The Landscape of Randomized Clinical Trial Meta-analyses on Statins for Aneurysmal Subarachnoid Hemorrhage: A Scoping Review.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is a type of non-traumatic SAH that can have detrimental effects on the central nervous system, resulting in severe disability or death. METHODS: Early nimodipine is currently the only strongly recommended pharmacological treatment that has shown efficacy in improving neurological/functional outcomes in aSAH patients. Whether statin treatment is of benefit to aSAH patients is an issue that has generated considerable interest and debate. In the present scoping review, we mapped and analyzed the available literature on metaanalyses of randomized clinical trials (RCTs) examining the effect of statins on aSAH. Seventeen meta-analyses of RCTs, published between 2008 and 2023, were identified. RESULTS: Treatments in included meta-analyses were based on various regimens of simvastatin, pravastatin, pitavastatin or atorvastatin for up to 21 days. Eleven of the included reports indicated some beneficial effect of statin treatment, reducing rates of at least one of the following: cerebral vasospasm, delayed cerebral ischemia/delayed ischemic neurologic deficit, mortality or functional/ neurological outcome. In contrast, six meta-analyses, showed no such effects. CONCLUSION: The limitations reported by several meta-analyses, included low patient numbers or disproportionate representation of patients from certain RCTs, differences in drug treatment, patient diagnostic criteria and outcome evaluation between RCTs, as well as poor data quality or lack of RCTs data. Knowledge of the reported limitations may aid the design of future clinical trials and/or their meta-analyses.

Advances on Liquid Biopsy Analysis for Glioma Diagnosis.

Gliomas comprise the most frequent primary central nervous system (CNS) tumors, characterized by remarkable genetic and epigenetic heterogeneity, difficulty in monitoring, and increased relapse and mortality rates. Tissue biopsy is an established method of tumor cell collection and analysis that enables diagnosis, classification of different tumor types, and prediction of prognosis upon confirmation of tumor's location for surgical removal. However, it is an invasive and often challenging procedure that cannot be used for frequent patient screening, detection of mutations, disease monitoring, or resistance to therapy. To this end, the minimally invasive procedure of liquid biopsy has emerged, allowing effortless tumor sampling and enabling continuous monitoring. It is considered a novel preferable way to obtain faster data on potential tumor risk, personalized diagnosis, prognosis, and recurrence evaluation. The purpose of this review is to describe the advances on liquid biopsy for glioma diagnosis and management, indicating several biomarkers that can be utilized to analyze tumor characteristics, such as cell-free DNA (cfDNA), cell-free RNA (cfRNA), circulating proteins, circulating tumor cells (CTCs), and exosomes. It further addresses the benefit of combining liquid biopsy with radiogenomics to facilitate early and accurate diagnoses, enable precise prognostic assessments, and facilitate real-time disease monitoring, aiming towards more optimal treatment decisions.

Toxicity and Lethal Effect of Greenhouse Insecticides on Coccinella septempunctata (Coleoptera: Coccinellidae) as Biological Control Agent of Myzus persicae (Hemiptera: Aphididae).

Deltamethrin and imidacloprid are commonly used insecticides for controlling sub-sucking insects in greenhouses. However, their application may cause sublethal effects on the aphid coccinellid predator Coccinella septempunctata (Coleoptera: Coccinellidae). Here, we study (i) the toxicity and the effect of two sublethal doses (LD10 and LD30) of deltamethrin and imidacloprid on C. septempunctata in a laboratory microcosm and (ii) the residual toxicity of the two insecticides in a greenhouse. The results showed that both insecticides reduced fecundity, longevity, the intrinsic rate of increase, the finite rate of increase and the net reproductive rate. However, the developmental time of the fourth instar larvae was prolonged by both insecticides at LD10 and LD30. Deltamethrin residues were toxic 21 DAT (days after treatment) to C. septempunctata fourth instar larvae. In contrast, imidacloprid began in the slightly harmful category (75%) 1 DAT and declined to the harmless category (18.33%) 21 DAT. These results indicate that deltamethrin and imidacloprid have potential risks to C. septempunctata. This study provides information to guide the development of integrated pest management (IPM) strategies in greenhouses.

Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas.

Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor-microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.

Toxicity and Influence of Sublethal Exposure to Sulfoxaflor on the Aphidophagous Predator Hippodamia variegata (Coleoptera: Coccinellidae).

