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Introduction: Cognitive decline is the core schizophrenia symptom, which is now well accepted. Holding a role in various aspects of cognition, lentiform nucleus (putamen and globus pallidus) dysfunction contributes to the psychopathology of this disease. However, the effects of lentiform nucleus function on cognitive impairments in schizophrenia are yet to be investigated.Objectives: We aim to detect the fractional amplitude of low-frequency fluctuation (fALFF) alterations in patients with schizophrenia, and examine how their behavior correlates in relation to the cognitive impairments of the patients.Methods: All participants underwent magnetic resonance imaging (MRI) and cognitive assessment (digit span and digit symbol coding tests). Screening of brain regions with significant changes in fALFF values was based on analysis of the whole brain. The data were analyzed between Jun 2020 and Mar 2021. There were no interventions beyond the routine therapy determined by their clinicians on the basis of standard clinical practice.Results: There were 136 patients (75 men and 61 women, 24.1 ± 7.4 years old) and 146 healthy controls (82 men and 64 women, 24.2 ± 5.2 years old) involved in the experiments seriatim. Patients with schizophrenia exhibited decreased raw scores in cognitive tests (p < 0.001) and increased fALFF in the bilateral lentiform nuclei (left: 67 voxels; x = −24, y = −6, z = 3; peak t-value = 6.90; right: 16 voxels; x = 18, y = 0, z = 3; peak t-value = 6.36). The fALFF values in the bilateral lentiform nuclei were positively correlated with digit span-backward test scores (left: r = 0.193, p = 0.027; right: r = 0.190, p = 0.030), and the right lentiform nucleus was positively correlated with digit symbol coding scores (r = 0.209, p = 0.016).Conclusion: This study demonstrates that cognitive impairments in schizophrenia are associated with lentiform nucleus function as revealed by MRI, involving working memory and processing speed.

ObjectivesWe aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT).DesignAnalysis of a multicentre prospective registry.SettingIn six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively.Participants224 patients with AIS were treated by MT.ResultsOf 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality.ConclusionsWe developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated.Trial registration numberChinese Clinical Trial Registry (ChiCTR-OOC-17013052).

To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days. The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran–Mantel–Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642

Klippel-Trénaunay syndrome (KTS) is a rare angio-osteo-hypertrophic syndrome characterized by vascular malformations, soft tissue and/or bone hypertrophy, and varicose veins. For the purpose of describing the imaging findings and elucidating the role of medical imaging in the diagnosis and assessment of patient with KTS, we have reviewed the imaging data of 14 KTS patients. The imaging features on different imaging modalities were analyzed. Unilateral lower limb involvement was evident in 71% of cases (n=10) and bilateral but asymmetric lower limb involvement in the remaining 29% of cases (n=4). The most commonly depicted imaging features were varicosities in 93% (n=13), muscle hypertrophy in 79% (n=11) and venous anomalies in 64% (n=9). Other less common imaging findings included lymphedema in 29% (n=4), arterial malformations 29% (n=4), soft tissue hemangiomas 21% (n=3), pelvic and thigh phleboliths 21% (n=3), venous aneurysms 21% (n=3), bone abnormalities 14% (n=2) and lymphadenopathy 14% (n=2). A severe unilateral lower limb deformity resulting in contractures and muscle atrophy of the whole limb was depicted in 1 case. The pathognomonic marginal vein of Servelle was identified in 2 cases. AV shunt was highly suspected in 4 cases and was confirmed by DSA in 1 case, making Klippel-Trénaunay-Weber syndrome a more apt diagnosis. Associated ipsilateral duplicated renal artery was found in 1 case. We have concluded that medical imaging is the cornerstone in the diagnosis and assessment of severity and complications, follow-up and differentiation of KTS from other similar conditions. Different imaging modalities play complementary roles in the evaluation of KTS patients.

Although several risk factors for metabolic syndrome (MetS) have been reported, there are few clinical scores that predict its incidence. Therefore, we created and validated a risk score for prediction of 3-year risk for MetS. Three-year follow-up data of 4395 initially MetS-free subjects, enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. Subjects at enrollment were randomly divided into the training and the validation cohort. Univariate and multivariate logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. The predictive performance of the model was tested by computing the area under the receiver operating characteristic curve (AUROC). Four independent predictors were chosen to construct the MetS risk score, including BMI (HR=1.906, 95% CI: 1.040–1.155), FPG (HR=1.507, 95% CI: 1.305–1.741), DBP (HR=1.061, 95% CI: 1.002–1.031), HDL-C (HR=0.539, 95% CI: 0.303–0.959). The model was created as –1.5 to 4 points, which demonstrated a considerable discrimination both in the training cohort (AUROC=0.674) and validation cohort (AUROC=0.690). Comparison of the observed with the estimated incidence of MetS revealed satisfactory precision. We developed and validated the MetS risk score with 4 risk factors to predict 3-year risk of MetS, useful for assessing the individual risk for MetS in medical practice.

