Depression can occur in the context of major depressive disorder or bipolar disorder. There are many effective and well-tolerated treatment options for most patients experiencing major depressive episodes, but for patients with treatment-resistant major depressive disorder or bipolar depression, current pharmacologic and non-pharmacologic options can be less efficacious, well tolerated, or accessible. Botulinum neurotoxin (BoNT) offers a novel approach to treating depression that is both safe and well-tolerated. Several potential mechanisms of action in depression are theorized, and studies support the efficacy of BoNT in major depressive disorder. Early data suggests that BoNT may be efficacious in bipolar depression and further study is warranted.

The medical records of 95 pit viper envenomations in client-owned dogs presented to an academic emergency hospital in the Southeastern United States during the period spanning 2018 and 2020 were retrospectively examined. This study's primary objectives were to record the clinical abnormalities and treatment responses associated with envenomation and their relation to outcome. Approximately 80% of the bites involved the head region associated with varying degrees of hemorrhagic lymphedema. Some of the most common additional symptoms observed were; hypotension (10%), cardiac dysrhythmias (17%), and coagulopathy (21%). Treatment in most cases consisted of intravenous fluids, antivenom, and analgesic drugs. Blood products were used as indicated for anemia and persistent bleeding. The average dose of the F('ab')2 was 1-2 vials. Additional vials (3-22) were administered as needed to counteract persistent or recurrent coagulopathy and hemolysis. Only 3% of the dogs had mild clinical signs of Type 1 hypersensitivity during their treatment period. Antihistamine use at the tertiary hospital was restricted to the three dogs showing signs of a suspected allergic reaction in response to antivenom administration; these patients received diphenhydramine intramuscularly. A glucocorticoid drug was used in only one dog prior to referral but not subsequently. Ninety dogs had a good outcome, while five died. Historically, pit viper envenomation in dogs in the southeastern United States has been a potentially life-threatening problem. Most dogs will survive if treated promptly and appropriately with adequate amounts of intravenous fluids, and antivenom titrated on severity of clinical presentation.

Post-stroke spastic movement disorder (PS-SMD) is one of the main causes of severe disability in the chronic phase after stroke. The prevalence of SMD goes up with time after stroke to more than 28% in the chronic phase., Its secondary complications such as contracture, abnormal postures and/or movement patterns, spasticity-associated pain also increase with time after stroke when physical and medical management of PS-SMD have been delayed in the early stroke phase. It has been published by several controlled studies that the earlier physical and medical measures, such as botulinum toxin type A (BoNT-A) therapy are included in rehabilitative strategies for the SMD, the fewer secondary complications, especially soft tissue contractures and pain occurred. Several studies showed that goal-orientated management of PS-SMD including BoNT-A therapy, applied within a few weeks and three months - in the early subacute phase after stroke onset - prevented or reduced the development of severe or disabling SMD and its secondary complications, more effective than late application of BoNT-A therapy - in the chronic phase after stroke. In multiple prospective cohort studies, various predictors and predictive approaches for detection of patients on risk to development PS-SMD were found. Based on that information and the controlled studies that showed reduction in PS-SMD complications following early treatment with BoNT-A nowadays, early treatment of PS-SMD in the early subacute phase following stroke is recommended to avoid or reduce the development of post-stroke disability and to improve the outcome of rehabilitation. In this review, we discuss the optimal timing to apply BoNT-A therapy in patients with already present as well as those at high risk of severe PS-SMD.

This study aims to report a spontaneous and experimental intoxication in cattle by Melanthera latifolia (Asteraceae) for the first time, and to describe its epidemiological, clinical, and pathological findings. An outbreak of acute toxic hepatopathy in cattle occurred from December of 2021 to January of 2022 in a beef cattle farm from Rio Grande do Sul state, Southern Brazil, and resulted in 94 deaths from a herd of 430 animals. At necropsy, lesions consisted of enhanced lobular pattern of the liver, transmural gallbladder edema, and hemorrhages on the surface of multiple organs. The main microscopic lesion was marked hepatocellular necrosis in the centrilobular region associated with hemorrhage and infiltration of neutrophils. During the outbreak, multiple specimens of M. latifolia were noted in the paddocks where affected cattle were grazing and many showed signs of consumption. No other known acute hepatotoxic plants were found. Two 12-month-old steers were experimentally intoxicated with a single oral dose of the fresh plant (flowers, leaves, and less fibrous stalks). One bovine ingested a dose of 10 g/kg and was euthanized after 48 h, and the other ingested 15 g/kg and was euthanized 17 h later. Clinical signs, macroscopic, and microscopic lesions in both animals were similar to those observed in the spontaneous cases. Thus, this study demonstrates that M. latifolia was the cause of the outbreak of acute toxic hepatopathy with significant mortality in cattle. M. latifolia nor any plant of the genus Melantherahad ever been reported as toxic.

