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PLoS Pathogens Dec 2021Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic...
Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.
Topics: Animals; Chlorocebus aethiops; Cytokines; Disease Models, Animal; Encephalitis Viruses, Tick-Borne; Encephalitis, Tick-Borne; Female; HEK293 Cells; Hemorrhagic Fevers, Viral; Humans; Lymph Nodes; Macaca nemestrina; Vero Cells; Viremia
PubMed: 34855915
DOI: 10.1371/journal.ppat.1009678 -
Journal of Neurology, Neurosurgery, and... Mar 2021To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this...
OBJECTIVE
To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting.
METHODS
Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy.
RESULTS
10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05).
CONCLUSIONS
Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.
Topics: Adolescent; Adult; Aged; Autoantibodies; Cohort Studies; Encephalitis; Epilepsies, Partial; Female; Humans; Immunotherapy; Male; Middle Aged; Nerve Tissue Proteins; Predictive Value of Tests; ROC Curve; Young Adult
PubMed: 33219046
DOI: 10.1136/jnnp-2020-325011 -
Toxicon : Official Journal of the... Sep 2014Ornithodoros brasiliensis, also known as the mouro tick, is an argasid tick only found in the highlands of Southern Brazil. O. brasiliensis parasitism is associated with...
Ornithodoros brasiliensis, also known as the mouro tick, is an argasid tick only found in the highlands of Southern Brazil. O. brasiliensis parasitism is associated with severe reactions in its hosts ranging from local pruritus and pain to systemic disturbances. Recently, the re-emergence of O. brasiliensis parasitism in humans and dogs drew attention to the clinical findings induced by its bite, which are poorly understood and described. Moreover, rare experimental data about tick bite effects under controlled conditions were available. Thus, this study aimed to describe clinical and pathological findings induced by O. brasiliensis bites in experimentally parasitized rats. Ticks feed for ∼40 min in rats, and their weight increased by approximately four times after the blood meal. Rats bitten by five adult ticks showed hyperemia of the oral/ocular mucosa, piloerection, tachypnea, claudication, ocular and nasal discharge, pruritus, and swollen and erythemic lesions. A large hemorrhagic lesion was observed on rat skin in tick attachment sites, reaching ∼17 mm in diameter 12 h after a bite. Bitten rats also presented an increased bleeding tendency (∼50%) 6 h after a tick bite, evaluated by the tail-cut rat model of bleeding. Blood samples of bitten rats were taken, and clinical pathology analysis showed significant alterations in the eosinophil and basophil counts, in creatine phosphokinase (CPK) and CPK MB fraction, and lactate dehydrogenase (LDH) activity, and fibrinogen level. Histopathological analysis revealed marked subcutaneous hemorrhage, edema and slight muscle degeneration at the bite site. Also, muscle degeneration and necrosis were observed in the myocardium of bitten rats 72 h after bites by histopathology and immunohistochemistry against troponin C. This work showed the ability of O. brasiliensis to cause severe disturbances in experimentally parasitized rats, compatible with a tick toxicosis syndrome. This observation associated with the re-emergence of O. brasiliensis parasitism makes this parasite as a public health hazard in southern Brazil.
Topics: Animals; Bites and Stings; Creatine Kinase; L-Lactate Dehydrogenase; Male; Ornithodoros; Rats; Rats, Wistar; Tick Infestations
PubMed: 24973739
DOI: 10.1016/j.toxicon.2014.06.017 -
PloS One 2015Previous studies have shown that a cardiac signature of emotionality (referred to as EK, which can be computed from the standard 12 lead electrocardiogram, ECG),...
BACKGROUND
Previous studies have shown that a cardiac signature of emotionality (referred to as EK, which can be computed from the standard 12 lead electrocardiogram, ECG), predicts inter-individual differences in the tendency to experience and express positive emotion. Here, we investigated whether EK values can be transiently modulated during stimulation with participant-selected music pieces and film scenes that elicit strongly positive emotion.
METHODOLOGY/PRINCIPAL FINDINGS
The phenomenon of aesthetic chills, as indicated by measurable piloerection on the forearm, was used to accurately locate moments of peak emotional responses during stimulation. From 58 healthy participants, continuous EK values, heart rate, and respiratory frequency were recorded during stimulation with film scenes and music pieces, and were related to the aesthetic chills. EK values, as well as heart rate, increased significantly during moments of peak positive emotion accompanied by piloerection.
CONCLUSIONS/SIGNIFICANCE
These results are the first to provide evidence for an influence of momentary psychological state on a cardiac signature of emotional personality (as reflected in EK values). The possibility to modulate ECG amplitude signatures via stimulation with emotionally significant music pieces and film scenes opens up new perspectives for the use of emotional peak experiences in the therapy of disorders characterized by flattened emotionality, such as depression or schizoid personality disorder.
Topics: Adult; Electrocardiography; Esthetics; Female; Heart; Heart Rate; Humans; Male; Motion Pictures; Music; Piloerection; Pleasure; Respiration; Surveys and Questionnaires; Young Adult
PubMed: 26083383
DOI: 10.1371/journal.pone.0130117 -
Molecular Human Reproduction Aug 2017Is resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice?
