Shigella Vaccines: The Continuing Unmet Challenge.

Shigellosis is a severe gastrointestinal disease that annually affects approximately 270 million individuals globally. It has particularly high morbidity and mortality in low-income regions; however, it is not confined to these regions and occurs in high-income nations when conditions allow. The ill effects of shigellosis are at their highest in children ages 2 to 5, with survivors often exhibiting impaired growth due to infection-induced malnutrition. The escalating threat of antibiotic resistance further amplifies shigellosis as a serious public health concern. This review explores Shigella pathology, with a primary focus on the status of Shigella vaccine candidates. These candidates include killed whole-cells, live attenuated organisms, LPS-based, and subunit vaccines. The strengths and weaknesses of each vaccination strategy are considered. The discussion includes potential Shigella immunogens, such as LPS, conserved T3SS proteins, outer membrane proteins, diverse animal models used in Shigella vaccine research, and innovative vaccine development approaches. Additionally, this review addresses ongoing challenges that necessitate action toward advancing effective Shigella prevention and control measures.

Application of a Novel Epitope- and Structure-Based Vaccinology-Assisted Fimbria-Toxin Multiepitope Fusion Antigen of Enterotoxigenic Escherichia coli for Development of Multivalent Vaccines against Porcine Postweaning Diarrhea.

Enterotoxigenic Escherichia coli (ETEC) strains producing K88 (F4) or F18 fimbriae and enterotoxins are the predominant cause of pig postweaning diarrhea (PWD). We recently identified neutralizing epitopes of fimbriae K88 and F18, heat-labile toxin (LT), heat-stable toxins type I (STa) and type II (STb), and Shiga toxin 2e (Stx2e). In this study, we explored a novel epitope- and structure-based vaccinology platform, multiepitope fusion antigen (MEFA), for PWD vaccine development. By using an epitope substitution LT toxoid, which lacks enterotoxicity but retains immunogenicity, as the backbone to present neutralizing epitopes of two ETEC fimbriae and four toxins, we generated PWD fimbria-toxin MEFA to mimic epitope native antigenicity. We then examined MEFA protein immunogenicity and evaluated MEFA application in PWD vaccine development. Mice subcutaneously immunized with PWD MEFA protein developed strong IgG responses to K88, F18, LT, and STb and moderate responses to the toxins Stx2e and STa. Importantly, MEFA-induced antibodies inhibited adherence of K88 or F18 fimbrial bacteria to pig intestinal cells and also neutralized LT, STa, STb, and Stx2e toxicity. These results indicated that PWD fimbria-toxin MEFA induced neutralizing antibodies against an unprecedent two fimbriae and four toxins and strongly suggested a potential application of this MEFA protein in developing a broadly protective PWD vaccine.IMPORTANCE ETEC-associated postweaning diarrhea (PWD) causes significant economic losses to swine producers worldwide. Currently, there is no effective prevention against PWD. A vaccine that blocks ETEC fimbriae (K88 and F18) from attaching to host receptors and prevents enterotoxins from stimulating water hypersecretion in pig small intestinal epithelial cells can effectively protect against PWD and significantly improves pig health and well-being. The fimbria-toxin MEFA generated from this study induced neutralizing antibodies against both ETEC fimbriae and all four ETEC toxins, suggesting a great potential of this fimbria-toxin MEFA in PWD vaccine development and further supporting the general application of this novel MEFA vaccinology platform for multivalent vaccine development.

Mapping the Neutralizing Epitopes of Enterotoxigenic Escherichia coli K88 (F4) Fimbrial Adhesin and Major Subunit FaeG.