Biological specialization reduces the size of niche space while increasing efficiency in the use of available resources. Specialization often leads to phenotypic changes via natural selection aligning with niche space constraints. Commonly observed changes are in size, shape, behavior, and traits associated with feeding. One often selected trait for dietary specialization is venom, which, in snakes, often shows variation dependent on diet across and within species. The Neotropical Blunt-headed Treesnake (Imantodes cenchoa) is a highly specialized, rear-fanged, arboreal, lizard hunter that displays a long thin body, enlarged eyes, and a large Duvernoy's gland. However, toxin characterization of I. cenchoa has never been completed. Here, we use RNA-seq and mass spectrometry to assemble, annotate, and analyze the venom gland transcriptomes of four I. cenchoa from across their range. We find a lack of significant venom variation at the sequence and expression levels, suggesting venom conservation across the species. We propose this conservation provides evidence of a specialized venom repertoire, adapted to maximize efficiency of capturing and processing lizards. Importantly, this study provides the most complete venom gland transcriptomes of I. cenchoa and evidence of venom specialization in a rear-fanged snake, giving insight into selective pressures of venom across all snake species.

An outbreak of poisoning by Lantana camara occurred in cattle when a herd sought refuge in a Eucalyptus forest heavily infested by this plant. The animals showed apathy, elevated serum activities of hepatic enzymes, severe photosensitivity, jaundice, hepatomegaly and nephrosis. After a clinical manifestation period of 2-15 days, 74 out of 170 heifers died. The main histological changes were random hepatocellular necrosis, cholestasis, biliary proliferation and, in one animal, centrilobular necrosis. Immunostaining for Caspase 3 detected scattered apoptotic hepatocytes.

Jellyfish stings pose a significant threat to humans in coastal areas worldwide, with venomous jellyfish species stinging millions of individuals annually. Nemopilema nomurai is one of the largest jellyfish species, with numerous tentacles rich in nematocysts. N. nomurai venom (NnV) is a complex mixture of proteins, peptides, and small molecules that serve as both prey-capture and defense mechanisms. Yet, the molecular identity of its cardiorespiratory and neuronal toxic components of NnV has not been clearly identified yet. Here, we isolated a cardiotoxic fraction, NnTP (Nemopilema nomurai toxic peak), from NnV using chromatographic methods. In the zebrafish model, NnTP exhibited strong cardiorespiratory and moderate neurotoxic effects. LC-MS/MS analysis identified 23 toxin homologs, including toxic proteinases, ion channel toxins, and neurotoxins. The toxins demonstrated a synergistic effect on the zebrafish, leading to altered swimming behavior, hemorrhage in the cardiorespiratory region, and histopathological changes in organs such as the heart, gill, and brain. These findings provide valuable insights into the mechanisms underlying the cardiorespiratory and neurotoxic effects of NnV, which could be useful in developing therapeutic strategies for venomous jellyfish stings.

Plant-derived triterpenoid saponins have been shown to play a powerful role in enhancing the cytotoxic activity of protein therapeutics. However, the mechanism of how saponins are acting is not clearly understood. In this study, momordin Ic (MIC), a triterpenoid saponin derived from Kochia scoparia (L.) Schrad., specifically enhance the antiproliferative effect of recombinant MAP30 (a type I ribosome inactivating protein, RIP) in breast cancer cells. Subsequently, the possible mechanism of how MIC enhanced the cytotoxicity of MAP30 was analyzed in detail. We observed the level of intracellular labeled MAP30 using fluorescence microscopy and flow cytometry. And a reporter protein, GAL9, was used to monitor the role of MIC in promoting endosomal escape. We found endosomal escape does not play a role for the enhancer effect of MIC while the effect of MIC on MAP30 is cholesterol dependent and that ganglioside GM1, a lipid raft marker, can competitively inhibit cytotoxicity of MAP30 enhanced by MIC. Finally, we provided some insights into the correlation between the sugar side chain of MIC and its role in enhancing of RIP cytotoxicity and altering of drug cell tropism.

Echium amoenum is an annual herb native to the northern mountains of Iran which has medicinal application. Petals of Echium amoenum (Gole-Gavzaban) is one of the most valuable medicinal plants in Iranian folk medicine. The dry petals of E. amoenum have long been used as a sedative, tonic, anxiolytic and as a treatment for sore throat, cough and inflammation. Previous studies have shown that petals of E. amoenum contain four toxic pyrrolizidine alkaloids but conflicting results have been acquired in experimental studies investigating the hepatotoxicy of E. amoenum. However, the direct effect of E. amoenum on liver cells and the complete mechanisms of its possible cytotoxic effects toward these cells remain to be defined. The main aim of this study was to assay the mechanisms underlying the toxic effects of E. amoenum toward hepG2 cells. E. amoenum extract was obtained by infusion of dried petals in hot water (90 centigrade) for 15 or 30 min. Cell viability and mechanistic parameters were determined following 12 h incubation of hepG2 with E. amoenum extract that was obtained after 15 or 30 min infusion. The results indicated that E. amoenum extract exerts cytotoxic effects on hepG2 cells, probably through mitochondrial and lysosomal damage induced by glutathione depletion and oxidative stress.

