Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia.

Nitric oxide is thought to have a role in the pathogenesis of achalasia. We performed a genetic analysis of 2 siblings with infant-onset achalasia. Exome analysis revealed that they were homozygous for a premature stop codon in the gene encoding nitric oxide synthase 1. Kinetic analyses and molecular modeling showed that the truncated protein product has defects in folding, nitric oxide production, and binding of cofactors. Heller myotomy had no effect in these patients, but sildenafil therapy increased their ability to drink. The finding recapitulates the previously reported phenotype of nitric oxide synthase 1-deficient mice, which have achalasia. Nitric oxide signaling appears to be involved in the pathogenesis of achalasia in humans.

Automated Analysis of Stereotypical Movements in Videos of Children With Autism Spectrum Disorder.

Importance: Stereotypical motor movements (SMMs) are a form of restricted and repetitive behavior, which is a core symptom of autism spectrum disorder (ASD). Current quantification of SMM severity is extremely limited, with studies relying on coarse and subjective caregiver reports or laborious manual annotation of short video recordings. Objective: To assess the utility of a new open-source AI algorithm that can analyze extensive video recordings of children and automatically identify segments with heterogeneous SMMs, thereby enabling their direct and objective quantification. Design, Setting, and Participants: This retrospective cohort study included 241 children (aged 1.4 to 8.0 years) with ASD. Video recordings of 319 behavioral assessments carried out at the Azrieli National Centre for Autism and Neurodevelopment Research in Israel between 2017 and 2021 were extracted. Behavioral assessments included cognitive, language, and autism diagnostic observation schedule, 2nd edition (ADOS-2) assessments. Data were analyzed from October 2020 to May 2024. Exposures: Each assessment was recorded with 2 to 4 cameras, yielding 580 hours of video footage. Within these extensive video recordings, manual annotators identified 7352 video segments containing heterogeneous SMMs performed by different children (21.14 hours of video). Main outcomes and measures: A pose estimation algorithm was used to extract skeletal representations of all individuals in each video frame and was trained an object detection algorithm to identify the child in each video. The skeletal representation of the child was then used to train an SMM recognition algorithm using a 3 dimensional convolutional neural network. Data from 220 children were used for training and data from the remaining 21 children were used for testing. Results: Among 319 behavioral assessment recordings from 241 children (172 [78%] male; mean [SD] age, 3.97 [1.30] years), the algorithm accurately detected 92.53% (95% CI, 81.09%-95.10%) of manually annotated SMMs in our test data with 66.82% (95% CI, 55.28%-72.05%) precision. Overall number and duration of algorithm-identified SMMs per child were highly correlated with manually annotated number and duration of SMMs (r = 0.8; 95% CI, 0.67-0.93; P < .001; and r = 0.88; 95% CI, 0.74-0.96; P < .001, respectively). Conclusions and relevance: This study suggests the ability of an algorithm to identify a highly diverse range of SMMs and quantify them with high accuracy, enabling objective and direct estimation of SMM severity in individual children with ASD.

The Role of Demographics in the Age of Autism Diagnosis in Jerusalem.

Early diagnosis of autism spectrum disorder (ASD) in children enables earlier access to services and better ability to predict subsequent development. A vast body of literature consistently shows discrepancies in the age of diagnosis between children from varying socio-economic levels, cultural and ethnic backgrounds. The present study examines the effect of sociodemographic factors on age of ASD diagnosis among the three primary ethnic sectors in Jerusalem region: secular and modern religious Jews, ultra-Orthodox Jews and Arabs. Findings indicate minimal differences in age of diagnosis prior to the age of six, although Arab children of this age were largely minimally verbal. After age six, no Arab children were referred for an evaluation.

Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 antagonist 4F-benzoyl-TN14003.

An increase in the number of stem cells in blood following mobilization is required to enhance engraftment after high-dose chemotherapy and improve transplantation outcome. Therefore, an approach that improves stem cell mobilization is essential. The interaction between CXCL12 and its receptor, CXCR4, is involved in the retention of stem cells in the bone marrow. Therefore, blocking CXCR4 may result in mobilization of hematopoietic progenitor and stem cells. We have found that the CXCR4 antagonist known as 4F-benzoyl-TN14003 (T-140) can induce mobilization of hematopoietic stem cells and progenitors within a few hours post-treatment in a dose-dependent manner. Furthermore, although T-140 can also increase the number of white blood cells (WBC) in blood, including monocytes, B cells, and T cells, it had no effect on mobilizing natural killer cells. T-140 was found to efficiently synergize with granulocyte colony-stimulating factor (G-CSF) in its ability to mobilize WBC and progenitors, as well as to induce a 660-fold increase in the number of erythroblasts in peripheral blood. Comparison between the CXCR4 antagonists T-140 and AMD3100 showed that T-140 with or without G-CSF was significantly more potent in its ability to mobilize hematopoietic stem cells and progenitors into blood. These results demonstrate that different CXCR4 antagonists may have different therapeutic potentials.