Enterotoxigenic Escherichia coli (ETEC) strains that produce immunologically heterogeneous fimbriae and enterotoxins are the primary cause of neonatal diarrhea and postweaning diarrhea in young pigs. A multivalent vaccine inducing protective immunity against ideally all ETEC fimbriae and enterotoxins could be effective against diarrhea in young pigs. However, developing a vaccine to broadly protect against various ETEC virulence determinants has proven challenging. Recently developed structure- and epitope-based multiepitope fusion antigen (MEFA) technology that presents neutralizing epitopes of various virulence determinants at a backbone immunogen and that mimics epitope native immunogenicity suggests the feasibility of developing multivalent vaccines. With neutralizing epitopes from ETEC fimbria F18 and enterotoxins being identified, it becomes urgent to identify protective epitopes of K88 (F4) fimbriae, which play a major role in pig neonatal and postweaning diarrhea. In this study, we identified B-cell immunodominant epitopes in silico from the K88ac fimbrial major subunit (also adhesin) FaeG and embedded each epitope in a heterogeneous carrier for epitope fusions. We then immunized mice with each epitope fusion protein and examined epitope antigenicity and also neutralizing activities of epitope-induced antibodies. Data showed that while all nine FaeG epitope fusions induced antibodies to K88ac fimbria, anti-K88 IgG antibodies derived from epitopes MTGDFNGSVD (ep1), LNDLTNGGTK (ep2), GRTKEAFATP (ep3), ELRKPDGGTN (ep4), PMKNAGGTKVGAVKVN (ep5), and RENMEYTDGT (ep8) significantly inhibited adherence of K88ac fimbrial bacteria to porcine intestinal cell line IPEC-J2, indicating that these peptides were the neutralizing epitopes of K88ac fimbrial major subunit FaeG and suggesting the future application of FaeG epitopes in ETEC vaccine development.IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) strains producing K88ac fimbriae and enterotoxins are a major cause of porcine neonatal diarrhea and postweaning diarrhea in the United States. Currently, there is no vaccine to induce broadly protective antiadhesin and antitoxin immunity against ETEC-associated diarrhea. To develop a broadly effective ETEC vaccine, we need to target the most important if not all ETEC virulence determinants. While conventional vaccinology approaches encounter difficulties at integrating or including heterogeneous ETEC fimbria and toxin antigens into a vaccine product, multiepitope fusion antigen (MEFA) structural vaccinology provides a new platform to combine neutralizing antigenic elements or epitopes from various heterogeneous virulence factors for broad immunity and protection. Identification of the neutralizing epitopes of K88ac fimbria from this study added the last antigens to an MEFA-based multivalent vaccine against ETEC-associated diarrhea in pigs. An effective vaccine against pig diarrhea can significantly improve swine health and well-being and reduce economic losses to the swine industry worldwide.

Action of chlorzoxazone on Ca2+movement and viability in human oral cancer cells.

Chlorzoxazone is a skeletal muscle relaxant. However, the effect of chlorzoxazone on intracellular Ca2+ concentrations ([Ca2+]i) in oral cancer cells is unclear. This study examined whether chlorzoxazone altered Ca2+ signaling and cell viability in OC2 human oral cancer cells. [Ca2+]iin suspended cells was measured using the fluorescent Ca2+-sensitive dye fura-2. Cell viability was examined by water-soluble tetrazolium-1 assay. Chlorzoxazone (250-1000 µM) induced [Ca2+]irises in a concentration-dependent manner. Ca2+ removal reduced the signal by approximately 50%. Mn2+ has been shown to enter cells through similar mechanisms as Ca2+ but quenches fura-2 fluorescence at all excitation wavelengths. Chlorzoxazone (1000 µM) induced Mn2+ influx, suggesting that Ca2+ entry occurred. Chlorzoxazone-induced Ca2+ entry was inhibited by 20% by inhibitors of store-operated Ca2+ channels and protein kinase C (PKC) modulators. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (TG) inhibited chlorzoxazone-evoked [Ca2+]irises by 88%. Conversely, treatment with chlorzoxazone-suppressed TG-evoked [Ca2+]irises 75%. Chlorzoxazone induced [Ca2+]irises by exclusively releasing Ca2+ from the endoplasmic reticulum. Inhibition of phospholipase C (PLC) with U73122 did not alter chlorzoxazone-induced [Ca2+]irises. PLC activity was not involved in chlorzoxazone-evoked [Ca2+]irises. Chlorzoxazone at 200-700 µM decreased cell viability, which was not reversed by pretreatment with Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl. In sum, in OC2 cells, chlorzoxazone induced [Ca2+]irises by evoking PLC-independent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via PKC-sensitive store-operated Ca2+ entry. Chlorzoxazone also caused Ca2+-independent cell death. Since [Ca2+]irises play a triggering or modulatory role in numerous cellular phenomena, the effect of chlorzoxazone on [Ca2+]iand cell viability should be taken into account in other in vitro studies.

