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Reumatologia 2016The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood.... (Review)
Review
The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood. Certain medications and environmental factors may have an influence on the occurrence of rheumatic diseases. Establishing a cause-effect relationship between a certain factor and disease induction is not always simple. It is important to administer the drug continuously or monitor exposure to a given factor in the period preceding the onset of symptoms. The lack of previously diagnosed autoimmune disease, or finally the lack of symptoms within a few weeks/months after discontinuation of the drug/cessation of exposure, is also important. The most frequently mentioned rheumatic diseases caused by drugs and environmental factors include systemic lupus erythematosus, scleroderma, systemic vasculitis, polymyositis, dermatomyositis, and Sjögren's syndrome. The objective of this study is to summarize current knowledge on rheumatic diseases induced by drugs and environmental factors.
PubMed: 27504022
DOI: 10.5114/reum.2016.61212 -
International Journal of Molecular... Sep 2021The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex,... (Review)
Review
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
Topics: Animals; Cilia; Ciliopathies; Hedgehog Proteins; Holoprosencephaly; Humans; Short Rib-Polydactyly Syndrome; Signal Transduction
PubMed: 34576017
DOI: 10.3390/ijms22189854 -
Proceedings of the National Academy of... Sep 2021Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic...
Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci ( and ) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies.
Topics: Animals; Bone and Bones; Ciliopathies; Craniosynostoses; Cytoskeletal Proteins; Disease Models, Animal; Ectodermal Dysplasia; Embryo, Nonmammalian; Musculoskeletal Abnormalities; Phenotype; Polycystic Kidney Diseases; Tubulin; Xenopus laevis
PubMed: 34548398
DOI: 10.1073/pnas.2106770118 -
Journal of Lipid Research Nov 2023Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding...
Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding PS synthase 1 (PSS1) in patients with a congenital disease called Lenz-Majewski syndrome (LMS). Patients with LMS show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1) have been shown to synthesize PS without control, but why the uncontrolled synthesis would lead to LMS is unknown. Here we investigated the effect of PSS1 on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1 did not affect the expression of OC-related genes but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1 showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1 did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. The introduction of a catalytically inactive mutation into PSS canceled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1. A gain-of-function mutant of PSS2 (PSS2 R97K) also impaired OC formation and caused changes in phospholipid composition similar to the changes caused by PSS1. Our results suggest that uncontrolled PS synthesis by PSS1 causes changes in the quantity or fatty acid composition of certain phospholipid classes, impairing OC formation and function, which might be a cause of osteosclerosis in patients with LMS.
Topics: Humans; Abnormalities, Multiple; Intellectual Disability; Osteoclasts; Phospholipids
PubMed: 37714410
DOI: 10.1016/j.jlr.2023.100443 -
Journal of Clinical Medicine Oct 2023Electrolyte disturbances related to sodium and potassium affect patients with mental disorders undergoing electroconvulsive therapy (ECT). The objective of this study... (Review)
Review
INTRODUCTION
Electrolyte disturbances related to sodium and potassium affect patients with mental disorders undergoing electroconvulsive therapy (ECT). The objective of this study was to systematically summarize the data regarding ECT and electrolyte disturbances related to sodium and potassium.
MATERIALS AND METHODS
A systematic literature review in accordance with PRISMA guidelines was conducted. Clinical studies of patients receiving ECT with electrolyte disturbances reported before or after treatment were included.
RESULTS
We identified nine case reports and two retrospective studies describing electrolyte abnormalities occurring before or after ECT. ECT was effective and safe in patients with hyponatremia and hypernatremia, including the elderly patient population. This treatment was also effective in treating psychiatric symptoms that may persist after ionic equalization. Electrolyte disturbances after ECT were rare. Reports have suggested that succinylcholine used as a muscle relaxant was the main cause of hyperkalemia after ECT.
CONCLUSIONS
Electrolyte control is a crucial aspect of guiding ECT therapy. In the context of sodium-related disorders, it is critical to control patient hydration as part of therapy. In addition, succinylcholine should not be used in patients with immobilization, such as catatonia or neuroleptic malignant syndrome. It is necessary to conduct further studies to clarify whether electrolyte concentration affects ECT parameters and clinical efficacy. In addition, it is necessary to assess the influence of various anesthetics on these conditions during ECT. The result of this review should be interpreted bearing in mind the small number of studies conducted to date and the low quality of the evidence they provide.
PubMed: 37892815
DOI: 10.3390/jcm12206677 -
American Journal of Medical Genetics.... Mar 2018The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular... (Review)
Review
The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz-Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.
Topics: Adult; Alleles; Child; Child, Preschool; Cutis Laxa; Exons; Facies; Female; Genetic Association Studies; Genotype; Humans; Hyperostosis; Male; Mutation; Nitrogenous Group Transferases; Phenotype; Radiography
PubMed: 29341480
DOI: 10.1002/ajmg.a.38604 -
European Journal of Human Genetics :... May 2015So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS)... (Review)
Review
So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with Meckel-Gruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients.
