged 40-80 years, who had undergone both polysomnography (PSG) and airway CT between March 2011 and October 2015. The carotid arterial calcium score (CarACS) was quantified using the modified Agatston method on each upper airway CT. The OSA severity was categorized as normal, mild, moderate, and severe using the PSG results. Clinical characteristics, comorbid diseases, and lipid profiles of all patients were analyzed, and the prevalence of CCVDs was investigated during the follow up period (52.2 ± 16.0 months). Results CCVD occurred in 27 patients (9.3%) at the end of follow-up, and the CCVD-present groups showed a significantly older mean age (57.5 years vs. 54.2 years), higher prevalence of hypertension (59% vs. 34%) and CarAC (51.9% vs. 20.8%), whereas sex, other comorbid diseases, and severity of OSA were not significantly different from the CCVD-absent group. A univariate analysis showed that age, hypertension, incidence of CarAC, and CarACS were risk factors for the occurrence of CCVD events. In a multivariate analysis, the incidence of CarAC was the only independent risk factor for CCVD. Conclusion CarAC is an independent risk factor for CCVD, whereas the severity of OSA is not a contributory risk factor in patients with OSA. Therefore, additional analysis of CarACS based on airway CT scans may be useful for predicting CCVD.

Purpose: This study examined the incidence of oral mucosa pressure ulcers (PUs) in intensive care unit (ICU) patients and the relationship between biomechanical and physiological variables in onset of PUs. Methods: A prospective observational descriptive study design was used. We recruited patients over 18 years of age with endotracheal tube (ETT) insertion in three ICUs in a tertiary hospital in Korea. We analysed 113 patient-days of data. Patient assessments and medical record reviews were conducted to gather biomechanical and physiological data. Fisher's exact tests and χ2 test and Spearman's rank correlations were used to compare data. Results: The highest incidence of oral mucosa PUs occurred in lower oral mucosa (36.3%). There was a significant relationship between lower oral mucosa PU stage and bite-block or airway use (r = .20, p = .036), commercial ETT holder use (r = 0.19, p = .048), sedative use (r = −0.22, p = .022), and plasma protein (r = 0.20, p = .033). Upper oral mucosa PU stage was related to commercial ETT holder use (r = 0.19, p = .044), haemoglobin(r = 0.24, p = .011), haematocrit (r = 0.27, p = .004), and serum albumin (r = −0.24, p = .012). Stage was related to commercial ETT holder use in both sites (r = 0.28, p = .003), haematocrit (r = 0.19, p = .039), and serum albumin (r = −0.23, p = .015). Conclusion: Oral mucosa PUs developed more frequently and healed more quickly than general skin PUs. Taken together, these data indicate that biomechanical and haematological variables are risk factors associated with PU incidence should be considered in intensive care patients.

Targeted temperature management (TTM, 32°C to 36°C) is one of the most successful achievements in modern resuscitation medicine. It has become standard treatment for survivors of sudden cardiac arrest to minimize secondary brain damage. TTM at 36°C is just as effective as TTM at 33°C and is actually preferred because it reduces adverse TTM-associated effects. TTM also likely has direct neuroprotective effects in ischemic brains in danger of stroke. It remains unclear, however, whether higher temperature TTM is equally effective in protecting the brain from the effects of stroke. Here, we asked whether TTM at 36°C is as effective as TTM at 33°C in improving outcomes in a middle cerebral artery occlusion (MCAO) model of ischemic stroke. After dividing rats randomly into MCAO, MCAO+33°C TTM, MCAO+36°C TTM, and sham groups, we subjected all of them except for the sham group to MCAO for 3 h (for the behavioral tests) or 4 h (for all other biochemical analyses). We found TTM protocols at both 33°C and 36°C to produce comparable reductions of infarct volumes in the MCAO territory and equally attenuate the extracellular release of high mobility group box 1 in postischemic brains. Both the TTM conditions prevent the mRNA induction of a major pro-inflammatory cytokine, tissue necrosis factor-α, in the ischemic penumbra region. Finally, both the TTM protocols produce similar improvements in neurological outcomes in rats, as measured by a battery of behavior tests 21 h after the start of reperfusion. These data acquired in a rat MCAO model suggest TTM at 36°C has excellent therapeutic potential for improving clinical outcomes for patients with acute ischemic stroke.

Clozapine is thought to induce obsessive compulsive symptoms (OCS) in schizophrenic patients. However, because OCS are often comorbid with schizophrenia regardless of clozapine treatment, it remains unclear whether clozapine can generate OCS de novo. Thus, it has been difficult to establish a causal link between clozapine and OCS in human studies. To address this question, we asked whether chronic treatment with clozapine can induce obsessive compulsive disorder (OCD)-like behavior in mice. We injected mice with long-term continuous release pellets embedded with clozapine four times at 60-day intervals and then monitored the mice for signs of OCD-like behavior up to 40 wk. of age. We found clozapine increases grooming behavior as early as 30 wk. of age. We also investigated the effect clozapine on grooming behavior in Sapap3 knockout (KO) mice, which are a well-known animal model of OCD. In Sapap3 heterozygous KO mice, clozapine increases grooming behavior much earlier than in wild-type mice, suggesting a clozapine-OCD gene interaction. Fluoxetine, which is often used in the treatment of OCS and OCD, reduced the grooming behavior induced by clozapine. These data demonstrate that chronic clozapine treatment can generate OCD-like behavior in mice and support the hypothesis that clozapine produces de novo OCS regardless of schizophrenia status.