Hippodamia variegata (Goeze), the variegated ladybug, is a predator of many insect pests, especially aphids. Sulfoxaflor is a chemical insecticide that can be used to control many sap-feeding insect pests, for instance, plant bugs and aphids, as an alternative to neonicotinoids in different crops. To improve the combination of the H. variegata and sulfoxaflor in an IPM (integrated pest management) program, we studied the ecological toxicity of the insecticide to the coccinellid predator at sublethal and lethal doses. We examined the influence of sulfoxaflor on larvae of H. variegata using exposure doses of 3, 6, 12, 24, 48 (maximum recommended field rate (MRFR)), and 96 ng a.i. per insect. In a 15-day toxicity test, we observed decreased adult emergence percentage and survival, as well as an increased hazard quotient. The LD50 (dose causing 50% mortality) of H. variegata due to sulfoxaflor decreased from 97.03 to 35.97 ng a.i. per insect. The total effect assessment indicated that sulfoxaflor could be grouped as slightly harmful for H. variegata. Additionally, most of the life table parameters were significantly decreased after exposure to sulfoxaflor. Overall, the results present a negative influence of sulfoxaflor on H. variegata when applied at the recommended field dose for controlling aphids in Greece, which demonstrates that this insecticide may only be employed with care when used in IPM programs.

Medial Pulvinar Stimulation in Temporal Lobe Epilepsy: A Literature Review and a Hypothesis Based on Neuroanatomical Findings.

While bilateral stimulation of the anterior thalamic nuclei remains the only approved deep brain stimulation (DBS) option for focal epilepsy, two additional thalamic targets have been proposed. Earlier work indicated the potential of centromedian thalamic nucleus stimulation with recent findings highlighting the medial pulvinar nucleus. The latter has been shown to exhibit electrophysiological and imaging alterations in patients with partial status epilepticus and temporal lobe epilepsy. On this basis, recent studies have begun assessing the feasibility and efficacy of pulvinar stimulation, with encouraging results on the reduction of seizure frequency and severity. Building on existing neuroanatomical knowledge, indicating that the medial pulvinar is connected to the temporal lobe via the temporopulvinar bundle of Arnold, we hypothesize that this is one of the routes through which medial pulvinar stimulation affects temporal lobe structures. We suggest that further anatomic, imaging, and electrophysiologic studies are warranted to deepen our understanding of the subject and guide future clinical applications.

Pesticides and tremor: An overview of association, mechanisms and confounders.

Pesticides are a heterogeneous class of chemicals mainly used for the protection of crops from pests. Because of their very widespread use, acute or/and chronic exposure to these chemicals can lead to a plethora of sequelae inflicting diseases, many of which involve the nervous system. Tremor has been associated with pesticide exposure in human and animal studies. This review is aimed at assessing the studies currently available on the association between the various types of pesticides/insecticides and tremor, while also accounting for potential confounding factors. To our knowledge, this is the first coherent review on the subject. After appraising the available evidence, we call for more intensive research on this topic, as well as intonate the need of implementing future preventive measures to protect the exposed populations and to reduce potential disabilities and social drawbacks.

Advances on Epigenetic Drugs for Pediatric Brain Tumors.

Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal progress in patients' prognosis. Emerging molecular targets and mechanisms have revealed novel approaches for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetic research and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination of chemoand immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could possibly be used against the most common malignant tumors of childhood, such as medulloblastomas, high-grade gliomas and ependymomas.

Toxicity, Sublethal and Low Dose Effects of Imidacloprid and Deltamethrin on the Aphidophagous Predator Ceratomegilla undecimnotata (Coleoptera: Coccinellidae).

Ceratomegilla undecimnotata (Coleoptera: Coccinellidae) is a common aphidophagous coccinellid predator used in biological control against aphid pests. Knowing toxicity, lethal, and sublethal effects of insecticides on natural enemies is essential in order to incorporate them into Integrated Pest Management (IPM). In the present study, the lethal and sublethal effects of imidacloprid and deltamethrin were evaluated on the fourth instar larvae of C. undecimnotata and subsequently on the full life cycle. Our results strongly suggest that sublethal and low doses of imidacloprid and deltamethrin at LD10 and LD30 affected fourth instar larvae duration time, adult preoviposition period, total preoviposition period, and fecundity. Moreover, the intrinsic (r) and finite (λ) rate of increase and the net reproduction rate (R0) significantly decreased in populations treated with imidacloprid compared to the control population. The data clearly suggest that imidacloprid and deltamethrin have a negative influence on population growth parameters of C. undecimnotata at sublethal and low doses and, therefore, these insecticides should be used with caution within the context of IPM.