To our knowledge, no study investigates the association of genetic variant distributions of WW domain-containing oxidoreductase (WWOX) gene with development of invasive cancer, clinicopathologic variables and patient survival in uterine cervical cancer for Taiwanese women. We therefore conducted this study to explore the clinical involvements of WWOX single nucleotide polymorphisms (SNPs) in cervical cancer. One hundred and thirty-one patients with cervical invasive cancer and 93 patients with precancerous lesions as well as 316 control women were consecutively enrolled. The genotypic frequencies of WWOX genetic variants rs73569323, rs383362, rs11545028, rs3764340 and rs12918952 were determined by real-time polymerase chain reaction. The results revealed that only WWOX SNP rs3764340 was associated between patients with cervical invasive cancer and normal controls among 5 WWOX genetic variants. Cervical cancer patients with genotypes GA/AA in WWOX SNP rs12918952 were associated with parametrium invasion and pelvic lymph node metastasis. Univariate analysis found that WWOX SNPs rs73569323 and rs11545028 were associated with patient survival, whereas multivariate analysis revealed CT/TT in rs11545028 was the only genetic variant, which could predict better overall survival, among 5 WWOX SNPs in Taiwan. In conclusion, Taiwanese women with CG/GG in WWOX SNP rs3764340 are susceptible to cervical invasive cancer. Cervical cancer patients with GA/AA in rs12918952 tend to have more risk to develop parametrium invasion and pelvic lymph node metastasis. Among 5 WWOX SNPs, rs11545028 is the only genetic variant associated with patient survival, in which CT/TT could predict better overall survival in Taiwanese women.

“Physical restraint” formerly used as a measure of protection for psychiatric patients is now widely used. However, existing studies showed that physical restraint not only has inadequate effect of protection but also has negative effects on residents. To analyzes the impact of educational program on the physical restraint use in long-term care facilities. Design: A systematic review with meta-analysis and meta-regression. Eight databases, including Cochrane Library, ProQuest, PubMed, EMBASE, EBSCO, Web of Science, Ovid Medline and Physiotherapy Evidence Database (PEDro), were searched up to January 2017. Eligible studies were classified by intervention and accessed for quality using the Quality Assessment Tool for quantitative studies. Sixteen research articles were eligible in the final review; 10 randomize control trail studies were included in the analysis. The meta-analysis revealed that the use of physical restraint was significantly less often in the experimental (education) group (OR = 0.55, 95% CI: 0.39 to 0.78, p < 0.001) compared to the control group. Meta-regression revealed the period of post education would have decreased the effect of the restraint educational program (β: 0.08, p = 0.002); instead, the longer education period and more times of education would have a stronger effect of reducing the use of physical restraint (β: −0.07, p < 0.001; β: −0.04, p = 0.056). The educational program had an effect on the reduced use of physical restraint. The results of meta-regression suggest that long-term care facilities should provide a continuous education program of physical restraint for caregivers.

Background Ziprasidone (ZIP) is often used with olanzapine (OLZ) in ‘switch’ and combination therapy but empirical evidence to support these strategies is limited. Objective This study was therefore designed to compare the efficacy and tolerability of switching from OLZ to ZIP, the combination of both medications, and OLZ and ZIP monotherapy, in patients with schizophrenia spectrum disorders (SSD). Methods In this 12 week open-label, assessor-blinded randomized trial, 148 patients with SSD who had not used antipsychotics for at least 3 months were assigned to ZIP (n = 49) or OLZ monotherapy (n = 31); OLZ for 4 weeks then a switch to ZIP (OLZ/ZIP, n = 35); or combination therapy (OLZ + ZIP, n = 33). The severity of psychosis and abnormal involuntary movements was evaluated at baseline, 1, 2, 4, 8, and 12 weeks using standard instruments. Baseline-to-endpoint changes in weight gain and metabolic measures were compared. Results The efficacy of both OLZ/ZIP and OLZ + ZIP was comparable OLZ monotherapy and better than ZIP monotherapy in reducing overall psychotic and negative symptoms at most 8 and 12 week measurement points. Changes in weight gain, glucose, and lipid measures did not differ between OLZ/ZIP and OLZ + ZIP, but were markedly higher following OLZ monotherapy. The OLZ + ZIP group had the lowest overall incidence of adverse events and extrapyramidal symptoms of all the treatment regimens. Conclusions We conclude that combining ZIP and OLZ at the outset of treatment is superior to switching from OLZ to ZIP in terms of improving psychotic symptoms and limiting movement side effects without increasing the risk of metabolic syndrome.