Association Between Polymorphisms in Dopamine-Related Genes and Orthopedic Pain Expression in a Chinese Elderly Population.

OBJECTIVES: The dopaminergic pathway plays a vital role in pain expression. Here, our aim was to investigate the effects of polymorphisms in genes encoding the dopamine active transporter (SLC6A3) and dopamine receptor D2 (DRD2) on preoperative pain expression among patients preparing for orthopedic surgery. METHODS: Chinese elderly patients scheduled for orthopedic surgery were enrolled. The VAS was used to evaluate pain intensity (score range 0 to 10; 0 = no pain; 10 = worst pain possible). Depressive symptoms were evaluated via the 15-item Geriatric Depression Scale. DNA was isolated from venous blood samples, and single-nucleotide polymorphisms of SLC6A3 and DRD2 were genotyped. Multiple linear regressions analyses were carried out to adjust the results for confounders. RESULTS: A total of 294 patients with a mean age of 73.82 ± 8.03 years were enrolled in this study. After adjustment for confounders, rs393795 in SLC6A3 showed a significant association with preoperative VAS scores. Patients with the A/A genotype reported lower mean pain scores than did those with the A/C genotype (P = 0.026). Subsequent depression-stratified analysis of rs6276 in DRD2 revealed that patients with the A/A genotype had higher pain scores than did those with the G/G genotype (P = 0.043). No associations were found for DRD2 rs6277 in the whole study population or depression-stratified groups. CONCLUSION: Genetic variations in SLC6A3 and DRD2 may play an important role in pain expression among the elderly prior to orthopedic surgery.

Enterotoxigenic Escherichia coli Adhesin-Toxoid Multiepitope Fusion Antigen CFA/I/II/IV-3xSTaN12S-mnLTG192G/L211A-Derived Antibodies Inhibit Adherence of Seven Adhesins, Neutralize Enterotoxicity of LT and STa Toxins, and Protect Piglets against Diarrhea.

Enterotoxigenic Escherichia coli (ETEC) strains are a leading cause of children's diarrhea and travelers' diarrhea. Vaccines inducing antibodies to broadly inhibit bacterial adherence and to neutralize toxin enterotoxicity are expected to be effective against ETEC-associated diarrhea. 6×His-tagged adhesin-toxoid fusion proteins were shown to induce neutralizing antibodies to several adhesins and LT and STa toxins (X. Ruan, D. A. Sack, W. Zhang, PLoS One 10:e0121623, 2015, https://doi.org/10.1371/journal.pone.0121623). However, antibodies derived from His-tagged CFA/I/II/IV-2xSTaA14Q-dmLT or CFA/I/II/IV-2xSTaN12S-dmLT protein were less effective in neutralizing STa enterotoxicity and were not evaluated in vivo for efficacy against ETEC diarrhea. Additionally, His-tagged proteins are considered less desirable for human vaccines. In this study, we produced a tagless adhesin-toxoid MEFA (multiepitope fusion antigen) protein, enhanced anti-STa immunogenicity by including a third copy of STa toxoid STaN12S, and examined antigen immunogenicity in a murine model. Moreover, we immunized pregnant pigs with the tagless adhesin-toxoid MEFA protein and evaluated passive antibody protection against STa+ or LT+ ETEC infection in a pig challenge model. Results showed that tagless adhesin-toxoid MEFA CFA/I/II/IV-3xSTaN12S-mnLTR192G/L211A induced broad antiadhesin and antitoxin antibody responses in the intraperitoneally immunized mice and the intramuscularly immunized pigs. Mouse and pig serum antibodies significantly inhibited adherence of seven colonization factor antigen (CFA) adhesins (CFA/I and CS1 to CS6) and effectively neutralized both toxins. More importantly, suckling piglets born to the immunized mothers acquired antibodies and were protected against STa+ ETEC and LT+ ETEC diarrhea. These results indicated that tagless CFA/I/II/IV-3xSTaN12S-mnLTR192G/L211A induced broadly protective antiadhesin and antitoxin antibodies and demonstrate that this adhesin-toxoid MEFA is a potential antigen for developing broadly protective ETEC vaccines.

