scholarly journals Skeletal Muscle in Cerebral Palsy: From Belly to Myofibril

2021 ◽  
Vol 12 ◽  
Author(s):  
Jason J. Howard ◽  
Walter Herzog
Keyword(s):  
Cerebral Palsy ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Clinical Work ◽  
Muscle Stiffness ◽  
Imaging Studies ◽  
Generating Capacity ◽  
Underlying Mechanisms ◽  
Muscle Homeostasis

This review will provide a comprehensive, up-to-date review of the current knowledge regarding the pathophysiology of muscle contractures in cerebral palsy. Although much has been known about the clinical manifestations of both dynamic and static muscle contractures, until recently, little was known about the underlying mechanisms for the development of such contractures. In particular, recent basic science and imaging studies have reported an upregulation of collagen content associated with muscle stiffness. Paradoxically, contractile elements such as myofibrils have been found to be highly elastic, possibly an adaptation to a muscle that is under significant in vivo tension. Sarcomeres have also been reported to be excessively long, likely responsible for the poor force generating capacity and underlying weakness seen in children with cerebral palsy (CP). Overall muscle volume and length have been found to be decreased in CP, likely secondary to abnormalities in sarcomerogenesis. Recent animal and clinical work has suggested that the use of botulinum toxin for spasticity management has been shown to increase muscle atrophy and fibrofatty content in the CP muscle. Given that the CP muscle is short and small already, this calls into question the use of such agents for spasticity management given the functional and histological cost of such interventions. Recent theories involving muscle homeostasis, epigenetic mechanisms, and inflammatory mediators of regulation have added to our emerging understanding of this complicated area.

scholarly journals Pan-American Lancehead Pit-Vipers: Coagulotoxic Venom Effects and Antivenom Neutralisation of Bothrops asper and B. atrox Geographical Variants

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 78
Author(s):  
Lachlan A. Bourke ◽  
Christina N. Zdenek ◽  
Edgar Neri-Castro ◽  
Melisa Bénard-Valle ◽  
Alejandro Alagón ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
In Vivo Studies ◽  
Factor X ◽  
Clotting Factors ◽  
Bothrops Asper ◽  
Species Specific

The toxin composition of snake venoms and, thus, their functional activity, can vary between and within species. Intraspecific venom variation across a species’ geographic range is a major concern for antivenom treatment of envenomations, particularly for countries like French Guiana that lack a locally produced antivenom. Bothrops asper and Bothrops atrox are the most medically significant species of snakes in Latin America, both producing a variety of clinical manifestations, including systemic bleeding. These pathophysiological actions are due to the activation by the venom of the blood clotting factors Factor X and prothrombin, thereby causing severe consumptive coagulopathy. Both species are extremely wide-ranging, and previous studies have shown their venoms to exhibit regional venom variation. In this study, we investigate the differential coagulotoxic effects on human plasma of six venoms (four B. asper and two B. atrox samples) from different geographic locations, spanning from Mexico to Peru. We assessed how the venom variation of these venom samples affects neutralisation by five regionally available antivenoms: Antivipmyn, Antivipmyn-Tri, PoliVal-ICP, Bothrofav, and Soro Antibotrópico (SAB). The results revealed both inter- and intraspecific variations in the clotting activity of the venoms. These variations in turn resulted in significant variation in antivenom efficacy against the coagulotoxic effects of these venoms. Due to variations in the venoms used in the antivenom production process, antivenoms differed in their species-specific or geographical neutralisation capacity. Some antivenoms (PoliVal-ICP, Bothrofav, and SAB) showed species-specific patterns of neutralisation, while another antivenom (Antivipmyn) showed geographic-specific patterns of neutralisation. This study adds to current knowledge of Bothrops venoms and also illustrates the importance of considering evolutionary biology when developing antivenoms. Therefore, these results have tangible, real-world implications by aiding evidence-based design of antivenoms for treatment of the envenomed patient. We stress that these in vitro studies must be backed by future in vivo studies and clinical trials before therapeutic guidelines are issued regarding specific antivenom use in a clinical setting.

scholarly journals Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 506
Author(s):  
Loris Zamai
Keyword(s):  
Chelating Agents ◽  
Ethylenediaminetetraacetic Acid ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Renin Angiotensin System ◽  
Experimental Models ◽  
Zinc Metalloprotease ◽  
Previous Hypothesis ◽  
Zinc Metalloproteases

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

scholarly journals The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1102
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Valeria Raia ◽  
Guido Kroemer ◽  
Maria Chiara Maiuri
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Predictive Biomarkers ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

scholarly journals Immunomodulatory Protein Hydrolysates and Their Application

Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 904 ◽  
Author(s):  
Mensiena Kiewiet ◽  
Marijke Faas ◽  
Paul de Vos
Keyword(s):  
Current Knowledge ◽  
Protein Hydrolysate ◽  
Protein Hydrolysates ◽  
Active Protein ◽  
Promising Application ◽  
Immunomodulatory Protein ◽  
Underlying Mechanisms ◽  
Number Of Individuals ◽  
Do So