Laughter is not always funny: breath-holding spells in familial dysautonomia.

Familial dysautonomia (FD) is a genetic disease characterized by primary autonomic dysfunction including parasympathetic hypersensitivity. Breath-holding spells (BHS) are believed to be caused by autonomic dysregulation mediated via the vagus nerve and increased in patients with a family history of BHS. Details and understanding of its pathophysiology are lacking. In this retrospective study of patients with FD, the incidence of BHS was higher at 53.3%, compared with previous studies in normal children. Laughter as a precipitating factor for BHS has not been previously reported in FD and occurred in 10% of patients in this study. Lower lung volumes, chronic lung disease, chronic CO2 retention, and inadequate autonomic compensation occur in those with FD leading to a higher incidence and severity of BHS when crying or laughing. Thus, FD may be a good model for understanding manifestations of the autonomic nervous system dysfunction and contribute to our knowledge of BHS mechanisms.

The role of biomechanical shoe orthoses in tibial stress fracture prevention.

BACKGROUND: Biomechanical orthoses have been shown to lower stress fracture incidence in infantry recruits. However, these results may not be applicable to running athletes. HYPOTHESIS: Training in either running shoes or military boots with custom biomechanical shoe orthoses lessens tibial bone strains and strain rates during walking and running. STUDY DESIGN: Randomized controlled laboratory study. METHODS: In vivo strain measurements were made in nine subjects to determine whether the use of biomechanical orthoses lowers tibial strains during both walking and running and whether such lowering depends on the type of shoe worn. Measurements were made during treadmill walking at 5 km/hr and then during serial 2-km treadmill runs at 13 km/hr with running shoes, with and without the orthoses, and during serial 1-km runs with army boots, with and without the orthoses. RESULTS: When soft or semirigid biomechanical orthoses were worn with boots, the tibial peak-to-peak strains were significantly lowered. Soft orthoses also significantly lowered the tension and compression strain rates when worn with boots. During running, semirigid orthoses significantly increased the compression and tension strain rates when worn with boots. CONCLUSIONS: The use of biomechanical orthoses may be warranted for tibial stress fracture prevention during training in which boots are worn and that mostly involves walking, but they are not warranted for activities that primarily involve running or are performed in running shoes.

CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth.

OBJECTIVE: The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the progression and dissemination of a diverse number of solid and hematological malignancies. Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways that regulate cell chemotaxis, adhesion, survival, proliferation, and apoptosis. MATERIALS AND METHODS: Here, we demonstrate that the CXCR4 antagonist, 4F-benzoyl-TN14003 (BKT140), but not AMD3100, exhibits a CXCR4-dependent preferential cytotoxicity toward malignant cells of hematopoietic origin. BKT140 significantly and preferentially stimulated multiple myeloma apoptotic cell death. BKT140 treatment induced morphological changes, phosphatidylserine externalization, decreased mitochondrial membrane potential, caspase-3 activation, sub-G1 arrest, and DNA double-stranded breaks. RESULTS: In vivo, subcutaneous injections of BKT140 significantly reduced, in a dose-dependent manner, the growth of human acute myeloid leukemia and multiple myeloma xenografts. Tumors from animals treated with BKT140 were smaller in size and weights, had larger necrotic areas and high apoptotic scores. CONCLUSIONS: Taken together, these results suggest a potential therapeutic use for BKT140 in multiple myeloma and leukemia patients.

Interaction between CXCR4 and CCL20 pathways regulates tumor growth.

The chemokine receptor CXCR4 and its ligand CXCL12 is overexpressed in the majority of tumors and is critically involved in the development and metastasis of these tumors. CXCR4 is expressed in malignant tumor cells whereas its ligand SDF-1 (CXCL12) is expressed mainly by cancer associated fibroblasts (CAF). Similarly to CXCR4, the chemokine CCL20 is overexpressed in variety of tumors; however its role and regulation in tumors is not fully clear. Here, we show that the chemokine receptor CXCR4 stimulates the production of the chemokine CCL20 and that CCL20 stimulates the proliferation and adhesion to collagen of various tumor cells. Furthermore, overexpression of CCL20 in tumor cells promotes growth and adhesion in vitro and increased tumor growth and invasiveness in vivo. Moreover, neutralizing antibodies to CCL20 inhibit the in vivo growth of tumors that either overexpress CXCR4 or CCL20 or naturally express CCL20. These results reveal a role for CCL20 in CXCR4-dependent and -independent tumor growth and suggest a therapeutic potential for CCL20 and CCR6 antagonists in the treatment of CXCR4- and CCL20-dependent malignancies.