Mutations in protocadherin 19 (PCDH19), which is on the X-chromosome, cause the brain disease Epilepsy in Females with Mental Retardation (EFMR). EFMR is also often associated with autism-like symptoms. In mice and humans, epilepsy occurs only in heterozygous females who have a mixture of PCDH19 wild-type (WT) and mutant cells caused by random X-inactivation; it does not occur in hemizygous PCDH19 mutant males. This unique inheritance pattern strongly suggests the underlying disease mechanism operates via interference between WT and mutant cells rather than being a result of complete loss of PCDH19 functions. Although it remains unclear whether the other symptoms of EFMR also conform to this unique genotype-phenotype relationship, PCDH19 mutant males were recently reported to demonstrate autism-like symptoms. We, therefore, used a Pcdh19 knockout (KO) mouse model to ask whether a complete lack of PCDH19 causes autism-like behaviors. Consistent with the autism observed in EFMR females, we found Pcdh19 heterozygous KO female mice (with mosaic expression of PCDH19) show defects in sociability in the 3-chamber test. Surprisingly, hemizygous Pcdh19 KO male mice (without any PCDH19 expression) exhibit impaired sociability in the 3-chamber test and reduced social interactions in the reciprocal social interaction test. We also observed that, compared to WT mice, mutant mice display more repetitive behaviors, including self-grooming and rearing. These findings indicate that hemizygous Pcdh19 KO male mice show autism-like phenotypes.

Increasing evidence suggests there is a relationship between cognitive impairment and metabolic dysfunction. Diabetes is a chronic disease, and metabolic factors affecting brain metabolisms, such as serum glucose, insulin, and glucagon, are altered according to disease progression. In our previous study, we applied hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy in prediabetic mice after feeding them a 60% high-fat diet (HFD) for 6 months. Ultimately, we detected significantly increased [1-13C]lactate conversion in the whole brain and an almost five-fold increased [1-13C]lactate/pyruvate ratio in the hippocampal region. In the present study, we induced diabetes in mice by injecting streptozotocin and feeding them an HFD for 6 months. Unlike in prediabetic mice, [1-13C]lactate conversion in the diabetic mice did not differ from that in the control group, but [1-13C]lactate/total 13C ratio showed an almost 1.4-fold increase in the hippocampal region. We measured the amount of the lactate and mRNA levels of glucose transporters from isolated hippocampus and cortex samples. In the hippocampus, significantly decreased GLUT1 mRNA levels and increased lactate were detected, suggesting an inconsistency between glucose and pyruvate metabolism. Pyruvate can be produced from oxaloacetate as well as glucose. We investigated ATP citrate lyase (ACLY) because it cleaves citrate into oxaloacetate and acetyl CoA. Phosphorylated ACLY (Ser455), the active form, was increased in both hippocampus and cortex samples of mice injected with streptozotocin and fed an HFD. Also, phosphorylated ACLY/total ACLY showed a positive correlation with lactate amount in the hippocampus. Our results suggest that the brain has different responses to diabetic progression, but, in the hippocampus, maintains metabolic alteration toward increasing lactate production from the prediabetic to the diabetic stage. We suggest that ACLY-mediated pyruvate be used to support lactate levels in the hippocampus in cases of limited glucose availability.

The oxytocin receptor (OXTR) is a potential candidate in the pathophysiology of obsessive-compulsive disorder (OCD). The present study investigated the association between common single-nucleotide polymorphism (SNPs) of the OXTR gene and the affected status of OCD or distinct clinical subtypes of OCD including the age at onset and symptom dimensions. Ten SNPs of OXTR were examined in 615 patients with OCD and 581 healthy controls. Single-marker and haplotype-based association analyses were conducted. While OXTR variants were not associated with the affected status of OCD or its clinical symptom dimensions, rs2268493 (p=0.00185) and rs13316193 (p=0.00461) of the OXTR gene were associated with the age at onset in patients with OCD. In addition, in haplotype-based association analyses, there was a significant association between the OXTR gene and the onset age in patients with OCD. In particular, the G-C-G haplotype of rs2268493-rs2254298-rs11316193 and the T-G-A haplotype of rs237887-rs2268490-rs4686301 were positively associated with late-onset OCD. Our results suggest that common variants of OXTR may exert a modulating effect on the onset age in OCD pathophysiology. The potential involvement of the oxytocin system in the development and expression of OCD warrants further longitudinal research.

Sialolithiasis, the most common salivary gland pathology, is caused by calculi in the gland itself and its duct. While patients with small sialoliths can undergo conservative treatment, those with standard-size or larger sialoliths require sialolithotomy. In the present case study, we removed two sialoliths located beneath the mucosa in the posterior and anterior regions of Wharton's duct, respectively. For the posterior calculus, we performed sialolithotomy via an intra-oral approach; thereafter, the small anterior calculus near the duct orifice was removed by hydraulic power. This method has not previously been reported. There were no complications either during the operation or postoperatively, and the salivary function of the gland remained normal.

The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from l-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3β and the accumulation of Aβ and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal.

The rate of hippocampal neurogenesis declines with aging. This is partly explained by decreased neural responsiveness to various cues stimulating metabolism. AMP-activated protein kinase (AMPK), a pivotal enzyme regulating energy homeostasis in response to metabolic demands, showed the diminished sensitivity in peripheral tissues during aging. AMPK is also known to be involved in neurogenesis. We aimed to see whether AMPK reactivity is also blunted in the aged hippocampus, and thus is associated with aging-related change in neurogenesis. Following subchronic (7days) intraperitoneal and acute intracerebroventricular (i.c.v.) administration of either 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR; AMPK activator) or saline (sham) to young (16-week-old) and old (72-week-old) mice, we measured changes in AMPK activity, brain-derived neurotrophic factor (BDNF) expression or neurogenesis in the hippocampus. AICAR-induced changes in AMPK activity were observed in the hippocampus of young mice after acute i.c.v. injection. However, neither subchronic nor acute treatment induced significant changes in AMPK activity in old mice. Intriguingly, directions of AICAR-induced changes in AMPK activity were opposite between the hippocampus (decrease) and skeletal muscle (increase). ATP levels were inversely correlated with hippocampal AMPK activity, suggesting that the higher energy levels achieved by AICAR treatment might deactivate neuronal AMPK in young mice. The blunted response of AMPK to AICAR in old age was also indicated by the observations that the levels of neurogenesis and BDNF expression were significantly changed only in young mice upon AICAR treatment. Our findings suggest that the blunted response of neuronal AMPK in old age might be responsible for aging-associated decline in neurogenesis. Therefore, in addition to activation of AMPK, recovering its sensitivity may be necessary to enhance hippocampal neurogenesis in old age.

