ABSTRACT
PURPOSE: This study aims to perform a network meta-analysis of hamstring graft preparation techniques to enhance anterior cruciate ligament (ACL) reconstruction guidelines and inform clinical decision-making in patients with primary ACL rupture. METHODS: A review of the literature, from 1 January 1990, to 31 August 2023, was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, focusing on the clinical outcomes of various hamstring graft preparation techniques. Forty-six studies (over 4800 knees) were analysed. Eight graft compositions: doubled hamstring (ST/G)-1978 grafts, doubled hamstring with augmentation (ST/G+A)-586 grafts, tripled semitendinosus (3ST)-124 grafts, quadrupled semitendinosus (4ST)-1273 grafts, five-strand tripled semitendinosus + doubled gracilis (3ST/2GR-839 grafts, six-strand tripled semitendinosus + tripled gracilis (3ST/3GR)-335 grafts, seven-strand quadrupled semitendinosus + tripled gracilis (4ST/3GR)-11 grafts and ≥eight strands-24 grafts were compared, considering graft sizes, laxity, muscle strength, range-of-motion, patient-reported outcome measures (PROMs), return to sport (RTS) and adverse events. RESULTS: The 4ST grafts fared better than the ST/G grafts in the International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS) Sport, KOOS Q and RTS (mean difference [MD], -1.69; p = 0.0159; MD, -1.55; p = 0.0325; MD, -1.93; p = 0.001; odds ratio: 3.13; p < 0.0001). The IKDC differed significantly between the 4ST and ST/G+A groups (MD, 1.88; p = 0.046). The ST/G+A resulted in the lowest knee laxity, surpassing the ST/G, 3ST and 4ST. The ST/G had the smallest diameter (ST/G vs. ST/G+A: MD, 1.26; 95% confidence interval [CI]: 0.67-1.86, p < 0.0001). Reduced failure rates were noted with the 3ST/2GR (3ST/2GR vs. ST/G: MD, 6.93; p = 0.009) and 3ST/3GR (3ST/3GR vs. ST/G: MD, 53.64; p = 0.006). CONCLUSION: The ideal hamstring graft for ACLR should be individualized. A 4ST graft is likely to yield good PROMs. For high stability and rapid RTS, adding augmentation to the graft is advisable. The ST/G is the thinnest graft possible. LEVEL OF EVIDENCE: Network meta-analysis of level I-III studies.
ABSTRACT
We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across in vivo mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (i.p.) administration, compound (R)-32, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED50 values of 73.9 mg/kg (MES test), 18.8 mg/kg (6 Hz, 32 mA test), and 26.5 mg/kg (6 Hz, 44 mA test). Furthermore, (R)-32 demonstrated efficacy in both the PTZ-induced kindling paradigm and the ivPTZ seizure threshold test. The expression of neurotrophic factors, such as mature brain-derived neurotrophic factor (mBDNF) and nerve growth factor (NGF), in the hippocampus and/or cortex of mice, and the levels of glutamate and GABA were normalized after PTZ-induced kindling by (R)-32. Importantly, besides antiseizure activity, (R)-32 demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (i.p.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and in vitro ADME-Tox data (i.e., high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, etc.) proved favorable drug-like properties of (R)-32. Thermal stability of (R)-32 shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The in vitro binding and functional assays indicated its multimodal mechanism of action. (R)-32, beyond TRPV1 antagonism, inhibited calcium and sodium currents at a concentration of 10 µM. Therefore, the data obtained in the current studies justify a more detailed preclinical development of (R)-32 for epilepsy and pain indications.
ABSTRACT
Epilepsy is a common brain disorder, characterized by spontaneous recurrent seizures, with associated neuropsychiatric and cognitive comorbidities and increased mortality. Although people at risk can often be identified, interventions to prevent the development of the disorder are not available. Moreover, in at least 30% of patients, epilepsy cannot be controlled by current antiseizure medications (ASMs). As a result of considerable progress in epilepsy genetics and the development of novel disease models, drug screening technologies and innovative therapeutic modalities over the past 10 years, more than 200 novel epilepsy therapies are currently in the preclinical or clinical pipeline, including many treatments that act by new mechanisms. Assisted by diagnostic and predictive biomarkers, the treatment of epilepsy is undergoing paradigm shifts from symptom-only ASMs to disease prevention, and from broad trial-and-error treatments for seizures in general to mechanism-based treatments for specific epilepsy syndromes. In this Review, we assess recent progress in ASM development and outline future directions for the development of new therapies for the treatment and prevention of epilepsy.