Depressive disorders among patients with gastric cancer in Taiwan: a nationwide population-based study.

BACKGROUND: In cancer patients, depressive disorder comorbidity is associated with greater suicide risk and poorer treatment outcomes, quality of life, and adherence to treatment. The aim of the study was to evaluate the incidence of newly-diagnosed depressive disorders after a gastric cancer diagnosis compared with a matched cohort using the National Health Insurance Research Database in Taiwan. METHODS: We conducted a retrospective cohort study of 57,506 patients (28,753 patients with gastric cancer and 28,753 matched patients) selected from the National Health Insurance Research Database. Patients were observed for a maximum of 12 years to determine the incidence of newly-diagnosed depressive disorders. Also, a Cox regression analysis which included death as an independent censor was performed to identify the potentially predictive variables for developing subsequent depressive disorders following a cancer diagnosis among the patients suffering from gastric cancer. RESULTS: The cumulative incidence of depressive disorders in the gastric cancer patients was significantly higher compared to those in the matched cohort (p < .001). The adjusted hazard ratio was 1.54 (95% confidence interval, CI = 1.39-1.70, P < .001) in the gastric cancer cohort compared with the matched cohort. Independent predictive variables for developing subsequent depressive disorders among the patients with gastric cancer included female sex and hypertension. CONCLUSIONS: In the study, higher incidence of new-onset depression, being defined by the records of the diagnostic codes combining antidepressants use in a nationwide database, was noted in the gastric cancer patients compared with the matched cohort. In addition, female sex and comorbid hypertension may be predictive variables for the subsequent depression among the patients with gastric cancer. Further clinical prospective studies were necessary to confirm these findings.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Effect of thymol on Ca²âº homeostasis and viability in PC3 human prostate cancer cells.

Thymol is a phenolic compound that affects physiology in different cell models. However, whether thymol affects Ca²âº homeostasis in prostate cancer cells is unknown. The action of this compound on cytosolic Ca²âº concentrations ([Ca²âº]i) and viability in PC3 human prostate cancer cells was explored. The results show that thymol at concentrations of 100-1500 µM caused [Ca²âº]i rises in a concentration-dependent manner. Removal of extracellular Ca²âº reduced thymol's effect by approximately 80%. Thymol-induced Ca²âº entry was confirmed by Mn²âº entry-induced quench of fura-2 fluorescence, and was inhibited by approximately 30% by Ca²âº entry modulators (nifedipine, econazole, SKF96365), and the protein kinase C (PKC) inhibitor GF109203X. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin abolished thymol-induced [Ca²âº]i rises. Treatment with thymol also abolished thapsigargin-induced [Ca²âº]i rises. Thymol-induced Ca²âº release from the endoplasmic reticulum was abolished by the phospholipase C (PLC) inhibitor U73122. Thymol at 100-900 µM decreased cell viability, which was not reversed by pretreatment with the Ca²âº chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in PC3 cells, thymol induced [Ca²âº]i rises by inducing PLC-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº entry via PKC-sensitive store-operated Ca²âº channels and other unknown channels. Thymol also induced Ca²âº-dissociated cell death.

Chronic obstructive pulmonary disease associated with increased risk of bipolar disorder.

