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Neuromodulation : Journal of the... Oct 2023Falls in extrapyramidal disorders, particularly Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP), are key milestones... (Review)
Review
BACKGROUND
Falls in extrapyramidal disorders, particularly Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP), are key milestones affecting patients' quality of life, incurring increased morbidity/mortality and high healthcare costs. Unfortunately, gait and balance in parkinsonisms respond poorly to currently available treatments. A serendipitous observation of improved gait and balance in patients with PD receiving spinal cord stimulation (SCS) for back pain kindled an interest in using SCS to treat gait disorders in parkinsonisms.
OBJECTIVES
We reviewed preclinical and clinical studies of SCS to treat gait dysfunction in parkinsonisms, covering its putative mechanisms and efficacies.
MATERIALS AND METHODS
Preclinical studies in animal models of PD and clinical studies in patients with PD, PSP, and MSA who received SCS for gait disorders were included. The main outcome assessed was clinical improvement in gait, together with outcome measures used and possible mechanism of actions.
RESULTS
We identified 500 references, and 45 met the selection criteria and have been included in this study for analysis. Despite positive results in animal models, the outcomes in human studies are inconsistent.
CONCLUSIONS
The lack of blind and statistically powered studies, the heterogeneity in patient selection and study outcomes, and the poor understanding of the underlying mechanisms of action of SCS are some of the limiting factors in the field. Addressing these limitations will allow us to draw more reliable conclusions on the effects of SCS on gait and balance in extrapyramidal disorders.
Topics: Humans; Parkinson Disease; Spinal Cord Stimulation; Quality of Life; Parkinsonian Disorders; Multiple System Atrophy; Gait
PubMed: 37452800
DOI: 10.1016/j.neurom.2023.06.003 -
CNS Neuroscience & Therapeutics Jul 2023Serpin is a superfamily of serine proteinase inhibitors. They have anticoagulative activities and immunoregulatory effects. The family has been widely studied in stroke... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Serpin is a superfamily of serine proteinase inhibitors. They have anticoagulative activities and immunoregulatory effects. The family has been widely studied in stroke patients and animal stroke models. However, results from clinical and preclinical studies are controversial. The systematic review and meta-analysis aimed to determine whether serpin activities are affected by stroke and whether members of the serpin family could be used in stroke treatment.
METHODS
Literature was systematically searched in six databases until September 5, 2022. In the included studies, 47 clinical studies (8276 subjects) reported concentrations of serpin proteins in stroke patients and healthy controls. In total, 41 preclinical studies (742 animals) reported neurological outcomes in animal models with serpin treatment and vehicle.
RESULTS
Meta-analysis of clinical studies showed that both ischemic (IS) and hemorrhagic stroke patients had higher thrombin-antithrombin complex (TAT) levels and lower antithrombin (AT) levels which were persistent in the acute and subacute phase of IS. Meta-analysis of preclinical studies reported the efficacy of serpins in treating stroke. C1-INH and FUT175 reduced brain infarct size and improved sensorimotor and motor behavior in a dose- and time-dependent manner in the MCAO models.
CONCLUSIONS
Our study confirmed the important roles serpin family proteins played in the onset, progression, and treatment of stroke. Among serpins, AT and TAT may be used as blood biomarkers in the early diagnosis of stroke. C1-INH and FUT175 could be potential medications for IS.
