Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.
- MeSH
- Induced Pluripotent Stem Cells metabolism MeSH
- Humans MeSH
- Mutation, Missense * MeSH
- Mutation MeSH
- Vesicular Transport Proteins * genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
INTRODUCTION: Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B. METHODS: Whole-exome/genome sequencing, multi-site recruitment, genotype-phenotype correlations, and DNA methylation episignature analysis were performed. RESULTS: We report four individuals from two families harboring the variant c.7693C > G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C > T, p.Arg2565Cys variant was identified. The observed phenotypic spectrum ranged from childhood-onset dystonia (N = 2) over unspecific intellectual disability syndromes (N = 2) to undiagnosed behavioral symptoms in adulthood (N = 1). Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the effect on methylation was less pronounced than in carriers of loss-of-function KMT2B variants. CONCLUSIONS: We established the existence of a KMT2B missense-mutation hotspot associated with varying degrees of disease severity and expression, providing information for patient counseling and elucidation of pathomechanisms.
- MeSH
- Child MeSH
- Adult MeSH
- Dystonic Disorders * genetics MeSH
- Dystonia genetics MeSH
- Histone-Lysine N-Methyltransferase * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation, Missense MeSH
- Adolescent MeSH
- Young Adult MeSH
- Pedigree * MeSH
- Exome Sequencing MeSH
- Developmental Disabilities genetics MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Úvod: Magnetická rezonance (MR) je používána v oblasti proximálního femuru k diagnostice okultních či inkompletních zlomenin krčku femuru a trochanterického segmentu více jak 20 let. Spolehlivost této metody byla opakovaně prokázána řadou studií vč. jejích výhod proti CT. MR tak pomohla racionalizovat léčbu okultních a inkompletních trochanterických zlomenin. Metoda: Do studie bylo zařazeno celkem 13 pacientů vyšetřených MR pro suspektní okultní či inkompletní zlomeninu trochanterického masivu během první 24 hod po úrazu. Vždy se jednalo o první poranění kyčelního kloubu, druhý kyčelní kloub byl intaktní. Výsledky: Frontální skeny prokázaly v oblasti linea intertrochanterica (přední kortikalis) výraznou lomnou linii, která probíhají od velkého trochanteru mediodistálně do mediální kortikalis femuru. Sklon lomné linie se však v předozadním směru měnil a těsně před zadní kortikalis byl téměř vertikální. Sagitální skeny zobrazily lomnou linii začínající ve velkém trochanteru, pokračující mediálně a oddělující zadní kortikalis od trochanterického segmentu. Závěr: Analýza MR nálezů prokázala, že primární lomná linie u pertrochanterických zlomenin vzniká v oblasti velkého trochanteru, odkud se šíří současně distálně, mediálně a anteriorně k přední kortikalis v oblasti linea intertrochanterica a k trochanter minor. Velký trochanter tak představuje locus minoris resistentiae a je vždy rozlomen na více fragmentů, než je patrné na RTG snímku.
Background and study aims: Magnetic resonance imaging (MRI) has been used for more than 20 years in the region of the proximal femur to diagnose occult, or incomplete, fractures of the femoral neck and the trochanteric segment. MRI has also potential to contribute to the understanding of the pathogenesis and pathoanatomy of trochanteric fractures. Methods: The group including 13 patients was examined by MRI for a suspected, or incomplete, fracture of the trochanteric segment within 24 hours post-injury. In all cases, this was the first injury to the hip joint, with the other hip joint remaining intact. Results: The coronal scans showed a marked fracture line which, in the region of the intertrochanteric line, extended from the base of the greater trochanter (GT) medially and distally and involved the medial cortex. This inclination, however, was gradually changing posteriorwards and close before the posterior cortex. The fracture line was passing vertically along the lateral trochanteric wall as far as the level of the lesser trochanter (LT). Then the fracture line changed its course and ran horizontally to the cortex of the LT. Sagittal scans showed clearly the primary fracture line originating in the greater trochanter, extending medially and starting to separate the posterior cortex. Conclusion: Analysis of MRI findings has documented that the primary fracture line in pertrochanteric fractures originates in the GT and extends distally, medially and anteriorly towards the anterior cortex, the intertrochanteric line and the LT. Thus, the GT presents a rather vulnerable site and is always broken into more fragments than shown by a radiograph.
