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Schizophrenia’s pathogenesis remains elusive. Cognitive dysfunction is the endophenotype and outcome predictor of schizophrenia. The LIM and SH3 domain protein (LASP1) protein, a component of CNS synapses and dendritic spines, has been related to the N-methyl-D-aspartate receptor (NMDAR) dysfunction hypothesis and schizophrenia. A single-nucleotide polymorphism (rs979607) in the LASP1 gene promoter region has been also implicated in schizophrenia susceptibility. The aim of this study was to investigate the role of the LASP1 rs979607 polymorphism in the cognitive functions of patients with schizophrenia. Two hundred and ninety-one Han Taiwanese patients with schizophrenia were recruited. Ten cognitive tests and two clinical rating scales were assessed. The scores of cognitive tests were standardized to T-scores. The genotyping of the LASP1 rs979607 polymorphism was performed using TaqMan assay. Among the 291 patients, 85 were C/C homozygotes of rs979607, 141 C/T heterozygotes, and 65 T/T homozygotes, which fitted the Hardy-Weinberg equilibrium. After adjusting age, gender, and education with general linear model, the C/C homozygotes performed better than C/T heterozygotes in overall composite score (p = 0.023), Category Fluency test (representing processing speed and semantic memory) (p = 0.045), and Wechsler Memory Scale (WMS)-III backward Spatial Span test (p = 0.025), albeit without correction for multiple comparisons for the latter two individual tests. To the best of our knowledge, this is the first study suggesting that the genetic variation of LASP1 may be associated with global cognitive function, category verbal fluency, and spatial working memory of patients with schizophrenia. The finding also lends support to the NMDAR dysfunction hypothesis of schizophrenia. More studies with longitudinal designs are warranted.

Background: Respiratory system infections are prevalent in patients with depression. However, it remains unclear if patients with depression are at an increased risk of developing pleural empyema. Methods: We conducted a retrospective cohort study using data from the National Health Insurance Research Database of Taiwan. The depression group included 42,283 newly diagnosed patients between 2000 and 2012. The comparison group included the same number of individuals without depression, frequency matched for age, sex, comorbidities, and the year of diagnosis. The occurrence of pleural empyema was monitored until the end of 2013. Results: The overall incidence of pleural empyema was 1.32-fold higher in the depression group than in the comparison group (3.94 versus 2.97 per 10,000 person-years), with an adjusted hazard ratio of 1.33 (95% confidence interval, 1.27−1.40). Stratified analyses by age, sex, and comorbidity revealed that the crude and adjusted hazard ratios of pleural empyema associated with depression were significant in all subgroups. The 30-day mortality for pleural empyema was higher, but not significantly, in the depression group compared to the comparison group (10.7% versus 6.4%, adjusted odds ratio = 2.23, 95% confidence interval, 0.77−6.49). Conclusion: An association between depression and the development of pleural empyema may exist; however, more evidence is required to support this association. The reviews of this paper are available via the supplemental material section.

Population-based cohort study investigating the depression risk for patients with uterine leiomyoma (UL) is unavailable. This study investigated the subsequent risk of depression among patients with UL in an Asian population.Using data from the National Health Insurance Research Database of Taiwan, we established a cohort with 21,168 patients diagnosed with UL between 2000 and 2010, and a non-UL cohort of 82,108 women without UL matched by age and year of diagnosis. The occurrence of depression and Cox method measured adjusted hazard ratios (aHRs) were monitored until the end of 2011. The depression risk altered by surgery was also evaluated.The overall incidence of depression was 54% higher in the UL cohort than in the non-UL cohort (7.48 vs. 4.88/1000 person-years, p0.001), with an aHR of 1.46 [95% confidence interval (CI)=1.36-1.57] for the UL cohort. The depression risk increased with age and with comorbidity in both cohorts. Surgical intervention reduced the depression incidence to 4.76/1000 person-years for women with UL, with an aHR of 0.64 (95% CI=0.51-0.81) compared with those without a surgical treatment.The risk of depression is significantly higher in patients with UL than in those without UL. Surgical intervention for UL could significantly reduce the risk of depression. Evaluation of psychiatric status in patients with UL is strongly recommended.

