Is the GABA System Related to the Social Competence Improvement Effect of Aripiprazole? An 18F-Fluoroflumazenil PET Study

Objective

Patients with schizophrenia who are treated with aripiprazole experience some benefits including an improvement of social competence, but the underlying mechanism of this improvement has not been investigated yet. This study aimed to provide preliminary evidence that the GABA system may be involved in the effect of aripiprazole on social competence.

Methods

Seventeen outpatients with schizophrenia (9 taking aripiprazole and 8 taking risperidone) and 18 healthy controls underwent ¹⁸F-fluoroflumazenil PET, and GABA_A receptor binding potential was compared between the three groups.

Results

Voxelwise one-way ANOVA showed that GABA_A receptor binding potentials in the right medial prefrontal cortex (p=0.04) and right dorsolateral prefrontal cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone group, and those in the left frontopolar cortex (p=0.03) and right premotor cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone and control groups.

Conclusion

Our results suggest that aripiprazole administration results in increased GABA transmission in the prefrontal regions, and that these increases may be a neural basis of aripiprazole''s clinical benefits on an improvement of social competence.     

Increased plasma levels of heat shock protein 70 in patients with vascular mild cognitive impairment

Heat shock proteins (Hsps) have been regarded as cytoprotectants that protect brain cells from damage encountered following cerebral ischemia or during the progression of neurodegenerative diseases. In this study, we assessed the plasma Hsp70 and Hsp27 levels in not cognitively impaired (NCI) subjects and in patients with mild cognitive impairment (MCI), vascular mild cognitive impairment (VMCI), and probable Alzheimer's disease (AD). Comparison of the plasma Hsp70 and Hsp27 levels of the 4 groups revealed that only the plasma Hsp70 level of VMCI patients (14.11 ng/ml) was significantly higher than that of NCI subjects (11.32 ng/ml), MCI patients (10.16 ng/ml), and patients with probable AD (10.16 ng/ml) after adjustment of age, sex, and education (F=4.231, d.f.=3, p=0.008). Furthermore, there was no difference in plasma Hsp27 levels among the 4 groups. These findings suggest that the plasma Hsp70 level may be related to vascular factors or inflammation.     

Changes of GABA(A) receptor binding and subunit mRNA level in rat brain by infusion of NOS inhibitor

In the present study, we have investigated the effects of prolonged inhibition of nitric oxide synthase (NOS) by infusion of NOS inhibitor, L-nitroarginine, to examine the pentobarbital-induced sleep, modulation of GABA(A) receptor binding, and GABA(A) receptor subunit mRNA level in rat brain. Pre-treatment with L-nitroarginine 30 min before pentobarbital treatment (60 mg/kg, i.p.) significantly increased the duration of sleep in rats. However, the duration of pentobarbital-induced sleep was shortened by the prolonged infusion of L-nitroarginine into ventricle. We have investigated the effect of NOS inhibitor on GABA(A) receptor binding characteristics in discrete areas of brain regions by using autoradiographic and in situ hybridization techniques. Rats were infused with L-nitroarginine (10, 100 pmol/10 microl/h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps. The levels of [(3)H]muscimol and [(3)H]flunitrazepam binding were markedly elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, and cerebellum. However, there was no change in the level of [(35)S]TBPS binding. The levels of beta2-subunit were elevated in the cortex, brainstem, and cerebellar granule layers. By contrast, the levels of beta3-subunit were significantly decreased in the cortex, hippocampus, and cerebellar granule layers in L-nitroarginine-infused rats. Following L-nitroarginine treatment, the levels of alpha6- and delta-subunits which were strictly localized to the cerebellum, were not changed in the cerebellar granule layer. These results show that the prolonged inhibition of NOS by L-nitroarginine-infusion markedly elevates [(3)H]muscimol and [(3)H]flunitrazepam binding throughout the brain, and alters GABA(A) receptor subunit mRNA levels in different directions. Chronic inhibition of NO generation has differential effects on the various expressions of GABA(A) receptor subunits. These suggest the involvement of different regulatory mechanisms for the NO-induced expression of GABA(A) receptor.     