Sepsis-induced myocardial dysfunction is the main reason for mortality and morbidity. Recent investigations have shown that inflammation and oxidative stress play a central role in lipopolysaccharide (LPS)-induced cardiac injury pathophysiology. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The present study aimed to investigate the effects of B. serrata pretreatment on LPS-induced cardiac damage in H9c2 cells. The cells were pretreated with various concentrations of B. serrata (5-45 μg/ml) for 24 h and then stimulated with LPS (10 μg/ml) for another 24 h. Afterward, the levels of cell viability, tumor necrosis factor (TNF)-α, prostaglandin (PGE)-2, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, nitric oxide (NO) and glutathione (GSH) were determined using enzyme-linked immunosorbent assay (ELISA), real time-PCR or appropriated biochemical methods. Our results demonstrated that LPS treatment caused a remarkable decrease in cell viability and GSH, and on the contrary, it led to a significant increase in the levels of gene and protein expression of inflammatory markers and NO. However, pretreatment of B. serrata (5, 15, and 45 μg/ml) decreased the levels of TNF-α, PGE2, IL-1β, COX-2, iNOS, IL-6, and NO production, while cell viability and GSH levels were increased. Taken together, our results demonstrated that B. serrata might be a potential therapeutic agent against LPS and endotoxemia-induced cardiac injury, through its anti-inflammatory and antioxidant properties.

India is home to a diverse spectrum of medically-significant snakes accounting for one of the world's largest burdens of envenoming, morbidity and mortality. Indian polyspecific antivenom is derived from the venom of four snake species (Daboia russelii, Echis carinatus, Naja naja and Bungarus caeruleus), considered to be responsible for the majority of snakebite morbidity and mortality in India. The treatment of envenoming from other less-commonly encountered venomous snake species can be challenging. In this report, we describe the case of a 32-year-old male who presented with local swelling and coagulopathy following a bite from Ovophis monitcola (mountain pit-viper) in Nagaland, Northeast India. Local and systemic envenoming, failed to respond to Indian polyspecific antivenom and venom-induced consumption coagulopathy, confirmed by bedside and laboratory-based clotting assays, persisted for more than three weeks. Remote consultation with a national-level Poison Control Centre helped establish the responsible snake species and guide appropriate medical management.

Bee stings represent a public health subject, but the mechanisms involved in bee venom toxicity are not yet fully understood. To evaluate the reactions of adrenocortical cells, through which organisms respond to stress, two honeybee venom components: melittin (Mlt) and phospholipase A2 (PLA2) were tested as potential chemical stressors. Modifications were investigated with transmission electron microscopy and microanalysis. A single dose of Mlt (31 mg/kg) or PLA2 (9.3 mg/kg) was injected in rats of groups ML and PL; daily doses of Mlt (350 μg/kg) or PLA2 (105 μg/kg) were injected 30 days in rats of groups M30 and P30. Adrenocortical cells in ML group showed ultrastructural degenerative alterations of nuclei, endoplasmic reticulum, and mitochondria that exhibited lipid inclusions and mitochondrial cristae (MC) re-organized into mono- or multimembrane large vesicles, and whorls of membranes. Many MC were degenerated. In the M30 group, similar ultrastructural changes, but of lower amplitude were noted; lipid cytosolic droplets were heterogenous. MC diameters in Mlt groups (melittin treated groups) were significantly higher than in control (C) group. In PL group, mitochondria contained large lipid inclusions, vesicular MC of different sizes and multiple membranes, and debris, or whorl structures. In P30 group MC were tubular with increased diameters. In both PLA2 groups (PLA2 treated groups) MC were significantly larger than in C group. We concluded that Mlt and PLA2 were powerful stressors, toxic at the tested doses, cellular reactions concerning in all groups mainly mitochondria, but also other cellular compartments. Apart from degenerative regression of MC, the rearrangement of tubular MC occurred into one or multiple large multimembrane vesicular MC. Reactions to the high doses were more pronounced, with the highest amplitude in ML group, and the lowest in P30 group.

Alcea glabrata from the family Malvaceae, was selected for evaluating its xanthine oxidase inhibitory, anti-malarial, and antioxidant activities. In addition, some phytochemical analysis upon different extracts of A. glabrata were performed. Aerial parts of the collected A. glabrata plant material were dried and solvent extracted via soxhlet apparatus using different solvents. Various chromatographic techniques were used for extra fractionation of the achieved extracts. Xanthine oxidase (XO) inhibitory, antimalarial and antioxidant activity assays upon different A. glabrata extracts and fractions were carried out and reported in terms of IC50s. Total phenolic and flavonoid contents of the A. glabrata methanol extract (MeOH) were determined using the 2,2-Di Phenyl-1-Picryl Hydrazyl (DPPH) assay, aluminum chloride colorimetric, and Folin-Ciocalteu reagents, respectively. In addition, A. glabrata essential oil was obtained through hydrodistillation by a Clevenger apparatus. Analysis and identification of essential oil compounds were carried out through gas chromatography mass spectrometry (GC-MS) analysis. MeOH extract showed the highest XO inhibitory activity with the IC50 of 0.37 ± 0.12 mg/mL antioxidant activity with the RC50 of 0.24 ± 0.06 mg/mL. While, chloroform extract revealed the strongest antimalarial activity with the IC50 of 0.4 ± 0.05 mg/mL. The total flavonoid and phenolic contents of the A. glabrata methanol extract were 39.8 mg quercetin equivalent and 6.1 g gallic acid equivalent per 100 g of dry plant material, respectively. GC-MS analysis showed that the monoterpenes were prevailing in A. glabrata essential oil where the major constituents: octacosane (30.7%), eugenol (12.3%), and anethole (12.0%). Concerning the results of this study, A. glabrata extracts and its ingredients could be considered as a novel promising herbal medicine in the design and also treatment of new drugs for the relief of gout and malaria diseases.