Aim The aim of this study was to determine the efficacy and safety of cranial electrotherapy stimulation (CES) as an add-on treatment for TD. Methods A randomized, double-blind, sham-controlled trial was conducted at an outpatient, single-center academic setting. A total of 62 patients aged 6–17 years with TD and lack of clinical response to 4 weeks’ pharmacotherapy were enrolled. Patients were divided randomly into 2 groups and given 4 weeks’ treatment, including 30 min sessions of active CES (500 μA–2 mA) or sham CES (lower than 100 μA) per day for 40 d on weekdays. Change in Yale Global Tic Severity Scale (YGTSS), Clinical Global Impression-severity of illness-severity (CGI-S) and Hamilton Anxiety Scale-14 items (HAMA-14) were performed at baseline, week 2, week 4. Adverse events (AEs) were also evaluated. Results 53 patients (34 males and 9 females) completed the trial, including 29 in the active CES group and 24 in the sham CES group. Both groups showed clinical improvement in tic severities compared to baseline respectively at week 4. Participants receiving active CES showed a reduction of 31.66 % in YGTSS score, compared with 23.96 % in participants in sham CES group, resulting in no significant difference between the two groups (t = 1.54, p = 0.13). Conclusion Four-week’s treatment of CES for children and adolescents with TD is effective and safe, but the improvement for tic severity may be related to placebo effect.

Up to date, no study explores the relationship of single nucleotide polymorphisms (SNPs) of long non-coding RNAs HOTAIR (lncRNAs HOTAIR) with cancer recurrence and patient survival in uterine cervical cancer for Taiwanese women. We therefore designed this study to investigate the clinical roles of lncRNAs HOTAIR SNPs in cervical cancer. One hundred and sixteen patients with cervical invasive cancer and 96 patients with preinvasive lesions as well as 318 control women were consecutively recruited. LncRNAs HOTAIR SNPs rs920778, rs12427129, rs4759314 and rs1899663 were analyzed and their genotypic frequencies were examined by real-time polymerase chain reaction. The results indicated that there were no genotypic differences between patients with cervical neoplasia and normal controls as well as among patients with invasive and invasive cancer, and normal controls. However, genotype GG in lncRNAs HOTAIR SNP rs920778 was demonstrated to be a predictor for poorer cancer recurrence probability [p=0.001, hazard ratio (HR): 7.25, 95% CI: 2.19-23.96]. Furthermore, cervical cancer patients with genotype GG in lncRNAs HOTAIR rs920778 had worse overall survival (p=0.002, HR: 7.22, 95% CI: 2.09-24.92). No significant associations exhibited between lncRNAs HOTAIR SNP rs920778 and clinicopathological parameters. In conclusion, this studied lncRNAs HOTAIR SNPs are not associated with cervical carcinongensis. However, lncRNAs HOTAIR SNP rs920778 may be regarded as an independent predictor of cancer recurrence probability and overall survival in cervical cancer patients.

Nonalcoholic fatty liver disease (NAFLD) has been linked to an increased risk of cardiovascular disease (CVD). To explore the impact of diabetes mellitus (DM) as a cardiovascular risk factor, this meta-analysis quantitatively assessed the association of NAFLD and CVD in diabetic patients.PubMed, EMBASE, and the Cochrane Library database were analyzed until the end of March 2017. Original studies analyzing the association between NAFLD and cardiovascular risk factors in the diabetic population were included. The available data related to outcome were extracted for the effect estimate using a random-effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.Of the 770 initially identified studies, 11 studies involving 8346 patients were finally included. The Newcastle-Ottawa Quality Assessment Scale scores suggested that the studies included were of high quality. The pooled effects estimate showed that diabetic patients with NAFLD showed a two times increased risk for CVD compared with patients without NAFLD (odds ratio=2.20, 95% confidence interval: 1.67-2.90). Subgroup analysis also yielded a markedly increased risk, with odds ratio (95% confidence interval) values of 2.28 (1.61-3.23) and 1.90 (1.48-2.45) in cross-sectional and cohort studies, respectively.This is the first meta-analysis investigating the relationship between NAFLD and CVD independent of the impact of DM. Our findings suggested that NAFLD increases the risk of CVD in populations with comparable DM profiles. Diabetic patients diagnosed with NAFLD might benefit from a more early cardiovascular risk assessment, thereby reducing CVD morbidity and mortality.

Neural substrates behind schizophrenia (SZ) and its heritability mediated by brain function are largely unknown. Cerebral blood flow (CBF), as a biomarker of activation in the brain, reflects the neuronal metabolism, and is promisingly used to detect cerebral alteration thereby shedding light on the features of individuals at high genetic risk. We performed a cross-sectional functional magnetic resonance imaging (MRI) study enrolling 45 first-episode drug-naïve patients with SZ, 32 unaffected first-degree relatives of these patients, and 51 healthy controls (HCs). We examined CBF, CBF connectivity, and CBF topological properties. SZ patients showed increased CBF in the left medial superior frontal gyrus and right precuneus compared with HCs, and decreased CBF in the left middle temporal gyrus compared with their relatives. Furthermore, unaffected relatives revealed higher level of CBF pronounced in regions within default mode network (DMN). Both SZ patients and their relatives exhibited dysconnectivity patterns. Notably, as for the network properties, unaffected relatives were with an intermediate level between SZ patients and HCs in the local efficiency and global efficiency. Our findings demonstrate the aberrant CBF of areas within DMN and the CBF connectivity pattern might be a familial feature in the brain of first-episode SZ patients and their relatives.