Unlike other G protein-coupled receptor (GPR)119 agonists, DA-1241 has shown long-term beneficial effects on glucose and lipid metabolism in previous studies. In this study, we investigated the antidiabetic effects of DA-1241 in vitro and in vivo. The efficacy of DA-1241 was evaluated by assessing the changes in glucagon-like peptide-1 (GLP-1) levels, gluconeogenesis, and hepatic autophagy. DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks (n=34), and serum insulin and GLP-1 levels were measured by oral glucose tolerance tests at week 8. The effects of DA-1241 on gluconeogenic enzyme expression and autophagic flow were evaluated in HepG2 cells and livers isolated from LC3-GFP-transgenic mice. DA-1241 improved oral glucose tolerance (no significant effect on intraperitoneal glucose tolerance test) with an increase in serum GLP-1 and insulin levels. Fasting blood glucose level decreased, and the insulinogenic index was improved after DA-1241 treatment in HFD-fed mice. However, no significant increase in insulin secretion in INS1E cells and isolated mouse islet with DA1241 treatment. DA-1241 reduced gluconeogenic enzyme expression and blocked autophagic flow in HepG2 cells. Additionally, DA1241 induced GFP fragmentation in liver from LC3-GFP-transgenic mice. These findings suggested that DA-1241 augmented glucose-dependent insulin release via improvement in GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control. Disclosure J. Kim: None. Y. Kim: None. R. Kim: None. M. Kim: None. H. Park: None. M. Lee: None. Y. Cho: None. J. Bae: None. S. Lee: None. I. Lee: None. H. Lee: None. C. Kim: None. E. Kang: None.

Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer’s disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6 months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p

Acute myocardial infarction (AMI) is lethal and causes myocardial necrosis via time-dependent ischemia due to prolonged occlusion of the infarct-related artery. No effective therapy or potential therapeutic targets can prevent myocardial ischemia/reperfusion (I/R) injury. Targeted temperature management (TTM) may reduce peri-infarct regions by inhibiting the extracellular release of high mobility group box-1 (HMGB1) as a primary mediator of the innate immune response. We used a rat left anterior descending (LAD) coronary artery ligation model to determine if TTM at 33°C and 36°C had similar myocardial protective effects. Rats were divided into sham, LAD I/R+37°C normothermia, LAD I/R+33°C TTM, and LAD I/R+36°C TTM groups (n = 5 per group). To verify the cardioprotective effect of TTM by specifically inhibiting HMGB1, rats were assigned to sham, LAD I/R, and LAD I/R after pre-treatment with glycyrrhizin (known as a pharmacological inhibitor of HMGB1) groups (n = 5 per group). Different target temperatures of 33°C and 36°C caused equivalent reductions in infarct volume after myocardial I/R, inhibited the extracellular release of HMGB1 from infarct tissue, and suppressed the expression of inflammatory cytokines from peri-infarct regions. TTM at 33°C and 36°C significantly attenuated the elevation of cardiac troponin, a sensitive and specific marker of heart muscle damage, after injury. Similarly, glycyrrhizin alleviated myocardial damage by suppressing the extracellular release of HMGB1. TTM at 33°C and 36°C had equivalent myocardial protective effects by similar inhibiting HMGB1 release against myocardial I/R injury. This is the first study to suggest that a target core temperature of 36°C is applicable for cardioprotection.

Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.

Objective To evaluate the relationship between obstructive sleep apnea (OSA) severity and carotid arterial calcification by quantitative analysis using airway computed tomography (CT). Methods This study included a total of 180 consecutive OSA patients aged 45–80 years underwent polysomnography and airway CT between March 2014 and October 2016. The subjects were divided into three groups based on the results of the respiratory disturbance index (RDI): mild (RDI 5–14, n = 29), moderate (RDI 15–29, n = 50), and severe (RDI ≥ 30, n = 101). The extent of carotid arterial calcification on each airway CT scan was quantified according to the modified Agatston scoring method. Differences among the three groups in clinical characteristics including age, gender, body mass index (BMI), comorbid disease, blood pressure, total cholesterol, and carotid arterial calcification score (CarACS) were analyzed. Results The severe OSA group showed significantly stronger predominance for male and smoker, higher prevalence of diabetes, and larger BMI than those of mild and moderate OSA groups. The mean CarACS was significantly different among the three groups (mild RDI: 4.3 ± 13.4, moderate RDI: 7.4 ± 28.8, severe RDI: 48.6 ± 121.6, P = 0.011). Univariate linear regression showed that RDI, age, hypertension, male sex and diabetes significantly influenced on the CarACS. In a multivariate linear regression model, the CarACS was related to age, male sex, and diabetes. Conclusions The patients with severe OSA showed larger CarACS and a higher prevalence of atherosclerotic risk factors. The CarACS was correlated with severity of OSA, which might be more dependent on the conventional risk factors of atherosclerosis.

Individual differences in stress vulnerability and resilience have been observed even within a single cohort of inbred rats or mice. Stress phenotypes are typically quantified as changes in the behavior of experimental animals, which is the outcome of altered electrical activity of the brain network. Although mGluR5 is associated with individual vulnerability to stress and can act as a sensitive biomarker of stress adaptation, our understanding of mGluR5-dependent modifications to neural network activities in vivo remains limited. Here, we examined individual rats for changes in hippocampal mGluR5 expression induced by restraint stress and found that these changes cause accompanying changes in hippocampal electroencephalography (EEG) activity. We found six days of restraint stress caused variable changes in hippocampal mGluR5 expression, ranging from 20.9% to 210.7% of the control group. The low mGluR5 protein group (LE) showed increased methylation of the mGluR5 CpG island, reduced mGluR5 mRNA levels, and unaltered basal EEG theta spectral power between stress day 1 and 6. In contrast, the high mGluR5 protein group (HE) showed reduced methylation of CpG sites, increased mGluR5 mRNA expression, and reduced basal theta spectral power on stress day 6. We also found that injection of lentiviruses expressing mGluR5-specific shRNAs into the hippocampus rescued this reduction in baseline theta power in HE rats. These data suggest a causal relationship between individual differences in the changes in hippocampal mGluR5 expression induced by repetitive restraint stress and the accompanying changes in ensemble neural activity in the hippocampus.

