scholarly journals Cavernous angiomas: deconstructing a neurosurgical disease

2019 ◽  
Vol 131 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Issam A. Awad ◽  
Sean P. Polster
Keyword(s):  
Clinical Care ◽  
Cavernous Angioma ◽  
Mendelian Inheritance ◽  
Vascular Lesion ◽  
Developmental Venous Anomaly ◽  
Loss Of Function ◽  
Immune Mediated ◽  
Familial Form ◽  
Disease Behavior ◽  
Key Aspects

Cavernous angioma (CA) is also known as cavernoma, cavernous hemangioma, and cerebral cavernous malformation (CCM) (National Library of Medicine Medical Subject heading unique ID D006392). In its sporadic form, CA occurs as a solitary hemorrhagic vascular lesion or as clustered lesions associated with a developmental venous anomaly. In its autosomal dominant familial form (Online Mendelian Inheritance in Man #116860), CA is caused by a heterozygous germline loss-of-function mutation in one of three genes—CCM1/KRIT1, CCM2/Malcavernin, and CCM3/PDCD10—causing multifocal lesions throughout the brain and spinal cord.In this paper, the authors review the cardinal features of CA’s disease pathology and clinical radiological features. They summarize key aspects of CA’s natural history and broad elements of evidence-based management guidelines, including surgery. The authors also discuss evidence of similar genetic defects in sporadic and familial lesions, consequences of CCM gene loss in different tissues at various stages of development, and implications regarding the pathobiology of CAs.The concept of CA with symptomatic hemorrhage (CASH) is presented as well as its relevance to clinical care and research in the field. Pathobiological mechanisms related to CA include inflammation and immune-mediated processes, angiogenesis and vascular permeability, microbiome driven factors, and lesional anticoagulant domains. These mechanisms have motivated the development of imaging and plasma biomarkers of relevant disease behavior and promising therapeutic targets.The spectrum of discoveries about CA and their implications endorse CA as a paradigm for deconstructing a neurosurgical disease.

scholarly journals A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 643
Author(s):  
Thibaud Kuca ◽  
Brandy M. Marron ◽  
Joana G. P. Jacinto ◽  
Julia M. Paris ◽  
Christian Gerspach ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Homozygosity Mapping ◽  
Mendelian Inheritance ◽  
Large Animal Model ◽  
Large Animal ◽  
Loss Of Function ◽  
Protein Coding ◽  
Positional Candidate ◽  
Genome Wide ◽  
A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

Approach to clinical care in humanitarian contexts

2019 ◽  
pp. 267-274
Author(s):  
Raghu Venugopal
Keyword(s):  
Clinical Care ◽  
Humanitarian Settings ◽  
Key Aspects

This chapter on the approach to clinical care in humanitarian contexts outlines the fundamentals of providing care in humanitarian settings, including overall guidance on clinical care, key aspects of patient triage, and approaches for paediatrics. It providers important overarching considerations for readers, recognizing the realities and challenges in providing care in the field.

Heparin-induced Thrombocytopenia – Pathogenesis and Treatment

1999 ◽  
Vol 82 (S 01) ◽  
pp. 148-156 ◽  
Author(s):  
A. Greinacher
Keyword(s):  
Randomized Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Thromboembolic Complications ◽  
Recombinant Hirudin ◽  
Heparin Induced Thrombocytopenia ◽  
Treatment Regimens ◽  
Immune Mediated ◽  
Therapeutic Concepts ◽  
Key Aspects

SummaryHeparin-induced thrombocytopenia (HIT) is now recognized as the most frequent immune-mediated adverse drug reaction. During the last decade, fundamental aspects of the pathogenesis of HIT have been resolved. The understanding of some the mechanisms underlying the development of new, paradox thromboembolic complications in HIT led to the concept that thrombin generation plays a key-role in clinically manifest HIT. Consequently new therapeutic concepts imply the use of drugs with either indirect of direct anti-thrombin activity such as donaparoid-sodium and the recombinant hirudin lepirudin. During the last years results of first prospective studies assessing various treatment regimens in HIT became available. Although data of randomized trials are still missing some treatment recommendations can already be drawn from these studies. This review summarizes key aspects of the pathogenesis of HIT and provides an overview of current treatment strategies.

scholarly journals Recent Advances in Understanding the Genetic Architecture of Autism

2020 ◽  
Vol 21 (1) ◽  
pp. 289-304 ◽  
Author(s):  
Caroline M. Dias ◽  
Christopher A. Walsh
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Recent Advances ◽  
Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus

2011 ◽  
Vol 43 (12) ◽  
pp. 1186-1188 ◽  
Author(s):  
Sulaiman M Al-Mayouf ◽  
Asma Sunker ◽  
Reem Abdwani ◽  
Safiya Al Abrawi ◽  
Fathiya Almurshedi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Loss Of Function ◽  
Systemic Lupus ◽  
Familial Form

scholarly journals Exome sequencing identifies novel AD-associated genes.