Supplemental material, Author_Response_1 for Depression is associated with subsequent risk of pleural empyema by Yi-Chen Shen, Kuang-Ming Liao, Yen-Sung Lin, Yu-Jhen Huang, Cheng-Li Lin, Chia-Wen Tsai, Wen-Shin Chang, Te-Chun Shen, Da-Tian Bau and Te-Chun Hsia in Therapeutic Advances in Respiratory Disease

Supplemental material, Reviewer_1_v.1 for Depression is associated with subsequent risk of pleural empyema by Yi-Chen Shen, Kuang-Ming Liao, Yen-Sung Lin, Yu-Jhen Huang, Cheng-Li Lin, Chia-Wen Tsai, Wen-Shin Chang, Te-Chun Shen, Da-Tian Bau and Te-Chun Hsia in Therapeutic Advances in Respiratory Disease

ObjectiveThoracic infection and pneumonia are prevalent in patients with schizophrenia; however, it is unclear whether patients with schizophrenia are at an increased risk of developing pleural empyema.DesignA retrospective cohort study with propensity-matched cohorts with and without schizophrenia.SettingUsing the National Health Insurance Research Database of Taiwan.ParticipantsWe identified 55 888 patients with schizophrenia newly diagnosed in 2000–2011 and same number of individuals without schizophrenia as the comparison cohort, frequency matched by propensity scores estimated using age, sex, occupation, income, urbanisation, year of diagnosis and comorbidities.Primary outcome measuresWe assessed incident pleural empyema by the end of 2011 and used the Cox proportional hazards model to calculate the schizophrenia cohort to comparison cohort HR of pleural empyema.ResultsThe overall incidence of pleural empyema was 2.44-fold greater in the schizophrenia cohort than in the comparison cohort (4.39vs1.80 per 10 000 person-years), with an adjusted HR of 2.87(95% CI 2.14 to 3.84). Stratified analyses by age, sex, occupation, income, urbanisation and comorbidity revealed significant hazards for pleural empyema associated with schizophrenia in all subgroups.ConclusionsPatients with schizophrenia are at an increased risk of developing pleural empyema and require greater attention and appropriate support.

Background The cystine/glutamate antiporter system xc−, playing a critical role in the regulation of glutamate release, might be implicated in the pathogenesis of schizophrenia. This study examined whether peripheral expressions of the system xc− subunits are characteristic of schizophrenia. Methods Expression of system xc− genes including SLC3A2 and SLC7A11 in peripheral WBCs of patients with schizophrenia and healthy individuals were measured using quantitative PCR. Both psychotropic-free and medicated patients with schizophrenia were recruited. Results A total of 96 schizophrenia patients (48 medicated and 48 drug-free) and 96 healthy individuals were enrolled. The mRNA expression levels using the 2−ΔΔCT Method of both SLC3A2 and SLC7A11 in WBCs of schizophrenia patients were markedly lower than that of healthy individuals (0.22 and 0.48, respectively, the mRNA expression level of normal controls was normalized to 1). There was no significant difference between medicated and drug-free patients in the mRNA expressions of both SLC3A2 and SLC7A11. The Receiver Operating Characteristics (ROC) analysis of SLC3A2 mRNA levels using ΔΔCT values for drug-free schizophrenia patients vs. healthy controls determined an optimal cutoff value, 0.801, with high sensitivity (1.000) and modest specificity (0.694) (area under curve of ROC = 0.794). Conclusion This is the first study indicating that the peripheral mRNA expression levels of SLC7A11 and SLC3A2 may be lower in patients with schizophrenia than healthy individuals. The finding supports the hypo-glutamatergic neurotransmission hypothesis in schizophrenia. Whether mRNA expression of system xc− subunits genes, particularly SLC3A2, could serve as a potential biomarker of schizophrenia needs further studies.

Depression is prevalent in patients with chronic rhinosinusitis (CRS). However, no population-based study has ever investigated this relationship. We used nationwide population insurance data to conduct a retrospective cohort study to evaluate the subsequent risk of depression among patients with CRS.We used the National Health Insurance Research Database (NHIRD) of Taiwan identified 15,371 CRS patients diagnosed during 2000-2010. The non-CRS group consisted of 61,484 individuals without CRS frequency matched by sex, age, and the year of diagnosis. The occurrence of depression was monitored until the end of 2011. The hazard ratios (HRs) of depression were estimated using the Cox proportional hazards model after adjusting for demographic characteristics and comorbidities.The overall incidence of depression was 77% higher in the CRS group than in the non-CRS group (8.25 vs. 4.66/1000 person-years, p0.001), with an adjusted HR of 1.56 (95% confidence interval=1.43-1.70). Further data analyses revealed that the adjusted HRs of depression in the CRS group compared with the non-CRS group by sex, age, urbanization level, monthly income, occupation category, and comorbidity were all significant. However, there was no difference in incidences of depression between CRS patients with and without surgical treatment (8.31 vs. 8.24/1000 person-years).The present study suggests that patients with CRS are at an increased risk of depression, compared with those without CRS. Therefore, we should pay attention to the psychiatric status of these patients and provide adequate support for them.