PURPOSE The purpose of this study is to investigate the prognostic significance of SOX2 gene amplification and expression in patients with American Joint Committee on Cancer stage III lung squamous cell carcinoma (SCC) who underwent surgery followed by adjuvant radiotherapy. MATERIALS AND METHODS Pathological specimens were obtained from 33 patients with stage III lung SCC treated with surgery followed by adjuvant radiotherapy between 1996 and 2008. SOX2 gene amplification and protein expression were analyzed using fluorescent in situ hybridization and immunohistochemistry, respectively. Patients were divided into two groups according to their SOX2 gene amplification and protein expression status. Kaplan-Meier estimates and a Cox proportional hazards model were used to identify the prognostic factors affecting patient survival. RESULTS The median follow-up period for surviving patients was 58 months (range, 5 to 102 months). SOX2 gene amplification was observed in 22 patients and protein overexpression in 26 patients. SOX2 overexpression showed significant association with SOX2 gene amplification (p=0.002). In multivariate analysis, SOX2 overexpression was a significant prognostic factor for overall survival (OS) (hazard ratios [HR], 0.1; 95% confidence interval [CI], 0.002 to 0.5; p=0.005) and disease-free survival (DFS) (HR, 0.15; 95% CI, 0.04 to 0.65; p=0.01). Age (HR, 0.33; 95% CI, 0.11 to 0.98; p=0.046) and total radiation dose (HR, 0.13; 95% CI, 0.02 to 0.7; p=0.02) were the independent prognostic factors for OS and DFS. Patients with SOX2 amplification did not show a longer OS (p=0.95) and DFS (p=0.48). CONCLUSION Our data suggested that SOX2 overexpression could be used as a positive prognostic factor in patients with stage III lung SCC receiving adjuvant radiotherapy.

Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats: [(18) F]FP-CIT for dopamine transporters and [(18) F]Mefway for serotonin 1A (5-HT1A ) receptors. Here, 6-OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests were drawn in the striatum and cerebellum for the dopamine system and hippocampus and cerebellum for the 5-HT system. The cerebellum was chosen as a reference region. Non-displaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, the degree of dopamine depletion was negatively correlated with rotational behavior (R(2) = 0.79, p = 0.003). In 6-OHDA lesioned rats, binding values for 5-HT1A receptors was 22% lower than the sham operated group. This decrement of 5-HT1A receptor binding was also correlated with the severity of depression (R(2) = 0.81, p = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. This article is protected by copyright. All rights reserved. Language: en

The purpose of the present study is to investigate the relationship between dopaminergic neuron destruction and 5-HT system changes in a hemiparkinsonian rat model. We performed PET imaging studies with trans -[ 18 F]Mefway in a hemiparkinsonian model of unilateral 6-hydroxydopamine (6-OHDA) rats. Region-of-interests (ROIs) were drawn in the hippocampus (HP) and cerebellum (CB). HP uptake, the ratios of specific binding to non-specific binding in the HP, and non-displaceable binding potential (BP ND ) in the HP were compared between 6-OHDA and control rats. As a result, unilateral 6-OHDA-lesioned rats exhibited significant bilateral reduction of HP uptake and trans -[ 18 F]Mefway BP ND compared to the intact control group. Therefore, the results demonstrate that destruction of the dopaminergic system causes the reduction of the serotonergic system.

The aim of the present study was to evaluate functional changes of mGluR5 expression in advanced Alzheimer's disease (AD) using positron emission tomography (PET) with an mGluR5 specific radiotracer ([18F]FPEB) in 5xFAD AD model. Subsequently, in the same animal, mGluR5 expression was quantified by immunoassay techniques. The non-displaceable binding potential values for mGluR5 was estimated by the Logan's graphical analysis. Brain PET imaging revealed that radioactivities in the hippocampus and the striatum were significantly lower in 5xFAD mice compared to control animals. Binding values were also significantly lowered in 5xFAD mice. This decline was validated by immunoblotting of protein isolates from brain tissues, as the mean band density for 5xFAD mice had a lower mGluR5 intensity than for wild type mice. These results indicated that mGluR5 levels in 5xFAD mice were down regulated in the limbic system.

PURPOSE To compare the cerebral uptake and binding potential of [18 F]FCWAY and [18 F]Mefway in the rodent to assess their potential for imaging serotonin 1A (5-HT1A ) receptors. MATERIALS AND METHODS In vitro liver microsomal studies were performed to evaluate the degree of defluorination. Dynamic positron emission tomography (PET) studies were then conducted for 2 h with or without an anti-defluorination agent. The regions of interest were the hippocampus and frontal cortex (5-HT1A target regions) and the cerebellum (5-HT1A nontarget region). The in vivo kinetics of the radioligands were compared based on the brain uptake values and target-to-nontarget ratio. We also performed a comparison of binding potential (BPND ) as a steady-state binding parameter. Finally, binding affinities to 5-HT1A receptors were assessed in Chinese hamster ovary cells (CHO-K1) cells expressing human recombinant 5-HT1A receptors. RESULTS The radiochemical yield of [18 F]Mefway was slightly higher than that of [18 F]FCWAY (19 vs. 15%). With regard to metabolic stability against defluorination, both compounds exhibited similar stability in rat liver microsomes, but [18 F]Mefway displayed higher stability in the human microsome (defluorination ratio at 30 min: 32 vs. 29 in rat liver microsomes, 31 vs. 64 in human liver microsomes for [18 F]Mefway and [18 F]FCWAY, respectively). There were no significant differences in brain uptake, the target-to-nontarget ratios, and the BPND (at hippocampus, peak brain uptakes: 6.9 vs. 8.5, target-to-nontarget ratios: 6.9 vs. 8.5, BPND : 5.2 vs. 6.2 for [18 F]Mefway and [18 F]FCWAY). The binding affinity of [18 F]Mefway was considerably higher than that of [18 F]FCWAY (IC50 : 1.5 nM vs. 2.2 nM). CONCLUSION [18 F]Mefway exhibits favorable characteristics compared to [18 F]FCWAY in rodents, and may be a promising radioligand for use in human subjects. Synapse 68:595-603, 2014. © 2014 Wiley Periodicals, Inc.