Idiopathic pulmonary fibrosis (IPF) is a severe and currently incurable disease that is associated with irreversible fibrotic remodeling of the lung parenchyma. Pathological remodeling of the lung leads to damage of the alveolo-capillary barrier. There is a reduction in the diffusing capacity of the lungs for respiratory gases. Later, changes in the mechanical properties of lung tissue occur - their compliance decreases and respiratory work increases. Impaired respiratory gases exchange with restrictive ventilatory failure lead to tissue hypoxia and muscle weakness. Progressive respiratory insufficiency develops. The triggers of fibrotic remodeling of the lung are currently unknown, as are the pathomechanisms that keep this process active. IPF can only be slowed pharmacologically, not reversed. It is therefore very important to start its treatment as soon as possible. Early detection of IPF patients requires a multidisciplinary approach. Diagnosis, treatment initiation, and monitoring in specialized centers offer the best chance of slowing disease progression, enhancing quality of life, and extending patient survival. In addition to antifibrotic therapy, good lifestyle management, maintenance of physical fitness and treatment of associated chronic diseases such as diabetes and cardiac comorbidities are important. Lung transplantation is an option for some patients with IPF. This is a challenging treatment modality, requiring close collaboration with transplant centers and expert selection of suitable candidates, influenced, among other things, by the availability of suitable donor lungs. Our article aims to provide current information about IPF, focusing on its functional consequences and clinical manifestation. We discuss the molecular and cellular mechanisms potentially involved in IPF development, as well as the morphological changes observed in lung biopsies and high-resolution computed tomography (HRCT) images. Finally, we summarize the existing treatment options. Key words: Idiopathic pulmonary fibrosis, Lung biopsy, HRCT, Antifibrotic therapy, Lung transplantation.
- MeSH
- Idiopathic Pulmonary Fibrosis * therapy diagnosis physiopathology pathology MeSH
- Humans MeSH
- Lung pathology physiopathology MeSH
- Lung Transplantation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Unilaterálna paréza hrtana môže viesť k narušeniu hlasu, poruche prehĺtania a k poruche dýchania. Patomechanizmom poruchy prehĺtania je zníženie senzitivity supraglotických štruktúr, narušenie ochrannej funkcie hrtana a oslabenie svalstva horného pažerákového zvierača. Predmetom kazuistiky je 85-ročný pacient, u ktorého sa po gastrofibroskopickom vyšetrení rozvinul klinický obraz unilaterálnej parézy hrtana s ťažkými dysfagickými príznakmi vedúcimi k vzniku aspiračnej pneumónie. Pacient bol v dlhodobej starostlivosti dysfagiologického tímu, ktorý realizoval diagnostiku a manažoval reštitúciu prehĺtania. Kazuistika opisuje patomechanizmus poruchy prehĺtania pri unilaterálnej paréze hrtana, jej možné príčiny vzniku (iatrogénna alebo postinfekčná príčina) a priebeh terapie dysfágie s využitím kompenzačných a reštitučných postupov a silového tréningu výdychového svalstva pri obnovovaní perorálneho príjmu
Unilateral laryngeal paresis can lead to dysphonia as well as respiratory and swallowing deficits. The pathomechanism of swallowing dysfunction in unilateral laryngeal paresis is decreased sensitivity of supraglottic structures, impaired protective function of reflexive cough and weakening of the upper oesophageal sphincter muscles. The subject of this case report is an 85-year-old man with unilateral laryngeal paresis, developed after gastrofibroscopy, with signs of severe oropharyngeal dysphagia leading to aspiration pneumonia. The patient was managed by a dysphagiology team leading the diagnostic and therapeutic process. This case study describes the pathomechanism of deglutition disorder in unilateral laryngeal paresis, its possible causes (iatrogenic or postinfectious) and the therapeutic process utilising compensatory and restitution techniques and expiratory muscle strength training in restoring peroral intake.
