Risk of schizophrenia in patients with polycystic ovary syndrome: a nationwide population-based cohort study from Taiwan.

OBJECTIVES: To investigate whether patients with polycystic ovary syndrome (PCOS) are at increased risk for incident schizophrenia and whether PCOS treatment (clomiphene, cyproterone, or metformin) affects the incidence of schizophrenia. METHODS: An overall of 7146 PCOS patients and 28,580 non-PCOS controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were included between 2000 and 2012 and followed up until 2013 using a validated nationally representative sample from Taiwan. Participants newly diagnosed as schizophrenia were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of the schizophrenia incidence rate between the two studied groups. RESULTS: PCOS patients were at increased risk of incident schizophrenia compared to non-PCOS controls after adjusting for age, CCI score, comorbidities, and different treatment options (0.49 versus 0.09 per 1000 person-years, HR: 6.93, 95% CI: 3.25-14.7). After adjusting for above-mentioned covariates, metformin treatment had a protective effect against the incident schizophrenia compared to non-users (HR: 0.16, 95% CI: 0.06-0.41). Also, treatment with clomiphene and cyproterone had only a limited impact on the incident schizophrenia. CONCLUSION: This study shows PCOS patients are at increased risk of incident schizophrenia, and the metformin treatment has a protective effect against incident schizophrenia.

Association between Graves' disease and risk of incident systemic lupus erythematosus: A nationwide population-based cohort study.

OBJECTIVE: Previous case reports have linked Graves' disease to incident systemic lupus erythematosus (SLE). It has also been reported that antithyroid drugs used to treat Graves' disease can induce SLE development. The purpose of this study was to investigate the risk of SLE in patients with Graves' disease. METHODS: A total of 8779 patients with Graves' disease and 8779 controls (without Graves' disease) matched by age, gender, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000-2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed SLE were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of SLE incidence rate between patients with Graves' disease and unaffected controls. RESULTS: Patients with Graves' disease had a significantly increased risk of SLE than unaffected controls (8.81 vs 2.83 per 10 000 person-years, HR: 5.45, 95% CI: 1.74-17.0) after adjusting for antithyroid therapies (antithyroid drugs, radioactive iodine ablation, and surgery). Diagnostic bias may be present as patients with Graves' disease may seek more help from healthcare providers. After excluding the first 0.5 and 1 year of observation period, similar results were obtained (excluding 0.5 year - HR: 4.30, 95% CI: 2.78-8.57; excluding 1 year - HR: 4.63, 95% CI: 2.33-7.79). CONCLUSION: This study shows that Graves' disease is associated with an increased risk of incident SLE. Further studies on the underlying pathogenesis linking Graves' disease and SLE are warranted.

Risk of Parkinson's disease in patients with hypothyroidism: A nationwide population-based cohort study.

INTRODUCTION: Hypothyroidism has been implicated in many other disease conditions, including neurodegenerative diseases. Parkinson's disease (PD) is one of the most common neurodegenerative diseases. The purpose of this study was to investigate the risk of PD in patients with hypothyroidism. METHODS: A total of 4725 patients with hypothyroidism and 4725 controls (without hypothyroidism) matched by age, gender, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed PD were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of PD incidence rate between patients with hypothyroidism and unaffected controls. RESULTS: Patients with hypothyroidism had a significantly increased risk of PD compared with unaffected controls (2.00 versus 1.10 per 1,000 person-years, HR: 1.77, 95% CI: 1.13-2.76) after adjusting for age, gender, CCI score, physical comorbidities (brain injury, cerebrovascular disease, hypertension, dyslipidemia, and diabetes mellitus), and duration of levothyroxine use. Also, older age (≥50 vs. <50 - HR:14.83), higher CCI score (CCI score 1-2 & ≥3 vs. 0 - HR: 1.66-1.74), and specific comorbidities (brain injury (HR: 1.78) and cerebrovascular disease (HR: 2.46)) significantly increased the risk of PD after adjusting for the variables mentioned above. CONCLUSIONS: Patients with hypothyroidism have an increased risk of developing PD. Other prospective studies that take into account genetic vulnerability and environmental exposures are warranted to confirm their relationship.

Risk of bipolar disorder in patients with polycystic ovary syndrome: A nationwide population-based cohort study.