This study is supposed to investigate the effect of FGF-23 on parathyroid hormone (PTH) secretion through ERK/MAPK signaling pathway in secondary hyperparathyroidism (SHPT) rat model. Thirty rats were equally served as the normal and SHPT groups. After transfection, parathyroid cells was assigned into blank, NC, pcDNA3.1-FGF-23, siRNA-FGF-23, U0126, and siRNA-FGF-23 + U0126 groups. The serum levels of Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), and PTH were detected. HE and immunohistochemical (IHC) staining were used for the histopathological changes and the FGF-23, EKR1/2, and pEKR1/2 expressions. qRT-PCR and Western blotting were performed to determine the mRNA and protein expression of FGF-23, PTH, MAPK, EKR1/2, and Klotho. The proliferation, apoptosis, and cell cycle were all measured for parathyroid cells by CCK-8 assay, TUNEL staining and Flow cytometry. Compared with the normal group, the SHPT group showed increased serum levels PTH, P, ALP, and FGF-23 and mRNA and protein expressions of FGF-23 and PTH, whereas declined Ca and p-ERK1/2 expression, mRNA and protein expression of Klotho, cell apoptosis rate was reduced. Furthermore, compared to the blank and NC groups, the pcDNA3.1-FGF-23 and U0126 groups had a decreased mRNA expression of Klotho, protein expression of EKR1/2 and Klotho, and cell apoptosis rate was down-regulated, whereas the RNA and protein expressions of FGF-23 and PTH were up-regulated, and cell proliferation was elevated. The opposite results were observed in the siRNA-FGF-23 group. Our study demonstrated that FGF-23 could inhibit signaling transduction of ERK/MAPK pathway and accelerate the secretion of PTH in rats with SHPT.

This study aimed to evaluate the accuracy of Transtek LS808-B according to the European Society of Hypertension International Protocol revision 2010 (ESH-IP2010).A total of 33 adult individuals (19 men and 14 women, mean age 46.8±15.8 years) were recruited; their systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using the mercury sphygmomanometer and Transtek LS808-B. A total of 99 pairs of measurements were obtained from these 33 participants for comparison in two parts with three grading phases.All the validation requirements were fulfilled. The number of absolute difference between the tested device and the observers within 5, 10, and 15 mmHg was 73, 94, and 98 for SBP and 78, 94, and 99 for DBP, respectively. The mean±SD of the device-observer difference was 0.5±4.4 mmHg for SBP and 0.2±4.1 mmHg for DBP. The number of participants with two or three device-observer differences within 5 mmHg was 24 for SBP and 27 for DBP. In addition, two of the participants had no device-observer difference within 5 mmHg for SBP and one of the participants had the same for DBP.Transtek LS808-B has passed all phases of ESH-IP 2010, and hence can be recommended for self/home measurement in adult populations.

Circulating tumor DNA (ctDNA) in peripheral blood is a “liquid biopsy” that contains representative tumor information including gene mutations. Additionally, repeated ctDNA samples can be easily obtained to monitor response to treatment and disease progression, which may be especially valuable to lung cancer patients with tumors that cannot be easily biopsied or removed. To investigate the changes in ctDNA after surgical tumor resection, tumor and blood samples obtained before and after surgery were collected prospectively from 41 non-small lung cancer (NSCLC) patients. Somatic driver mutations in tumor DNA (tDNA) and pre- and post-op plasma ctDNA sample pairs were identified by targeted sequencing in several genes including EGFR, KRAS, and TP53 with an overall study concordance of 78.1% and sensitivity and specificity of 69.2% and 93.3%, respectively. Importantly, the frequency of 91.7% of ctDNA mutations decreased after surgery and these changes were observed as little as 2 days post-op. Moreover, the presence of ctDNA had a higher positive predictive value than that of six tumor biomarkers in current clinical use. This study demonstrates the use of targeted sequencing to reliably identify ctDNA changes in response to treatment, indicating a potential utility of this approach in the clinical management of NSCLC.

Purpose In terms of drug resistance, cancer cells usually benefit from high clusterin (CLU) expression on chemotherapy. In contrast, CLU expression has been found to be a favorable prognostic factor in lung cancer patients. The aims of this study are to determine the association between CLU expression and chemotherapeutic sensitivity and the potential role of CLU in migration in human non-small-cell lung cancer (NSCLC) cell lines.

Fungal immunomodulatory protein, FIP-fve, has been isolated from Flammulina velutipes, and its immunomodulatory effects are believed to be associated with the enhanced activation of IFN-gamma-releasing Th1 cells. However, the mechanisms of FIP-fve-mediated signal transduction in the regulation of interferon-gamma (IFN-gamma) gene expression in human peripheral blood mononuclear cells (PBMCs) are still poorly understood. Using fluo-3 AM, we found that FIP-fve induces a rapid elevation in calcium concentration. ELISA, RT-PCR and Western blot assays demonstrated significant increases in the production and mRNA expression of IFN-gamma and protein kinase C-alpha (PKC-alpha) activation in activated PBMCs, which were abolished by EGTA, nifedipine and GO6976. In conclusion, Ca2+ release and PKC-alpha activation are required for IFN-gamma production induced by FIP-fve in PBMCs.