- MeSH
- Humans MeSH
- Vocal Cord Paralysis * complications MeSH
- Deglutition Disorders * etiology MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Case Reports MeSH
Diabetes mellitus is known to produce various cell-damaging events and thereby underlie heart dysfunction and remodeling. However, very little is known about its inflammation-associated pathomechanisms due to necrosis-like cell death. For this purpose, we aimed to investigate signaling pathways of necroptosis and pyroptosis, known to produce plasma membrane rupture with the resultant promotion of inflammation. One-year old Zucker diabetic fatty (ZDF) rats did not exhibit significant heart dysfunction as revealed by echocardiographic measurement. On the other hand, there was a decrease in heart rate due to diabetes. Immunoblotting analysis showed that the left ventricles of ZDF rats overexpress neither the main necroptotic proteins including receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase-like pseudokinase (MLKL), nor the pyroptotic regulators including NLR family pyrin domain containing 3 protein (NLRP3), caspase-1, interleukin-1 beta (IL-1beta and the N-terminal gasdermin D (GSDMD-N). On the other hand, the increased activation of the RIP3 kinase due to phosphorylation was found in such hearts. In summary, we showed for the first time that the activation of cardiac RIP3 is upregulated due to disturbances in glucose metabolism which, however, did not proceed to necrosis-like cell death. These data can indicate that the activated RIP3 might also underlie other pleiotropic, non-necroptotic signaling pathways under basal conditions.
- MeSH
- Apoptosis MeSH
- Diabetes Mellitus, Type 2 * MeSH
- Rats MeSH
- Necrosis MeSH
- Rats, Zucker MeSH
- Protein Kinases metabolism MeSH
- Pyroptosis * MeSH
- Signal Transduction MeSH
- Inflammation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Ulcerative colitis (UC) is presently considered a multifactorial pathology, which may lead to persistent inflammatory action of the gastrointestinal tract (GIT) because of an improperly managed immunological reactivity to the intestinal microbiota found in the GIT. The immune response to common commensal microbes plays an essential role in intestinal inflammation related to UC synbiotics, and it is an important element in the optimal therapy of UC. Therefore, synbiotics, i.e., a mixture of prebiotics and probiotics, may help control the diseased state. Synbiotics alleviate the inflammation of the colon by lowering the reactive oxygen species (ROS) and improving the level of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD). Prebiotic supplementation is not a common practice at the moment, despite numerous research findings proving that the benefits of both probiotics and prebiotics encourage their continued existence and positioning in the GIT, with positive effects on human health by managing the inflammatory response. However, the fact that there have been fewer studies on the treatment of UC with different probiotics coupled with selected prebiotics, i.e., synbiotics, and the outcomes of these studies have been very favorable. This evidence-based study explores the possible role of ROS, SOD, and synbiotics in managing the UC. The proposed review also focuses on the role of alteration of gut microbiota, antioxidant defense in the gastrointestinal tract, and the management of UC. Thus, the current article emphasizes oxidative stress signaling in the GI tract, oxidative stress-based pathomechanisms in UC patients, and UC therapies inhibiting oxidative stress' effects.
- Publication type
- Journal Article MeSH
- Review MeSH
Rinovírusy paria medzi najčastejšie sa vyskytujúcich pôvodcov respiračných ochorení rozličného charakteru od „bežného prechladnutia“ až po klinicky závažné bronchiolitídy či pneumónie u dojčiat a batoliat. Problematika vzťahu rinovírusových infekcií u predisponovaných jedincov, najmä detí v dojčenskom a batolivom veku s následným rizikom rozvoja bronchiálnej astmy bola za posledné dve dekády predmetom mnohých klinických štúdií. Početné zložité a komplexné interakcie rinovírusov s epiteliálnymi bunkami a jednotlivými zložkami imunitného systému ešte nie sú dostatočne a podrobne ozrejmené. Niektoré špecifické patomechanizmy a ich následky, ktoré indukuje vstup a replikácia rinovírusov v bunkách respiračného epitelu, sú už známe. Z klinického pohľadu je vynakladaná čoraz väčšia snaha čo najexaktnejšie identifikovať vonkajšie a vnútorné faktory, ktoré v kontexte opakovaných rinovírusových infekcií predisponujú nositeľa k rekurentným vírusmi indukovaným bronchospazmom a rizikom nadobudnutia astmy. V prvej časti prehľadového príspevku sú rinovírusy analyzované z virologického a epidemiologického hľadiska s prihliadnutím na determinujúce vonkajšie faktory rinovírusových infekcií.
Rhinoviruses are one of the most common causative agents of respiratory diseases from common cold to clinically severe bronchiolitis and pneumonia in infants and toddlers. The relationship of rhinovirus infections in predisposed individuals, especially infants and toddlers, with subsequent risk of bronchial asthma development has been the aim of many clinical studies over the last two decades. The multiple complex and involved interactions of rhinoviruses with epithelial cells and various elements of the immune system have not yet been sufficiently and extensively understood. Some specific pathomechanisms and their consequences induced by the entry and replication of rhinoviruses in respiratory epithelial cells are already known. From a clinical point of view, increasing effort is being devoted to identifying extrinsic and intrinsic factors that, in the context of recurrent rhinovirus infections, predispose the host to recurrent virus-induced bronchospasm and risk of asthma development. In this first part of the review, rhinoviruses are analysed from a virological and epidemiological point of view, with consideration of the determining external factors of rhinovirus infections.