Lethal and sub-lethal effects of imidacloprid on the aphidophagous coccinellid hippodamia variegata.

Hippodamia variegata is one of the most abundant ladybird species in Greece, preying on several aphid species and other arthropods, of which many are pests of cultivated plants. Imidacloprid, a neonicotinoid insecticide, is commonly used for controlling sucking insects; at the same time, however, it can cause various sub-lethal effects on non-target organisms. The development of IPM programs against pests requires an evaluation of the side effects of insecticides on natural enemies. We evaluated the sub-lethal effects of imidacloprid on H. variegata. Our results demonstrate that imidacloprid at a LC10 (3.92 mg (a.i.) L-1 and LC30 (8.69 mg (a.i.) L-1) decreased adult longevity and survival rate. In addition, demographic parameters, such as the intrinsic rate of increase (r), finite rate of increase (λ) and net reproductive rate (R0), were reduced when exposed to sub-lethal concentrations of imidacloprid. These results demonstrate a negative influence of imidacloprid at sub-lethal concentrations on H. variegata which could reduce biological control services provided by this predator.

Evolution of imidacloprid resistance in Myzus persicae in Greece and susceptibility data for spirotetramat.

BACKGROUND: Myzus persicae s.l. is a major crop pest globally and has evolved resistance to a range of insecticide classes making it increasingly difficult to control in some areas. Here we compare bioassay monitoring data for two important compounds, imidacloprid and spirotetramat, on field samples/clones collected in Greece. RESULTS: A total of 122 aphid samples/clones from central and northern Greece were examined in dose-response bioassays with imidacloprid. There was an overall increase in the level of resistance (resistance factor = 15-40) within tobacco-collected samples from 78.7% in 2007 to 86.7% in 2015. The corresponding frequencies for peach samples were 13.3% and 6.7%. These results were confounded however by the first identification of the R81T target mutation in Greece during 2015 (4.3% as heterozygotes in peach) and 2016 (21.3% as heterozygotes in peach). No resistance to spirotetramat was found at the 60 clones collected in 2015. CONCLUSION: Resistance to imidacloprid is continuing to increase within Greek M. persicae s.l. populations and the situation is likely to deteriorate further with the recent identification of the R81T resistance mutation. Resistance to spirotetramat has not been found and is therefore a good alternative to neonicotinoids for resistance management. © 2017 Society of Chemical Industry.

Insecticide resistance status of Myzus persicae in Greece: long-term surveys and new diagnostics for resistance mechanisms.

BACKGROUND: Myzus persicae nicotianae is an important pest in Greece, controlled mainly by neonicotinoids. Monitoring of the aphid populations for resistance mechanisms is essential for effective control. RESULTS: Two new RFLP-based diagnostics for the detection of the M918T (super-kdr pyrethroid resistance) and nAChR R81T (neonicotinoid resistance) mutations were applied, along with other established assays, on 131 nicotianae multilocus genotypes (MLGs) collected from tobacco and peach in Greece in 2012-2013. Furthermore, we present resistance data from aphid clones (>500, mainly nicotianae) collected in 2006-2007. About half of the clones tested with a diagnostic dose of imidacloprid were tolerant. The R81T mutation was not found in the 131 MLGs and 152 clones examined. Over half (58.6%) of a subset of 29 clones showed a 9-36-fold overexpression of CYP6CY3. M918T was found at low to moderate frequencies. The kdr and MACE mechanisms and carboxylesterase-based resistance were found at high frequency in all years. CONCLUSION: The aphid retains costly resistance mechanisms even in the absence of pressure from certain insecticides, which could be attributed to factors related to climate and genetic properties of the populations. The indication of build-up of resistance/tolerance to neonicotinoids, related to CYP6CY3 overexpression, is a matter of concern. © 2015 Society of Chemical Industry.

Efficacy of the pyrethroid alpha-cypermethrin against Bactrocera oleae populations from Greece, and improved diagnostic for an iAChE mutation.