ABSTRACT
Identification of transient receptor potential cation channel, subfamily V member 1 (TRPV1), also known as capsaicin receptor, in 1997 was a milestone achievement in the research on temperature sensation and pain signalling. Very soon after it became evident that TRPV1 is implicated in a wide array of physiological processes in different peripheral tissues, as well as in the central nervous system, and thereby could be involved in the pathophysiology of numerous diseases. Increasing evidence suggests that modulation of TRPV1 may also affect seizure susceptibility and epilepsy. This channel is localized in brain regions associated with seizures and epilepsy, and its overexpression was found both in animal models of seizures and in brain samples from epileptic patients. Moreover, modulation of TRPV1 on non-neuronal cells (microglia, astrocytes, and/or peripheral immune cells) may have an impact on the neuroinflammatory processes that play a role in epilepsy and epileptogenesis. In this paper, we provide a comprehensive and critical overview of currently available data on TRPV1 as a possible molecular target for epilepsy management, trying to identify research gaps and future directions. Overall, several converging lines of evidence implicate TRPV1 channel as a potentially attractive target in epilepsy research but more studies are needed to exploit the possible role of TRPV1 in seizures/epilepsy and to evaluate the value of TRPV1 ligands as candidates for new antiseizure drugs.
ABSTRACT
The lake minnow Eupallasella percnurus is a small leuciscid fish. In Poland, this species has been in a continuous decline since the mid-20th century and is presently considered as a extremely endangered. According to Polish law, E. percnurus is a strictly protected species that requires active conservation measures. In Poland, one the most common and effective measure of active protection E. percnurus is initiation of new populations. For this purpose, in 2004-2012, juvenile individuals originating from aquaculture conditions were translocated to group of isolated water bodies not inhabited by this species. The juveniles were offspring of parental fish belonging to the same local population, which is extinct at present. Five of those attempts were successful. The aim of the present study was to assess the genetic variation in a group new populations and compare genetic variation indicators with 13 old populations that had existed for decades. The polymorphism of 13 microsatellite markers was investigated, significance of differences in the genetic variation indicators between the groups were tested using a one-way analysis of variance (ANOVA). The mean values of all summary statistics under study, i.e. observed heterozygosity, expected heterozygosity and the total number of alleles, were higher in the group of new populations compared to almost all old ones. A similar dependence was found for Garza-Williamson M values, where the mean for the group of new populations was higher than in almost all old populations. Our results indicate that all recently established E. percnurus populations have not yet experienced any extensive founder effects or bottlenecks. They have preserved a large part of the genetic variability typical of their maternal population, which might also have been relatively high. This feature of new populations, may give them a relatively high ability to adapt to changing environments in the future.
Subject(s)
Cyprinidae , Endangered Species , Genetic Variation , Microsatellite Repeats , Animals , Poland , Microsatellite Repeats/genetics , Cyprinidae/genetics , Lakes , Conservation of Natural Resources , Genetics, PopulationABSTRACT
In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the in vivo and in vitro assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds 26 and 28 displayed the following pharmacological values: ED50 = 64.3 mg/kg (MES), ED50 = 15.6 mg/kg (6 Hz, 32 mA), ED50 = 29.9 mg/kg (6 Hz, 44 mA), and ED50 = 34.9 mg/kg (MES), ED50 = 12.1 mg/kg (6 Hz, 32 mA), ED50 = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, 26 and 28 were effective in the ivPTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound 28 was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, 28 revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and in vitro ADME-Tox data proved favorable drug-like properties of 28. The patch-clamp recordings in rat cortical neurons showed that 28 at a concentration of 10 µM significantly inhibited fast sodium currents. Therefore, 28 seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.