A series of star-shaped multi-polar chromophores (compounds 1-3) containing functionalized quinoxaline and quinoxalinoid (indenoquinoxaline and pyridopyrazine) units has been synthesized and characterized for their two-photon absorption (2PA) properties both in the femtosecond and the nanosecond time domain. Under our experimental conditions, these model fluorophores are found to manifest strong and wide-dispersed two-photon absorption in the near-infrared region. It is demonstrated that molecular structures with multi-branched π frameworks incorporating properly functionalized quinoxalinoid units would possess large molecular nonlinear absorptivities within the studied spectral range. Effective optical-power attenuation and stabilization behaviors in the nanosecond time domain of a selected representative dye molecule (i.e., compound 2) from this model compound set were also investigated and the results indicate that such structural motif could be a useful approach for the molecular design toward strong two-photon-absorbing material systems for quick-responsive and broadband optical-suppressing-related applications, particularly to confront long laser pulses.

Dementia has become an all-important disease because the population is aging rapidly and the cost of health care associated with dementia is ever increasing. In addition to cognitive function impairment, associated behavioral and psychological symptoms of dementia (BPSD) worsen patient's quality of life and increase caregiver's burden. Alzheimer's disease is the most common type of dementia and both behavioral disturbance and cognitive impairment of Alzheimer's disease are thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dysfunctional glutamatergic neurotransmission had been reported in behavioral changes and cognitive decline in Alzheimer's disease. We review the literature regarding dementia (especially Alzheimer's disease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the effects of memantine, a NMDA receptor antagonist, and NMDA-enhancing agents, such as D-serine and D-cycloserine. Literatures suggest that behavioral disturbance and cognitive impairment of Alzheimer's disease may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in Alzheimer's disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms. We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of Alzheimer's disease. Prospective study using NMDA enhancers in patients with Alzheimer's disease and associated behavioral disturbance is needed to verify this hypothesis.

A set of novel multi-branched chromophores consisting of two groups of fluorene/oxadiazole-based analogues with generic skeletons of donor-π-acceptor (unsymmetrical) and donor-π-acceptor-π-donor (symmetrical) type has been synthesized and shown to display strong and broadly dispersed two-photon absorptivities in the near infrared (NIR) region on irradiation with femtosecond laser pulses. It is also demonstrated that structural parameters such as the number of donor units attached and the substitution pattern are closely connected to the molecular two-photon activities of these model compounds.

A new multi-branched fluorophore derived from tetra-quinoxalinylethylene as the core with diphenylaminofluorene units incorporated at the peripheral positions has been synthesized via Pd-catalyzed Suzuki coupling and experimentally shown to possess strong solvent effect on its fluorescence emission and lifetime behaviors. The initial characterization also found that this dye molecule exhibits two-photon activities and effective optical power limiting properties in the near-IR region under the irradiation of nanosecond laser pulses.

A novel multi-branched chromophore containing 2,3-diarylquinoxalinyl units as the electron-acceptors had been synthesized and its nonlinear optical properties were characterized in the femtosecond and nanosecond regime. The experimental results show that the studied fluorophore possesses strong and wide-dispersed two-photon absorption in near infrared (NIR) region. It is demonstrated that the incorporation of 2,3-disubstituted quinoxaline moieties as a part of π-conjugation in a dye molecule could be a useful approach toward large molecular two-photon absoptivities within the studied spectral region. Effective optical-power-attenuation behaviors in the nanosecond time domain of this compound were also investigated and the results indicate that such dye molecule can be a potential material as a broadband and quick-responsive optical limiter especially when against those laser lights with longer pulses.

