Polymorphisms in the dopamine receptor 4 gene: is there an association with clinical response to clozapine in patients with treatment-resistant schizophrenia?

BACKGROUND: Clozapine is the treatment of choice for treatment-resistant schizophrenia (TRS). Its use is, however, often associated with variable clinical outcomes. It acts as an antagonist of dopamine receptors, with a high affinity for dopamine receptor 4 (DRD4). Polymorphisms in the DRD4 gene have been suggested to contribute to variable drug responses seen. OBJECTIVES: The aim of this study was to determine whether a 120 base-pair duplication polymorphism in the DRD4 gene affects response to clozapine. METHODS: Patients diagnosed to have TRS, on stable doses of clozapine were the subjects of the study. Genomic DNA was isolated from peripheral venous blood from the patients, and genotyped for the polymorphism. Serum clozapine levels were also measured. Participants’ socio-demographic and clinical profiles were recorded. Standard assessment schedules were used to assess premorbid adjustments, response to traumatic events, cognitive status and disability. Clozapine response was defined a priori; allelic and genotypic frequencies were determined and correlated with the clinical responses. RESULTS: No genotypic association was found between the polymorphism and serum clozapine levels or response to treatment with clozapine in patients with TRS. However, among the adverse effects, hyper-salivation is significantly associated with the polymorphism of interest (p=0.0009). Presence of the 120-bp duplication in DRD4 appears to confer risk for sialorrhea in response to clozapine therapy. These results suggest that routine screening for DRD4 120-bp repeat polymorphism before clozapine therapy may not be useful as a predictor for clinical response to clozapine. It may, however, help to identify those at high risk for clozapine-induced hyper-salivation

Comprehensive \u3ci\u3ein vitro\u3c/i\u3e and \u3ci\u3ein vivo\u3c/i\u3e evaluation of therapeutic potential of Bacopa-derived asiatic acid against a human oral pathogen \u3ci\u3eStreptococcus mutans\u3c/i\u3e

Dental caries is a common human oral disease worldwide, caused by an acid-producing bacteria Streptococcus mutans. The use of synthetic drugs and antibiotics to prevent dental caries has been increasing, but this can lead to severe side effects. To solve this issue, developing and developed countries have resorted to herbal medicines as an alternative to synthetic drugs for the treatment and prevention of dental caries. Therefore, there is an urgent need for plant-derived products to treat such diseases. Bacopa monnieri, a well-documented medicinal plant, contains 52 phytocompounds, including the pentacyclic triterpenoid metabolite known as asiatic acid (ASTA). Hence, this study aimed to demonstrate, for the first time, the antibacterial activity of phytocompound ASTA against S. mutans. The findings revealed that ASTA significantly inhibited the growth of S. mutans and the production of virulence factors such as acidurity, acidogenicity, and eDNA synthesis. Molecular docking analysis evaluated the potential activity of ASTA against S. mutans virulence genes, including VicR and GtfC. Furthermore, toxicity assessment of ASTA in human buccal epithelial cells was performed, and no morphological changes were observed. An in vivo analysis using Danio rerio (zebrafish) confirmed that the ASTA treatment significantly increased the survival rates of infected fish by hindering the intestinal colonization of S. mutans. Furthermore, the disease protection potential of ASTA against the pathognomonic symptom of S. mutans infection was proven by the histopathological examination of the gills, gut, and kidney. Overall, these findings suggest that ASTAmay be a promising therapeutic and alternative drug for the treatment and prevention of oral infection imposed by S. mutans

Comprehensive in vitro and in vivo evaluation of therapeutic potential of Bacopa-derived asiatic acid against a human oral pathogen Streptococcus mutans