BACKGROUND: The most important pest of olive orchards worldwide is the olive fruit fly Bactrocera oleae (Gmelin). Its control in Greece has been based on organophosphates (OPs), but their intense use has led to the development of resistance. A test previously developed to monitor the trait may not be as robust as originally thought. The pyrethroid alpha-cypermethrin has recently been registered for bait sprays, as an alternative to OPs. RESULTS: The susceptibility of 20 B. oleae populations to alpha-cypermethrin was examined. Variation was observed in their response, with LD(50) ranging from 0.14 to 3.28 ng insect(-1) and resistance factors from 2.3 to 54.7. Resistance mechanisms were investigated. Cytochrome P450 monoxygenase activities showed an association with resistance. Sequences in the domain IIS4-IIS6 of the B. oleae para-type sodium channel were also analysed, but no resistance-associated mutations were identified. Finally, a novel diagnostic assay able to reliably monitor the frequency of the iAChE G488S resistance mutation was developed. CONCLUSION: This is the first attempt to evaluate the efficacy of alpha-cypermethrin against B. oleae from Greece. Data showed that it can be used effectively, but also highlighted the importance of continuous monitoring. The IIS4-IIS6 sodium channel region is the default area in which to look for resistance mutations if target-site resistance to pyrethroids arises. The application of the novel iAChE molecular diagnostic may facilitate the introduction of pyrethroids alongside OPs currently in use.

Insecticide resistance status of Myzus persicae (Hemiptera: Aphididae) populations from peach and tobacco in mainland Greece.

The susceptibility of 88 and 38 field samples of Myzus persicae (Sulzer) to imidacloprid and deltamethrin respectively was examined using the FAO dip test bioassay. The field samples were collected from tobacco and peach from various regions of Greece in the period from 2004 to 2006. In addition, 497, 349 and 370 clones originating from peach and tobacco were screened for the three known resistance mechanisms, elevated esterases, modified acetylcholinesterase (MACE) and knockdown resistance (kdr) respectively, using biochemical and DNA diagnostics. Most of the samples assayed with imidacloprid showed low resistance factors (RFs)-39% below 5 and 21% between 5 and 10. However, 9% of the samples (all from tobacco) showed relatively high RF values (24-73). Differences were found between crops, with higher RF values recorded in samples from tobacco than in those from peach. Bioassays with deltamethrin revealed the development of strong resistance in the populations examined. The RFs were mostly higher than 23, and in 29% of the samples they were extremely high (152-436). Finally, the three known resistance mechanisms were found in high frequencies in the populations examined, although some differences between crops and years were detected. The implications of the study for management schemes against M. persicae are discussed.

Organophosphate resistance in olive fruit fly, Bactrocera oleae, populations in Greece and Cyprus.

The olive fruit fly Bactrocera oleae (Gmelin) (Diptera: Tephritidae) is the most important pest of olives in countries around the Mediterranean basin. Its control has been based mostly on bait sprays with organophosphate insecticides (usually dimethoate or fenthion) for about 40 years. In the present study, the resistance status of olive fruit fly populations to dimethoate was examined in Greece and Cyprus over 2 years. Thirty-one populations from various regions of Greece, nine from Cyprus and one laboratory susceptible strain, which served as a control, were assayed by topical application of dimethoate. Considerable variation in the resistance levels to dimethoate was recorded in the populations of B. oleae, with resistance ratios ranging from 6.3 to 64.4 (ED(50) values 12.5-128.7 ng dimethoate per insect). The highest resistance ratios were found in populations from Crete, and the lowest in those from Cyprus. This variation could be attributed to different selection pressures from insecticidal applications among populations from the various regions. Migration of resistant genotypes, either autonomous or via commerce, may also be involved.

Transmission of Potato virus Y in Tobacco Plants by Myzus persicae nicotianae and M. persicae s.str.

The transmission efficiency of Potato virus Y N (PVYN) from and to tobacco plants by Myzus persicae nicotianae, a tobacco specialist, and M. persicae s.str. (Hemiptera: Aphididae), a generalist, was evaluated. In direct transmission tests, 1,004 spring migrants collected as nymphs from peach and 1,434 wingless females from 12 clonal lineages of both taxa were examined. Both the winged and wingless females were starved before being transferred individually for a 3-min acquisition period on infected plants and then moved to healthy plants for a 10-min inoculation access period. Little variation in transmission efficiency was observed. Although not statistically significant, M. persicae nicotianae was slightly more effective. This may suggest similar genetic properties (e.g., virion receptors in mouthparts) between the taxa in relation to virus transmission. M. persicae s.str. transmitted the virus less efficiently when a shorter inoculation period was given. This may indicate differences in probing behavior during the early phase of host selection. Nevertheless, behavioral differences related to host selection have been found using arena tests with infected and healthy tobacco plants where 180 winged females from each taxon were tested. M. persicae s.str. had significantly higher propensity to transmit PVYN than M. persicae nicotianae (31.9 versus 15.3%).