Supplemental Digital Content is available in the text, Incretin hormone-based therapy in type 2 diabetes has been widely used, and dipepdityl peptidase-4 (DPP-4) inhibitors, which prevent incretin degradation, have become popular oral hypoglycemic agents. The efficacy of DPP-4 inhibitors varies from individuals, and factors determining responses to DPP-4 inhibitors have not been fully established. We aimed to investigate whether genetic variations in glucagon-like peptide (GLP-1) receptor are associated with responses to DPP-4 inhibitors in patients with type 2 diabetes. Genetic variations of rs3765467 in GLP-1 receptor were explored in 246 patients with type 2 diabetes who received DPP-4 inhibitors treatment for 24 weeks in addition to previous medication. Patients with glycated hemoglobin (HbA1c) > 7% and who were naive to any DPP-4 inhibitors were enrolled. Responders were defined as those who showed a > 10% reduction in HbA1c after DPP-4 inhibitor treatment. DPP-4 inhibitors improved glycemic parameters and lipid profiles. Compared to the major genotype (GG), a larger proportion of patients with the minor allele genotype (GA/AA) were responders (P = 0.018), and also showing greater HbA1c reductions (1.3 ± 1.1 vs 0.9 ± 1.2%; P = 0.022). This genetic effect remained significant even after adjustment for other confounding factors (OR = 2.00, 95% CI = 1.03–3.89). Polymorphism in the GLP-1 receptor may influence DPP-4 inhibitor response. Further studies in larger population will help determine the association between genetic variation and interindividual differences in DPP-4 inhibitor therapy.

Periventricular leucomalacia has long been investigated as a leading cause of motor and cognitive dysfunction in patients with spastic diplegic cerebral palsy. However, patients with periventricular leucomalacia on conventional magnetic resonance imaging do not always have motor dysfunction and preterm children without neurological abnormalities may have periventricular leucomalacia. In addition, it is uncertain whether descending motor tract or overlying cortical injury is related to motor impairment. To investigate the relationship between motor pathway injury and motor impairment, we conducted voxelwise correlation analysis using tract-based spatial statistics of white matter diffusion anisotropy and voxel-based-morphometry of grey matter injury in patients with periventricular leucomalacia and spastic diplegia ( n = 43, mean 12.86 ± 4.79 years, median 12 years). We also evaluated motor cortical and thalamocortical connectivity at resting state in 11 patients using functional magnetic resonance imaging. The functional connectivity results of patients with spastic diplegic cerebral palsy were compared with those of age-matched normal controls. Since γ-aminobutyric acidA receptors play an important role in the remodelling process, we measured neuronal γ-aminobutyric acidA receptor binding potential with dynamic positron emission tomography scans ( n = 27) and compared the binding potential map of the patient group with controls ( n = 20). In the current study, white matter volume reduction did not show significant correlation with motor dysfunction. Although fractional anisotropy within most of the major white matter tracts were significantly lower than that of age-matched healthy controls ( P

Objectives. To evaluate the effect of nicotine on the production of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) in human umbilical vein endothelial cells (HUVECs) and trophoblast cells, and to assess the involvement of alpha 7 nicotinic acetylcholine receptor (α7 nAChR) in this process. Methods. Commercially available full-term placental trophoblasts and HUVECs derived from the umbilical cord of a normal pregnancy were used. The expression of α7 nAChR was assessed by immunostaining, RT-PCR, and western blotting. The expression of sFlt-1 and sEng protein in the cell media after 6 and 24 hours of treatment with nicotine was evaluated using a commercially available ELISA. To determine the involvement of α7 nAChR in the nicotinic effect, cells were treated with the α7 nAChR antagonist α-bungarotoxin (α-BGT) prior to the nicotine exposure. Levels of significance were determined using the Student's t-test and one-way ANOVA, and a p-value < 0.05 was considered significant. Main outcome measures. The levels of sFlt-1 and sEng protein were evaluated before and after the nicotine treatment with or without α-BGT pre-treatment. Results. In trophoblast cells, a significant reduction of sFlt-1 and sEng protein was observed after 24 hours of nicotine treatment as compared to the untreated group (p = 0.002, 0.000). In HUVECs, nicotine only had a suppressive effect on the expression of sEng at 6 hours (p = 0.03); there was no effect on sFlt-1 expression. However, pre-treatment with α-BGT did not reverse the nicotine-induced suppressive effect on the expression of sFlt-1 and sEng in trophoblasts and HUVECs. Conclusions. Nicotine reduced the production of sFlt-1 and sEng in trophoblasts and sEng in HUVECs. This effect was not mediated by α7 nAChR.

Background. Posttransplantation diabetes mellitus (PTDM) is a major metabolic complication in renal transplant recipients. Recent genome-wide association studies have identified several genes associated with type 2 diabetes. Here, we examined the association between PTDM and 17 single nucleotide polymorphisms (SNPs) located within 15 genes in a cohort of renal allograft recipients in Korea. Materials and Methods. A total of 589 patients who received kidney transplants between 1989 and 2007, without a history of diabetes and had a pretransplant fasting glucose less than 5.5 mmol/L were included in this study. We analyzed the association between the PTDM development and the following SNPs: TCF7L2 rs7903146, SLC30A8 rs13266634, HHEX (rs1111875, rs7923837, and rs5015480), CDKAL1 rs10946398, CDKN2A/B rs10811661, IGF2BP2 rs4402960, FTO rs8050136, WFS1 rs734312, JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs1092391, and KCNQ1 rs2237892. Results. Eight SNPs in six genes were significantly associated with the PTDM development: TCF7L2 rs7903146 (odds ratio [OR]2.20, P0.016), SLC30A8 rs13266634 (OR1.52, P0.003), HHEX rs1111875 (OR1.47, P0.007), HHEX rs7923837 (OR2.32, P0.014), HHEX rs5015480 (OR1.59, P0.003), CDKAL1 rs10946398 (OR1.43, P0.008), CDKN2A/B rs10811661 (OR1.33, P0.039), and KCNQ1 rs2237892 (OR1.46, P0.009). Conclusions. These data suggest that genetic variations in TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, and KCNQ1 are associated with PTDM in Korea.