The aim of our study was to determine the effects of aeruginosin 98 A (ARE-A), microginin-FR1 (MG-FR1), anabaenopeptin-A (ANA-A) cylindrospermopsin (CYL) and their binary and quadruple mixtures on the survival and the levels of oxidative stress biomarkers in Daphnia magna: total glutathione (GSH), catalase (CAT), dismutase (SOD) and malondialdehyde (MDA). The biochemical indicators were measured with ELISA kits and the interactive effects were determined by isobole and polygonal analysis with Compusyn® computer software. The study revealed that oligopeptides did not decrease daphnid survival, only CYL inhibited this parameter, with synergistic effects when it was used as a component. The single metabolites at the two highest concentrations and all the binary and quadruple mixtures at all concentrations diminished GSH level, however both in the binary and in the quadruple mixtures most of the interactions between the metabolites were antagonistic. Nearly additive effects were found only in AER-A + CYL and MG-FR1+CYL. On the other hand, CAT activity was slightly increased in daphnids exposed to the binary mixtures with antagonistic interactions, however nearly addivive effects were found in animals exposed to the mixture of AER-A + ANA-A and synergistic in the quadruple mixture. SOD was elevated in daphnids exposed to single AER-A and MG-FR1, however it was diminished in the animals exposed to ANA-A and CYL. Binary mixtures in which CYL was present as a component decreased the level of this enzyme with nearly additive interactions in ANA-A + CYL. The quadruple mixture increased SOD level, with antagonistic interactions. Both single cyanobacterial metabolites, their binary and quadruple mixtures induced lipid peroxidation measured by MDA level and most of interactions in the binary mixtures were synergistic. The study suggested that antioxidative system of Daphnia magna responded to the tested metabolites and the real exposure to mixtures of these products may lead to various interactive effects with varied total toxicity.

African trypanosomiasis is an infectious disease caused by hemoparasites of the genus Trypanosoma and remains a major health problem in Africa - killing around 4000 people and animals worth an estimated $5 billion, annually. The absence of a vaccine and satisfactory drug against African trypanosomiasis (AT) necessitates the continued search for new chemotherapy options. Owing to the rich biochemical diversity in snake venom, it has recently become a source of therapeutic peptides that are being explored for the development of novel drug candidates for diverse ailments such as cancers and infectious diseases. To explore this, Echis ocellatus venom (EOV) was investigated for the presence of an anti-Trypanosoma factor, with the subsequent aim to isolate and identify it. Crude EOV was collected and tested in vitro on the bloodstream form (BSF) i.e. long and slender morphological form of Trypanosoma brucei and T. congolense. This initial testing was followed by a sequential anti-trypanosomal assay guided purification of EOV using ethanol precipitation, distillation, and ion exchange (IEX) chromatography to obtain the active trypanocidal component. The purified anti-Trypanosoma factor, estimated to be a 52-kDa protein on SDS-PAGE, was subjected to in-gel trypsin digestion and 2D RP HPLC-MS/MS to identify the protein. The anti-Trypanosoma factor was revealed to be a zinc-dependent metalloproteinase that contains the HEXXHXXGXXH adamalysin motif. This protein may provide a conceptual framework for the possible design of a safe and effective anti-trypanosomal peptide for the treatment of AT.

A 60-year-old man presented with acute gastroenteritis, hypovolemic shock, acute renal failure (BUN/Cr, 56.7/4.24 mg/dl), and aspiration pneumonia. The previous day, he ingested 30 caps of mushrooms of an unknown species. The patient was treated with a massive intravenous infusion, renal replacement therapy, and antimicrobial agents. Late-onset mild liver injury peaked on day 11 (AST/ALT, 62/67 IU/l). Acute renal failure improved once before worsening, with the worst symptoms on day 19 (BUN/Cr, 99/6.61 mg/dl). Thereafter, the patient showed gradual improvement, and renal replacement therapy was discontinued on day 23. His general condition improved fully and he was transferred to another hospital for rehabilitation on day 47. The mushrooms were later identified as Galerina sulciceps by the Basic Local Alignment Search Tool, and toxicologic analysis using liquid chromatography-tandem mass spectrometry revealed an average of 85 ppm α-amanitin and 330 ppm β-amanitin in the tissue of the mushrooms brought in by the patient's family. Galerina sulciceps is distributed mainly in tropical and subtropical regions of Southeast Asia and had never been identified before in Japan. The heat of fermentation generated by the thick layer of wood chips on the ground or global warming may have contributed to its growth in Japan. Interestingly, our patient did not have liver dysfunction, which is one main and typical amatoxin poisoning symptom. Variation in clinical presentation may be attributed to the different ratios of α-amanitin to β-amanitin in different mushroom species.