The prevalence of Alzheimer's disease (AD) in the elderly is growing rapidly worldwide, and the deteriorating clinical course of AD places a heavy burden on both the patients and their families. Early detection and intervention of mild cognitive impairment in the early phase of AD is vital for the purpose of improving the cognitive performance of patients and preventing the existing deficits from worsening. However, the main compounds currently used to treat early AD, acetylcholinesterase inhibitors (AChEIs), are unsatisfactory in efficacy and safety. Moreover, evidence indicates that AChEIs are ineffective in treating AD at extremely early stages, which implies that mechanisms other than those targeted by AChEIs underlie the pathogenesis of AD. Dysfunctional glutamatergic neurotransmission, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been reported to play a role in the pathophysiology of AD. The NMDA receptor (NMDAR) regulates synaptic plasticity, memory, and cognition, and the attenuation of NMDAR-mediated neurotransmission can result in impaired neuroplasticity and cognitive deficits in the aging brain. Furthermore, NMDARs also interact with amyloid beta peptide/amyloid precursor protein and tau protein, whose production represents the main manifestations of AD. In this paper, we review the evidence supporting NMDA dysfunction in both animal models of AD and patients afflicted with AD, and we also review the literature that suggests that NMDA-enhancing agents such as glycine and D-cycloserine can improve cognitive functions. The benefits and limitations of NMDAR antagonists that can diminish the excitatory neurotoxicity triggered by glutamate are also addressed in relation to AD. We propose that enhancing glutamatergic neurotransmission by activating the NMDAR may be effective in treating the cognitive decline that occurs in AD. Prospective studies on AD in which NMDA-enhancing agents are used are required to verify this hypothesis and confirm the long-term efficacy and safety of the treatment agents.

BackgroundFacial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception.MethodsOne hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed.ResultsRegarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM).ConclusionsTo our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed.

Recent evidence indicates that enhancing N-methyl-D-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as D-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia. To compare these two novel approaches, 60 patients with chronic schizophrenia were enrolled into a 6-wk double-blind, placebo-controlled trial of add-on treatments at the reported effective dosages (2 g/d). Clinical assessments were conducted every other week. Treatment group x treatment duration interaction analysis by multiple linear regression showed that sarcosine was superior to placebo at all four outcome measures of Positive and Negative Syndrome Scale (PANSS) total (p=0.005), Scale for the Assessment of Negative Symptoms (SANS) (p=0.021), Quality of Life (QOL) (p=0.025), and Global Assessment of Functioning (GAF) (p=0.042). However, d-serine did not differ significantly from placebo in any measure. Sarcosine treatment was better than d-serine in effect sizes for all outcome measures. Sarcosine also surpassed placebo in most of the measures of five PANSS factors and five SANS subscales. All treatments were well tolerated. These findings suggest that the GlyT-1 inhibitor is more efficacious than the NMDA/glycine site agonist in treatment for schizophrenia, including life quality and global function, at the dosages tested.

The association between cholelithiasis and depression remains unclear. We examined the risk of depression in patients with cholelithiasis. From the National Health Insurance population claims data of Taiwan, we identified 14071 newly diagnosed cholelithiasis patients (4969 symptomatic and 9102 asymptomatic) from 2000 to 2010. For each cholelithiasis patient, 4 persons without cholelithiasis were randomly selected in the control cohort from the general population frequency matched by age, sex, and diagnosis year. Both cohorts were followed up until the end of 2011 to monitor the occurrence of depression. Adjusted hazard ratios (aHRs) of depression were estimated using the Cox proportional hazards model after controlling for age, sex and comorbidities. The overall incidence rates of depression were 1.87- and 1.83-fold greater in the symptomatic and asymptomatic cholelithiasis subcohorts than in the control cohort (incidence, 10.1 and 9.96 vs 5.43 per 1000 person-years, respectively). The multivariable Cox proportional hazards regression analysis revealed higher variable-specific aHRs in women than in men, in younger patients than in older patients, and in those without comorbidities than in those with any comorbidity. Cholecystectomy reduced the hazard of developing depression with aHRs of 0.79 (95% confidence interval [CI] 0.62–0.99) for symptomatic cholelithiasis patients and 0.76 (95% CI 0.60–0.96) for asymptomatic patients. Patients with cholelithiasis are at a higher risk of developing depression than the general population. Patients could be benefited from cholecystectomy and have the hazard of developing depression significantly reduced.