Aim Central obesity, hypertension and diabetes mellitus have been related individually to cognitive dysfunction. We aimed to study the interactive effects of these co-occurring risk factors on cognitive decline, which remain unclear in older patients with diabetes. Methods We assessed metabolic profiles and neuropsychological functions in 60 older out-patients with Type 2 diabetes to examine the associations of central obesity with cognitive functions, while controlling for other confounding factors in these subjects. Results Waist circumference was associated with poor performance in digits forward (r2 = 0.11, P = 0.02), choice reaction time (r2 = 0.08, P = 0.04) and cognitive reaction time (r2 = 0.07, P

According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.

OBJECTIVE—Posttransplantation diabetes mellitus (PTDM) is a major metabolic complication in renal transplant recipients, and insulin secretory defects play an important role in the pathogenesis of PTDM. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8, has been reported to be associated with type 2 diabetes and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in the SLC30A8 gene and PTDM in renal allograft recipients. RESEARCH DESIGN AND METHODS—A total of 624 unrelated renal allograft recipients without previously diagnosed diabetes were enrolled. Rs13266634 was genotyped in the cohort, which consisted of 174 posttransplantation diabetic patients and 450 non-posttransplantation diabetic subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR. RESULTS—The prevalence of PTDM was 33.8% in patients carrying the R/R genotype, 26.8% in patients with the R/W genotype, and 19.8% in patients with the W/W genotype. There was a strong association between the number of W-alleles and PTDM risk reduction (P for trend = 0.007). Patients with at least one T-allele showed a decreased risk of PTDM compared with those with the R/R genotype (R/W, risk ratio [RR] 0.78, P = 0.126; W/W, RR 0.52, P = 0.007). The effect of the SLC30A8 genotype remained significant after adjustments for age, sex, body weight gain, and type of immunosuppressant (R/W, hazard ratio [HR] 0.77, P = 0.114; W/W, HR 0.58, P = 0.026). CONCLUSIONS—These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of PTDM in renal allograft recipients.

Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β (TGF-β1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes.

Skull-base osteomyelitis is a rare disease affecting the medulla of the temporal, sphenoid, and occipital bones. In general, it occurs due to external ear canal infections caused by malignant external otitis. Skull-base osteomyelitis usually affects elderly diabetic patients. The patient, a 58-year-old man, was referred for evaluation and management of the left jaw. Clinical examination of the patient revealed pain in the left jaw and mouth-opening deflection to the left. The maximum active mouth opening was measured to about 27 mm. Panoramic, CT, and CBCT revealed bone resorption patterns in the left condyle. Through control of diabetes, continued pharmacological treatment, arthrocentesis, and occlusal stabilization appliance therapy were carried out. The extent of active mouth opening was increased to 45 mm, and pain in the left jaw joint was alleviated. This was a case wherein complications caused by failure to control diabetes induced skull-base osteomyelitis. There is a need for continued discussion about the advantages and disadvantages of arthrocentesis with lavage for patients with skull-base osteomyelitis and other treatment options.

Keratocystic odontogenic tumors can occur in any area of the maxilla or mandible. According to their size, location, and relations with surrounding structures, they are treated by cyst enucleation or enucleation after either marsupialization or decompression. Enucleation is performed when cysts are not large and when only minor damage to adjacent anatomical structures is expected. Although marsupialization and decompression follow the same basic bone-regeneration principle, which is to say, by reducing the pressure within the cyst, the former leaves a large defect after healing due to the large fistula necessary to induce the conversion of the cyst-lining epithelia to oral epithelia; the latter leaves only a relatively small defect, because of the continuous washing carried out by means of a tube inserted into a small hole in the cyst. In the latter case too, a decompressor appropriate for the focal position is required, owing to the importance of maintaining the device and controlling for oral hygiene. We report herein decompression treatment with a patient-customized device for an extensive cyst in the anterior region of the mandible.

Facial asymmetry is found in patients with or without cosmetic facial alterations. Some patients have facial asymmetry that manifests underlying skeletal problems, while others have only limited soft-tissue facial asymmetry. Orthognathic surgery brings about a dermatic change, as soft tissue covers underlying bones. Limited soft-tissue asymmetry, meanwhile, is difficult to correct. The treatment modalities for the creation or restoration of an esthetically pleasing appearance were autogenous fat grafts, cartilage graft, and silicon injections. A young female patient had right-side facial asymmetry. The clinical assessment involved visual inspection of the face and palpation to differentiate soft tissue and bone. Although the extra-oral examination found facial asymmetry with skin atrophy, the radiographic findings revealed no mandibular atrophy or deviation. She was diagnosed as localized scleroderma with muscle spasm. In conclusion, facial asymmetry patients with skeletal asymmetry can be esthetically satisfied by orthognathic surgery; however, facial atrophy patients with skin or subdermal tissue contraction need treatment by cosmetic dermatological surgery and orthodontic correction.

In the central nervous system (CNS), insulin resistance (I/R) can cause defective neurite outgrowth and neuronal cell death, which can eventually lead to cognitive deficits. Recent research has focused on the relationship between I/R and the cognitive impairment caused by dementia, with the goal of developing treatments for dementia. Insulin signal transduction mediated by insulin receptor substrate (IRS-1) has been thoroughly studied in the CNS of patients with I/R. In the present study, we investigated whether the impairment of IRS-1-mediated insulin signaling contributes to neurite outgrowth and neuronal loss, both in mice fed a high-fat diet and in mouse neuroblastoma (Neuro2A) cells. To investigate the changes caused by the inhibition of IRS-1-mediated insulin signaling in the brain, we performed Cresyl Violet staining and immunochemical analysis. To investigate the changes caused by the inhibition of IRS-1-mediated insulin signaling in neuroblastoma cells, we performed Western blot analysis, reverse transcription-PCR, and immunochemical analysis. We show that the deactivation of IRS-1-mediated insulin signaling can inhibit neuronal outgrowth and aggravate neuronal cell death in the insulin-resistant CNS. Thus, IRS-1-mediated insulin signal transduction may be an important factor in the treatment of cognitive decline induced by I/R.