Epidemiological studies have identified a trend in the development of depressive and anxiety disorders following a diagnosis of chronic obstructive pulmonary disease (COPD). However, the relationship between COPD and subsequent bipolar disorder remains unclear. From January 1, 2000, we identified adult patients with COPD from the Taiwan National Health Insurance Research Database. A nationwide population-based study was conducted; 46,778 COPD patients and 46,778 age-, sex-, and comorbidity-matched subjects between 2000 and 2011 were enrolled. The two cohorts were followed up till December 31, 2011 and observed for occurrence of bipolar disorder. We observed the COPD and comparison cohorts for 263,020 and 267,895 person-years, respectively, from 2000 to 2011. The incidence rate for bipolar disorder was 1.6/1000 person-years in the COPD cohort and 1.2/1000 person-years in the comparison cohort ( p < 0.001). After multivariate adjustment, the hazard ratio (HR) for subsequent bipolar disorder among the COPD patients was 1.42 (95% confidence interval [CI], 1.22-1.64; p < 0.001). In the COPD patients, short-acting beta-agonists (SABAs) was associated with a significantly increased risk of bipolar disorder development (HR = 1.83, 95% CI = 1.25-2.69, p = 0.002). Other COPD medications were not associated with the risk of bipolar disorder development. The study results indicate that COPD may be an independent risk factor for the development of bipolar disorder. The regular use of SABAs might increase the risk of bipolar disorder in COPD patients.

Ca2+ Signaling and Cell Death Induced by Protriptyline in HepG2 Human Hepatoma Cells.

The effect of protriptyline on Ca2+ physiology in human hepatoma is unclear. This study explored the effect of protriptyline on [Ca2+ ]i and cytotoxicity in HepG2 human hepatoma cells. Protriptyline (50-150 µM) evoked [Ca2+ ]i rises. The Ca2+ entry was inhibited by removal of Ca2+ . Protriptyline-induced Ca2+ entry was confirmed by Mn2+ -induced quench of fura-2 fluorescence. Except nifedipine, econazole, SKF96365, GF109203X, and phorbol 12-myristate 13 acetate did not inhibit Ca2+ entry. Treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) inhibited 40% of protriptyline-induced response. Treatment with protriptyline abolished BHQ-induced response. Inhibition of phospholipase C (PLC) suppressed protriptyline-evoked response by 70%. At 20-40 µM, protriptyline killed cells which was not reversed by the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in HepG2 cells, protriptyline induced [Ca2+ ]i rises that involved Ca2+ entry through nifedipine-sensitive Ca2+ channels and PLC-dependent Ca2+ release from endoplasmic reticulum. Protriptyline induced Ca2+ -independent cell death.

Increased risk of benign paroxysmal positional vertigo in patients with anxiety disorders: a nationwide population-based retrospective cohort study.

BACKGROUND: The objective of this study was to evaluate the risk of benign peripheral persistent vertigo (BPPV) among patients with anxiety disorders by using the Taiwan National Health Insurance Research Database (NHIRD). METHODS: We conducted a retrospective study of 15,470 participants (7735 anxiety disorder patients and 7735 control patients) selected from the NHIRD. Patients were observed for a maximum of 9 years to determine the rates of newly diagnosed BPPV. A Cox regression model was used to evaluate the risk of BPPV among the patients with anxiety disorders. RESULTS: During the 9-year follow-up period, 178 (2.05 per 1000 person-years) anxiety disorder patients and 71 (0.81 per 1000 person-years) control patients were diagnosed with BPPV. The incidence risk ratio of BPPV between anxiety disorder patients and control patients was 2.52 (95 % confidence interval [CI], 1.90-3.37, P < .001). After adjustment for age, sex, and comorbidities, patients with anxiety disorders were found to be 2.17 times more likely to develop BPPV (95 % CI, 1.63-2.90, P < .001) than the control patients. Furthermore, female sex (HR = 1.81, 95 % CI, 1.31-2.50, P < .001) and cerebrovascular disease (HR = 1.53, 95 % CI, 1.00-2.34, P = .050) were independent risk factors for developing new-onset BPPV in patients with anxiety disorders. CONCLUSIONS: Anxiety disorder patients may have an increased risk of developing BPPV, especially those who are female or have cerebrovascular disease.