Topics: Animals; Serpins; Biomarkers; Models, Animal; Stroke
PubMed: 37017398
DOI: 10.1111/cns.14205 -
Journal of Cachexia, Sarcopenia and... Feb 2024Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed... (Meta-Analysis)
Meta-Analysis Review
Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed sarcopenia. The extent of skeletal muscle wasting in clinical and preclinical CKD populations is unclear. We evaluated skeletal muscle atrophy in preclinical and clinical models of CKD, with multiple sub-analyses for muscle mass assessment methods, CKD severity, sex and across the different preclinical models of CKD. We performed a systematic literature review of clinical and preclinical studies that measured muscle mass/size using the following databases: Ovid Medline, Embase and Scopus. A random effects meta-analysis was utilized to determine standard mean difference (SMD; Hedges' g) between healthy and CKD. Heterogeneity was evaluated using the I statistic. Preclinical study quality was assessed via the Systematic Review Centre for Laboratory Animal Experimentation and clinical studies quality was assessed via the Newcastle-Ottawa Scale. This study was registered in PROSPERO (CRD42020180737) prior to initiation of the search. A total of 111 studies were included in this analysis using the following subgroups: 106 studies in the primary CKD analysis, 18 studies that accounted for diabetes and 7 kidney transplant studies. Significant atrophy was demonstrated in 78% of the preclinical studies and 49% of the clinical studies. The random effects model demonstrated a medium overall SMD (SMD = 0.58, 95% CI = 0.52-0.64) when combining clinical and preclinical studies, a medium SMD for the clinical population (SMD = 0.48, 95% CI = 0.42-0.55; all stages) and a large SMD for preclinical CKD (SMD = 0.95, 95% CI = 0.76-1.14). Further sub-analyses were performed based upon assessment methods, disease status and animal model. Muscle atrophy was reported in 49% of the clinical studies, paired with small mean differences. Preclinical studies reported significant atrophy in 78% of studies, with large mean differences. Across multiple clinical sub-analyses such as severity of CKD, dialysis modality and diabetes, a medium mean difference was found. Sub-analyses in both clinical and preclinical studies found a large mean difference for males and medium for females suggesting sex-specific implications. Muscle atrophy differences varied based upon assessment method for clinical and preclinical studies. Limitations in study design prevented conclusions to be made about the extent of muscle loss with disease progression, or the impact of dialysis. Future work would benefit from the use of standardized measurement methods and consistent clinical staging to improve our understanding of atrophy changes in CKD progression, and analysis of biological sex differences.
Topics: Humans; Female; Male; Renal Insufficiency, Chronic; Muscular Atrophy; Renal Dialysis; Muscle, Skeletal; Diabetes Mellitus
PubMed: 38062879
DOI: 10.1002/jcsm.13400 -
BMJ Open Science 2022Systematic review and meta-analysis are a gift to the modern researcher, delivering a crystallised understanding of the existing research data in any given space. This...
Systematic review and meta-analysis are a gift to the modern researcher, delivering a crystallised understanding of the existing research data in any given space. This can include whether candidate drugs are likely to work or not and which are better than others, whether our models of disease have predictive value and how this might be improved and also how these all interact with disease pathophysiology. Grappling with the literature needed for such analyses is becoming increasingly difficult as the number of publications grows. However, narrowing the focus of a review to reduce workload runs the risk of diminishing the generalisability of conclusions drawn from such increasingly specific analyses. Moreover, at the same time as we gain greater insight into our topic, we also discover more about the flaws that undermine much scientific research. Systematic review and meta-analysis have also shown that the quality of much preclinical research is inadequate. Systematic review has helped reveal the extent of selection bias, performance bias, detection bias, attrition bias and low statistical power, raising questions about the validity of many preclinical research studies. This is perhaps the greatest virtue of systematic review and meta-analysis, the knowledge generated ultimately helps shed light on the limitations of existing research practice, and in doing so, helps bring reform and rigour to research across the sciences. In this commentary, we explore the lessons that we have identified through the lens of preclinical systematic review and meta-analysis.
PubMed: 35360370
DOI: 10.1136/bmjos-2021-100219 -
Frontiers in Psychiatry 2023The endocannabinoid (eCB) system disruption has been suggested to underpin the development of psychosis, fueling the search for novel, better-tolerated antipsychotic...
INTRODUCTION
The endocannabinoid (eCB) system disruption has been suggested to underpin the development of psychosis, fueling the search for novel, better-tolerated antipsychotic agents that target the eCB system. Among these, palmitoylethanolamide (PEA), an N-acylethanolamine (AE) with neuroprotective, anti-inflammatory, and analgesic properties, has drawn attention for its antipsychotic potential.
METHODS
This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant systematic review aimed at reappraising all clinical and preclinical studies investigating the biobehavioral role of PEA in psychosis.