Ischemic stroke results in diverse pathophysiologies, including cerebral inflammation, neuronal loss, cognitive dysfunction, and depression. Studies aimed at identifying therapeutic solutions to alleviate these outcomes are important due to the increase in the number of stroke patients annually. Recently, many studies have reported that orexin, commonly known as a neuropeptide regulator of sleep/wakefulness and appetite, is associated with neuronal cell apoptosis, memory function, and depressive symptoms. Here, we briefly summarize recent studies regarding the role and future perspectives of orexin in post-ischemic stroke. This review advances our understanding of the role of orexin in post-stroke pathologies, focusing on its possible function as a therapeutic regulator in the post-ischemic brain. Ultimately, we suggest the clinical potential of orexin to regulate post-stroke pathologies.

In the central nervous system (CNS), hyperglycemia leads to neuronal damage and cognitive decline. Recent research has focused on revealing alterations in the brain in hyperglycemia and finding therapeutic solutions for alleviating the hyperglycemia-induced cognitive dysfunction. Adiponectin is a protein hormone with a major regulatory role in diabetes and obesity; however, its role in the CNS has not been studied yet. Although the presence of adiponectin receptors has been reported in the CNS, adiponectin receptor-mediated signaling in the CNS has not been investigated. In the present study, we investigated adiponectin receptor (AdipoR)-mediated signaling in vivo using a high-fat diet and in vitro using neural stem cells (NSCs). We showed that AdipoR1 protects cell damage and synaptic dysfunction in the mouse brain in hyperglycemia. At high glucose concentrations in vitro, AdipoR1 regulated the survival of NSCs through the p53/p21 pathway and the proliferation- and differentiation-related factors of NSCs via tailless (TLX). Hence, we suggest that further investigations are necessary to understand the cerebral AdipoR1-mediated signaling in hyperglycemic conditions, because the modulation of AdipoR1 might alleviate hyperglycemia-induced neuropathogenesis.

The aim of this study is to compare [(18)F]FPEB and [(18)F]FDEGPECO for the quantification of mGlu5 receptors in rodent brains. After preparation of radioligands, dynamic PET data was acquired for 90min. Estimated non-displaceable binding potential (BPND) values were calculated from the non-invasive Logan's graphical analysis method. Although both radioligands showed similar radiochemical amenability, [(18)F]FPEB PET showed higher brain uptake and superior binding potential values than those of [(18)F]FDEGPECO PET (peak brain uptakes in the hippocampus and the striatum: 7.2-8.7 vs. 5.0-6.2, BPND: 7.3-9.6 vs. 0.3-0.4 for [(18)F]FPEB and [(18)F]FDEGPECO, respectively). In addition, the target-to-reference ratios for [(18)F]FPEB is4 fold than those of [(18)F]FDEGPECO. From this evidence, we conclude that [(18)F]FPEB is a superior radioligand for mGlu5 imaging in preclinical studies.

Aim: The purpose of this study was to describe the status of ventilator use, respiratory problems, and caregiver well-being relating to patients with amyotrophic lateral sclerosis (ALS) using a home-based ventilator as well as to examine the relationship among ventilator use, respiratory problems, and caregiver well-being. Methods: Patients with ALS (n = 141) registered in the Severe-Rare Disease Center of the Korean Center for Disease Control and their caregivers (n = 83) were surveyed from August 2008 to April 2009. Trained research assistants visited patient homes; collected data using questionnaires; and then performed analyses with descriptive statistics, # 2 test, and t test as well as partial correlation analysis using SPSS WIN 18.0. Results: Thirty-two patients used noninvasive ventilation (NIV), and 109 used tracheostomy and mechanical ventilation (TMV). One hundred of the TMV patients used the ventilator 24 hours per day. The ventilator circuit exchange cycle was 0.96 times per month for NIV patients and 1.17 times per month for TMV patients (t = j4.91, p G .001). However, NIV patients had a higher level of tidal volume than TMV patients (t = 3.34, p = .001). Approximately 22% of NIV patients and 24% of TMV patients used one or more physiotherapies for airway clearance. There was a significant relationship between hypoventilation symptoms and caregiver burden (r = .31, p = .006). Hypoventilation symptoms were positively related to physiotherapy (r = .24, p = .042), and physiotherapy was positively related to caregiver burden (r = .24, p = .043). Conclusion: On the basis of the findings of this study, care management for patients with ALS with a home-based ventilator as well as their caregiver’s well-being was relatively inappropriate. We recommend that community-based support programs and burden relief programs be considered as managerial interventions.

Objective Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (i.e., tyrosine 705 -phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, the type of estrogen receptor that mediates this regulation is unknown. We investigated the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus. Materials/methods Regulation of STAT3 activation by E2, G-1, a specific agonist of GPR30 and G-15, a specific antagonist of GPR30 was analyzed in vitro and in vivo . Effect of GPR30 activation on eating behavior was analyzed in vivo . Results E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. G-1 induced pSTAT3, and G-15 inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. A cerebroventricular injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. Conclusions These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus.

