Minimally Invasive Tissue Sampling for Postmortem Diagnosis of Tuberculous Meningitis in Zambian Adults.

BD is a complex and recurrent psychiatric disorder characterized by alternating episodes of mania or hypomania and depression (). Manic or hypomanic episodes are typically characterized by abnormally elevated or irritable mood, increased energy or activity, inflated self-esteem, decreased need for sleep, impulsivity, and risk-taking behavior, whereas depressive episodes commonly involve persistent low mood, anhedonia, reduced energy, impaired concentration, and, in severe cases, suicidal ideation or behavior (; ). BD usually emerges in late adolescence or early adulthood and is associated with frequent relapse, high psychiatric and medical comorbidity, and substantial functional impairment (). Epidemiological studies have estimated the lifetime prevalence of BD to be approximately 2.4%, with a lifetime suicide attempt rate of approximately 29.2% (; ). Therefore, BD imposes a considerable burden on patients, families, healthcare systems, and society (; ). Current treatment strategies for BD primarily include pharmacotherapy, psychotherapy, and psychosocial interventions. Pharmacological treatment includes mood stabilizers, atypical antipsychotics, and, in selected cases, adjunctive antidepressants; however, treatment response varies substantially across individuals (). Studies on the efficacy of lithium treatment show that about one-third or more of patients do not respond well, and about half of patients require further treatment or experience relapse during long-term follow-up. Additionally, the efficacy criteria used in different studies are inconsistent (). Other mood stabilizers, such as lamotrigine or valproate, and atypical antipsychotics may be effective in specific clinical phases, but their long-term effectiveness, tolerability, and safety profiles remain important clinical considerations (). Overall, relapse prevention, treatment-response heterogeneity, adverse effects, and the lack of reliable predictors of therapeutic outcomes continue to represent major challenges in BD management. These limitations highlight the need to better understand the biological mechanisms underlying disease heterogeneity and treatment response. DNA methylation is a key epigenetic modification in which a methyl group is added to cytosine residues, primarily at CpG sites, through the activity of DNA methyltransferases (DNMTs). Generally, promoter-region hypermethylation is often associated with transcriptional repression, whereas the functional consequences of low methylation or methylation changes in gene bodies and other regulatory regions are context-dependent (). In the nervous system, DNA methylation has been implicated in neural development, synaptic plasticity, learning, memory, and activity-dependent gene regulation (; ). These methylation-related processes may regulate synapse formation and plasticity, thereby influencing signal transduction and neurotransmitter-system function. Such changes may be relevant to memory, behavioral regulation, and BD-related neurobiological abnormalities, although their direct relationship with clinical symptoms remains to be further clarified. More importantly, DNA methylation is reversible and modifiable, making it a potential regulatory target for mechanistic and therapeutic research. However, whether precise modulation of abnormal methylation can safely and effectively improve gene-expression dysregulation in BD remains to be established ().