Developmental abnormalities of mid and hindbrain: A study of 23 Egyptian patients

Introduction: With the advent of neuroimaging modalities specifically, magnetic resonance imaging (MRI), recognition of developmental defects of posterior fossa has greatly improved. The Aim: Is to delineate the clinical, cytogenetics and radiological features of patients with mid-hindbrain anomalies. Patient and Methods: Twenty-three patients with mid-hind brain malformations were included in this study. Complete clinical evaluation, cytogenetic analysis and neuroradiological study were done for each patient. Patients\' sex ratio was (M: F/ 0.9:1) and the mean age was 2.17 years. Parental consanguinity was 86.9 % and positive family history was recorded in 7 families. Based on clinico-radiological findings, patients were categorized as Joubert syndrome and related cerebellar disorders (34.8%), pontocerebellar hypoplasia (26.1%), lissencephaly cerebellar hypoplasia (13%), isolated cobblestone lissencephaly with normal muscle and eye (8.7%), isolated vermian hypoplasia (13%) and retrocerebellar cyst (4.4%). Results: Cytogenetic analysis revealed abnormalities in 3 patients (13%); pericentric inversion of chromosome 8 in a patient with lissencephaly cerebellar hypoplasia, del 5p14.3-pter delineating Cri du chat syndrome and associated with vermian hypoplasia and del 18q21.1-qter in a patient with retrocerebellar cyst due to paternal balanced translocation t (4;18). FISH for specific locus and whole chromosomal painting were used to document the assigned aberrations. Although most of the cerebellar malformations are of Mendelian inheritance, this study emphasizes the importance of chromosomal analysis for patients with posterior fossa anomalies. With more researches describing clinico-radiological characterization of hind brain dysgenesis will allow better understanding of these disorders, further delineation of relevant syndromes and new genes identification. Keywords: Cerebellar, hindbrain, joubert syndrome, cobblestone lissencephalypontocerebellar hypoplasia, cri du chat syndrome- del 18q21.1-qterEgyptian Journal of Medical Human Genetics Vol. 9 (2) 2008: pp. 215-23

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Severe lung damage in COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways and genes present across the spectrum of histopathological damage in COVID-19 lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from areas of interest within well preserved post-mortem lung samples from three patients. Despite substantial inter-patient heterogeneity we discovered evidence for a common immune cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines including CXCL9, CXCL10 and CXCL11 which are known to promote the recruitment of CXCR3+ immune cells. The tumour necrosis factor (TNF) superfamily members BAFF ( TNFSF13B ) and TRAIL ( TNFSF10 ) were found to be consistently upregulated in the areas with severe tissue damage. We used published spatial and single cell SARS-CoV-2 datasets to confirm our findings in the lung tissue from additional cohorts of COVID-19 patients. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies. One Sentence Summary Spatial analysis identifies IFNγ response signatures as focal to severe alveolar damage in COVID-19 pneumonitis

Phosphodiesterase Inhibition Increases CREB Phosphorylation and Restores Orientation Selectivity in a Model of Fetal Alcohol Spectrum Disorders

Background: Fetal alcohol spectrum disorders (FASD) are the leading cause of mental retardation in the western world and children with FASD present altered somatosensory, auditory and visual processing. There is growing evidence that some of these sensory processing problems may be related to altered cortical maps caused by impaired developmental neuronal plasticity. Methodology/Principal Findings: Here we show that the primary visual cortex of ferrets exposed to alcohol during the third trimester equivalent of human gestation have decreased CREB phosphorylation and poor orientation selectivity revealed by western blotting, optical imaging of intrinsic signals and single-unit extracellular recording techniques. Treating animals several days after the period of alcohol exposure with a phosphodiesterase type 1 inhibitor (Vinpocetine) increased CREB phosphorylation and restored orientation selectivity columns and neuronal orientation tuning. Conclusions/Significance: These findings suggest that CREB function is important for the maturation of orientation selectivity and that plasticity enhancement by vinpocetine may play a role in the treatment of sensory problems in FASD

Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer

Abstract: Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for ‘selfish’ traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby ‘selfish’ positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells

Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.

Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.fals

Structural predictors of response to intra-articular steroid injection in symptomatic knee osteoarthritis

© 2017 The Author(s). Background: The aim was to examine if structural factors could affect response to intra-articular steroid injections (IASI) in knee osteoarthritis (OA). Method: Persons with painful knee OA participated in an open-label trial of IASI where radiographic joint space narrowing (JSN) and Kellgren-Lawrence (KL) grade, whole-organ magnetic resonance imaging (MRI) scores (WORMS) and quantitative assessment of synovial tissue volume (STV) were assessed on baseline images. Participants completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) and a question about knee pain with a visual analogue scale for pain during nominated activity (VAS NA ), and Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) criteria were used to assess responder status within 2 weeks (short term) and 6 months (longer term). Regression models were used to examine predictors of short and longer term response to IASI. Results: Subjects (n = 207) attended and had IASI. Information on responder status was available on 199 participants. Of these, 188 subjects, mean age 63.2 years (standard deviation (SD) 10.3), 97 (51.6%) female, had x-rays and 120 had MRI scans available. Based on the OMERACT-OARSI criteria, 146 (73.4%) participants responded to therapy and 40 (20.1%) were longer term responders. A few factors were associated with a reduced KOOS-pain and VAS NA response though none were associated with OMERACT-OARSI responder status in the short term. Higher MRI meniscal damage (odds ratio (OR) = 0.74; 95% CI 0.55 to 0.98), increasing KL maximal grade (OR = 0.43; 95% CI 0.23 to 0.82) and joint space narrowing (JSN) maximal score (OR = 0.60; 95% CI 0.36 to 0.99) were each associated with a lower odds of longer term responder status. Baseline synovitis was not associated with treatment response. The predicted probability of longer term response decreased from 38% to 12% as baseline maximal JSN increased from grade 0 to 3. Conclusion: Compared with those who have mild structural damage, persons with more severe knee damage on either MRI or x-ray are less likely to respond to knee IASI. Trial registration: ISRCTN.com, ISRCTN07329370. Registered 21 May 2010. Retrospectively registere