2020 ◽  
Author(s):  
Henne Holstege ◽  
Marc Hulsman ◽  
Camille Charbonnier ◽  
Benjamin Grenier-Boley ◽  
Olivier Quenez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Variants ◽  
Rare Variants ◽  
Mendelian Inheritance ◽  
Loss Of Function ◽  
App Processing ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

scholarly journals Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

2019 ◽  
Vol 19 (1) ◽  
pp. 131-153 ◽  
Author(s):  
H. Mitoma ◽  
A. Buffo ◽  
F. Gelfo ◽  
X. Guell ◽  
E. Fucà ◽  
...  
Keyword(s):  
Environmental Enrichment ◽  
Pathological Process ◽  
Current Evidence ◽  
Loss Of Function ◽  
Therapeutic Implications ◽  
Ocular Movements ◽  
Immune Mediated ◽  
Wide Range ◽  
Cerebellar Diseases ◽  
Cerebellar Ataxias

AbstractCerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

Duration of treatment (DOT) with targeted therapies (TT) or immunotherapy (IO) in PBRM1 mutated metastatic renal cell carcinoma (mRCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 622-622 ◽  
Author(s):  
Nazli Dizman ◽  
Paulo Gustavo Bergerot ◽  
Cristiane Decat Bergerot ◽  
Joann Hsu ◽  
Sumanta K. Pal
Keyword(s):  
Systemic Treatment ◽  
Clinical Care ◽  
Current Evidence ◽  
Loss Of Function ◽  
Background Current ◽  
Duration Of Treatment ◽  
Treatment Groups ◽  
Routine Clinical Care ◽  
Literature Highlight ◽  
Redwood City

622 Background: Current evidence indicates improved outcome with IO in mRCC patients (pts) with PBRM1 loss of function mutations (Miao et al., Nature, 2018). We seek to demonstrate an association between PBRM1 mutation and treatment duration with IO and TT in a retrospective cohort. Methods: Consecutive patients with mRCC who had genomic profiling in the course of routine clinical care were identified from an institutional database. GP assessments included testing either tissue or blood with 1 of the 3 CLIA certified commercial panels (Foundation Medicine, Cambridge, MA; Ashion Analytics, Phoenix, AZ; Guardant Health, Redwood City, CA). Information regarding systemic treatment was collected. Median DOT with first targeted therapy and first immunotherapy received was calculated for each patient. DOT was compared across treatment groups in PBRM1+ and PBRM1- patients. Only PBRM1 mutations with functional significance documented in COSMIC were considered. Results: Among 104 pts (72:32 M:F) with mRCC, 82 pts received TT, 35 pts received IO, and 45 pts received both. GP was performed in blood and tissue in 84 and 63 pts, respective, and 25 pts (24%) with PBRM1 mutations were identified. Among PBRM1+ pts, median DOT was 8.8 months (95% CI, 7.6-9.6) mos and 2.3 mos (95% CI, 1.7 – 2.8) mos with TT and IO, respectively (p=0.049). Among PBRM1- pts, median DOT was 5.5 mos and 2.8 mos with TT and IO, respectively (p=0.544). There were 11 PBRM1+ pts and 34 PBRM- pts who received both TT and IO. The ratio of DOT on IO to DOT on TT (DOTIO/TT) was higher in PBRM1- pts than PBRM1+ pts (0.76 versus 0.37 respectively, p=0.014). Conclusions: We failed to replicate the results from Miao et al, suggesting clinical benefit with IO in PBRM1 mutated patients. PBRM1 mutation did appear to predict benefit with TT versus IO. Although limited by sample size, the contrasting results of the current study with literature highlight the importance of clinical validation in a large and prospective setting.

Abstract 14950: SLCO1B1 Genotype is Associated With Atorvastatin Discontinuation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Deepak Voora ◽  
Jordan Baye ◽  
Adam D Mcdermaid ◽  
Smitha N Gowda ◽  
Larson A Eric ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Testing ◽  
Smoking Status ◽  
Clinical Care ◽  
Musculoskeletal Symptoms ◽  
Loss Of Function ◽  
Diagnosis Codes ◽  
Increased Risk ◽  
Patients At Risk ◽  
Concomitant Medications