Subject(s)
Analgesics , Anticonvulsants , Seizures , Animals , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/chemical synthesis , Analgesics/pharmacology , Seizures/drug therapy , Male , Rats , Mice , Disease Models, Animal , Rats, Wistar , Hippocampus/drug effects , Hippocampus/metabolism , Electroshock , Neurons/drug effects , Neurons/metabolismABSTRACT
This review provides insights at the molecular level into the current and old methods for treating meniscal injuries. Meniscal injuries have been found to have a substantial impact on the progression of osteoarthritis. In line with the "save the meniscus" approach, meniscectomy is considered a last-resort treatment. Nevertheless, it is important to note that mechanical repair alone may not achieve the complete restoration of the meniscus. A deep understanding of the healing pathways could lead to future improvements in meniscal healing. The inclusion of cytokines and chemokines has the potential to facilitate the process of tear repair or impede the inflammatory catabolic cascade. MicroRNA (miRNA) could serve as a potential biomarker for meniscal degeneration, and RNA injections might promote collagen and growth factor production. The critical aspect of the healing process is angiogenesis within the inner zone of the meniscus. The use of collagen scaffolds and the implantation of autologous meniscus fragments have been successfully integrated into clinical settings. These findings are encouraging and underscore the need for well-designed clinical trials to explore the most effective factors that can enhance the process of meniscal repair.
Subject(s)
Arthroplasty, Replacement, Knee , Molecular Biology , Cytokines , Embryo Implantation , CollagenABSTRACT
Introduction: The experiment was set to determine the effects of long-term (55-day) use of three commercial prebiotics including Saccharomyces cerevisiae-derived ß-glucans and one including inulin on juvenile vimba (Vimba vimba) reared intensively under controlled conditions. Material and Methods: Six-month-old fish were fed commercial feed (Control group, n = 90), or the same feed supplemented with 0.02% Leiber Beta-S (BS group, n = 90), 0.20% Biolex MB40 (MB group, n = 90), 0.30% CeFi (CE group, n = 90) or 1.00% inulin Orafti GR (IN group, n = 90) for 55 days. Results: In the BS group, the final growth parameters were significantly lower than in the Control group, while the feed conversion ratio was significantly higher. No significant differences were found between any other group and the Control group in the respective parameters. The respiratory burst activity of the head-kidney phagocytes was significantly lower in all fish groups fed the prebiotic-supplemented diets compared to the Control group. The proliferative response of the head-kidney lymphocytes stimulated by concanavalin A was lower in the BS group than in the Control group, while in other groups this response was not affected. No significant differences were found in histopathological analyses of the digestive tract, liver or pancreas. Conclusion: The long-term supplementation of fish diets with prebiotics can negatively influence the growth, feed conversion, nonspecific cellular resistance and proliferative activity of the T lymphocytes of vimba juveniles.
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Aim: To develop lipid nano-antiretrovirals (LNAs) for the treatment of HIV-infected macrophages. Materials & methods: LNAs were prepared with docosahexaenoic acid to facilitate brain penetration and surface-decorated with folate considering that infected macrophages often overexpress folate receptors. Results: Folate-decorated LNAs loading rilpivirine (RPV) were efficiently taken up by folate receptor-expressing cell types including activated macrophages. The intracellular Cmax of the RPV-LNAs in activated macrophages was 2.54-fold and the area under the curve was 3.4-fold versus free RPV, translating to comparable or higher (p < 0.01; RPV ≤6.5 ng/ml) activities against HIV infectivity and superior protection (p < 0.05) against HIV cytotoxicity. LNAs were also effective in monocyte-derived macrophages. Conclusion: These findings demonstrate the potential of LNAs for the treatment of infected macrophages, which are key players in HIV reservoirs.
HIV can infect and hide inside certain types of white blood cells that make up the immune system and help defend our body, such as macrophages. Because these infected cells tend to carry the virus to certain organs where antiviral drugs have a hard time reaching, the virus is able to avoid treatment from the drug. In this study, the authors developed very small devices known as nanocarriers to carry antiviral drugs. These nanocarriers were designed to seek out infected macrophages. The nanocarriers were successfully built with oils and lipids that are safe for patients and could easily deliver antiviral drugs to macrophages infected by HIV. Excellent anti-HIV effects were observed using these nanocarriers. In summary, the authors developed a promising device with the potential to fight HIV in a smart and safe manner.