The lack of a human papillomavirus (HPV)-infected skin cancer cell line has hampered the investigation of the interaction of UV and HPV in skin carcinogenesis. We identified a human basal cell carcinoma (BCC-1/KMC) cell line integrated with E6 and E7 genes of high-risk HPV type 18 and demonstrated that repression of E6 and E7 results in proliferation inhibition. Sublethal ultraviolet-B (UVB) irradiation induced the expressions of interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as viral E6 and E7 genes, in BCC-1/KMC cells. When E6 and E7 expressions were inhibited, IL-6/IL-8 expressions were repressed. Furthermore, IL-6/IL-8 remained inducible by UVB irradiation when E6 and E7 were inhibited. These results indicated that IL-6 and IL-8 can be upregulated by viral E6 and E7 proteins without UVB irradiation. Moreover, chronic exposure to UVB upregulates IL-6 and IL-8 when E6/E7 is induced by UVB.

The effects of exogenous corticosterone and restraint stress on the number and percentage of lymphocyte subpopulations in the spleen and thymus were evaluated. The data were used to generate linear models that describe the relationship between these parameters and the area under the corticosterone concentration vs time curve (AUC). Comparison of the models revealed that the number of nucleated cells in the spleen was decreased similarly by exogenous corticosterone and restraint (at equivalent corticosterone AUC values). However, exogenous corticosterone caused a greater decrease in cell number in the thymus than it did in the spleen. Corticosterone preferentially depleted CD4+CD8+ cells in the thymus, whereas the same corticosterone exposure produced by restraint stress did not. In the spleen, cell number for all major cell types was decreased by both treatments, but there were minor differences in the change in percentage of some subpopulations induced by exogenous corticosterone as compared to restraint. The models derived here provide quantitative data that indicate the magnitude of corticosterone and stress-induced effects on lymphocyte populations in the spleen and thymus. These results have mechanistic implications, and they may be useful in future efforts to extrapolate from mouse to human by completing a risk assessment parallelogram.

Background: Acute administration of EtOH suppresses basal NK cell lytic function in mice, and this suppression is caused, in part, by neuroendocrine mediators induced by EtOH. There is also evidence that a smaller part of the suppression is caused by direct action of EtOH. However, activation of NK cells to higher levels of lytic activity may be more important than basal NK cell lytic function in resistance to cancer or infectious agents. Therefore, the study described here examined the effects of acute EtOH exposure on activation of NK cells by polyinosinic-polycytidilic acid (poly I:C). Methods: Ethanol was administered by gavage as a 32% solution in water, and poly I:C was administered to activate NK cells. NK cell activity was measured using a standard 4 hr 51 Cr release assay with YAC-1 tumor cells. The effects of corticosterone were evaluated by administration of a glucocorticoid antagonist (RU 486) or a dosage of corticosterone previously shown to induce similar blood levels as treatment with EtOH. Results: EtOH at 5-7 g/kg suppressed poly I:C-induced increases in NK cell lytic activity, and at least the lower end of this dosage range yields blood EtOH levels that are relevant for humans (0.25-0.3%). This suppression was partially blocked in mice that were pretreated with a glucocorticoid antagonist, and administration of exogenous corticosterone also suppressed NK cell activation. Conclusions: EtOH-induced increases in corticosterone are apparently involved in the suppression of NK cell activation. This conclusion was supported by the lack of a direct effect of EtOH or its major metabolites (acetaldehyde and acetate) on NK cell activation by poly I:C in vitro.

The present study was done to delineate cause-effect relationships between the ethanol (EtOH)-induced stress response, natural-killer (NK)-cell activity, and resistance to experimental metastases of B16F10 melanoma cells in mice. Increased numbers of metastatic nodules were noted in the lungs of mice treated with dosages of EtOH that produce peak blood levels of 0.25-0.4%. EtOH caused only a minor depletion of NK cells or NK-cell activity from the spleen or lungs of normal or B16F10-challenged mice. However, in earlier studies we have shown consistent, significant decreases in NK-cell activity (approx. 50%) in spleen preparations from EtOH-treated mice. Depletion of NK cells by a monoclonal antibody increased the number of B16F10 nodules in the lungs, confirming an important role for NK cells for resistance to B16F10 metastases. Treatment of NK-cell-depleted mice with EtOH caused no further decrease in resistance to B16F10 cells, indicating that suppression of NK-cell activity is the major mechanism by which EtOH suppresses resistance to B16F10 metastases. Adrenalectomy or a glucocorticoid antagonist partially prevented EtOH-induced increases in the number of metastatic nodules in the lungs. Administration of exogenous corticosterone increased the number of B16F10 nodules to an extent similar to that caused by EtOH. These results indicate a role for the EtOH-induced stress response in decreasing resistance to B16F10 metastases. EtOH-induced decreases in resistance to cancer have also been reported in rats. The findings of the present study support the possibility that this is a generalized phenomenon, which could occur in humans.

