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Summary: Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase that plays a key role in tau phosphorylation and regulation of the mammalian target of rapamycin (mTOR) pathway. Abnormal tau phosphorylation and dysregulation of the mTOR pathway are implicated in neurodegenerative and neurodevelopmental disorders. Here, we report a gain-of-function variant in MARK4 in two siblings with childhood-onset neurodevelopmental disability and dysmorphic features. The siblings carry a germline heterozygous missense MARK4 variant c.604T>C (p.Phe202Leu), located in the catalytic domain of the kinase, which they inherited from their unaffected, somatic mosaic mother. Functional studies show that this amino acid substitution has no impact on protein expression but instead increases the ability of MARK4 to phosphorylate tau isoforms found in the fetal and adult brain. The MARK4 variant also increases phosphorylation of ribosomal protein S6, indicating upregulation of the mTORC1 pathway. In this study, we link a germline monoallelic MARK4 variant to a childhood-onset neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic features.

The efficiency of photopolymerisation significantly impacts achieving a high degree of conversion and, consequently, determines the success and strength of resin-based composite (RBC) restorations. The study aimed to measure the light irradiance of selected LED curing lamps, taking into account various exposure modes and the increased distance of the light source from the radiometer surface. The study material consisted of 21 LED polymerisation lamps of a single type (Woodpecker Medical Instrument Co., Guilin, China) with three exposure modes: standard, soft start, and pulse. During the measurement, the distance was increased from 0 mm to 8 mm, every 2 mm. Light irradiance measurements were made with a Bluephase Meter II photometer (Ivoclar Vivadent, Opfikon, Switzerland). Increasing the distance affected the soft mode the most, causing a significant drop in light irradiance on the photometer. Standard mode coped best with distance. Even at a distance of 0 mm, the soft start mode does not reach the power of the standard and pulse modes. The standard mode seems to be the most clinically effective, especially if it is planned to polymerise a material in a deep cavity. The soft start mode, as the least resistant to increasing distance, is recommended for use in front teeth or the cervical area.

BackgroundCanine gastric dilatation volvulus (GDV) is characterized by tissue ischemia, reperfusion, and systemic inflammation. Evidence exists that lidocaine exerts anti-inflammatory properties and potentially improves outcome.Design and settingProspective, randomized observational cohort study in client-owned dogs with GDV.ObjectiveThe primary objective of the study was the determination of pro- and anti-inflammatory biomarker concentrations in dogs with GDV with and without intravenous (IV) lidocaine therapy. The second objective was the evaluation of side effects of lidocaine.MethodsOf 35 dogs included in the study, 20 dogs were assigned to receive lidocaine (LIDO) (2 mg/kg initially, followed by a continuous infusion at a rate of 50 μg/kg/min over 24 h) and 15 dogs not to receive lidocaine (NO-LIDO). Plasma concentrations of cytokines interleukin (IL)-6, IL-7, IL-8, IL-10, IL-15, IL-18, interferon gamma, keratinocyte chemotactic-like, monocyte chemotactic protein, and C-reactive protein (CRP) were measured at admission (prior any therapeutic intervention, T0), immediately after surgery (T1), at 24 h (T24), and at 48 h (T48) post-surgery.ResultsNo significant differences in concentrations of any cytokines were found between the LIDO- and the NO-LIDO group. Significant lower CRP concentrations (median [range]) were found in dogs with lidocaine compared to dogs without at T24 (97.5 pg/mL [46.3–161.7] vs. 127.9 pg/mL [26.9–182.0]; p = 0.046) and T48 (73.7 pg/mL [18.4–169.4] vs. 116.3 pg/mL [71.4–176.8]; p = 0.002). Dogs receiving lidocaine exhibited significantly impaired mentation, a prolonged period of anorexia, and longer hospitalization compared to dogs without lidocaine.ConclusionLidocaine administration had no impact on the plasma levels of cytokines during the 48-h study period, but significantly lower CRP concentrations were found at T24 and T48. Lidocaine’s potential side effects require careful decision making regarding its use.