Subject(s)
Anti-HIV Agents , HIV Infections , Humans , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Rilpivirine/therapeutic use , Anti-Retroviral Agents , Macrophages , Lipids/therapeutic use , Folic AcidABSTRACT
Objective: Translocator protein (TSPO) targeting positron emission tomography (PET) imaging radioligands have potential utility in epilepsy to assess the efficacy of novel therapeutics for targeting neuroinflammation. However, previous studies in healthy volunteers have indicated limited test-retest reliability of TSPO ligands. Here, we examine test-retest measures using TSPO PET imaging in subjects with epilepsy and healthy controls, to explore whether this biomarker can be used as an endpoint in clinical trials for epilepsy. Methods: Five subjects with epilepsy and confirmed mesial temporal lobe sclerosis (mean age 36 years, 3 men) were scanned twice-on average 8 weeks apart-using a second generation TSPO targeting radioligand, [11C]PBR28. We evaluated the test-retest reliability of the volume of distribution and derived hemispheric asymmetry index of [11C]PBR28 binding in these subjects and compared the results with 8 (mean age 45, 6 men) previously studied healthy volunteers. Results: The mean (± SD) of the volume of distribution (VT), of all subjects, in patients living with epilepsy for both test and retest scans on all regions of interest (ROI) is 4.49 ± 1.54 vs. 5.89 ± 1.23 in healthy volunteers. The bias between test and retest in an asymmetry index as a percentage was small (-1.5%), and reliability is demonstrated here with Bland-Altman Plots (test mean 1.062, retest mean 2.56). In subjects with epilepsy, VT of [11C]PBR28 is higher in the (ipsilateral) hippocampal region where sclerosis is present than in the contralateral region. Conclusion: When using TSPO PET in patients with epilepsy with hippocampal sclerosis (HS), an inter-hemispheric asymmetry index in the hippocampus is a measure with good test-retest reliability. We provide estimates of test-retest variability that may be useful for estimating power where group change in VT represents the clinical outcome.
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In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.4 × 1012, 1.4 × 1013 and 1.4 × 1014 genome copies/kg) resulted in broad and functional biodistribution of AAV9-EBT-001 to known tissue reservoirs of SIV. No off-target effects or abnormal pathology were observed, and animals returned to their normal body weight after receiving EBT-001. Importantly, the macaques that received the 2 highest doses of EBT-001 showed improved absolute lymphocyte counts as compared to antiretroviral-treated controls. Taken together, these results demonstrate safety, biodistribution, and in vivo proviral DNA editing following IV administration of EBT-001, supporting the further development of CRISPR-based gene editing as a potential therapeutic approach for HIV in humans.
ABSTRACT
Post-translational glycosylation of the HIV-1 envelope protein involving precursor glycan trimming by mannosyl oligosaccharide glucosidase (MOGS) is critically important for morphogenesis of virions and viral entry. Strategic editing of the MOGS gene in T lymphocytes and myeloid origin cells harboring latent proviral DNA results in the production of non-infectious particles upon treatment of cells with latency reversal agents. Controlled activation of CRISPR-MOGS by rebound HIV-1 mitigates production of infectious particles that exhibit poor ability of the virus to penetrate uninfected cells. Moreover, exclusive activation of CRISPR in cells infected with HIV-1 alleviates concern for broad off-target impact of MOGS gene ablation in uninfected cells. Combination CRISPR treatment of peripheral blood lymphocytes prepared from blood of people with HIV-1 (PWH) tailored for editing the MOGS gene (CRISPR-MOGS) and proviral HIV-1 DNA (CRISPR-HIV) revealed a cooperative impact of CRISPR treatment in inhibiting the production of infectious HIV-1 particles. Our design for genetic inactivation of MOGS by CRISPR exhibits no detectable off-target effects on host cells or any deleterious impact on cell survival and proliferation. Our findings offer the development of a new combined gene editing-based cure strategy for the diminution of HIV-1 spread after cessation of antiretroviral therapy (ART) and its elimination.