Snakebite envenoming is a major global public health problem and disproportionately affects children. To study the differences in clinical presentation and outcomes between children and adults, 2922 snakebite patients of whom 30.3% were children were analysed. Most bites (>75%) were in the lower. Features of local envenoming were commoner among children compared to adults (p < 0.05), while systemic envenoming features, mortality and complications were similar, p = 0.356, p = 0.12, and p = 0.16 respectively.

Plant-based natural products have shaped traditional knowledge systems due to their numerous biological and pharmacological utility. However, in addition to their extensive utilization, some of these plants are also known for their toxicological properties. Since the foundation of human civilization, these toxic plants were used for fishing, hunting and safeguarding against enemies. In this study, a total of five plant species used in ethnofishery were considered for the toxicological study. The toxicities of these plants were evaluated using Brine Shrimp Lethality Assay (BSLA) and LC50 values were estimated. All the plants have displayed the toxic effect and have been graded to be highly toxic (i.e., LC50 of 0-100 μg/ml or LC50 < 1000 μg/ml). Furthermore, with the lowest LC50 (0.14 in 12 h of incubation), the plant species D. scandens was reported to be the most toxic. The toxic plants have an important role in rural livelihood; however, if the concentration of these compounds from poisonous plants reaches a high concentration in the vulnerable biological system, it could bring a devastating health-related issue for the frequent consumers.

Tityus obscurus has caused mild, moderate and severe accidents of medical relevance in the eastern Brazilian Amazon and French Guiana. Tityus obscurus has sexual dimorphism although males and females have uniform black coloration. In the Amazon, one of the habitats of this scorpion is seasonally flooded forests (igapós and várzeas). However, most stings occur in terra firme forest areas (non-flooded region), where most rural communities are located. Adults and children stung by T. obscurus may experience an "electric shock" sensation for more than 30 h after the sting. Our data shows that people inhabiting remote forest areas, including rubber tappers, fishermen and indigenous people, with no access to anti-scorpion serum, use parts of native plants, such as seeds and leaves, against pain and vomiting caused by scorpion stings. Although there is a technical effort to produce and distribute antivenoms in the Amazon, many cases of scorpion stings are geographically unpredictable in this region, due to the lack of detailed knowledge of the natural distribution of these animals. In this manuscript, we compile information on the natural history of T. obscurus and the impact of its envenoming on human health. We identify the natural sites that host this scorpion in the Amazon, in order to warn about the risk of human envenoming. The use of specific antivenom serum is the recommended treatment for accidents involving venomous animals. However, atypical symptoms not neutralized by the available commercial antivenom are reported in the Amazon region. Facing this scenario, we present some challenges to the study of venomous animals in the Amazon rainforest and possible experimental bottlenecks and perspectives for establishing a method aimed at producing an efficient antivenom.

Snakebite envenomation is regarded as a high-priority neglected tropical disease by the World Health Organisation, as it results in significant loss of lives and permanent disabilities. Russell's viper is one of the important venomous snakes that causes morbidities, mortalities and disabilities in India. The clinical presentation of Russell's viper envenomation is characterised by local envenoming effects including tissue damage, venom-induced coagulopathy, neurotoxicity, and kidney injury. However, venom composition and its mechanisms of toxicity are highly variable even within snakes of the same species including Russell's viper. This variation in venom composition results in a broad range of clinical complications. Here, we present a previously undocumented case of neutrophil-mediated erythrophagocytosis in a healthy 28-year-old female following Russell's viper bite. Systemic envenomation effects and bleeding abnormalities in this patient were corrected by the administration of polyvalent antivenom. Two days later, the patient developed progressive swelling and ecchymosis in the bitten limb. Observed abnormal limits within blood testing were followed up by a peripheral blood smear where it was found that 30% of neutrophils had phagocytosed erythrocytes as they were found within the cytoplasm. The patient underwent a fasciotomy for compartmental syndrome and received packed red cells and a course of corticosteroids. Following this treatment, the patient made a full recovery. This case report outlines a previously undocumented pathological event induced by Russell's viper envenomation, guiding diagnosis and treatment. Clinicians' knowledge of the mechanisms of toxicity of Russell's viper envenomation and its clinical manifestations are essential for improving the treatment of snakebites to achieve positive outcomes.