Pretreatment Clinical Mediastinal Nodal Bulk and Extent do not Influence Survival in N2-Positive Stage IIIA Non-small Cell Lung Cancer Patients Treated with Trimodality Therapy

Background

Treatment for patients with N2-positive stage IIIA non-small cell lung cancer has been a controversial issue. The current study evaluated the outcomes in patients treated with trimodality therapy, which consisted of neoadjuvant radiation therapy concurrent with chemotherapy followed by surgical resection, with emphasis on clinical and pathologic nodal status.

Methods

We reviewed the records of 355 patients who were treated with trimodality therapy between 1997 and 2011.

Results

After completion of neoadjuvant chemoradiation, overall down-staging and complete response rates were 50.4 % (179 patients), and 13.2 % (47 patients), respectively. With median follow-up of 35.3 months, median times of progression-free survival (PFS) and overall survival (OS) were 16.3 months and 45.5 months, respectively. Seventeen patients (4.8 %) died of postoperative complications, and the remaining 338 patients were analyzed on prognostic factors. Old age (p = 0.032), pneumonectomy (p < 0.001), and ypN+ (p < 0.001) were found to be the significant prognosticators for worse PFS, and old age (p = 0.013), pneumonectomy (p < 0.001), and ypN+ (p < 0.001) were related to worse OS. Clinical N2 status did not influence either OS or PFS: the number of involved stations (single station vs. multi-station; p = 0.187 for PFS; p = 0.492 for OS), and bulk (clinically evident vs. microscopic; p = 0.902 for PFS; p = 0.915 for OS).

Conclusion

ypN stage was the most important prognosticator for both PFS and OS; however, neither initial bulk nor extent of cN2 disease influenced prognosis. Surgery following neoadjuvant chemoradiation should have contributed to improved clinical outcomes regardless of clinical nodal bulk and extent.     

Quantitative apparent diffusion coefficients and T2 relaxation times in characterizing contrast enhancing brain tumors and regions of peritumoral edema

PURPOSE: To investigate the potential value and relationship of in vivo quantification of apparent diffusion coefficients (ADCs) and T2 relaxation times for characterizing brain tumor cellularity and tumor-related edema. MATERIALS AND METHODS: A total of 26 patients with newly diagnosed gliomas, meningiomas, or metastases underwent diffusion-weighted and six-echo multisection T2-preparation imaging. Regions of interest (ROIs) were drawn on conventional MR images to include tumor (as defined by contrast agent enhancement) and immediate and peripheral edema. Areas of necrosis were excluded. Median values of ADCs and T2 in the ROIs were calculated. RESULTS: ADCs for gliomas were similar to those for meningiomas or metastases in all regions. Tumor T2 values for gliomas (159.5+/-30.6 msec) were significantly higher than those for meningiomas or metastases (125.0+/-31.1 msec; P=0.005). Immediate-edema T2 values for meningiomas or metastases (226.0+/-44.1 msec) were significantly higher than those for gliomas (203.5+/-32.8 msec; P=0.033). Peripheral-edema T2 values for gliomas (219.5+/-41.9 msec) were similar to those for meningiomas or metastases (202.5+/-26.5 msec; P=0.377). Both immediate- and peritumoral-edema ADCs and T2 values were significantly higher than those in tumor for both tumor types. ADCs and T2 values from all regions correlated significantly for gliomas (r=0.95; P<0.0001) and for meningiomas or metastases (r=0.81; P<0.0001). CONCLUSION: The higher immediate-edema T2 values for nonglial tumors than for gliomas suggest tumor-related edema (vasogenic vs. infiltrated) can be further characterized by using T2 values. There were significant correlations between ADC and T2 values.     