BACKGROUND: The study investigated the risk of newly developed bipolar disorder (BD) in patients with polycystic ovary syndrome (PCOS) and examined the relationship between PCOS treatment (hormone therapy (clomiphene or cyproterone) or metformin) and risk of BD development. METHODS: In all, 7175 PCOS patients and 28,697 non-PCOS controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were included between 2000 and 2012, then followed until the end of 2013. Participants newly diagnosed as BD by board-certified psychiatrists were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence interval (CI) of the BD incidence rate between two studied groups. RESULTS: PCOS patients had a significantly increased risk of developing BD compared to unaffected controls after adjusting for age, CCI score, and different treatment options (1.05 vs. 0.12 per 1,000 person-years, HR: 8.29, 95% CI: 4.65-14.7). Also, the use of metformin in PCOS patients showed a significantly reduced risk of developing BD compared to non-users after adjusting for the above-mentioned variables (HR: 0.36, 95% CI: 0.16-0.81). Although hormone therapy in PCOS patients showed a lower incidence rate of BD development compared to non-users, the risk estimate was not statistically significant (HR: 0.68, 95% CI: 0.35-1.32). LIMITATIONS: This study didn't assess the PCOS severity, which reduced the chances of showing the effects of PCOS severity on BD development. CONCLUSION: This study shows PCOS patients have an increased risk of developing BD, and the use of metformin may reduce its risk.

Risk of hyperglycemic crisis episode in diabetic patients with bipolar disorder: A nationwide population-based cohort study.

BACKGROUND: Suboptimal management of diabetes can lead to a hyperglycemic crisis episode (HCE), which could be further enhanced in the presence of bipolar disorder (BD) and the prescription of antipsychotics. This study aims to investigate the risk of HCE in diabetic patients with BD. Additionally, the duration of antipsychotic prescription on HCE risk is examined. METHODS: Using the Taiwan National Health Insurance Research Database, 6099 diabetic patients with BD and 24,378 diabetic patients without BD matched by gender, age, index year, and Charlson Comorbidity Index score were enrolled between 1999 and 2010 and followed to the end of 2013. Participants who developed HCE during the follow-up period were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence interval (CI) of the HCE incidence rate between two groups studied. RESULTS: Diabetic patients with BD were associated with an increased risk of HCE compared with unaffected controls after adjusted for baseline demographics and duration of antipsychotic prescription (3.84 versus 2.71 per 1,000 person-years, HR: 1.41, 95% CI: 1.15-1.71). Also, this study revealed that male gender, more comorbidities, and a longer duration of antipsychotic prescription were potential risk factors for developing HCE. LIMITATIONS: This study only deals with data on the duration of antipsychotic prescription, without showing the effects of different antipsychotics on HCE risk. CONCLUSION: This study highlights the need to pay attention to the risk of HCE in diabetic patients with BD and the importance of careful prescription of antipsychotics to reduce the HCE incident.

Systemic autoimmune diseases are associated with an increased risk of obsessive-compulsive disorder: a nationwide population-based cohort study.

PURPOSE: Studies suggested autoimmunity plays a role in the etiology of obsessive-compulsive disorder (OCD). The purpose of this study was to determine if a history of systemic autoimmune diseases (SADs) is associated with an increased risk of subsequent onset of OCD. METHODS: Patients with or without SADs were identified in the Taiwan National Health Insurance Program. The SADs cohort consisted of 63,165, while the comparison cohort consisted of 315,825 patients. The incidence rates of OCD with a maximum follow-up period of 10 years between patients with and without SADs were compared using a Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: The major finding was the discovery of a higher incidence of subsequent OCD among patients with SADs (HR: 1.85; 95% CI 1.41-2.43) after adjusted for other demographic characteristics. Specifically, the risk of OCD was observed to be significant increase in systemic lupus erythematosus (1.65, 1.07-2.54) dermatomyositis (3.25, 1.04-10.17), and Sjögren's syndrome (2.38, 1.53-3.72). Also, this study revealed some potential risk factors for developing OCD, including younger age (less than or equal to 50-year-old) and some comorbidities (alcohol use disorder, liver cirrhosis, and malignancies). Conversely, this study found that steroid use was a potential protective factor for the development of OCD. CONCLUSIONS: This study confirms that SADs are associated with higher incidence of OCD, suggesting that abnormal autoimmune process is associated with increased expression of psychiatric disturbances.

Risk of obstructive sleep apnea in patients with bipolar disorder: A nationwide population-based cohort study in Taiwan.