Immunomodulatory protein hydrolysate consumption may delay or prevent western immune-related diseases. In order to purposively develop protein hydrolysates with an optimal and reproducible immunomodulatory effect, knowledge is needed on which components in protein hydrolysates are responsible for the immune effects. Important advances have been made on this aspect. Also, knowledge on mechanisms underlying the immune modulating effects is indispensable. In this review, we discuss the most promising application possibilities for immunomodulatory protein hydrolysates. In order to do so, an overview is provided on reported in vivo immune effects of protein hydrolysates in both local intestinal and systemic organs, and the current insights in the underlying mechanisms of these effects. Furthermore, we discuss current knowledge and physicochemical approaches to identify the immune active protein sequence(s). We conclude that multiple hydrolysate compositions show specific immune effects. This knowledge can improve the efficacy of existing hydrolysate-containing products such as sports nutrition, clinical nutrition, and infant formula. We also provide arguments for why immunomodulatory protein hydrolysates could be applied to manage the immune response in the increasing number of individuals with a higher risk of immune dysfunction due to, for example, increasing age or stress.

scholarly journals Parkinson's disease and mitophagy: an emerging role for LRRK2

2021 ◽  
Author(s):  
Francois Singh ◽  
Ian G. Ganley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Muscle Stiffness ◽  
Substantia Nigra Pars Compacta ◽  
Common Mutation ◽  
Common Denominator

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

scholarly journals Neutrophil Reverse Migration Becomes Transparent with Zebrafish

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Taylor W. Starnes ◽  
Anna Huttenlocher
Keyword(s):  
Immune Responses ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
The Novel ◽  
Imaging Studies ◽  
Advanced Imaging ◽  
Precise Control ◽  
Reverse Migration ◽  
A Site

The precise control of neutrophil-mediated inflammation is critical for both host defense and the prevention of immunopathology. In vivo imaging studies in zebrafish, and more recently in mice, have made the novel observation that neutrophils leave a site of inflammation through a process called neutrophil reverse migration. The application of advanced imaging techniques to the genetically tractable, optically transparent zebrafish larvae was critical for these advances. Still, the mechanisms underlying neutrophil reverse migration and its effects on the resolution or priming of immune responses remain unclear. Here, we review the current knowledge of neutrophil reverse migration, its potential roles in host immunity, and the live imaging tools that make zebrafish a valuable model for increasing our knowledge of neutrophil behavior in vivo.

Radiotracers for Amyloid Imaging in Neurodegenerative Disease: State-of-the-Art and Novel Concepts

2018 ◽  
Vol 25 (26) ◽  
pp. 3131-3140 ◽  
Author(s):  
Angelina Cistaro ◽  
Pierpaolo Alongi ◽  
Federico Caobelli ◽  
Laura Cassalia
Keyword(s):  
Pet Imaging ◽  
State Of The Art ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Cerebral Atrophy ◽  
Positron Emission ◽  
Amyloid Deposits ◽  
Imaging Probes ◽  
The Common

The pathological accumulation of different peptides is the common base of many neurodegenerative processes, such as Alzheimer’s disease (AD). AD is characterized by amyloid deposits which may cause alterations in neurotransmission, activation of inflammatory mechanisms, neuronal death and cerebral atrophy. Diagnosis in vivo is challenging as the criteria rely mainly on clinical manifestations, which become evident only in a late stage of the disease. While AD can currently be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. In this regard, the detection of cerebral amyloid plaques with positron emission tomography (PET) is likely to improve diagnosis and allow for a prompt start of an effective therapy. Many PET imaging probes for AD-specific pathological modifications have been developed and proved effective in detecting amyloid deposits in vivo. We here review the current knowledge on PET imaging in the detection of amyloid deposits and their application in the diagnosis of AD.

scholarly journals Glutamate and dopamine in schizophrenia: An update for the 21st century

2015 ◽  
Vol 29 (2) ◽  
pp. 97-115 ◽  
Author(s):  
Oliver Howes ◽  
Rob McCutcheon ◽  
James Stone
Keyword(s):  
Current Knowledge ◽  
Indirect Evidence ◽  
Risk Groups ◽  
Clinical High Risk ◽  
Imaging Studies ◽  
Future Directions ◽  
Pharmacological Studies ◽  
Post Mortem Findings ◽  
New Evidence

The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.

Ion Channel Remodelling in Atrial Fibrillation

2011 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
Author(s):  
Niels Voigt ◽  
Dobromir Dobrev ◽  
◽  
Keyword(s):  
Atrial Fibrillation ◽  
Ion Channel ◽  
Antiarrhythmic Drugs ◽  
Current Knowledge ◽  
Bleeding Complications ◽  
Large Size ◽  
Cardiovascular Morbidity And Mortality ◽  
Number Of Patients ◽  
Life Threatening ◽  
Underlying Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication. Present drugs used for the therapy of AF (antiarrhythmics and anticoagulants) have major limitations, including incomplete efficacy, risks of life-threatening proarrhythmic events and bleeding complications. Non-pharmacological ablation procedures are efficient and apparently safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. These limitations largely result from limited knowledge about the underlying mechanisms of AF and there is a hope that a better understanding of the molecular basis of AF may lead to the discovery of safer and more effective therapeutic targets. This article reviews the current knowledge about AF-related ion-channel remodelling and discusses how these alterations might affect the efficacy of antiarrhythmic drugs.

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies

2016 ◽  
Vol 55 (01) ◽  
pp. 21-28 ◽  
Author(s):  
C. Antke ◽  
H. Hautzel ◽  
H.-W. Mueller ◽  
S. Nikolaus
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Sites ◽  
Human Subjects ◽  
Synaptic Cleft ◽  
Presynaptic Terminal ◽  
Imaging Studies ◽  
Psychiatric Conditions ◽  
Da Release

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

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