Influences of passivating elements on the corrosion and biocompatibility of super stainless steels

Biometals need high corrosion resistance since metallic implants in the body should be biocompatible and metal ion release should be minimized. In this work, we designed three kinds of super stainless steel and adjusted the alloying elements to obtain different microstructures. Super stainless steels contain larger amounts of Cr, Mo, W, and N than commercial alloys. These elements play a very important role in localized corrosion and, thus, their effects can be represented by the "pitting resistance equivalent number (PREN)." This work focused on the behavior which can arise when the bare surface of an implant in the body is exposed during walking, heavy exercise, and so on. Among the experimental alloys examined herein, Alloy Al and 316L stainless steels were mildly cytotoxic, whereas the other super austenitic, duplex, and ferritic stainless steels were noncytotoxic. This behavior is primarily related to the passive current and pitting resistance of the alloys. When the PREN value was increased, the passivation behavior in simulated body solution was totally different from that in acidic chloride solution and, thus, the Cr(2)O(3)/Cr(OH)(3) and [Metal oxide]/[Metal + Metal oxide] ratios of the passive film in the simulated body solution were larger than those in acidic chloride solution. Also, the critical current density in simulated body solution increased and, thus, active dissolution may induce metal ion release into the body when the PREN value and Ni content are increased. This behavior was closely related to the presence of EDTA in the simulated body solution.     

Antireflux surgery normalizes cyclooxygenase-2 expression in squamous epithelium of the distal esophagus

BACKGROUND: In some patients GERD presents with heartburn and regurgitation symptoms but a relative paucity of endoscopic and clinical findings, while in others symptoms may be minor or absent yet there is significant mucosal damage on endoscopy including the presence of Barrett's esophagus. The initial injury of gastroesophageal reflux is to the squamous esophageal mucosa, but while substantial research has been devoted to determining which genes are involved in the progression of Barrett's to dysplasia and cancer, little is known about the gene expression alterations in the squamous mucosa of patients with reflux. We hypothesized that the expression of cyclooxygenase-2 (Cox-2) might be increased in the squamous esophageal mucosal of patients with reflux, and might be a molecular indicator of reflux injury. Further, we hypothesized that Cox-2 expression in the squamous mucosa would be reduced following the elimination of reflux with an antireflux operation. METHODS: Biopsies of the distal esophageal squamous mucosa were taken 3 cm above the squamocolumnar junction (SCJ) in 28 GERD patients before and after Nissen fundoplication. Following microdissection and RNA isolation, quantitative real-time PCR was used to measure Cox-2 gene expression in paraffin-embedded (N = 16) and fresh frozen (N = 12) tissue. Biopsies from patients (paraffin N = 15, frozen N = 14) with normal acid exposure and no evidence of mucosal injury were analyzed as controls. RESULTS: Median Cox-2 expression in the squamous epithelium from paraffin embedded biopsies in patients with reflux disease was significantly increased compared to controls (p = 0.04). The presence of esophagitis or Barrett's esophagus did not significantly alter the expression of Cox-2 compared to patients with nonerosive reflux disease (NERD). After antireflux surgery median Cox-2 expression values were significantly reduced (p = 0.0003) and were normalized to levels similar to controls without reflux (p = 0.74). Similar results were observed in the prospectively obtained fresh frozen tissue. CONCLUSIONS: Cox-2 gene expression is increased in the distal esophageal squamous mucosa of most patients with GERD, and the elevation was similar whether there was mucosal injury in the form of esophagitis or Barrett's or no visible mucosal injury. This suggests that increased Cox-2 expression may serve as a molecular marker of reflux disease. The increased Cox-2 expression in patients with reflux was usually normalized following antireflux surgery. These findings demonstrate for the first time that gene expression can be altered by surgical correction of reflux. Thus, in addition to symptom control and improvement in the quality of life, perhaps future studies assessing the efficacy of antireflux therapy should also focus on the impact of the therapy on gene expression in the esophageal squamous mucosa.     