The neuroendocrine response to stressors increases the concentration of several endogenous mediators, some of which are immunosuppressive. However, quantitative aspects of these effects have been overlooked. Although it should be possible to predict the degree of suppression of particular immunological functions by measuring the concentrations of stress-related mediators such as corticosterone, this cannot be done with data presently available. This study was designed to develop regression models to predict the relationship between the area under the corticosterone concentration vs. time curve (AUC) and two immunological parameters. Models were developed using mice treated with exogenous corticosterone and mice subjected to various periods of restraint stress. The latter treatment was included to determine if the effects of corticosterone were different from those of corticosterone in association with the other mediators induced in a restraint-stress response. Models relating corticosterone AUC to expression of MHC class II proteins on splenocytes were very similar, whether the corticosterone was exogenous or produced as part of a restraint-stress response. This was also true for splenic natural killer (NK) cell activity. However, MHC class II expression was more sensitive to the effects of corticosterone or restraint than was NK cell activity. The corticosterone and restraint models predicted the previously published effect of a chemical stressor (ethanol) on MHC class II expression, but neither model predicted the suppression of NK cell activity by ethanol. These results have mechanistic implications, which are discussed in the context of previous studies. The quantitative models described here should be useful in determining and predicting the stress-related portion of chemical-induced immunosuppression. In addition, these models provide quantitative data essential for a complete understanding of stress-induced immunosuppression.

A mouse model for binge drinking has been developed in this laboratory, and several aspects of this model have been characterized. Many of the immunosuppressive effects of ethanol (EtOH) in this model seem to be mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis and consequent increases in the concentration of glucocorticoids, catecholamines, and perhaps other immunosuppressive mediators. The purpose of the work described here is to examine three important issues regarding the EtOH-induced neuroendocrine response in this model: 1) Are Ro15-4513-sensitive gamma aminobutyric acid type A (GABA-A) receptors involved in activation of the HPA axis by EtOH? 2) Does daily administration of EtOH produce tolerance with regard to activation of the HPA axis or with regard to suppression of natural killer cell activity? 3) Is the HPA axis activated by similar blood EtOH concentrations in humans and in the mouse model? Ro15-4513, a partial inverse agonist of GABA-A receptors, did not affect EtOH-induced increases in blood corticosterone levels. This suggests that Ro15-4513-sensitive GABA-A receptors are not involved in EtOH-induced activation of the HPA axis and that inhibition of corticosterone production is not the mechanism by which Ro-15-4513 blocks EtOH-induced immunosuppression. To evaluate tolerance, mice were given a daily dose of EtOH (6.5 g/kg by gavage) or vehicle (water) for 10 days. Control groups received vehicle or EtOH only on the last day of the experiment. At the optimum time after EtOH administration serum corticosterone and splenic NK cell activity were measured. The results indicate no significant alterations in the response to EtOH of mice exposed to EtOH for 10 days compared to those exposed only once. To compare the HPA axis response of mice and humans, lower EtOH dosages than generally used in our model were administered to mice, and the corticosterone response was compared to published data for humans who had similar ranges of blood EtOH levels. The results suggest that humans and mice exhibit activation of the HPA axis only when blood EtOH levels exceed approximately 0.14%. Together these results further characterize a mouse model for binge drinking that seems to provide a reasonable representation of many aspects of binge drinking in humans.

Ethanol (EtOH) suppresses splenic natural killer (NK) cell activity in a mouse binge drinking model. Direct effects of EtOH and its metabolites are not the major cause of this suppression. Also, catecholamines do not completely explain this suppression. This implicates the involvement of other neuroendocrine mediators in this suppression. Previous studies in this laboratory have shown that RU 486 at a dosage of 100 mg/kg did not affect EtOH-induced suppression of NK cell activity. However, in the present study, RU 486 at a dosage of 200 mg/kg partially blocked the suppression of NK cell activity induced by EtOH. Moreover, corticosterone at levels expected in the free (unbound) form in EtOH-treated mice decreased NK cell activity in vitro. Nadolol in combination with RU 486 blocked the suppression of NK cell activity in EtOH-treated mice. Although there were reasons to suspect that EtOH-induced changes in the levels of growth hormone or prolactin might also contribute to the suppression of NK cell activity; evidence obtained herein did not indicate such involvement. Thus, glucocorticoids and catecholamines seem to be involved in EtOH-induced suppression of NK cell activity. Together, with the direct effects of EtOH, these neuroendocrine mediators seem to be sufficient to explain all of the suppression of NK cell activity caused by EtOH.