Topics: Abnormalities, Multiple; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Cerebellar Vermis; Cerebellum; DNA Mutational Analysis; Eye Abnormalities; Female; Genotype; High-Throughput Nucleotide Sequencing; Humans; Infant; Intracellular Signaling Peptides and Proteins; Kidney Diseases, Cystic; Magnetic Resonance Imaging; Male; Membrane Proteins; Mutation; Phenotype; Radiography; Retina; Tooth
PubMed: 25118024
DOI: 10.1038/ejhg.2014.160 -
Journal of Physiology and Pharmacology... Feb 2016The kynurenine pathway (KP) of L-tryptophan metabolism produces several neuroactive metabolites with an amino acid structure. These metabolites may play an important... (Review)
Review
The kynurenine pathway (KP) of L-tryptophan metabolism produces several neuroactive metabolites with an amino acid structure. These metabolites may play an important role in the pathophysiology of irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, AIDS-dementia complex, depression, epilepsy and the aging process. Modulation of the KP through inhibition or stimulation of enzyme synthesis and activity can be an alternative approach to traditional therapy. Furthermore, it may be responsible for the altered functioning of the enteric nervous system and the central nervous system. There is evidence that the KP is sensitive to changes in the concentration of many vitamins and minerals that play a crucial role as coenzymes and cofactors in the de novo synthesis of nicotinamide adenine dinucleotide coenzyme. A reduction in the availability of the active form of vitamin B6 (pyridoxal 5'-phosphate, PLP) is known to affect tryptophan hydroxylase, kynurenine aminotransferase and kynureninase (KYNU). Vitamin B2 deficiencies result in a reduction in the activity of the flavin adenine dinucleotide dependent enzyme, kynurenine 3-monooxygenase. Minerals are also responsible for the proper functioning of enzymes engaged in L-tryptophan metabolism. Mn(2+), Zn(2+), Co(2+) and Cu(2+) influence KYNU activity, and Mg(2+) regulates quinolinate phosphoribosyl transferase. Fe(2+) is responsible for the proper functioning of both indoleamine 2,3-dioxygenase and 3-hydroxy-anthranilic acid dioxygenase. Changes in the concentration of KP metabolites and in enzymatic activity have been found in many pathological states. Therefore, it is justifiable to regulate the concentration of certain kynurenines or enzymes in the KP which may provide a potential therapeutic target for the treatment of various health impairments. This review demonstrates the role of vitamin and mineral activity on the KP, which may have an effect on the proper functioning of the human organism. Surplus administration of vitamins did not elicit any beneficial effects on L-tryptophan metabolism. Whether a mineral surplus influences L-tryptophan metabolism is still not established. It seems that cofactor deficiencies influence the KP far more than surpluses.
Topics: Animals; Humans; Hydrolases; Kynurenine; Minerals; Signal Transduction; Transaminases; Tryptophan; Vitamins
PubMed: 27010891
DOI: No ID Found -
The American Journal of Pathology Feb 2022To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression...
To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.
Topics: Animals; COVID-19; Cricetinae; Disease Models, Animal; Female; Lung; Male; Mesocricetus; SARS-CoV-2
PubMed: 34767812
DOI: 10.1016/j.ajpath.2021.10.009 -
F1000Research 2019Lenz-Majewski syndrome (LMS) is characterized by osteosclerosis and hyperostosis of skull, vertebrae and tubular bones as well as craniofacial, dental, cutaneous, and...
Lenz-Majewski syndrome (LMS) is characterized by osteosclerosis and hyperostosis of skull, vertebrae and tubular bones as well as craniofacial, dental, cutaneous, and digit abnormalities. We previously found that LMS is caused by dominant missense mutations in the gene, which encodes phosphatidylserine synthase 1 (PSS1), an enzyme that catalyses the conversion of phosphatidylcholine to phosphatidylserine. The mutations causing LMS result in a gain-of-function, leading to increased enzyme activity and blocking end-product inhibition of PSS1. Here, we have used transpose-mediated transgenesis to attempt to stably express wild-type and mutant forms of human ubiquitously or specifically in chondrocytes, osteoblasts or osteoclasts in zebrafish. We report multiple genomic integration sites for each of 8 different transgenes. While we confirmed that the ubiquitously driven transgene constructs were functional in terms of driving gene expression following transient transfection in HeLa cells, and that all lines exhibited expression of a heart-specific cistron within the transgene, we failed to detect gene expression at either the RNA or protein levels in zebrafish. All wild-type and mutant transgenic lines of zebrafish exhibited mild scoliosis with variable incomplete penetrance which was never observed in non-transgenic animals. Collectively the data suggest that the transgenes are silenced, that animals with integrations that escape silencing are not viable, or that other technical factors prevent transgene expression. In conclusion, the incomplete penetrance of the phenotype and the lack of a matched transgenic control model precludes further meaningful investigations of these transgenic lines.
Topics: Animals; Animals, Genetically Modified; CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; Cell Lineage; HeLa Cells; Humans; Nitrogenous Group Transferases; Short Rib-Polydactyly Syndrome; Transgenes; Zebrafish
PubMed: 31231513
DOI: 10.12688/f1000research.17314.1