RESULTS
Overall, 13 studies were eligible for data extraction (11 human, 2 animal). Observational studies investigating PEA tone in psychosis patients converged on the evidence for increased PEA plasma (6 human) and central nervous system (CNS; 1 human) levels, as a potential early compensatory response to illness and its severity, that seems to be lost in the longer-term (CNS; 1 human), opening to the possibility of exogenously supplementing it to sustain control of the disorder. Consistently, PEA oral supplementation reduced negative psychotic and manic symptoms among psychosis patients, with no serious adverse events (3 human). No PEA changes emerged in either preclinical psychosis model (2 animal) studied.
DISCUSSION
Evidence supports PEA signaling as a potential psychosis biomarker, also indicating a therapeutic role of its supplementation in the disorder.
SYSTEMATIC REVIEW REGISTRATION
https://doi.org/10.17605/OSF.IO/AFMTK.
PubMed: 37533892
DOI: 10.3389/fpsyt.2023.1231710 -
International Journal of Environmental... May 2021Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped... (Review)
Review
Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped behaviors. Although its genetic basis is unquestionable, the involvement of environmental factors such as exposure to pesticides has also been proposed. Despite the systematic analyses of this relationship in humans, there are no specific reviews including both human and preclinical models. The present systematic review summarizes, analyzes, and discusses recent advances in preclinical and epidemiological studies. We included 45 human and 16 preclinical studies. These studies focused on Organophosphates (OP), Organochlorine (OC), Pyrethroid (PT), Neonicotinoid (NN), Carbamate (CM), and mixed exposures. Preclinical studies, where the OP Chlorpyrifos (CPF) compound is the one most studied, pointed to an association between gestational exposure and increased ASD-like behaviors, although the data are inconclusive with regard to other ages or pesticides. Studies in humans focused on prenatal exposure to OP and OC agents, and report cognitive and behavioral alterations related to ASD symptomatology. The results of both suggest that gestational exposure to certain OP agents could be linked to the clinical signs of ASD. Future experimental studies should focus on extending the analysis of ASD-like behaviors in preclinical models and include exposure patterns similar to those observed in human studies.
Topics: Autism Spectrum Disorder; Chlorpyrifos; Female; Humans; Pesticides; Pregnancy; Prenatal Exposure Delayed Effects; Pyrethrins
PubMed: 34068255
DOI: 10.3390/ijerph18105190 -
Frontiers in Bioengineering and... 2021Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has... (Review)
Review
Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has been proposed as a possible approach to improve or augment bone healing with the potential to provide true functional regeneration. While large numbers of studies have been performed or in small animal models that support the use of gene therapy for bone repair, these systems do not recapitulate several key features of a critical or complex fracture environment. Larger animal models are therefore a key step on the path to clinical translation of the technology. Herein, the current state of orthopedic gene therapy research in preclinical large animal models was investigated based on performed large animal studies. A summary and an outlook regarding current clinical studies in this sector are provided. It was found that the results found in the current research literature were generally positive but highly methodologically inconsistent, rendering a comparison difficult. Additionally, factors vital for translation have not been thoroughly addressed in these model systems, and the risk of bias was high in all reviewed publications. These limitations directly impact clinical translation of gene therapeutic approaches due to lack of comparability, inability to demonstrate non-inferiority or equivalence compared with current clinical standards, and lack of safety data. This review therefore aims to provide a current overview of ongoing preclinical and clinical work, potential bottlenecks in preclinical studies and for translation, and recommendations to overcome these to enable future deployment of this promising technology to the clinical setting.
PubMed: 33816447
DOI: 10.3389/fbioe.2021.626315 -
Animals : An Open Access Journal From... May 2021Glucosamine and chondroitin sulfate have been proposed due to their physiological and functional benefits in the management of osteoarthritis in companion animals.... (Review)
Review
Glucosamine and Chondroitin Sulfate: Is There Any Scientific Evidence for Their Effectiveness as Disease-Modifying Drugs in Knee Osteoarthritis Preclinical Studies?-A Systematic Review from 2000 to 2021.