Introduction: Atorvastatin is commonly prescribed to prevent cardiovascular disease; however, long-term adherence can be eroded by statin associated musculoskeletal symptoms (SAMS). Genetic variants in SLCO1B1 are associated with SAMS in patients using simvastatin; the association of these variants with adherence or SAMS has been less well characterized for atorvastatin. Methods: We tested the association between a loss of function genetic variant in SLCO1B1 and atorvastatin discontinuation in a large multi-specialty group practice. Using the electronic medical record (EMR) at Sanford Health, we defined a retrospective cohort of 8453 patients who were tested for SLCO1B1*5 (rs4149056, Val174Ala) through routine clinical care. Patients were included if they had received an atorvastatin prescription prior to genetic testing and had valid SLCO1B1 results. Patients were classified as discontinued (or not) based on their active medication list at the time of genetic testing. Clinical characteristics including demographics, diagnosis codes, smoking status, concomitant medications, and laboratory values for renal function and all creatine kinase (CK) values prior to testing, were extracted from the EMR. A Kruskal-Wallis test was used to compare longitudinal CK values vs. discontinuation. Logistic regression was used to test the relationship between SLCO1B1*5 and atorvastatin discontinuation for any reason. Results: There were 1752 patients available for analysis (mean age 64 years, 44% female, 2% non-Caucasian, 89% primary prevention indication). 1025 (58%) discontinued atorvastatin prior to SLCO1B1 testing. The number of SLCO1B1*5 alleles was associated with atorvastatin discontinuation (odds ratio per allele = 1.22, 95% confidence interval = 1.004 - 1.47, p = 0.04). Among the 495 patients with available CK levels, atorvastatin discontinuation was associated with higher mean CK levels than those who continued (Kruskal-Wallis test, p = 0.02). Conclusions: Atorvastatin discontinuation is common in real world patients at risk for cardiovascular disease. Carriers of SLCO1B1*5 are at increased risk for premature atorvastatin discontinuation - an effect which may reflect an excess risk of statin myopathy.

The Role Of tet2 DNA Methylcytosine Dioxygenase In Zebrafish Early Hematopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1204-1204
Author(s):  
Huan-Chau Lin ◽  
Ken-Hong Lim ◽  
Yi-Hao Chiang ◽  
Wei-Ting Wang ◽  
Ching-Sung Lin ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Mendelian Inheritance ◽  
Stem Cell Markers ◽  
Loss Of Function ◽  
Transcription Activator ◽  
Hematopoietic Stem ◽  
Mature Adult ◽  
Knock Out ◽  
Knock Down

Abstract Loss-of-function mutations in Ten-Eleven-Translocation 2 (TET2) gene have been identified in various human myeloid and lymphoid malignancies. Recently, the TET gene family (TET1, TET2, and TET3) was found to function as DNA methylcytosine dioxygenase that is able to oxidize 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). In Tet2-deficient mouse models, Tet2 has been shown to play an important role in regulating self-renewal and differentiation of hematopoietic stem cells. These Tet2-deficient mice would gradually develop a chronic myeloid neoplasm resembling human chronic myelomonocytic leukemia suggesting that TET2 may function as a tumor suppressor. In the present study, we investigated the role of tet2 in zebrafish early hematopoiesis. During zebrafish early development, the expression of tet1, tet2, and tet3 by qRT-PCR can be detected mainly after the segmentation stage (26-somite), with fluctuated expression levels thereafter. Whole-mount in situ hybridization revealed that tet2 expression was strong over aorta-gonad-mesonephros region at 48 hours post-fertilization (hpf). Morpholino oligonucleotide (MO) knock-down of tet2 increased the expression of tet1, tet3, dnmt3aa, gata-1, alpha-Hb and fli1a (48 hpf) as well as rag2 and lck (4 days post-fertilization), and the expression of spi1b and mpo decreased (48 hpf). The expression of primitive hematopoietic stem cell markers scl and lmo2, as well as dnmt3ab, beta-Hb, l-plastin, and rag1 were unaffected. The levels of 5-mC and 5-hmC measured by ELISA were also decreased after MO knock-down of tet2. The number of gata-1 expressing red blood cells increased after tet2 MO knock-down as evaluated by flow-cytometry indicating that tet2 deficiency increased erythropoiesis. These preliminary results suggest that tet2 might play a role in the epigenetic regulation of zebrafish early hematopoiesis including erythropoiesis. Recently, transcription activator-like effector nuclease (TALEN) has been shown to generate targeted genomic editing in zebrafish. To validate our observation, we therefore utilized customized TALENs pair to generate tet2 knock-out zebrafish animal model. We designed a pair of TALENs targeting first exon of tet2 and our tet2 TALENs were able to generate insertion and/or deletion in targeted region of tet2 exon 1 in 25% to 44% zebrafish embryos. We obtained a total of fifteen different tet2 mutation genotypes F1 fish, and seven of them were predicted to cause early termination of transcription. The in-cross of these F1 genotypes matched the Mendelian inheritance. The tet2-/- knock-out F2 zebrafish is not embryonic lethal and can grow to sexually mature adult fish. The detailed analysis of tet2-/- knock-out zebrafish early hematopoiesis will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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