Dental caries is a common human oral disease worldwide, caused by an acid-producing bacteria Streptococcus mutans. The use of synthetic drugs and antibiotics to prevent dental caries has been increasing, but this can lead to severe side effects. To solve this issue, developing and developed countries have resorted to herbal medicines as an alternative to synthetic drugs for the treatment and prevention of dental caries. Therefore, there is an urgent need for plant-derived products to treat such diseases. Bacopa monnieri, a well-documented medicinal plant, contains 52 phytocompounds, including the pentacyclic triterpenoid metabolite known as asiatic acid (ASTA). Hence, this study aimed to demonstrate, for the first time, the antibacterial activity of phytocompound ASTA against S. mutans. The findings revealed that ASTA significantly inhibited the growth of S. mutans and the production of virulence factors such as acidurity, acidogenicity, and eDNA synthesis. Molecular docking analysis evaluated the potential activity of ASTA against S. mutans virulence genes, including VicR and GtfC. Furthermore, toxicity assessment of ASTA in human buccal epithelial cells was performed, and no morphological changes were observed. An in vivo analysis using Danio rerio (zebrafish) confirmed that the ASTA treatment significantly increased the survival rates of infected fish by hindering the intestinal colonization of S. mutans. Furthermore, the disease protection potential of ASTA against the pathognomonic symptom of S. mutans infection was proven by the histopathological examination of the gills, gut, and kidney. Overall, these findings suggest that ASTA may be a promising therapeutic and alternative drug for the treatment and prevention of oral infection imposed by S. mutans

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression

Kinetics of IgM and IgG antibodies after scrub typhus infection and the clinical implications

Objectives: The serological detection of IgM antibodies is the most widely used test to diagnose scrub typhus infection. However, the kinetics of IgM and IgG antibodies post-infection remain elusive, which could contribute to false positivity. The objective of this study was to document the nature of the evolution of these antibody titres after infection. Methods: Adult patients previously confirmed to have scrub typhus by IgM ELISA, positive PCR, or both, were included in this cross-sectional study. The levels of IgM and IgG antibodies in serum samples were tested using an ELISA and the distribution curve was plotted. Results: Two hundred and three patients were included in this study. Post-infection serum sampling was done between 1 month and 46 months after documented infection. IgM levels declined gradually but remained elevated above the diagnostic cut-off for up to 12 months post-infection. However, IgG levels continued to rise reaching a peak at 10 months, followed by a gradual decline over several months. In the majority of cases, the IgG levels remained above the cut-off threshold for more than 36 months. Conclusions: Clinicians need to be cautious in using a single serum sample for the detection of IgM to diagnose scrub typhus, as it remains elevated for up to 12 months after the infection, whereas the serum IgG level could be used as an indicator of past infection

Fabrication of nanocomposites mediated from aluminium nanoparticles/Moringa oleifera gum activated carbon for effective photocatalytic removal of nitrate and phosphate in aqueous solution

The removal of nitrate and phosphate in polluted water is a challenging environmental problem. This study was designed to use a different light spectrum to enhance carbon-based metal nanocomposites adsorbent for the augmented removal of nitrate and phosphate from aqueous solution. Synthesis of aluminium oxide nanoparticle (Al2O3NPs)/Moringa oleifera gum activated carbon (MOGAC) based nanocomposites was conducted using sol-gel method. Incidentally, prepared nanocomposite was subject to evaluate the photocatalytic removal of nitrate and phosphate under different LED light irradiations. The microscopic image of MOGAC showed the pores on its surface, which resembles a honeycomb-like structure. The bandgap energy values of the Al2O3 and Al2O3/MOGAC were 3.16 and 3.22 eV, which corresponded to the reflectance edge of 420 nm. The surface area of Al2O3/MOGAC nanocomposites resolute was recorded as 176.92 m2/g−1. Photocatalytic activity against nitrate and phosphate was carried out by the synthesized nanocomposites under the different LED light spectrum. The red LED light spectrum and 10 mg/L of nanocomposite removed nitrate and phosphate ions up to 94% and 95% after 105 min and 75 min of irradiation, respectively. Overall, the Al2O3/MOGAC nanocomposites maintained good stability after four cycles of nitrate and phosphate reduction