Estimating average glucose levels from glycated albumin in patients with end-stage renal disease

Purpose

In patients with diabetic end stage renal disease (ESRD), glycated albumin (GA) reflects recent glycemic control more accurately than glycated hemoglobin (HbA_1c). We evaluated the relationship between GA and average blood glucose (AG) level and developed an estimating equation for translating GA values into easier-to-understand AG levels.

Materials and Methods

A total of 185 ESRD patients, including 154 diabetic and 31 non-diabetic participants, were enrolled (108 hemodialysis, 77 peritoneal dialysis). Patients were asked to perform four-point daily self-monitoring of capillary blood glucose (SMBG) at least three consecutive days each week for four weeks. Serum levels of GA, HbA_1c and other biochemical parameters were checked at baseline, as well as at 4 and 8 weeks.

Results

Approximately 74.3±7.0 SMBG readings were obtained from each participant and mean AG was 169.1±48.2 mg/dL. The correlation coefficient between serum GA and AG levels (r=0.70, p<0.001) was higher than that of HbA_1c and AG (r=0.54, p<0.001). Linear regression analysis yielded the following equation: estimated AG (eAG) (mg/dL)=4.71×GA%+73.35, and with this formula, serum GA levels could be easily translated to eAG levels. Multivariate analysis revealed significant contributions of postprandial hyperglycemia (β=0.25, p=0.03) and serum albumin (β=0.17, p=0.04) in determining serum GA level, independent to other clinical parameters.

Conclusion

Compared to HbA_1c, serum GA levels were better correlated with AG levels. Using the estimating equation, an average blood glucose level of 155-160 mg/dL could be matched to a GA value of 18-19% in patients with ESRD.     

Chemoradiotherapy followed by surgery in rectal cancer: improved local control using a moderately high pelvic radiation dose

Background: To determine complete resection and sphincter preservation rates,down-staging, local control and survival associated with concurrentchemoradiotherapy (CCRT) using a moderately high pelvic radiationdose before surgery in rectal cancer. Methods: Fifty-seven patients with histologically proven adenocarcinomaof the mid to lower rectum were treated using preoperative CCRTand surgery. Median radiation dose to the pelvis was 5400 cGy(5040–5580 cGy). CCRT was administered during thefirst and fifth weeks of radiotherapy with bolus intravenous5-fluorouracil (5-FU) 400 mg/m²/day and leucovorin (LV)20 mg/m²/day for 5 days. Surgery was attempted 4–8weeks after completing preoperative CCRT. Post-operative chemotherapywas then added for up to four cycles of intravenous 5-FU andLV. Results: Toxicities during CCRT were generally mild and manageable: Grade1/2 anemia, 3.5%; Grade 1/2 leukopenia, 45.6%; Grade 3 leukopenia,3.5%; Grade 1/2 diarrhea, 22.8%; Grade 1/2 abdominal discomfort,7%; and perianal skin reaction, 5.3%. No late complication requiringsurgical intervention occurred. Complete surgical resectionwith a negative resection margin was achieved in 98.2% of patients,and the down-staging rate was 52.6% (30/57; 95% CI 39.6–65.6%).Complete pathologic response was obtained in 5.3% patients (3/57;95% CI 0-11.1%) and in other 2 patients only sporadic tumorcells nests were noted in surgical specimens. The sphincterpreservation rate was 77.2% (44/57; 95% CI 66.3–88.1%).Of 30 patients with tumors located within 5 cm from theanal verge, sphincter preservation was possible in 18 patients(60.0%; 95% CI 47.3–72.7%). With a median follow-up durationof 40 months, overall and disease-free survival (DFS) ratesover 3 years were 91.8% (95% CI 85.5–98.2%) and 79.7%(95% CI 71.2–88.2%), respectively. At univariate analysis,significant factors for DFS was LN involvement status (P = 0.024).Local and distant failure rates over the same period were 5.3and 21.1%, respectively. Conclusions: Preoperative CCRT produced encouraging down-staging rates andwas found to facilitate complete resection and sphincter savingin distal rectal cancer with acceptable toxicity. Further studiesare warranted using this moderately high radiation dose to thepelvis to improve the local control.