Purposes: Lung cancer is prevalent worldwide and improvements in timely and effective diagnosis are need. Pentraxin-3 as a novel serum marker for lung cancer (LC) has not been validated in large cohort studies. The aim of the study was to assess its clinical value in diagnosis and prognosis. Methods: We analyzed serum PTX-3 levels in a total of 1,605 patients with LC, benign lung diseases and healthy controls, as well as 493 nonlung cancer patients including 12 different types of cancers. Preoperative and postoperative data were further assessed in patients undergoing LC resection. The diagnostic performance of PTX-3 for LC and early-stage LC was assessed using receiver operating characteristics (ROC) by comparing with serum carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1). Results: Levels of PTX-3 in serum were significantly higher in patients with LC than all controls. ROC curves showed the optimum diagnostic cutoff was 8.03ng/mL (AUC 0.823, [95%CI 0.789-0.856], sensitivity 72.8%, and specificity 77.3% in the test cohort; 0.802, [95%CI 0.762-0.843], sensitivity 69.7%, and specificity 76.4% in the validate cohort). Similar diagnostic performance of PTX-3 was observed for early-stage LC. PTX-3 decreased following surgical resection of LC and increased with tumor recurrence. Significantly elevated PTX-3 levels were also seen in patients with non-lung cancers. Conclusions: The present data revealed that PTX-3 was significantly increased in both tissue and serum samples in LC patients. PTX-3 is a valuable biomarker for LC and improved identification of patients with LC and early-stage LC from those with non-malignant lung diseases.

Quetiapine, an atypical antipsychotic, may have efficacy as augmentation therapy in treatment resistant depression (TRD), but evidence is limited and the underlying mechanism remains poorly understood. Therefore, this study was aimed to investigate whether and how quetiapine can be served as an augmentation agent in fluoxetine treatment resistant depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, the effects of CUMS regimen and antidepressant treatment were assessed by behavioral tests and hippocampal neurogenesis. Approximately 20-30% of depressive rats respond poorly to fluoxetine treatment. In their hippocampus, a significant decrease of neurogenesis was also observed. However, quetiapine add-on therapy significantly improved the depressive behaviors and increased the number of the newborn neurons in the hippocampus of fluoxetine treatment resistant depressive rats. Thus, our results suggest that quetiapine may be used as an augmentation agent in the treatment resistant depression partly mediated by increasing the number of newborn neurons in the hippocampus.

Background We aimed to perform a systematic review and meta-analysis of the diagnostic performance of pleural fluid procalcitonin (PCT) or C-reactive protein (CRP) in differentiating parapneumonic effusion in patients with pleural effusion. Methods We searched the EMBASE, MEDLINE, and Cochrane database in December 2011. Original studies that reported the diagnostic performance of PCT alone or compared with that of other biomarkers for differentiating the characteristics of pleural effusion were included. Results We found 6 qualifying studies including 780 patients with suspected parapneumonic effusion and 306 confirmed cases of parapneumonic effusion. Six studies examined the diagnostic performance of pleural fluid PCT, 3 also tested for serum PCT, and another 3 tested for serum CRP. The bivariate pooled sensitivity and specificity were as follows 0.67 (95% confidence interval [CI], 0.54-0.78) and 0.70 (95% CI, 0.63-0.76), respectively, for pleural fluid PCT; 0.65 (95% CI, 0.55-0.74) and 0.68 (95% CI, 0.62-0.74), respectively, for serum PCT; and 0.54 (95% CI, 0.47-0.61) and 0.77 (95% CI, 0.72-0.81), respectively, for serum CRP. There was evidence of significant heterogeneity ( I 2 =55.0%) for pleural fluid or serum PCT but not for CRP ( I 2 =0.0%). Conclusion The existing literature suggests that both pleural fluid and serum PCT tests have low sensitivity and specificity for differentiating parapneumonic effusion from other etiologies of pleural effusion. Compared with PCT, serum CRP has higher specificity and a higher positive likelihood ratio, and thus, it has a higher rule-in value than PCT.

Our previous studies showed serum insulin-like growth factor-I (IGF-I) concentrations significantly decreased in infants with congenital ventricular septal defect (VSD) and that they were associated with increased concentrations of growth hormone. In order to confirm the relationship between IGF-I axis and VSD, we further compared the IGF-I and insulin-like growth factor-I receptor(IGF-IR) gene expressions in the cardiac tissue of VSD infants.Right atrium biopsies of 27 infants were studied. Five infants not having VSD were classified as controls (Group I). Twenty VSD patients were then divided into 2 groups according to their shunting magnitude index (level of pulmonary vascular resistance compared with systemic vascular resistance, Qp/Qs). VSD patients with minor shunts (Qp/Qs1.7) were classified as Group II; VSD patients with larger shunts (Qp/Qsor =2) as Group III. Besides, seven tetralogy of fallot (TOF) with shunt (Qp/Qs4) infants were classified as the Group IV. A non-radioactive DIG-RNA probe detection system, western blotting and immunohistochemistry were used to detect the gene expression levels and protein products of IGF-I and IGF-IR in the right atrium samples of VSD infants.The relative protein levels of IGF-I were 0.96+/-0.05, 0.43+/-0.03, 0.15+/-0.04, 0.12+/-0.03 and IGF-IR were 0.80+/-0.08, 0.57+/-0.03, 0.38+/-0.02, 0.24+/-0.04 in the right atrium of 4 group patients. The relative mRNA levels of IGF-I were 0.95+/-0.01, 0.41+/-0.03, 0.29+/-0.05, 0.15+/-0.01 and IGF-IR were 0.85+/-0.05, 0.56+/-0.03, 0.17+/-0.01, 0.18+/-0.01, respectively. There was a significantly greater but more gradual decrease in protein levels and in mRNA levels of IGF-I and IGF-IR in Group II (p0.05), Group III and IV (p0.01) than in Group I. The results of immunohistochemistry also demonstrated a similar decrease in VSD patients. In addition, the decrease of mRNA and protein levels in IGF-I/IGF-IR of VSD patients show related to the saturation of oxygen in the right atrium and the ratio of systolic right ventricular pressure to left ventricular pressure.We further confirmed the down regulation of IGF-I/IGF-IR in cardiac tissue of VSD infants and the decrease to be associated with shunt magnitude and the severity of hypoxemia in the cardiac chamber of VSD.