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Treatment of HIV-1ADA-infected CD34+ NSG-humanized mice with long-acting ester prodrugs of cabotegravir, lamivudine, and abacavir in combination with native rilpivirine was followed by dual CRISPR-Cas9 C-C chemokine receptor type five (CCR5) and HIV-1 proviral DNA gene editing. This led to sequential viral suppression, restoration of absolute human CD4+ T cell numbers, then elimination of replication-competent virus in 58% of infected mice. Dual CRISPR therapies enabled the excision of integrated proviral DNA in infected human cells contained within live infected animals. Highly sensitive nucleic acid nested and droplet digital PCR, RNAscope, and viral outgrowth assays affirmed viral elimination. HIV-1 was not detected in the blood, spleen, lung, kidney, liver, gut, bone marrow, and brain of virus-free animals. Progeny virus from adoptively transferred and CRISPR-treated virus-free mice was neither detected nor recovered. Residual HIV-1 DNA fragments were easily seen in untreated and viral-rebounded animals. No evidence of off-target toxicities was recorded in any of the treated animals. Importantly, the dual CRISPR therapy demonstrated statistically significant improvements in HIV-1 cure percentages compared to single treatments. Taken together, these observations underscore a pivotal role of combinatorial CRISPR gene editing in achieving the elimination of HIV-1 infection.
Subject(s)
HIV Infections , HIV Seropositivity , Mice , Animals , Humans , Anti-Retroviral Agents/therapeutic use , Gene Editing , Proviruses/genetics , Receptors, CCR5ABSTRACT
BACKGROUND: Hamstring tendon grafts are the most common choice for anterior cruciate ligament (ACL) reconstruction (ACLR). Previous studies have provided evidence that offers conflicting opinions concerning the most favorable graft choice. PURPOSE: To identify whether the use of a quadrupled semitendinosus tendon (ST) or doubled semitendinosus tendon and gracilis tendon (ST/G) graft provides comparable anterior tibial translation (ATT) with similar functional results and similar donor site morbidity. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This was a prospective, patient- and surgeon-blinded, randomized trial set in a busy orthopaedic and traumatology department at a university hospital. Between 2015 and 2017, a total of 162 patients with ACL lesions were randomized to undergo ACLR with either a quadrupled ST or doubled ST/G graft. The primary endpoint was ATT assessed with the KT-1000 arthrometer. Clinical outcomes were assessed using the patient-reported outcome measures (PROMs) of the visual analog scale (VAS), International Knee Documentation Committee (IKDC) subjective evaluation form, Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner activity scale, and Lysholm knee scoring scale. RESULTS: Preoperative demographic data, ATT, and PROM scores showed no significant differences. At 4.5 years, no significant differences were found between the ST and ST/G groups with respect to PROM scores and KT-1000 arthrometer, Lachman test, and pivot-shift test findings. Differences in functional results between groups were significant (muscle strength). Subgroup analysis revealed significantly increased ATT in female patients undergoing ACLR with a quadrupled ST graft during the 4.5-year observation period, as assessed by the KT-1000 arthrometer, as well as inferior KOOS, IKDC, Lysholm, and VAS scores. CONCLUSION: This study showed a significant increase in ATT as well as inferior results on PROMs during a 4.5-year observation period in female patients undergoing ACLR with a quadrupled ST graft. In male patients, the study provided evidence of the noninferiority of ACLR with an ST graft, with no influence on donor site morbidity. TRIAL REGISTRATION: clinicaltrials.gov: NCT03626883.