AIM: Previous studies have found a high prevalence of risk factors for obstructive sleep apnea (OSA) in patients with bipolar disorder (BD). This study aimed to determine whether BD patients are associated with an increased risk of incident OSA. METHODS: Using the National Health Insurance Research Database of Taiwan, 3650 BD patients and 18 250 non-BD controls matched by sex and age were enrolled between 2000 and 2010 and followed until the end of 2013. Patients who developed OSA confirmed by a polysomnographic examination during the follow-up period were identified. Cox regression analysis was performed to examine the risk of OSA between BD patients and comparative controls. RESULTS: BD patients were prone to developing OSA in the crude analysis (hazard ratio [HR]: 1.63, 95% confidence interval [CI]: 1.07-2.49). After adjusting for demographics and comorbidities, the HR declined and was only marginally significant (HR: 1.54, 95%CI: 0.99-2.37). The stratification analysis by sex revealed that the risk trend with BD and subsequent OSA was mainly contributed by male BD patients (HR: 1.72, 95%CI: 1.02-2.91) and female BD patients weakened the overall association. Additionally, this study found that older age, higher income, living in urbanized areas, and some metabolic comorbidities were potential risk factors for developing OSA. CONCLUSION: This study shows that male BD patients are associated with an increased risk of OSA, which has direct implications for the development of targeted prevention interventions or the implementation of a screening algorithm for OSA to reduce its negative health impact.

Autoimmune diseases are associated with an increased risk of schizophrenia: A nationwide population-based cohort study.

OBJECTIVES: Studies have suggested a possible autoimmune contribution in a subset of patients with schizophrenia. The purpose of this study was to determine if a history of autoimmune diseases (AD) is associated with an increased risk of later onset of schizophrenia. METHODS: Taiwan's National Health Insurance Research Database was used to identify a total of 64,817 AD patients and an equal number of age-matched control patients. The incidence rates of schizophrenia with a maximum follow-up period of 10 years between patients with and without AD were compared using a Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: The main finding was the discovery of a higher incidence of subsequent schizophrenia in patients with AD (HR: 1.72, 95% CI: 1.23-2.4) after adjustment for other demographic characteristics. Specifically, the risk of schizophrenia was observed to be a significant increase in systemic lupus erythematosus (3.73, 2.07-6.72), rheumatoid arthritis (2.89, 1.97-4.23), dermatomyositis (5.85, 1.32-25.94) and autoimmune vasculitis (2.44, 1.17-5.06). Also, this study revealed some potential risk factors for developing schizophrenia, including younger age (less than or equal to 50 years) and some comorbidities (hypertension, chronic obstructive pulmonary disease, and alcohol use disorder). Conversely, this study found that steroid use was a potential protective factor for the development of schizophrenia. CONCLUSIONS: This study found that AD were associated with an increased risk of developing schizophrenia, suggesting that the abnormal autoimmune process was associated with an increase in the expression of psychiatric disturbances.

Schizophrenia is associated with an increased risk of sexually transmitted infections: A nationwide population-based cohort study in Taiwan.

OBJECTIVES: In Taiwan, there has been a growing emphasis on physical health screening, health education and improving access to treatment in patients with schizophrenia (SCZ). However, sexual health needs, including screening and prevention of sexually transmitted infections (STI), are neglected in this population. The study aimed to investigate the association between SCZ and the subsequent incident STI and to examine potential risk factors. METHODS: Using the National Health Insurance Research Database of Taiwan, 58,948 SCZ patients and 235,784 controls matched by gender and age were enrolled between 2000 and 2010 and followed until the end of 2011. Participants who developed any STI (HIV, syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis) during the follow-up period were identified. Cox regression analysis was performed to examine the risk of STI between SCZ patients and controls. RESULTS: SCZ patients were predisposed to developing STI (hazard ratio (HR): 1.11, 95% confidence interval (95% CI): 1.01-1.21) that could be caused by syphilis (HR: 2.58, 95% CI: 2.14-3.10) or possibly HIV (Crude HR: 1.39, 95% CI: 1.04-1.86; adjusted HR: 1.11, 95% CI: 0.81-1.52). Additionally, this study found that female, young adults, low-income, living in less urbanized areas, and comorbid substance abuse were potential risk factors for developing STI. CONCLUSION: This study shows that SCZ is associated with an increased risk of developing STI, which has direct implications for the development of targeted prevention interventions or regular sexual health screening in mental health clinics to reduce the disproportionate burden of HIV and other STI in SCZ patients.