Cooking oil fumes (COF) exposure was demonstrated to be associated with lung cancer development in Taiwanese nonsmoking women. Previous studies identified Cox-2 overexpression and oxidative DNA damage in lung adenocarcinoma cells after exposure to COF. Involvement of COF in lung tumorigenesis may be associated with cell survival, as well as proliferation of lung adenocarcinoma. To test this hypothesis, A549, a lung adenocarcinoma cell line, was used, and MTT assay data showed that the cell viability of A549 was significantly increased in a concentration-dependent manner by COF treatment for 48 h. Flow cytometery results indicated that the proportion of A549 cell at S-phase was markedly increased after exposure of COF. To elucidate whether the anti-apoptotic c-IAP2 (IAP2) was involved in COF-improved cell survival, IAP2 protein levels was determined by Western blot, and the results showed it was significantly induced by COF in a concentration-dependent manner. Moreover, the suppression of BAY, a nuclear factor (NF)-kappaB binding inhibitor, or the COF-induced IAP2 protein levels indicated that NF-kappaB activation by COF may partly be involved in IAP2 induction. These results showed that the positive impact of COF on cell survival and proliferation of A549 lung tumor cells may be through an induction of IAP2 overexpression.

Aryl hydrocarbon receptor (AhR)-regulated cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) have been shown to metabolically activate some carcinogens. In the present study, we utilized the real-time reverse transcription-polymerase chain reaction (RT-PCR) assay to compare AhR, CYP1A1 and CYP1B1 mRNA levels in peripheral leukocytes from 42 lung cancer patients and 59 non-cancer subjects. We found that CYP1A1 and CYP1B1 levels, but not AhR, were significantly higher in patients than in non-cancer subjects. After stratified by gender, CYP1A1 levels were significantly higher in female patients than in female controls. After controlling for age, smoking status and gender, lung cancer patients were more likely to be CYP1B1 high expressers (P < 0.05). Neither AhR nor CYP1A1 levels was associated with lung cancer incidence. Leu-Val polymorphism of CYP1B1 was not associated with lung cancer risk in our study. These data indicated that CYP1B1 mRNA levels were elevated in peripheral leukocytes of lung cancer patients.

artery disease (CAD), we seek to evaluate the association of Gly1057Asp of IRS-2 with CAD in Taiwanes. Methods: Patients receiving coronary angiography were enrolled. Mild CAD is defined as presence of significant stenosis (diameter stenosis>50%) in none or one coronary artery and severe CAD in two or three. Gly1057Asp of IRS2 are determined by polymerase chain reaction and restriction fragment length polymorphism and confirmed by DNA sequencing. Results: 481 patients were enrolled. 207 patients have severe CAD. The Gly allele frequency is 66.2% in patients with severe CAD and 54.0% in mild CAD (p

AIM: Transfer and expression of insulin gene in vivo are an alternative strategy to improve glycemic control in type 1 diabetes. Hydrodynamics-based procedure has been proved to be very efficient to transfer naked DNA to mouse livers. The basal hepatic insulin production mediated by this rapid tail vein injection was studied to determine its effect on the resumption of glycemic control in type 1 diabetic mice. METHODS: Engineered insulin cDNA was inserted into plasmid vectors under a CMV promoter, and transferred into STZ induced diabetic mice by hydrodynamic procedure. Glucose levels, body weight of treated mice, insulin levels, immunohistology of the liver, and quantity of insulin mRNA in the liver were assayed to identify the improvement of hyperglycemic complication after plasmid administration. Sleeping Beauty, a transposon system, was also used to prolong the insulin expression in the liver. RESULTS: After plasmid administration, Plasma insulin was significantly increased in the diabetic mice and the livers were insulin-positive by immunostaining. At the same time the hyperglycemic complication was improved. The blood glucose levels of mice were reduced to normal. Glucose tolerance of the treated diabetic mice was improved. Body weight loss was also ameliorated. The rapid tail vein injection did not cause any fatal result. CONCLUSION: Our results suggested that insulin gene could be efficiently transferred into the livers of diabetic mice via rapid tail vein injection and it resulted in high level of insulin expression. The basal hepatic insulin production mediated by hydrodynamics-based administration improved the glycemic control in type 1 diabetes dramatically and ameliorated diabetic syndromes. Hydrodynamics-based administration offers a simple and efficient way in the study of gene therapy for type 1 diabetes.