Two-pore channels (TPCs) are cation-permeable channels located on endolysosomal membranes and important mediators of intracellular Ca 2+ signalling. TPCs are involved in various pathophysiological processes, including cell growth and development, metabolism, and cancer progression. Most studies of TPCs have used TPC –/– cell or whole-animal models, or Ned-19, an indirect inhibitor. The TPC activation mechanism remains controversial, which has made it difficult to develop selective modulators. Recent studies of TPC structure and their interactomes are aiding the development of direct pharmacological modulators. This process is still in its infancy, but will facilitate future research and TPC targeting for therapeutical purposes. Here, we review the progress of current research into TPCs, including recent insights into their structures, functional roles, mechanisms of activation, and pharmacological modulators.

Background : Prophylactic voriconazole use is recommended in children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential due to its narrow therapeutic index. Known covariates do not sufficiently explain large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. Objectives : We investigated genetic and clinical covariate association with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. Methods : This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. Results : We analyzed plasma voriconazole and n-oxide metabolite concentrations from 58 children aged <21 years (n=12 in age <2 years). A two-compartment parent mixed linear/nonlinear model best described our data. CYP2C19 phenotype and body weight were significant covariates (both p<0.05). Our model performance in age <2 years was comparable to other age groups. Simulation of the final model suggested the following dosages to attain target steady-state trough concentrations of 1.5 - 5.0 mg/L in CYP2C19 normal phenotype: 16 mg/kg (weight <15 kg), 12 mg/kg (weight 15-30 kg), 10 mg/kg (weight >30 kg), whereas dosages were 33-50% lower for CYP2C19 poor/intermediate and 25-50% higher for CYP2C19 rapid/ultrarapid phenotypes. Conclusions : We propose a new starting dosage regimen, combined with therapeutic drug monitoring for intravenous voriconazole in children of all ages. Future studies should validate this dosing regimen.

[F]FCh uptake of parathyroid adenomas is strongly correlated with preoperative PTH serum concentration. Therefore, the preoperative PTH level might potentially be able to predict success of [F]FCh-PET imaging in hyperparathyroidism, with higher lesion-to-background ratios being expected in patients with high PTH. PET/MR is accurate in estimating the volume of parathyroid adenomas.

Factor XII (FXII) deficiency is a rare genetic blood disorder. It can lead to a higher risk of developing deep vein thrombosis or acquired thrombotic disorders than the general population. This retrospective study evaluated patients who opted for surgery and were found to have abnormal clotting profiles and clotting factors on preoperative routine blood. Patients were included regardless of whether they were symptomatic or asymptomatic. The cohort comprised 115 patients with a mean FXII level of 128.04 ± 36.93%. Two (1.79%) patients, both of whom were women, had FXII levels <60%. The mean FXII level was 58 ± 1.41 (range, 57–59%) in this group. The present study shows the prevalence of FXII in the asymptomatic Saudi population. The results provide the normal range for FXII. The findings of our study provide the basis for diagnosing F XII deficiency in the asymptomatic Saudi population.