Enhanced Osteogenic Differentiation of Stem Cells on Phase-Engineered Graphene Oxide.

Graphene oxide (GO) has attracted significant interest as a template material for multiple applications due to its two-dimensional nature and established functionalization chemistries. However, for applications toward stem cell culture and differentiation, GO is often reduced to form reduced graphene oxide, resulting in a loss of oxygen content. Here, we induce a phase transformation in GO and demonstrate its benefits for enhanced stem cell culture and differentiation while conserving the oxygen content. The transformation results in the clustering of oxygen atoms on the GO surface, which greatly improves its ability toward substance adherence and results in enhanced differentiation of human mesenchymal stem cells toward the osteogenic lineage. Moreover, the conjugating ability of modified GO strengthened, which was examined by auxiliary osteogenic growth peptide conjugation. Overall, our work demonstrates GO's potential for stem cell applications while maintaining its oxygen content, which could enable further functionalization and fabrication of novel nano-biointerfaces.

Simultaneous drug delivery and cellular imaging using graphene oxide.

Graphene oxide (GO), a derivative of graphene, and its related nanomaterials have attracted much attention in recent years due to the excellent biocompatibility and large surface area of GO with abundant oxygen functional groups, which further enable it to serve as a nano-bio interface. Herein, we demonstrate the induction of blue fluorescence in GO suspensions via a mild thermal annealing procedure. Additionally, this procedure preserves the oxygen functional groups on the graphene plane which enables the conjugation of cancer drugs without obvious cytotoxicity. Consequently, we demonstrate the capability of GO to simultaneously play the dual-role of a: (i) cellular imaging agent and (ii) drug delivery agent in CT26 cancer cells without the need for additional fluorescent protein labeling. Our method offers a simple, controllable strategy to tune and enhance the fluorescence property of GO, which shows potential for biomedical applications and fundamental studies.

Systemic autoimmune diseases are associated with an increased risk of bipolar disorder: A nationwide population-based cohort study.

BACKGROUND: Studies suggested autoimmunity plays a role in the etiology of bipolar disorder (BD). This study aimed to investigate the association between systemic autoimmune diseases (SADs) and the subsequent development of BD, and examine the potential risk factors for developing BD. METHODS: Patients with SADs were identified in the Taiwan National Health Insurance Program (NHIP). A comparison cohort was created by matching patients without SADs with age. The SADs cohort consisted of 65,498 while the comparison cohort consisted of 261,992 patients. The incidence of BD was evaluated in both cohorts. RESULTS: The major finding was the discovery of a higher incidence of subsequent BD among patients with SADs (adjusted hazard ratio: 1.98). Specifically, the risk of BD was observed to be significant increase in systemic lupus erythematosus, rheumatoid arthritis, autoimmune vasculitis, Sicca syndrome and Crohn's disease. Furthermore, our study revealed some potential risk factors for developing BD including female, younger age and patients who lived in eastern Taiwan. Also, some comorbidities including dyslipidemia, chronic obstructive pulmonary disease, diabetes mellitus, asthma, cerebrovascular disease, alcohol used disorder, liver cirrhosis, and malignancies were potential risk factors for incident BD. LIMITATIONS: The diagnosis of SADs was based on the catastrophic illness certificate defined by Taiwanese NHIP. Thus, not every form of SADs was explored for subsequent developing BD. CONCLUSION: This study confirms that SADs are associated with higher incidence of BD, suggesting that abnormal autoimmune process is associated with increased expression of psychiatric disturbances.

Delusions of control in a case of schizophrenia coexisting with a large cerebellar arachnoid cyst.

Arachnoid cyst is a benign, congenital space-occupying brain lesion, which has been found in patients with schizophrenia. The association between arachnoid cyst and schizophrenia remains controversial, but the location of the arachnoid cyst may give rise to a specific symptom presentation in schizophrenia. We present a 31-year-old woman with an established diagnosis of schizophrenia coexisting with a large cerebellar arachnoid cyst who presented mainly with delusions of control. This cerebellar arachnoid cyst and schizophrenia may have been found together coincidentally or brain dysfunction due to this cerebellar arachnoid cyst may have caused or contributed to the appearance of psychotic symptoms. The patient had an unsteady gait accompanied by delusions of control, and she showed a poor response to high-dose olanzapine treatment, suggesting the arachnoid cyst was associated with her schizophrenic symptoms. The cyst was over the right posterior fossa with cerebellum compression, which may have caused abnormality in the cerebellar-parietal network resulting in her delusions of control. This case indicates that there might be relationships between cerebellar lesions, schizophrenia, and delusions of control.