This paper summarizes the use of video enhanced visual analysis (VEVA) as a muscle selection assistance method for abnormal foot postures in adults with upper motor neuron syndrome (UMNS) treated with botulinum neurotoxin (BoNT-A) in a real-world setting. This pilot study used a prospective treatment study design with persons in an outpatient, rehabilitation hospital. Participants had acquired brain injury (ABI) of >6-month duration who had a spastic ankle foot deformity amenable to treatment with botulinum toxin A and able to independently ambulate a minimum of 10 m. Participants were evaluated before abobotulinumtoxinA injection (500 U-1500 U) to the identified lower limb muscles and four to five weeks post injection. Main Outcome Measures: Temporal spatial data (self-selected and maximal walking velocities (SSWV/MWV); step length and stance time); Modified Ashworth Scale (MAS); Tardieu Scale (TS) and ankle Passive Range of Motion (PROM) change from baseline to follow-up (f/u). Data is presented on ten of the eleven consecutive participants enrolled in the study. One participant withdrew due to study unrelated opposite ankle pain before reassessment. Mean SSWV increased post treatment by 21% in the barefoot condition and 8% when walking with shoes. For the MWV condition, there was a 15% mean increase post treatment in the barefoot condition and 10% when walking with shoes. Participants showed improved symmetry in step length and stance time in both post-treatment walking conditions. Ankle MAS and TS improved with knee flexed or extended. Ankle PROM increased post treatment with knee flexed by 8° and knee extended by 11.7°. VEVA in addition to clinical evaluation appears to facilitate muscle identification and selection of ankle deformities for treatment with BoNT-A. Our findings show marked improvement in ankle MAS, TS and PROM as indicators of pharmacological activity and increase in SSWV as a marker of functional improvement.

The spider's genus Loxosceles (also known as "brown spiders") is one of the few ones of medical importance in Brazil, being Loxosceles anomala a species of common occurrence in the Southeast region. This species is usually smaller in size than the other members of the Loxosceles group. A single human accident involving L. anomala was reported to date and the clinical picture shared similar characteristics with accidents caused by other Loxosceles species. Despite the potential relevance of L. anomalafor loxocelism in Minas Gerais state, its venom activity has never been characterized. In this work, we provide a preliminary characterization of L. anomala venom, considering its most relevant enzymatic activities and its venom immunorecognition by current therapeutic antivenoms. The results showed that L. anomala venom is immunorecognised by therapeutic antivenoms and by anti-phospholipase D antibodies. Its venom also shows enzymatic activities (sphingomyelinase activity, fibrinogenolytic) described for other Loxosceles venoms. This work contributes to a better knowledge on the venom content and activities of synanthropic Loxosceles species that have the potential of causing relevant human accidents.

The province of Azilal is one of the most scorpion-infested areas in Morocco. The current study aims to investigate the clinical and epidemiological characteristics of scorpion envenomation in the Azilal province, as well as to contribute to the study of its scorpio-faunistic diversity. We examined clinical and epidemiological data from 5684 scorpion stings recorded between 2017 and 2021. Prospections on the ground were carried out in the study area. The species were identified using the taxonomic keys. Distribution maps of inventoried species have been created using SIG. 5684 scorpions stings were reported in the study area, with 18 cases of deaths. Most of the cases was reported in the summer especially at night (64%). A positive significant correlation was found between scorpion stings incidence and season (P < 0.005; r = 0.56). A positive correlation was found between scorpion stings incidence and mortality (r = 0.09). Pediatric mortality was higher compared to lethality in adults (P < 0.05). A positive correlation was found between the number of stung children (Age <15 years) and the number of patients presenting clinical signs of severe envenomation (Class III) (r = 0.40). The percentage of patients that use traditional remedies was significantly higher in the rural areas (P < 0.05). Most scorpion stings occurred in human habitat (54.5%) or in their neighbourhood (24.5%). Six species were identified in the study area. The findings of this study have highlighted the extent of scorpion envenomation and have elucidated certain characteristics of the scorpio-faunistic biodiversity in the Azilal province.

Pathological tau aggregates propagate across functionally connected neuronal networks in human neurodegenerative pathologies, such as Alzheimer's disease. However, the mechanism underlying this process is poorly understood. Several studies have showed that tau release is dependent on neuronal activity and that pathological tau is found in the extracellular space in free form, as well as in the lumen of extracellular vesicles. We recently showed that metabotropic glutamate receptor activity and SNAP25 integrity modulate the release of pathological tau from human and mouse synaptosomes. Here, we have leveraged botulinum neurotoxins (BoNTs), which impair neurotransmitter release by cleaving specific synaptic SNARE proteins, to dissect molecular mechanisms related to tau release at synapses. In particular, we have tested the effect of botulinum neurotoxin A (BoNT/A) on the synaptic release of tau in primary mouse neurons. Hippocampal neurons were grown in microfluidic chambers and transduced with lentiviruses expressing human tau (hTau). We found that neuronal stimulation significantly increases the release of mutant hTau, whereas wild-type hTau is unaffected. Importantly, BoNT/A blocks mutant hTau release, indicating that this process is controlled by SNAP25, a component of the SNARE complex, in intact neurons. These results suggest that BoNTs are potent tools to study the spreading of pathological proteins in neurodegenerative diseases and could play a central role in identifying novel molecular targets for the development of therapeutic interventions to treat tauopathies.

