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Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra‐rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14‐year‐old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C‐terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders. [ABSTRACT FROM AUTHOR]

• Only 6 % of randomized trials of antidepressants assess the prevention of relapse. • Only 28 % of randomized trials of antidepressants assess functional remission. • Most randomized trials of antidepressants have stringent eligibility criteria. • 84 % of randomized trials of antidepressants exclude older adults. • Modification of the design of trials of antidepressants should be considered. The purpose of this study was to analyze the key aspects of the design of contemporary placebo-controlled randomized clinical trials (RCTs) of antidepressants enrolling patients with major depressive disorder (MDD) aged 18 years or older, especially the outcome measures and the eligibility criteria. The study included 122 RCTs registered with ClinicalTrials.gov and started from 2008 through 2022. Most RCTs assessed only clinical remission, with proportion of trials with outcome measures related to functional remission being rather low (n = 34; 28 %). Clinical remission was mostly evaluated in acute phase of depression, and only 7 (6 %) trials assessed the prevention of relapse. Proportion of trials utilizing self-report questionnaires that provide important information complementary to clinician-rated scales was moderate (n = 66; 54 %). Another problem in included RCTs was common use of stringent eligibility criteria. For instance, minimal symtpom severity required for the patient's inclusion was listed in 104 RCTs (85 %), and 41 RCTs (34 %) excluded patients based on comorbid anxiety disorders. Most RCTs (n = 103; 84 %) excluded older patients, and only 6 (5 %) trials were dedicated exclusively to them. To ensure optimal development of clinical pharmacotherapy of MDD, the investigators should consider modification of some of the key aspects of the design of RCTs of antidepressants. [ABSTRACT FROM AUTHOR]

RUNX2 (Runt‐related transcription factor 2) is a master regulator of osteoblast differentiation, cartilage and bone development. Pathogenic variants in RUNX2 have been linked to the Cleidocranial dysplasia (CCD), which is characterized by hypoplasia or aplasia of clavicles, delayed fontanelle closure, and dental anomalies. Here, we report 11 unrelated Polish patients with CCD caused by pathogenic alterations located in the Runt domain of RUNX2. In total, we identified eight different intragenic variants, including seven missense and one splicing mutation. Three of them are novel: c.407T>A p.(Leu136Gln), c.480C>G p.(Asn160Lys), c.659C>G p.(Thr220Arg), additional three were not functionally tested: c.391C>T p.(Arg131Cys), c.580+1G>T p.(Lys195_Arg229del), c.652A>G p.(Lys218Glu), and the remaining two: c.568C>T p.(Arg190Trp), c.673C>T p.(Arg225Trp) were previously reported and characterized. The performed transactivation and localization studies provide evidence of decreased transcriptional activity of RUNX2 due to mutations targeting the Runt domain and prove that impairment of nuclear localization signal (NLS) affects the subcellular localization of the protein. Presented data show that pathogenic variants discovered in our patients have a detrimental effect on RUNX2, triggering the CCD phenotype. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are a pivotal part of our innate immune response. They recognize a wide variety of pathogens and instigate an immune response, thus facilitating the removal of the disease-causing agent. Due to the intense nature of this response its strict control is of key importance, as a prolonged inflammatory signal leads to carcinogenesis and autoimmune disorders. The signaling cascade initiated by the activated TLR is complex and consists of multiple stages. It involves a variety of adaptor proteins, protein kinases and effector transcription factors. The number of stages in this process enables many possible checkpoints and ways of regulation. Signal modulation involves differentiated expression of TLRs, splicing variants of their adaptor proteins, enzymes modifying proteins engaged in the cascade and many more. This review focuses on endogenous factors responsible for controlling the TLR-dependent inflammatory response as well as on pharmacological therapies designed for regulating the innate immune response. [ABSTRACT FROM AUTHOR]

Depression, anxiety, and aggression accompany neuropathic pain. Effective treatment of these comorbidities enhances the outcomes of pain management. Therefore, the study was designed to analyze the relationship between the intensity of depression, anxiety, and aggression and the pharmacotherapy applied in the daily practice of treating neuropathic pain. The aim of the study was to evaluate the frequency of using antidepressants (ADs), benzodiazepine anxiolytics (BDAs), and hypnotics, and the influence of administering these on the intensity of depression, anxiety, and aggression in patients diagnosed with neuropathic pain. A multi-center survey was conducted among 421 patients. An evaluation of the severity of depression, anxiety, and aggression was made using the Hospital Anxiety and Depression Scale—Modified Version (HADS-M). Among the patients treated due to neuropathic pain, ADs are used much more often than BDAs and hypnotics. Depression was well controlled, while anxiety was identified as a possible uncontrolled therapeutic problem in these patients, despite the correlation between the frequency of AD and hypnotics usage and the severity of anxiety. We also found that women show a higher level of intensity in both anxiety and depression, but this does not influence the frequency of their being administered ADs, BDAs, and hypnotics. [ABSTRACT FROM AUTHOR]

Chiral, smectogenic pendant groups have been covalently attached to cyclic oligosiloxanes by hydrosilylation. Differential scanning calorimetry, optical polarising microscopy, and X-ray diffraction measurements reveal liquid crystalline properties for all synthesized monomers and oligomers. The monomers, which differ by the nature of the rigid mesogenic core or end groups, showed enantiotropic smectic A phases. Almost all of cyclic oligosiloxanes present enantiotropic chiral smectic C phases. The mesomorphic range of these oligomers is greatly enhanced relative to the type of monomers and the ring size as well. [ABSTRACT FROM AUTHOR]

Introduction: In cell trafficking to the airways in asthma, among integrins the most important are those containing α4 and β2 subunits. We have previously shown that also blocking of collagen receptors, α1β1 and α2β1 integrins, inhibits transmigration of eosinophils of asthmatic subjects through a monolayer of skin microvascular endothelial cells seeded on collagen IV coated inserts. However, it was not clear whether this observation was limited to asthma or depended on the type of microvascular cell and collagen IV used as a base. Materials & methods: In the current study we performed a transmigration assay using human lung microvascular endothelial cells seeded directly on a plastic surface as a base and blood cells isolated from 12 representatives of each of two groups, asthmatics and healthy donors, by gradient centrifugation, followed by immunomagnetic negative separation of eosinophils. Isolated eosinophils and peripheral blood mononuclear cells (PBMC) were inhibited by snake venom-derived integrin antagonists including viperistatin and VP12, as inhibitors of α1β1 and α2β1 integrin, respectively, and VLO5 and VLO4, as inhibitors of α4β1 and α5β1 integrin, respectively. Results: All snake venom-derived anti-adhesive proteins were effective in inhibiting eosinophil transmigration, whilst only VLO5 and VLO4 reduced PBMC mobility in this assay. This observation was similar in both groups of subjects studied. Discussion: α1β1 and α2β1 integrins could be involved in transmigration of eosinophil to the inflammatory site. Migratory inhibition was observed in asthma subjects as well as in healthy donors, and did not depend on origin of endothelial cells or the extracellular matrix component used as a base. [ABSTRACT FROM AUTHOR]