Glucosamine and chondroitin sulfate have been proposed due to their physiological and functional benefits in the management of osteoarthritis in companion animals. However, the scientific evidence for their use is still controversial. The purpose of this review was to critically elucidate the efficacy of these nutraceutical therapies in delaying the progression of osteoarthritis, evaluating their impact on the synovial knee joint tissues and biochemical markers in preclinical studies by systematically reviewing the last two decades of peer-reviewed publications on experimental osteoarthritis. Three databases (PubMed, Scopus and, Web of Science) were screened for eligible studies. Twenty-two articles were included in the review. Preclinical studies showed a great heterogeneity among the experimental designs and their outcomes. Generally, the evaluated nutraceuticals, alone or in combination, did not seem to prevent the subchondral bone changes, the synovial inflammation or the osteophyte formation. However, further experimental studies may be needed to evaluate their effect at those levels. Regarding the cartilage status and biomarkers, positive responses were identified in approximately half of the evaluated articles. Furthermore, beneficial effects were associated with the pre-emptive administrations, higher doses and, multimodality approaches with some combined therapies. However, additional studies in the long term and with good quality and systematic design are required.
PubMed: 34072407
DOI: 10.3390/ani11061608 -
Clinical Oral Investigations Dec 2023To assess whether in animals or patients with ≥ 1 tooth extracted, hyaluronic acid (HyA) application results in superior healing and/or improved complication... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To assess whether in animals or patients with ≥ 1 tooth extracted, hyaluronic acid (HyA) application results in superior healing and/or improved complication management compared to any other treatment or no treatment.
MATERIALS AND METHODS
Three databases were searched until April 2022. The most relevant eligibility criteria were (1) local application of HyA as adjunct to tooth extraction or as treatment of alveolar osteitis, and (2) reporting of clinical, radiographic, histological, or patient-reported data. New bone formation and/or quality were considered main outcome parameters in preclinical studies, while pain, swelling, and trismus were defined as main outcome parameters in clinical studies.
RESULTS
Five preclinical and 22 clinical studies (1062 patients at final evaluation) were included. In preclinical trials, HyA was applied into the extraction socket. Although a positive effect of HyA was seen in all individual studies on bone formation, this effect was not confirmed by meta-analysis. In clinical studies, HyA was applied into the extraction socket or used as spray or mouthwash. HyA application after non-surgical extraction of normally erupted teeth may have a positive effect on soft tissue healing. Based on meta-analyses, HyA application after surgical removal of lower third molars (LM3) resulted in significant reduction in pain perception 7 days postoperatively compared to either no additional wound manipulation or the application of a placebo/carrier. Early post-operative pain, trismus, and extent of swelling were unaffected.
CONCLUSIONS
HyA application may have a positive effect in pain reduction after LM3 removal, but not after extraction of normally erupted teeth.
CLINICAL RELEVANCE
HyA application may have a positive effect in pain reduction after surgical LM3 removal, but it does not seem to have any impact on other complications or after extraction of normally erupted teeth. Furthermore, it seems not to reduce post-extraction alveolar ridge modeling, even though preclinical studies show enhanced bone formation.
Topics: Humans; Animals; Tooth Socket; Hyaluronic Acid; Trismus; Dry Socket; Tooth Extraction; Molar, Third; Pain
PubMed: 37963982
DOI: 10.1007/s00784-023-05227-4 -
Brain Circulation 2022Ischemic stroke is a disease with worldwide economic and social negative effects. It is a serious disease with high disability and mortality. Ionic imbalance,... (Review)
Review
Ischemic stroke is a disease with worldwide economic and social negative effects. It is a serious disease with high disability and mortality. Ionic imbalance, excitotoxicity, oxidative stress, and inflammation are induced during and after ischemic stroke. Cellular dysfunction, apoptosis, and necrosis are activated directly or indirectly mechanisms. The studies about neuroprotection in neurodegenerative diseases have increased in recent years. Data about the mechanisms of progressive molecular improvement in the brain tissue are increasing in acute ischemic stroke. Based on these data, preclinical and clinical studies on new neuroprotective treatments are being designed. An effective neuroprotective strategy can prolong the indication period of recanalization treatments in the acute stage of ischemic stroke. In addition, it can reduce neuronal necrosis and protect the brain against ischemia-related reperfusion injury. The current review has evaluated the recent clinical and experimental studies. The molecular mechanism of each of the neuroprotective strategies is also summarized. This review may help develop future strategies for combination treatment to protect the cerebral tissue from ischemia-reperfusion injury.
PubMed: 37181847
DOI: 10.4103/bc.bc_52_22