Although all-trans retinoic acid (ATRA) is an efficient pattern in acute promyelocytic leukemia (APL) therapy, further studies are required due to the extant clinical limitations of ATRA. It has been reported that Silymarin, an anti-cancer herbal substance extracted from milk thistle (Silybum marianum), is able to regulate apoptosis in various types of cancer cells through different mechanisms of action. This study investigated the apoptosis-inducing effect of Silymarin (SM) alone and in combination with ATRA on human acute promyelocytic NB4 cells. Examination using MTT assay indicated that SM treatment leads to growth inhibition in NB4 cells in a dose-dependent manner. The IC50 values of SM and ATRA were calculated 90 μM and 2 μM, respectively. Cell cycle analysis by flow cytometry revealed that a more increase in the sub-G1 phase (a sign of apoptosis) when cells were exposed to SM in combination with ATRA. The incidence of apoptosis was confirmed through Hoechst 33258 staining and Annexin V-FITC analysis. The results showed that Silymarin enhances ATRA-induced apoptosis. The flow cytometric analysis also indicated an enhancement in levels of ROS in the treated cells with both compounds. The real-time PCR illustrated that SM targets apoptosis by down-regulation in Survivin and Bcl-2 while up-regulation in Bax. The findings showed that the combination of the two compounds is more effective in the induction of apoptosis in NB4 cells. Molecular docking studies indicated that Sylibin, as a primary compound of the SM, binds to the BH3 domain of Bcl-2 and the BIR domain of Survivin with various affinities. Based on the findings, it seems that SM used alone and in combination with ATRA may be beneficial for inducing apoptosis in APL cells.

Paris saponin I, II, and VII are three important components in Paris polyphylla, which have been widely studied as tumor cytotoxic drugs, but their safety in vivo has not been reported. Therefore, this study evaluated the safety of these three drugs based on the zebrafish model. Firstly, the lethality curves and lethal concentration of 50% (LC50) values of the three saponins were determined and the results showed the values of LC50 of Paris saponin I, II, and VII were 122.2, 210.7, 566.2 ng/mL, respectively. And then our data revealed that Paris saponin I, II and VII had definite hepatotoxicity, as shown by their significant reduction in the liver area and fluorescence intensity of zebrafish. Besides, Paris saponin Ⅰ affected the heart rate of zebrafish obviously, suggesting its cardiovascular toxicity. Afterwards, we found Paris saponin Ⅰ and Ⅶ reduced the area and fluorescence intensity of kidney in zebrafish, and had mild nephrotoxicity. And when treated with Paris saponin I, the pathological section of liver tissue in zebrafish showed vacuoles, severe necrosis of hepatocytes, and then the apoptosis of hepatocytes could be observed by TUNEL staining. Eventually, we found that the genes expression of p53, Bax and β-catenin changed significantly in the administration group of Paris saponin I. In general, our study proved Paris saponin Ⅰ was the most toxic of the three saponins, and the most definite toxic target sites were liver and cardiovascular. And it was further inferred that the totoxicity of Paris saponin Ⅰ may be related to the regulation of p53 pathway and Wnt pathway. These results above showed the toxicity of the three saponins in zebrafish, suggesting their safety should be paid more attention in the future.

Previous studies on viper bites in France have focused on clinical consequences of envenomation, efficacy of antivenom and epidemiology of bites. Herein, we wanted to clarify temporal and spatial patterns in bite incidence using a fine spatial scale (municipality level). We focused on viper bites recorded over the last 10 years in 4 regions of western France. We addressed the determinants of bite occurrence and number of bites considering the following variables: predicted probability of viper presence, species (V. aspis or V. berus), climatic data, tourism function rate, soil transformation and landscape use. 703 bite cases were retained with significant disparities between areas. Bites occurred either during a garden-related activity (339 cases, 51.2%) or during an activity in the countryside (300 cases, 45.3%). The probability of presence of a viper at the municipality level positively influenced the risk of being bitten (multiplied by 3 for a variation in probability of 0.25 from 0.5) but varied between species (lower in V. berus than V. aspis). Artificial land development had a positive effect on bite risks. Finally, a tourism function rate above 50 beds/100 inhabitants was strongly associated with an increase in the risk of occurrence and frequency of bites. Overall, viper bites recorded in our study were concentrated on the south coastline of Pays de la Loire region. The coastal towns are significant areas of tourist attraction and are located close to preserved semi-natural landscapes that provide favorable habitats for vipers. This convergence may favor human/wildlife encounters.