STUDY QUESTION
Is resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice?
SUMMARY ANSWER
Resveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling.
WHAT IS KNOWN ALREADY
Genital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor.
STUDY DESIGN, SIZE, DURATION
An in vivo animal study was conducted. On Day 15 of pregnancy, mice received at 8:00 h a dose of vehicle (40% ethanol in saline solution) or resveratrol (3 mg/kg in vehicle) via oral gavage followed by two doses of LPS or vehicle administered intraperitoneally (i.p.), the first one at 10:00 h (0.17 mg/kg in 0.1 ml of sterile saline solution) and the second at 13:00 h (0.5 mg/kg in 0.1 ml of sterile saline solution). The mice were closely observed for any signs of morbidity (piloerection, decreased movement, and diarrhea), vaginal bleeding or preterm delivery. The beginning of preterm delivery was defined by early delivery of the first pup. Normal term labor occurs on Day 19 of gestation.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Time of labor, pregnancy outcome and morphological features were evaluated after LPS and/or resveratrol administration. Uterine stripes were collected 5 h after the last LPS injection and prostaglandin and endocannabinoid profiling was analyzed by mass spectrometry. Nitric oxide synthase (NOS) activity was measured by radioconversion assay. Cyclooxygenase-2 (Cox-2) and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh) mRNA levels were analyzed by RT-PCR whilst the protein expression of inducible nitric oxide synthase (iNOS), COX-1 and COX-2 were studied by western blot.
MAIN RESULTS AND THE ROLE OF CHANCE
In vivo treatment of 15-day pregnant BALB/c mice with resveratrol prevented the LPS-induced preterm birth in 64% of the cases, whereas only 15% of mice with LPS alone escaped preterm birth. Treatment with resveratrol resulted in a reduced NOS activity (P < 0.05) in the uterus of LPS-treated mice. Similarly, resveratrol reduced the expression of LPS-induced pro-inflammatory agents such as iNOS (P < 0.05), COX-2 (P < 0.05), prostaglandin E2 (PGE2) (P < 0.05) and anandamide (AEA) (P < 0.05). Moreover, resveratrol administration resulted in changes in the uterine endocannabinoid profiling altered by LPS.
LARGE SCALE DATA
N/A.
LIMITATIONS, REASONS FOR CAUTION
Since our experimental design involves the use of mice, the extrapolation of the results presented here to humans is limited.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings provide evidence for the tocolytic effects of resveratrol.
STUDY FUNDING AND COMPETING INTEREST(S)
Dr Ana María Franchi was funded by Agencia Nacional para la Promoción Científica y Tecnológica (PICT 2013/0097) and by Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 2012/0061). Dr Heather B. Bradshaw was funded by NIH (DA006668). The authors have no competing interests.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Endocannabinoids; Female; Inflammation; Lipopolysaccharides; Mice, Inbred BALB C; Obstetric Labor, Premature; Pregnancy; Prostaglandins; Protective Agents; Resveratrol; Stilbenes; Uterus
PubMed: 28810692
DOI: 10.1093/molehr/gax036 -
Journal of Basic and Clinical Pharmacy Sep 2014In general, organic solvents are inhibiting many physiological enzymes and alter the behavioural functions, but the available scientific knowledge on laboratory solvent...
BACKGROUND
In general, organic solvents are inhibiting many physiological enzymes and alter the behavioural functions, but the available scientific knowledge on laboratory solvent induced organ specific toxins are very limited. Hence, the present study was planned to determine the sub-chronic toxic effects of petroleum ether (boiling point 40-60°C), a laboratory solvent in Sprague-Dawley (SD) rats.
MATERIALS AND METHODS
The SD rats were divided into three different groups viz., control, low exposure petroleum ether (250 mg/kg; i.p.) and high exposure petroleum ether (500 mg/kg; i.p.) administered group. The animals were exposed with petroleum ether once daily for 2 weeks. Prior to the experiment and end of the experiment animals behaviour, locomotor and memory levels were monitored. Before initiating the study animals were trained for 2 weeks for its learning process and its memory levels were evaluated. Body weight (BW) analysis, locomotor activity, anxiogenic effect (elevated plus maze) and learning and memory (Morris water navigation task) were monitored at regular intervals. On 14(th) day of the experiment, few ml of blood sample was collected from all the experimental animals for estimation of biochemical parameters. At the end of the experiment, all the animals were sacrificed, and brain, liver, heart, and kidney were collected for biochemical and histopathological analysis.
RESULTS
In rats, petroleum ether significantly altered the behavioural functions; reduced the locomotor activity, grip strength, learning and memory process; inhibited the regular body weight growth and caused anxiogenic effects. Dose-dependent organ specific toxicity with petroleum ether treated group was observed in brain, heart, lung, liver, and kidney. Extrapyramidal effects that include piloerection and cannibalism were also observed with petroleum ether administered group. These results suggested that the petroleum ether showed a significant decrease in central nervous system (CNS) activity, and it has dose-dependent toxicity on all vital organs.