A critical role of oxidative stress has been implicated in ischemic brain damage. Mild ischemic pretreatment and/or synthesis of heat shock proteins (HSPs) has been suggested to protect against oxidative brain damage. However, experimental support of this suggestion have proven to be difficult partly because sensitive indices to assess oxidative consequences of ischemic brain damage were few. In this study, we have attempted to establish biochemical assay systems to quantitate oxidative brain damage following ischemia. We produced experimental brain ischemia in the Mongolian gerbil (Meriones unguiculatus) and examined the hippocampus for ischemic brain damage. The results obtained from ischemic gerbil hippocampus demonstrated that oxidative brain damage can be quantitated by determining glutathione oxidation ratio together with the accumulation of the oxidative DNA damage product, 8-hydroxy-2'-deoxyguanosine (8 ohdG). Our results also demonstrated a role for mild ischemic pretreatment and synthesis of HSPs against oxidative brain damage. We showed that mild 2-min ischemic pretreatment reduced the degree of both glutathione oxidation ratio and 8 ohdG accumulation in gerbil hippocampus subsequent to 10 min ischemic challenge. We also showed that the accumulation of HSP70 was closely associated with the reduction of oxidative brain damage. To our knowledge, this is the first report to investigate glutathione redox states and oxidative DNA damage levels to evaluate a protective role of mild ischemic pretreatment and HSP synthesis following brain ischemia. Our data validate the previous suggestions and provide new additional data that argue for the protective role of mild ischemic pretreatment and HSP70 synthesis against oxidative brain damage.

We investigated the effects of environmental enrichment (EE) on the function of transplanted adipose stem cells (ASCs) and the combined effect of EE and ASC transplantation on neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in 7-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At 6 weeks of age, the mice were randomly injected with either ASCs or PBS into the striatum and were randomly assigned to either EE or standard cages (SC), comprising ASC-EE ( n = 18), ASC-SC ( n = 19), PBS-EE ( n = 12), PBS-SC ( n = 17), and untreated controls ( n = 23). Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. The fate of transplanted cells and the levels of endogenous neurogenesis, astrocyte activation, and paracrine factors were also measured. As a result, EE and ASC transplantation synergistically improved rotarod latency, forelimb-use asymmetry, and grip strength compared to those of the other groups. The number of engrafted ASCs and βIII-tubulin+ neurons derived from the transplanted ASCs was significantly higher in mice in EE than those in SC. EE and ASC transplantation also synergistically increased BrdU+βIII-tubulin+ neurons, GFAP+ astrocytic density, and fibroblast growth factor 2 (FGF2) level but not the level of CS-56+ glial scarring in the striatum. In conclusion, EE and ASC transplantation synergistically improved neurobehavioral functions. The underlying mechanisms of this synergism included enhanced repair processes such as higher engraftment of the transplanted ASCs, increased endogenous neurogenesis and astrocytic activation coupled with upregulation of FGF2.

Background: The dipeptidyl peptidase-4 (DPP4) inhibitors have become widely used antidiabetic medication. They control glycemia by interacting with serum DPP4 to interfere catalyzation of incretins. The aim of this pilot study was to discover the DPP4 polymorphisms that could affect the efficacy of vildagliptin, a DPP-4 inhibitor in diabetic patients. Methods: Genetic variations in DPP4 were identified in 48 patients with type 2 diabetes who received vildagliptin treatment at least 12 weeks following metformin monotherapy. Luciferase assay was performed to estimate the effect of the regulatory single nucleotide polymorphism (SNP) on expression of DPP4. Results: Eight tagging SNPs were genotyped in a sample of 24 patients. Additional sample of 24 patients was used to discover further regulatory SNPs and coding SNPs. In all 48 patients, responders (degree of HbA1c and/or fasting glucose level decrease greater than 10% of baseline after 12 weeks of vildagliptin add-on treatment) did not show any significant difference in selected six DPP4 polymorphisms from non-responders. DPP4 expression was not different according to g.-234A/C in luciferase assay. Conclusion: Our pilot study could not find any significant genetic variant which is associated with vildagliptin response in patients with type 2 diabetes. Further studies in large population are warranted.

Background: Autosomal dominant hypocalcemia (ADH) is a rare disorder characterized by benign hypocalcemia, inappropriately low parathyroid hormone (PTH) levels and mostly hypercalciuria. ADH can be caused by activating mutations of the calcium-sensing receptor (CaSR) gene located on chromosome 3q13.3-21. Calcium-sensing receptor plays a pivotal role in the regulation of calcium homeostasis and is abundantly expressed in parathyroid gland, thyroid C cell, and renal tubular system. Activation of CaSR by increased Ca2+ inhibits PTH secretion, stimulates calcitonin secretion, and promotes urinary Ca2+ excretion, and thereby maintains the Ca2+ at the normal level. Herein, we report a novel activating mutation in the CaSR gene in a Korean family with ADH. Meanwhile, antagonist of the CaSR, calcilytics could be a therapeutic option in the treatment of ADH. Method: We identified a 55-yr-old woman with mild hypocalcemia (7.7 mg/dL) and hypercalciuria (24-hr urine Ca: 868 mg/d) caused by missense mutations of the CaSR gene. She showed low normal serum PTH level (10.14 pg/mL). We performed mutational analysis of the genes encoding GCMB, pre-pro-PTH and CaSR using PCR-amplified genomic DNA in her family members. The ability of wild-type and mutant CaSR to activate the MAPK signaling cascade was assessed by examining phosphorylation of ERK1/2. Intacellular Ca2+ concentration was measured by Fura-2 dye. Blocking of CaSR with calcilytics, AXT914 was also tested by Fura-2 with a variety of concentrations. Result: Direct sequencing analysis of the CaSR gene showed that the proband and her daughter possess a T to A transition at nucleotide 1230 resulting in a D410E missense mutation in exon 4 of the CaSR. No mutation was detected in GCMB and Prepro-PTH genes. HEK293 cells were stably transfected with plasmids encoding wild-type or mutant CaSR genes. Escalation of the extracellular Ca2+ concentration from 0.5 to 5.0 mM resulted in increased phosphorylation of ERK1/2 and escalation of the extracellular Ca2+ concentration from 1.0 to 10 mM resulted in increased intracellular Ca2+ detected by Fura-2 in mutant CaSR-expressing cell than wild-type-expressing one. These results indicate that D410E mutation of CaSR is associated with ADH in this family. Finally, AXT914 successively blunted the increased intracellular signaling via CaSR. Conclusion: Over 60 activating mutations in the CaSR gene have been identified to cause ADH so far. Here we add one more activating mutation that causes ADH. This could be of interest because this novel mutation occurred in the loop 3 region of the VFT domain in CaSR where little was known to be important in its function. Further clinical study is needed to validate the effectiveness of calcilytics in the treatment of ADH in vivo.