Children's disclosure of sexual abuse during early forensic psychiatric evaluation in Southern Taiwan.

BACKGROUND/PURPOSE: Many surveys of child sexual abuse (CSA) in Western countries focus on the victims' disclosures and their associated factors during forensic interviews, but similar data in Asian countries is scarce. We explored the disclosure rate of CSA allegations during forensic interviews in South Taiwan and the factors predicting such disclosure. We compared our findings with those of previous studies. METHODS: Data were collected from written forensic psychiatric reports of CSA victims who underwent early forensic psychiatric evaluation at two hospitals in Kaohsiung City from 2010 to 2015. All cases were divided into categories of full or nonfull disclosures. We identified the variables that distinguished between the two groups in bivariate analyses using the independent t test and the Chi-square test. Binary logistic regression analysis was done to determine whether those significant correlates in the bivariate analyses were independent predictors of full disclosure. RESULTS: Among the 55 cases, 32 (58%) were full disclosures. Older age at first interview (odds ratio=1.39), no diagnosis of mental retardation (odds ratio=0.04), and experiencing sexual abuse more than once (odds ratio=5.90) were positive factors independently related to the full disclosure of CSA allegations. CONCLUSION: The rate of disclosure under the program was comparable to that of prior studies. This may suggest a role for early forensic psychiatric evaluation of children to promote disclosure of CSA allegations. We hope the findings may serve as a basis for future studies of CSA disclosure and associated factors in Taiwanese society.

Effect of NPC15199 on [Ca²âº]i and viability in SCM1 human gastric cancer cells.

NPC15199 is a synthesized compound that inhibits inflammation in some models. However, whether NPC15199 affects Ca²âº homeostasis in human gastric cancer is unclear. This study examined the effect of NPC15199 on cytosolic free Ca²âº concentrations ([Ca²âº]i) and viability in SCM1 human gastric cancer cells. The Ca²âº-sensitive fluorescent dye fura-2 was used to measure [Ca²âº]i. NPC15199 evoked [Ca²âº]i rises concentration-dependently. The response was reduced by removing extracellular Ca²âº. NPC15199-evoked Ca²âº entry was not inhibited by store-operated channel inhibitors (nifedipine, econazole and SKF96365) and protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate, PMA), or PKC inhibitor (GF109203X). In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) nearly abolished NPC15199-evoked [Ca²âº]i rises. Conversely, treatment with NPC15199 also nearly abolished thapsigargin or BHQ-evoked [Ca²âº]i rises. Inhibition of phospholipase C (PLC) with U73122 did not affect NPC15199-evoked [Ca²âº]i rises. NPC15199 at concentrations of 100-900 µM induced concentration-dependent, Ca²âº-independent decrease in viability. Together, in SCM1 cells, NPC15199 induced [Ca²âº]i rises that involved Ca²âº entry through PKC-insensitive non-store-operated Ca²âº channels and PLC-independent Ca²âº release from the endoplasmic reticulum. NPC15199 also induced Ca²âº-independent cell death.

Effect of protriptyline on [Ca2+]i and viability in MG63 human osteosarcoma cells.

Tricyclic antidepressants (TCA) have been clinically prescribed in the auxiliary treatment of cancer patients. Although protriptyline, a type of TCA, was used primarily in the clinical treatment of mood disorders in cancer patients, the effect of protriptyline on physiology in human osteosarcoma is unknown. This study examined the effect of protriptyline on cytosolic free Ca2+ concentrations ([Ca2+]i) and viability in MG63 human osteosarcoma cells. Protriptyline between 50 and 250 µM evoked [Ca2+]i rises concentration-dependently. Protriptyline induced influx of Mn2+, indirectly implicating Ca2+ influx. Protriptyline-evoked Ca2+ entry was inhibited by nifedipine by 20% but was not altered by econazole, SKF96365, GF109203X, and phorbol-12-myristate-13-acetate (PMA). In Ca2+-free medium, treatment with protriptyline inhibited the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin-evoked [Ca2+]i rises. Conversely, treatment with thapsigargin inhibited 45% of protriptyline-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter protriptyline-evoked [Ca2+]i rises. Protriptyline at 50-250 µM decreased cell viability, which was not reversed by pretreatment with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, our data suggest that in MG63 cells, protriptyline induced [Ca2+]i rises by evoking Ca2+ release from the endoplasmic reticulum and other stores in a PLC-independent manner, and Ca2+ entry via a nifedipine-sensitive Ca2+ pathway. Protriptyline also caused Ca2+-independent cell death.