CONCLUSION
The dose-dependent CNS and organ specific toxicity was observed with sub-chronic administration of petroleum ether in SD rats.
PubMed: 25316988
DOI: 10.4103/0976-0105.141943 -
Experimental Neurology Aug 2016The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in...
The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced motor neuron excitability for weeks after resolution of sepsis. To assess whether additional contributions from myopathy, neuropathy and defects in neuromuscular transmission contributed to the reduction in force generation, we measured whole-muscle force production in response to electrical stimulation of the muscle nerve. We found no abnormality in force generation that would suggest the presence of myopathy, neuropathy or defective neuromuscular transmission. These data suggest disruption of repetitive firing of motor neurons is an important contributor to weakness induced by sepsis in rats and raise the possibility that reduced motor neuron excitability contributes to disability that persists after resolution of sepsis.
Topics: Action Potentials; Analysis of Variance; Animals; Disease Models, Animal; Electric Stimulation; Electromyography; Motor Neurons; Muscle Weakness; Patch-Clamp Techniques; Rats; Sepsis; Spinal Cord; Synaptic Transmission
PubMed: 27118372
DOI: 10.1016/j.expneurol.2016.04.020 -
Scientific Reports Jan 2021Hair regenerative medicine has emerged as a promising approach for the treatment of severe hair loss. Recent advances in three-dimensional tissue engineering, such as...
Hair regenerative medicine has emerged as a promising approach for the treatment of severe hair loss. Recent advances in three-dimensional tissue engineering, such as formation of hair follicle germs (HFGs), have considerably improved hair regeneration after transplantation in animal models. Here, we proposed an approach for fabricating HFGs containing vascular endothelial cells. Epithelial, dermal papilla, and vascular endothelial cells initially formed a single aggregate, which subsequently became a dumbbell-shaped HFG, wherein the vascular endothelial cells localized in the region of dermal papilla cells. The HFGs containing vascular endothelial cells exhibited higher expression of hair morphogenesis-related genes in vitro, along with higher levels of hair shaft regeneration upon transplantation to the dorsal side of nude mice, than those without vascular endothelial cells. The generated hair follicles represented functional characteristics, such as piloerection, as well as morphological characteristics comparable to those of natural hair shafts. This approach may provide a promising strategy for fabricating tissue grafts with higher hair inductivity for hair regenerative medicine.
Topics: Alopecia; Animals; Cells, Cultured; Endothelium, Vascular; Female; Hair Follicle; Humans; Mice; Mice, Inbred ICR; Mice, Nude; Regeneration; Regenerative Medicine; Stem Cells; Tissue Engineering
PubMed: 33436760
DOI: 10.1038/s41598-020-79722-z -
Toxicology Reports Jun 2024(Fabaceae) crude extracts are key ingredients of several licensed and unlicensed herbal products in East Africa. However, there is limited and often contradicting...
(Fabaceae) crude extracts are key ingredients of several licensed and unlicensed herbal products in East Africa. However, there is limited and often contradicting information regarding its toxicity. We therefore evaluated the acute and subacute toxicity of the ethanolic stem bark extract of in mature healthy Wistar albino rats following Lorke's method and OECD guidelines 407. The LD of the ethanolic stem bark extract of was 2000 mg/kg. The acute toxicity signs observed included piloerection, hyperventilation, lethargy, and loss of righting reflex. There was a significant increase in aspartate aminotransferase, alkaline phosphatase, red blood cells and haemoglobin in rats after 28 days at the dose of 500 mg/kg. Histological analyses revealed multifocal random parenchymal necrosis and scattered periportal mononuclear inflammatory cells infiltration in the liver, interstitial nephritis in the kidney and multifocal lymphoid accumulation in the peribronchiolar and perivascular lung tissue at 500 mg/kg. The ethanolic stem bark of was therefore moderately toxic to the rats when administered in a single high oral dose within 24 h. The extract caused a dose dependent toxicity with significant damage to the kidney, liver and lung tissues at a dose of 500 mg/kg after 28 days. Herbal medicines containing extracts should be consumed cautiously due to likelihood of toxicity particularly at higher doses greater than 500 mg/kg.
PubMed: 38304700
DOI: 10.1016/j.toxrep.2024.01.005 -
Case Reports in Neurology 2021Autonomic status epilepticus (Aut SE) is a condition characterized by ongoing focal autonomic seizure lasting for >30 min. Aut SE can show a variety of clinical...
Autonomic status epilepticus (Aut SE) is a condition characterized by ongoing focal autonomic seizure lasting for >30 min. Aut SE can show a variety of clinical manifestations including vomiting, nausea, changes in heart rate, piloerection, pupillary abnormalities, and visual abnormalities. Although Aut SE is a common finding in childhood in the context of Panayiotopoulos syndrome, few reports have described this condition during adulthood. In the present report, we describe a case of Aut SE in an adult patient with parasellar meningioma and bilateral frontotemporal epileptiform activity on EEG record.
PubMed: 35111030
DOI: 10.1159/000519944