Ordering genetic testing by neurologists: points to consider.

A significant challenge limiting the comprehensive utilization of genomic medicine is the lack of timely access to genetics specialists. Although neurologists see patients for whom genetic testing should be considered, the knowledge regarding the choice of the optimal genetic test for each case and the management of the test results are out of the scope of their everyday practice. In this review, we provide a step-by-step guide for non-geneticist physicians through the decision-making process when ordering diagnostic genetic testing for monogenic neurological diseases and when dealing with their results.

Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas.

Purpose: Exome sequencing (ES) could detect pathogenic variants that are unrelated to the test indication, including findings that may have an impact for patients considering conception/reproduction (reproduction-related findings [RRFs]), deliberately searched secondary findings (SFs), and incidental findings (IFs). We aimed to examine the detection rate of clinically actionable findings and to present counseling dilemmas in 840 parents of probands undergoing clinical trio ES testing.

Methods: RRFs/IFs/SFs were actively searched for in the parents as part of ES data analysis.

Azithromycin and Sildenafil May Have Protective Effects on Retinal Ganglion Cells via Different Pathways: Study in a Rodent Microbead Model.

Decreased blood flow to the optic nerve (ON) and neuroinflammation are suggested to play an important role in the pathophysiology of glaucoma. This study investigated the potential neuroprotective effect of azithromycin, an anti-inflammatory macrolide, and sildenafil, a selective phosphodiesterase-5 inhibitor, on retinal ganglion cell survival in a glaucoma model, which was induced by microbead injection into the right anterior chamber of 50 wild-type (WT) and 30 transgenic toll-like receptor 4 knockout (TLR4KO) mice. Treatment groups included intraperitoneal azithromycin 0.

A Whey-Based Diet Can Ameliorate the Effects of LPS-Induced Growth Attenuation in Young Rats.

Chronic inflammation in childhood is associated with impaired growth. In the current study, a lipopolysaccharide (LPS) model of inflammation in young rats was used to study the efficacy of whey-based as compared to soy-based diets to ameliorate growth attenuation. Young rats were injected with LPS and fed normal chow or diets containing whey or soy as the sole protein source during treatment, or during the recovery period in a separate set of experiments.

Proteinoid Polymers and Nanocapsules for Cancer Diagnostics, Therapy and Theranostics: In Vitro and In Vivo Studies.

Proteinoids-simple polymers composed of amino acids-were suggested decades ago by Fox and coworkers to form spontaneously by heat. These special polymers may self-assemble in micrometer structures called proteinoid microspheres, presented as the protocells of life on earth. Interest in proteinoids increased in recent years, in particular for nano-biomedicine.

Possible biallelic inheritance in TIE1 in a family with congenital lymphedema, intestinal lymphangiectasia and cutis aplasia.

A short report of two male siblings born with cutis aplasia, lymphedema and intestinal lymphangiectasia, one found to carry bi-allelic variants in the TIE1 gene known to be associated with congenital lymphedema.

MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome.

Beneficial Effect of Vitamin D on Non-Alcoholic Fatty Liver Disease (NAFLD) Progression in the Zebrafish Model.

A major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) results from excessive liver fat accumulation. Vitamin D (VitD) plays multiple important roles in diverse physiologic processes. Here, we describe the role of VitD in the complex pathogenesis of NAFLD and explore the possible therapeutic role of VitD supplementation in NAFLD therapy.

Human intestinal epithelial cells can internalize luminal fungi LC3-associated phagocytosis.

Background: Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3-associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo.

Modulating the proliferative and cytotoxic properties of patient-derived TIL by a synthetic immune niche of immobilized CCL21 and ICAM1.

A major challenge in developing an effective adoptive cancer immunotherapy is the generation of tumor-reactive cells in sufficient numbers and with enhanced cytotoxic potential. It was recently demonstrated that culturing of activated murine CD8+ T-cells on a "Synthetic Immune Niche" (SIN), consisting of immobilized CCL21 and ICAM-1, enhances T-cell expansion, increases their cytotoxicity against cultured cancer cells and suppresses tumor growth . In the study reported here, we have tested the effect of the CCL21+ICAM1 SIN, on the expansion and cytotoxic phenotype of Tumor Infiltrating Lymphocytes (TIL) from melanoma patients, following activation with immobilized anti-CD3/CD28 stimulation, or commercial activation beads.

Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.

DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset.

Prenatal gender-customized head circumference nomograms result in reclassification of microcephaly and macrocephaly.

Background: Local and worldwide prenatal charts for estimated fetal weight and postnatal charts for head circumference are gender specific. However, prenatal head circumference nomograms are not gender customized.

Objective: This study aimed to create gender-customized curves to assess between-gender head circumference differences and to study the clinical significance of using such gender-customized curves.

Effect of Opioid Receptor Activation and Blockage on the Progression and Response to Treatment of Head and Neck Squamous Cell Carcinoma.