Anxiety and depressive disorders among patients with esophageal cancer in Taiwan: a nationwide population-based study.

BACKGROUND: The comorbidity of depression with anxiety disorders is associated with poorer treatment outcomes, worse quality of life, poorer adherence to treatment, and greater suicide risk in cancer patients. OBJECTIVE: To assess the risk of comorbid anxiety and depressive disorders after the diagnosis of esophageal cancer compared with a matched cohort by using the Taiwan National Health Insurance Research Database (NHIRD). METHODS: We conducted a retrospective study of 28,454 patients (14,227 patients with esophageal cancer and 14,227 matched patients) who were selected from the NHIRD. Patients were observed for a maximum of 12 years to determine the incidence of new-onset anxiety and depressive disorders for which antidepressants had been prescribed. A Cox regression analysis was performed to identify the risk factors associated with anxiety and depressive disorders in esophageal cancer patients. RESULTS: The cumulative incidence of anxiety and depressive disorders in the esophageal cancer patients was significantly higher than that in the matched cohort (P < .001). The adjusted hazard ratio (HR) was 2.24 (95 % confidence interval, CI = 1.95-2.56, P < .001) in the esophageal cancer cohort compared with the matched cohort. Independent risk factors for developing anxiety and depressive disorders among the patients with esophageal cancer included cirrhosis, cerebrovascular disease, and surgical treatment. CONCLUSION: Esophageal cancer may be a prominent risk factor for anxiety and depressive disorders. Based on our data, we suggest that attention should be focused on esophageal cancer patients with comorbid cirrhosis and cerebrovascular disease and those who have received surgical interventions.

The association between prostate cancer and mood disorders: a nationwide population-based study in Taiwan.

BACKGROUND: This study identified possible risk factors for newly diagnosed mood disorders, including depressive and bipolar disorders, in prostate cancer patients. METHODS: From 2000 to 2006, two cohorts were evaluated on the occurrence of mood disorder diagnosis and treatment. For the first cohort, data of patients diagnosed with prostate cancer was obtained from the Taiwan National Health Insurance (NHI) Research Database. As the second cohort, a cancer-free comparison group was matched for age, comorbidities, geographic region, and socioeconomic status. RESULTS: Final analyses involved 12,872 men with prostate cancer and 12,872 matched patients. Increased incidence of both depressive (IRR 1.52, 95% CI 1.30-1.79, P <0.001) and bipolar disorder (IRR 1.84, 95% CI 1.25-2.74, P = 0.001) was observed among patients diagnosed with prostate cancer. Multivariate matched regression models show that cerebrovascular disease (CVD) and radiotherapy treatment could be independent risk factors for developing subsequent depressive and bipolar disorders. CONCLUSION: We observed that the risk of developing newly diagnosed depressive and bipolar disorders is higher among Taiwanese prostate cancer patients. Clinicians should be aware of the possibility of increased depressive and bipolar disorders among prostate cancer patients in Taiwan. A prospective study is necessary to confirm these findings.

Effect of Antidepressant Doxepin on Ca²âº Homeostasis and Viability in PC3 Human Prostate Cancer Cells.