Subject(s)
Anterior Cruciate Ligament Reconstruction , Hamstring Muscles , Hamstring Tendons , Humans , Female , Male , Prospective Studies , Tendons , Double-Blind MethodABSTRACT
A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the time course of writhings after intraperitoneal injection of acetic acid in mice. The model was applied to investigate the antinociceptive effect of trazodone and gabapentin alone and in combination. Writhings time course was described by a transit compartment model with the delay due to the transit of the acetic acid being represented by a chain of intermediate compartments. In the drug-treated animals, the number of writhings decreases according to a k2 factor linking drug concentration and antinociceptive effect. Compounds' potency parameters were 10.9 and 0.0459 L/µmoles/min for trazodone and gabapentin, respectively, indicating a much higher in vivo potency of trazodone in the PD writhing test. The PK/PD parameters were used to simulate the expected writhing counts in mice at combined doses without efficacy alone, assuming pharmacological additivity. Simulation results indicated that, at low dose combinations, experimental data were mostly below the simulated writhings median, suggesting possible synergic effect. Such hypothesis was tested by adding the γ parameter in the PK/PD model to represent the deviation from the assumption of no-interaction, leading to a reduction of the objective function compared to the additive model. On this basis, several simulations were performed to identify possible starting dose combinations of trazodone and gabapentin in humans, by selecting doses yielding systemic exposures close to those being synergic in the mouse. Simulations indicated that doses of 50-100 mg trazodone could enhance gabapentin antinociceptive effect in humans, supporting the development of a low dose combination for optimal analgesia treatment.
Subject(s)
Neuralgia , Trazodone , Humans , Mice , Animals , Gabapentin , Trazodone/pharmacology , Rodentia , Analgesics/pharmacology , Neuralgia/drug therapy , Acetic Acid , Models, BiologicalABSTRACT
Clinical manifestations of human coronavirus (HCoV)-related diseases are mostly related to the respiratory system, although secondary complications such as headache, anosmia, ageusia, and myalgia have been reported. HCoV infection and replication in chemosensory cells associated with ageusia and anosmia is poorly understood. Here, we characterized HCoV-OC43 and SARS-CoV-2 infection in two types of chemosensory cells, olfactory and taste cells, with their unique molecular and histological characteristics. We first assessed HCoV-OC43 infection in in vitro cultured human olfactory epithelial cells (hOECs) and fungiform taste papilla (HBO) cells. Interestingly, while both cell types were susceptible to HCoV-OC43 infection, viral replication rates were significantly reduced in HBO cells compared to hOECs. More interestingly, while culture media from hOECs was able to produce secondary infection in Vero cells, there was very limited secondary infection from HBO cells, suggesting that HBO cells may not be able to release infectious virus. On the other hand, unlike HCoV-OC43, SARS-CoV-2 showed comparable levels of viral infection rates in both hOECs and HBO cells. Furthermore, our RT-qPCR-based gene array studies revealed that several key genes involved in taste and olfactory functions were significantly altered by SARS-CoV-2 infection. These results may suggest a possible mechanism associated with chemosensory symptoms, such as anosmia and ageusia in patients infected with SARS-CoV-2.
Subject(s)
Ageusia , COVID-19 , Coinfection , Coronavirus OC43, Human , Animals , Chlorocebus aethiops , Humans , Vero Cells , Anosmia , SARS-CoV-2 , Coronavirus OC43, Human/geneticsABSTRACT
(R)-7 [(R)-AS-1] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. (R)-7 [(R)-AS-1] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, (R)-7 [(R)-AS-1] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.
Subject(s)
Anticonvulsants , Epilepsy , Animals , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Epilepsy/chemically induced , Epilepsy/drug therapy , Mice , Molecular Docking Simulation , Pentylenetetrazole , Seizures/chemically induced , Seizures/drug therapyABSTRACT
Total knee replacement (TKA) is a frequent modality performed in patients with osteoarthritis. Specific circumstances can make it much more difficult to execute successfully, and additional procedures such as osteotomy may be required. The aim of this study was to perform a meta-analysis and systematic review of osteotomies combined with TKA. METHODS: In June 2022, a search PubMed, Embase, Cochrane, and Clinicaltrials was undertaken, adhering to PRISMA guidelines. The search included the terms "osteotomy" and "total knee arthroplasty". RESULTS: Two subgroups (tibial tubercle osteotomy and medial femoral condyle osteotomy) were included in the meta-analysis. Further subgroups were described as a narrative review. The primary outcome showed no significant difference in favor to TTO. Secondary outcomes showed improved results in all presented subgroups compared to preoperative status. CONCLUSION: This study showed a significant deficit of randomized control trials treated with osteotomies, in addition to TKA, and a lack of evidence-based surgical guidelines for the treatment of patients with OA in special conditions: posttraumatic deformities, stiff knee, severe varus, and valgus axis or patella disorders.