Foods contaminated by Aflatoxin B1 (AFB1) frequently happen in the world and can cause a lot healthy damages to human beings, meanwhile, some of these foods are easily irritate food allergy. To investigate the effect of AFB1 exposure on food allergy, three doses of AFB1 were set, including 0.3 μg/kg · bw (LDAF), 7.5 μg/kg · bw (MDAF), and 100.0 μg/kg · bw (HDAF), respectively; food allergy model was constructed by the BALB/c mice allergy to ovalbumin (OVA). The changes of titer in OVA-specific immunoglobulin E (IgE), IgG, IgG1, IgG2a, as well as level of the mMCP-1 in sera were determined by enzyme linked immunosorbent assay (ELISA), respectively; the levels of interleukin (IL-4, IL-5, IL-13) and interferon (IFN)-γ in spleen were separately assessed using ELISA kits, and their relative genes expression were verified by Real-time fluorescence quantitative PCR (Q-PCR); the population of Th1/Th2/Treg cells were analyzed by flow cytometry. Results showed that when OVA-allergic mice were exposed to AFB1, the production of OVA-specific IgE, IL-4, IL-5 and IL-13, and mMCP-1 were all increased, whereas the level of IFN-γ was decreased; the Th1/Th2 balance was disrupted and the development of Th cells tilted to the Th2 phenotype. The study would contribute to further understand the risk of fungal toxins in food allergy.

Accidents involving snakes from Bothrops spp. and Crotalus spp. constitute the most important cause of envenomation in Brazil and Argentina. Musa spp. (banana) have been reported to be used in popular medicine against snakebite by the members of the Canudos Settlement, located in Goiás. In this way, the aim of this work was to evaluate the antivenom effect of the Ouro (AA), Prata (AAB), Prata-anã (AAB) and Figo (ABB) cultivars against in vitro (phospholipase, coagulation and proteolytic) and in vivo (lethality and toxicity) activities caused by the venoms and toxicity (Artemia salina nauplii and Danio rerio embryos) of Musa spp. as well as the annotation of chemical compounds possibly related to these activities. From the in vitro antiophidic tests with the sap, we observed 100% inhibition of the phospholipase and coagulant activities with the cultivars Prata-anã and Figo against the venoms of B. alternatus and C. d. collineatus, B. diporus and B. pauloensis, respectively, and neutralisation of the lethality against the B. diporus venom. It was observed that the cultivars of Musa spp. did not show toxicity against Artemia salina nauplii and Danio rerio embryos. The sap analysis via HPLC-MS/MS allowed the annotation of the 13 compounds: abscisic acid, shikimic acid, citric acid, quinic acid, afzelechin, Glp-hexose, glucose, sucrose, isorhamnetin-3-O-galactoside-6-raminoside, kaempferol-3-glucoside-3-raminoside, myricetin-3-O-rutinoside, procyanidin B1 and rutin. Therefore, it can be seen that Musa spp. is a potential therapeutic agent that can act to neutralise the effects caused by snakebites.

Rhomb-I, a 23-kDa metalloproteinase was isolated from L. m. rhombeata venom. Its dimethylcasein proteolysis was abolished by metal chelators, and slightly enhanced by Ca2+ and Mg2+ ions, but inhibited by Co2+, Zn2+ and α2-macroglobulin. In aqueous solution, rhomb-I autoproteolyzed to a 20- and 11-kDa fragments at 37 °C. The amino acid sequence showed high homology with other snake venom metalloproteinases. Rhomb-I causes hemorrhage that may be ascribed to hydrolysis of essential basement membrane, extracellular matrix and plasma proteins. It preferentially cleaves the α-chains of fibrin (ogen). Rhomb-I inhibited convulxin- and von Willebrand factor (vWF)-induced aggregation on human platelets without significant effect on collagen-stimulated aggregation or other effectors. It digests vWF into a low-molecular-mass multimers of vWF and a rvWF-A1 domain to a 27-kDa fragment as revealed by western blotting with mouse anti-rvWF A1-domain IgG. Incubation of platelets with rhomb-I resulted in adhesion to and cleavage of platelet receptors glycoprotein (GP)Ibα and GPVI to release a 55-kDa soluble form. Both membrane glycoproteins GPIbα that binds vWF, together with GPVI which binds collagen, play a key role in mediating platelet adhesion/activation and can initiate (patho)physiological thrombus formation. Conclusions: rhomb-I is implicated in the pathophysiology of Lachesis envenoming by disrupting vasculature, hemostasis and platelet aggregation through impairing vWF-GPIb axis and blocking GPVI-collagen binding.

Ipsilateral hemi facial spasm, trigeminal autonomic orofacial pain and occipital neuralgia may occur due to close proximity of V and VII nerves in pons and inter-neuronal interconnections of trigeminocervical complex. In this report, we describe management of a patient with long standing untreated left hemi facial spasm of ten years with contralateral trigeminal autonomic orofacial pain and occipital neuralgia present for last five years. Repeated intramuscular injections of Botulinum neurotoxin A were given for hemi facial spasm which completely resolved the twitches for 5-8 months with decreased baseline twitches noted before next cycle of injections. Addition of Botulinum neurotoxin A in nerve block injections for occipital neuralgia resulted in prolonged relief of five months and decreased baseline pain scores. Addition of Botulinum neurotoxin A to nerve block injections for trigeminal autonomic orofacial pain decreased autonomic features and baseline pain scores.