The effect of the antidepressant doxepin on cytosolic Ca²âº concentrations ([Ca²âº](i)) and viability in PC3 human prostate cancer cells was explored. The Ca²âº-sensitive fluorescent dye fura-2 was applied to measure [Ca²âº](i). Doxepin at concentrations of 500-1000 µM induced a [Ca²âº](i) rise in a concentration-dependent manner. The response was reduced partly by removing Ca²âº. Doxepin-evoked Ca²âº entry was suppressed by Ca²âº entry blockers (nifedipine, econazole, SK&F96365), and protein kinase C (PKC) modulators. In the absence of extracellular Ca²âº, incubation with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) partly inhibit doxepin-induced [Ca²âº](i) rise. Incubation with doxepin nearly inhibited thapsigargin or BHQ-induced [Ca²âº](i) rise. Inhibition of phospholipase C (PLC) with U73122 failed to alter doxepin-induced [Ca²âº](i) rise. At concentrations of 200-250 µM, doxepin killed cells in a concentration-dependent manner. This cytotoxic effect was not reversed by chelating cytosolic Ca²âº with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid/acetoxy methyl (BAPTA/AM). Annexin V/PI staining data implied that doxepin (200 and 250 µM) did not induce apoptosis. Collectively, in PC3 cells, doxepin induced a [Ca²âº](i) rise by evoking PLC-independent Ca²âº release from stores including the endoplasmic reticulum and Ca²âº entry via PKC-sensitive store-operated Ca²âº channels. Doxepin caused cell death that was independent of [Ca²âº](i) rises.

Understanding the experiences of Mandarin-speaking patients diagnosed with life-threatening cancer in Australia.

OBJECTIVE: People from ethnic minority groups who receive cancer care outside their country of origin may experience poor survival and psychological outcomes relative to that nation's majority groups. This exploratory qualitative study aimed to understand the experience of a large minority group of Mandarin-speaking cancer patients (MSCPs) after diagnosis and treatment of their cancer in Australia, with a view to delineate if cultural or linguistic factors affected the quality of care provided. METHOD: We employed an exploratory qualitative design involving interviews with 22 MSCPs who were treated during 2009 at the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Participants were interviewed by a bilingual psychiatrist, audiotaped, transcribed in Mandarin, and then translated into English before being subjected to thematic analysis by two independent researchers. RESULTS: MSCPs experienced notable challenges as a result of both language difficulties and differing cultural approaches, which often limited their understanding of their disease and impeded their ability to access quality care and adequate support. The results call for Australia and other Western nations with increasingly diverse populations to consider how cancer care can be modified to better support people from minority groups to effectively cope with their diagnosis and treatment. SIGNIFICANCE OF RESULTS: This study raises several suggestions for service improvement, including the development of bilingual communication aids, improved educational opportunities for clinical staff to aid their mastery of cultural issues and effective interpreter consultations, and improved access to supportive services offering culturally specific strategies.

Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study.

BACKGROUND: TN is one of the most common causes of facial pain. A higher prevalence of psychiatric co-morbidities, especially depressive disorder, has been proven in patients with TN; however, a clear temporal-causal relationship between TN and specific psychiatric disorders has not been well established. We performed a nationwide population-based retrospective cohort study to explore the relationship between TN and the subsequent development of psychiatric disorders, including schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. METHODS: We identified subjects who were newly diagnosed with TN between January 1, 2000 and December 31, 2010 in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed for patients without TN who were matched according to age and sex. All TN and control patients were observed until diagnosed with psychiatric disorders, death, withdrawal from the National Health Institute system, or until December 31, 2010. RESULTS: The TN cohort consisted of 3273 patients, and the comparison cohort consisted of 13,092 matched control patients without TN. The adjusted hazard ratio (aHR) of depressive disorder, anxiety disorder and sleep disorder in subjects with TN was higher than that of the controls during the follow-up [aHR: 2.85 (95% confidence interval: 2.11-3.85), aHR: 2.98 (95% confidence interval: 2.12-4.18) and aHR: 2.17 (95% confidence interval: 1.48-3.19), respectively]. CONCLUSIONS: TN might increase the risk of subsequent newly diagnosed depressive disorder, anxiety disorder, and sleep disorder, but not schizophrenia or bipolar disorder. Additional prospective studies are required to confirm these findings.