- MeSH
- Asthma * epidemiology virology MeSH
- Child MeSH
- Humans MeSH
- Disease Susceptibility * microbiology MeSH
- Virus Replication physiology MeSH
- Rhinovirus * physiology classification MeSH
- Virulence MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Review MeSH
Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disorder with high prevalence among middle-aged women. Collagen-induced arthritis (CIA) is the most widely used animal model of RA, however, sex differences and long-term effects of CIA in mice are poorly described in the literature. Aim: Therefore, the present study aimed to analyze the long-term effects of CIA on the joints of middle-aged mice of both sexes and to describe potential sex differences. Materials and methods: CIA was induced in middle-aged DBA/1J mice by immunization with bovine type II collagen and complete Freund's adjuvant. Saline was administered to control mice. Arthritis score assessment, plethysmometry, and thermal imaging of the joints were performed weekly for 15 weeks. Locomotor activity, micro-computed tomography, joint histology and biochemical analyses were performed at the end of the experiment. Results: Our results indicate a similar prevalence of arthritis in both sexes of mice-67% (8/12) of females and 89% (8/9) males with an earlier onset in males (day 14 vs. day 35). After the arthritis scores peaked on day 56 for males and day 63 for females, they steadily declined until the end of the experiment on day 105. A similar dynamics was observed in paw volume and temperature analyzing different aspects of joint inflammation. Long-term consequences including higher proteinuria (by 116%), loss of bone density (by 33.5%) and joint damage in terms of synovial hyperplasia as well as bone and cartilage erosions were more severe in CIA males compared to CIA females. There were no significant differences in locomotor activity between CIA mice and CTRL mice of any sex. Conclusion: This is the first study to describe the long-term effects of the CIA model in terms of sex differences in DBA/1J mice. Our results indicate sex differences in the dynamics, but not in the extent of arthritis. An earlier onset of arthritis and more severe consequences on joints, bones and kidneys were found in males. The underlying immune pathomechanisms responsible for the limited duration of the arthritis symptoms and the opposite sex difference in comparison to RA patients require further investigation.
- Publication type
- Journal Article MeSH
Horúčka je častým javom na neurologických jednotkách intenzívnej starostlivosti. Etiologicky najčastejšie ide o infekčnú príčinu, v menšej miere prichádzajú následne do úvahy neinfekčné príčiny, ako trombembolizmus, medikamentózne navodený stav, postoperačné príčiny a v neposlednom rade centrálna neurogénna hypertermia. Ide o diagnózu per exclusionem, ktorá doteraz nemá štandardizované diagnostické kritériá ani liečbu. Rovnako tak nie je úplne objasnený ani patomechanizmus jej vzniku. Článok sa zaoberá prehľadom dostupných údajov o fyziológii termoregulácie, predostiera predpokladaný patofyziologický pôvod danej entity (s dôrazom na problematiku z pohľadu neurológa), zmieňuje sa o prejavoch a dôsledkoch ochorenia, napokon uvádza stručný prehľad možností liečby vrátane off‐label preparátov.
Fever is a common phenomenon within neurological intensive care units. Etiologically, it is most often an infectious cause, to a lesser extent, non-infectious causes come into consideration such as thromboembolism, medically induced condition, postoperative causes and, last but not least, central neurogenic hyperthermia. This is a diagnosis per exclusionem, which does not yet have standardized diagnostic criteria or treatment. Likewise, the pathomechanism of its formation is not fully clarified. The article deals with an overview of available data from the physiology of thermoregulation, lays out the presumed pathophysiological background of the given entity (with an emphasis on the issue from the neurologist's point of view), mentions the symptoms and consequences of the disease, and finally gives a brief overview of treatment options, including off-label preparations.
- MeSH
- Hyperthermia * diagnosis etiology drug therapy physiopathology therapy MeSH
- Hypothalamus physiology MeSH
- Humans MeSH
- Brain physiopathology MeSH
- Nervous System Diseases classification physiopathology MeSH
- Neurons physiology classification MeSH
- Risk Factors MeSH
- Body Temperature physiology MeSH
- Body Temperature Regulation physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Case Reports MeSH
- Review MeSH