Anxiety and depression are improved by continuous positive airway pressure treatments in obstructive sleep apnea.

Background Obstructive sleep apnea involves repeated nocturnal desaturation and sleep fragmentation that leads to poor sleep quality, anxiety, and depression. This study aimed to investigate short- and long-term improvements in the anxiety and depression of patients with different obstructive sleep apnea treatments. Methods This is a prospective, non-randomized hospital-based study evaluated 55 patients (46 male, 9 female) with obstructive sleep apnea. The patients were divided into three groups based on different treatment: uvulopalatopharyngoplasty group, continuous positive airway pressure group, and no treatment group (by their own decision). They completed the Beck Depression Inventory II, Beck Anxiety Inventory, and Pittsburgh Sleep Quality Index before treatment and at one and six months after treatment. Results Compared to the no treatment group, the surgery and continuous positive airway pressure groups had higher body mass index, AHI, and Epworth sleepiness scale, but no difference in Pittsburgh Sleep Quality Index, Chinese Health Questionnaire-12, Beck Depression Inventory II, and Beck Anxiety Inventory. The continuous positive airway pressure and surgery groups still had no improvements in Pittsburgh Sleep Quality Index, Chinese Health Questionnaire-12, Beck Depression Inventory II, and Beck Anxiety Inventory scores one month after treatment. At six months after treatment, the continuous positive airway pressure group had significantly decreased Pittsburgh Sleep Quality Index, Chinese Health Questionnaire-12, Beck Depression Inventory II, and Beck Anxiety Inventory, whereas the surgery group had significant difference in Beck Anxiety Inventory only and the no treatment group still had no significant difference in any of the parameters. Conclusions Continuous positive airway pressure can improve the sleep quality, quality of life, depression, and anxiety of obstructive sleep apnea patients after six months of treatment. However, surgery can significantly improve anxiety only in the same period.

Genetic and functional analyses of the gene encoding synaptophysin in schizophrenia.

OBJECTIVES: Synaptophysin (SYP) has been shown to be critical for regulating neurotransmitter release and synaptic plasticity, a process thought to be disrupted in schizophrenia. In addition, abnormal SYP expression in different brain regions has been linked to this disorder in postmortem brain studies. We investigated the involvement of the SYP gene in the susceptibility to schizophrenia. METHODS: We searched for genetic variants in the promoter region, all exons, and both UTR ends of the SYP gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study. RESULTS: We identified 2 common SNPs (c.*4+271A>G and c.*4+565T>C) in the SYP gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. In addition, we identified 6 rare variants in 7 out of 586 patients, including 1 variant (g.-511T>C) located at the promoter region, 1 synonymous (A104A) and 2 missense variants (G293A and A324T) located at the exonic regions, and 2 variants (c.*31G>A and c.*1001G>T) located at the 3'UTR. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated the influence of g.-511T>C and c.*1001G>T on the regulatory function of the SYP gene, while that the influence of c.*31G>A may be tolerated. In silico analysis demonstrated the functional relevance of other rare variants. CONCLUSION: Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and provides genetic clues that indicate the involvement of SYP in this disorder.

Genetic and functional analysis of the gene encoding GAP-43 in schizophrenia.

OBJECTIVES: In earlier reports, growth-associated protein 43 (GAP-43) has been shown to be critical for initial establishment or reorganization of synaptic connections, a process thought to be disrupted in schizophrenia. Additionally, abnormal GAP-43 expression in different brain regions has been linked to this disorder in postmortem brain studies. In this study, we investigated the involvement of the gene encoding GAP-43 in the susceptibility to schizophrenia. METHODS: We searched for genetic variants in the promoter region and 3 exons (including both UTR ends) of the GAP-43 gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study. RESULTS: We identified 11 common polymorphisms in the GAP-43 gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 4 rare variants in 5 out of 586 patients, including 1 variant located at the promoter region (c.-258-4722G>T) and 1 synonymous (V110V) and 2 missense (G150R and P188L) variants located at exon 2. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing c.-258-4722T was significantly lower as compared to the wild type construct (c.-258-4722G; p<0.001). In silico analysis also demonstrated the functional relevance of other rare variants. CONCLUSIONS: Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and it provides genetic clues that indicate the involvement of GAP-43 in this disorder.