Recent studies suggest that opioids have a role in the progression of HNSCC mediated by mu opioid receptors (MOR), however, the effects of their activation or blockage remains unclear. Expression of MOR-1 was explored in seven HNSCC cell lines using Western blotting (WB). XTT cell proliferation and cell migration assays were performed on four selected cell lines (Cal-33, FaDu, HSC-2, and HSC-3), treated with opiate receptor agonist (morphine), antagonist (naloxone), alone and combined with cisplatin.

Visual Outcomes Following Plasma Exchange for Optic Neuritis: An International Multicenter Retrospective Analysis of 395 Optic Neuritis Attacks.

Purpose: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON).

Methods: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset.

Clinical utility of expanded non-invasive prenatal screening compared with chromosomal microarray analysis in over 8000 pregnancies without major structural anomaly.

Objectives: To evaluate the theoretical added value of two types of non-invasive prenatal screening (NIPS) expansions in pregnancies without major structural anomalies over the commonly used NIPS for chromosomes 13, 18, 21, X and Y (5-NIPS) and to compare them with the added value of chromosomal microarray analysis (CMA).

Methods: This was a retrospective cohort study based on CMA results of all pregnancies with normal ultrasound (including pregnancies with soft markers and with abnormal maternal serum screening) that had undergone amniocentesis between January 2013 to February 2022 and were registered in the database of the Rabin Medical Center genetic laboratory. We calculated the theoretical yield of 5-NIPS and compared the added value of expanded 5-NIPS for common microdeletions (1p36.

Optical Coherence Tomography Angiography for the Differentiation of Glaucoma from Pituitary Macroadenoma Related Optic Disc Measurements.

Objective: To determine the potential of optical coherence tomography (OCT) and OCT angiography (OCTA) to distinguish between glaucoma and pituitary macroadenoma by optic disc appearance.

Methods: This prospective case-control study comprised 31 patients: 23 with glaucoma (18 male, 5 female) and 8 with pituitary macroadenoma and chiasmatic compression (3 male, 5 female). The corresponding mean ages were 72.

[GENETIC PANELS FOR THE DIAGNOSIS OF RARE CONGENITAL HEMATOLOGICAL DISORDERS].

Genetic diagnosis of congenital hematological disorders is complicated by the overlap of the clinical and laboratory presentation across different diseases and the large number of genes involved in each syndrome. Nonetheless, an accurate genetic diagnosis is essential for directing the follow-up and treatment program of the patients, as well as for identifying asymptomatic family members, choosing a non-affected related donor for hematopoietic stem cell transplantation and for offering a prenatal diagnosis. In recent years, a novel method of targeted next generation sequencing using gene panels was developed.

Serum claudin-5 levels among patients with unipolar and bipolar depression in relation to the pro-inflammatory cytokine tumor necrosis factor-alpha levels.

Accumulating evidence indicates that inflammation and neurovascular unit (NVU) dysfunction contribute to depression via disrupted blood-brain barrier (BBB) integrity. Claudin-5, an endothelial tight-junction protein expressed in the NVU and contributing to BBB integrity, has been implicated in psychiatric disorders, including major depressive disorder (MDD) and schizophrenia. In an animal model of depressive-like behavior, the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) was found to affect BBB permeability and claudin-5 expression of NVU endothelial cells.

Early prediction of residual disease after neoadjuvant chemoradiotherapy and cetuximab for locally advanced esophageal cancer using F-FDG PET-CT imaging: a prospective cohort study.

Background: Previous studies in locally advanced esophageal cancer (LAEC) suggested that a change in the tumor's metabolic response, i.e., decrease of its interim F-FDG uptake compared with baseline, may predict histopathological response.

Urine soluble triggering receptor expressed on myeloid cells-1 is a novel biomarker for active lupus nephritis: a case-control study.

Objectives: To determine the value of plasma and urine sTREM-1 levels as a biomarker of lupus nephritis (LN) as well as extra-renal systemic lupus erythematosus (SLE).

Methods: Consecutive adult patients with SLE attending a tertiary lupus clinic in 2016-2018 were prospectively divided into 3 groups according to SLEDAI-2K and renal-SLEDAI scores: active renal lupus (ARL), active non-renal lupus (ANL), and inactive lupus (IL). Blood and spot urine samples from each group and matched healthy subjects were analysed by means of ELISA for plasma and urine sTREM-1 levels.

Gestational hemodilution as a putative risk factor for postpartum depression: A large-scale nationwide longitudinal cohort study.

Background: While anemia during pregnancy has been linked to increased postpartum depression (PPD) risk, longitudinal studies on the association between gestational hemodilution, represented by decreased hematocrit (Hct) during the transition from the 1st to 2nd trimester, and PPD risk, are scarce. The current study aimed to investigate this association in a nationwide cohort over the perinatal period.

Methods: This retrospective cohort study included 104,715 women who gave birth between January 2008 and December 2015.

Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience.

Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene () is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features.

Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN- variants.

Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed.