B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling.

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia.

Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment-Refractory Depression.

We aimed to develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery-Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.

Toll-Like Receptor 4 in Pain: Bridging Molecules-to-Cells-to-Systems.

Pain impacts the lives of billions of people around the world - both directly and indirectly. It is complex and transcends beyond an unpleasant sensory experience to encompass emotional experiences. To date, there are no successful treatments for sufferers of chronic pain.

New pharmacological perspectives and therapeutic options for opioids: Differences matter.

Opioids remain the major drug class for the treatment of acute, chronic and cancer pain, but have major harmful effects such as dependence and opioid-induced ventilatory impairment. Although no new typical opioids have come onto the market in the past almost 50 years, a plethora of new innovative formulations has been developed to meet the clinical need. This review is intended to shed light on new understanding of the molecular pharmacology of opioids, which has arisen largely due to the genomic revolution, and what new drugs may become available in the coming years.

Large variability in plasma efavirenz concentration in Papua New Guinea HIV/AIDS patients associated with high frequency of CYP2B6 516T allele.

Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.

Instability of Efavirenz Metabolites Identified During Method Development and Validation.

Accurate quantification of efavirenz metabolites in patient samples is required to investigate their potential contribution to efavirenz adverse events. This study aimed to validate a LC-MS/MS method to quantify and investigate the stability of efavirenz and metabolites in human plasma. Compounds were extracted from plasma by supported liquid extraction and resolved on a C18 column.

Innate Immune and Neuronal Genetic Markers Are Highly Predictive of Postoperative Pain and Morphine Patient-Controlled Analgesia Requirements in Indian but Not Chinese or Malay Hysterectomy Patients.

Objective: Pain severity and opioid requirements in the postoperative period show substantial and clinically significant inter-patient variation due mainly to factors such as age, surgery type, and duration. Genetic factors have not been adequately assessed except for the neuronal OPRM1 rs1799971 and COMT rs4680, whereas the contribution of innate immune signaling pathway genetics has seldom been investigated.

Setting: Hospital surgical ward.

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients.

Aims: Long-term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intrarenal exposure.

No Major Effect of Innate Immune Genetics on Acute Kidney Rejection in the First 2 Weeks Post-Transplantation.

Background: Innate immunity contributes to acute rejection after kidney transplantation. Genetic polymorphisms affecting innate immunity may therefore influence patients' risk of rejection. -330T > G, -1082G > A, -819C > T, and -592C > A, and -308G > A are not associated with acute rejection incidence in Caucasian kidney transplant recipients receiving a calcineurin inhibitor, ciclosporin or tacrolimus (TAC).

High and variable population prevalence of HLA-B*56:02 in indigenous Australians and relation to phenytoin-associated drug reaction with eosinophilia and systemic symptoms.

Phenytoin drug reaction with eosinophilia and systemic symptoms (DRESS) in 3 Aboriginal Australians positive for HLA-B*56:02 has been previously reported. We report the allele frequency of HLA-B*56:02 in 2 South Australian populations, 1 Aboriginal (4.8%, 95% confidence interval 2.

How context influences the interpretation of facial expressions: a source localization high-density EEG study on the "Kuleshov effect".

Few studies have explored the specificities of contextual modulations of the processing of facial expressions at a neuronal level. This study fills this gap by employing an original paradigm, based on a version of the filmic "Kuleshov effect". High-density EEG was recorded while participants watched film sequences consisting of three shots: the close-up of a target person's neutral face (Face_1), the scene that the target person was looking at (happy, fearful, or neutral), and another close-up of the same target person's neutral face (Face_2).

Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation.

Background: CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression.

Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety.

Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide.

CYP3A5*3 and ABCB1 61A>G Significantly Influence Dose-adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post-Kidney Transplantation.

Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolizing enzymes cytochromes P450 3A4/5 (CYP3A4/5), P-glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2) and CYP3A co-factor cytochrome P450 reductase (POR) have been studied for their effects on tacrolimus disposition.

Corticosterone Preexposure Increases NF-κB Translocation and Sensitizes IL-1β Responses in BV2 Microglia-Like Cells.

Corticosterone (CORT), a critical mediator of the hypothalamus pituitary adrenal axis in rodents, is a stress hormone that is classically viewed as possessing immune-suppressive properties. CORT is now appreciated to also mediate the neuroimmune-priming effect of stress to innate-immune stimulation, and hence serves as a mechanistic link to the neuroimmune involvement in stress-related disorders. However, these dichotomous actions of CORT remain poorly defined.

How Context Influences Our Perception of Emotional Faces: A Behavioral Study on the Kuleshov Effect.

Facial expressions are of major importance in understanding the mental and emotional states of others. So far, most studies on the perception and comprehension of emotions have used isolated facial expressions as stimuli; for example, photographs of actors displaying facial expressions corresponding to one of the so called 'basic emotions.' However, our real experience during social interactions is different: facial expressions of emotion are mostly perceived in a wider context, constituted by body language, the surrounding environment, and our beliefs and expectations.

Ethnicity-dependent influence of innate immune genetic markers on morphine PCA requirements and adverse effects in postoperative pain.

Although several genetic factors have been associated with postsurgical morphine requirements, those involving the innate immune system and cytokines have not been well investigated. The aim of this study was to investigate the contribution of genetic variability in innate immune signalling pathways to variability in morphine dosage after elective caesarean section under spinal anaesthesia in 133 Indian, 230 Malay, and 598 Han Chinese women previously studied. Twenty single nucleotide polymorphisms in 14 genes involved in glial activation (TLR2, TLR4, MYD88, MD2), inflammatory signalling (IL2, IL6, IL10, IL1B, IL6R, TNFA, TGFB1, CRP, CASP1), and neuronal regulation (BDNF) were newly investigated, in addition to OPRM1, COMT, and ABCB1 genetic variability identified previously.

Does the Kuleshov Effect Really Exist? Revisiting a Classic Film Experiment on Facial Expressions and Emotional Contexts.

According to film mythology, the Soviet filmmaker Lev Kuleshov conducted an experiment in which he combined a close-up of an actor's neutral face with three different emotional contexts: happiness, sadness, and hunger. The viewers of the three film sequences reportedly perceived the actor's face as expressing an emotion congruent with the given context. It is not clear, however, whether or not the so-called "Kuleshov effect" really exists.

Innate Immune Signalling Genetics of Pain, Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl.

Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients.

Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-desmethyl imatinib.

1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown.

Pharmacogenomics of methadone maintenance treatment.

Methadone is the major opioid substitution therapy for opioid dependence. Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines. Nevertheless many genetic factors have been investigated including those affecting its metabolism (CYP2B6-consistent results), efflux transport (P-gp-inconsistent results), target μ-opioid receptor (μ-opioid receptor-inconsistent results) and a host of other receptors (DRD2) and signaling elements (GIRK2 and ARRB2; not replicated).