-
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 -
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 -
ALTEX 2021Animal testing for toxicity assessment of chemicals and pharmaceuticals must take the 3R principles into consideration. During toxicity testing in vivo, clinical signs...
Animal testing for toxicity assessment of chemicals and pharmaceuticals must take the 3R principles into consideration. During toxicity testing in vivo, clinical signs are used to monitor animal welfare and to inform about potential toxicity. This study investigated possible associations between clinical signs, body weight change and histopathological findings observed after necropsy. We hypothesized that clinical signs and body weight loss observed during experiments could be used as early markers of organ toxicity. This represents a potential for refinement in terms of improved study management and decreasing of pain and distress experienced during animal experiments. Data from three sequential toxicity studies of an anti-cancer drug candidate in rats were analyzed using the multivariate partial least squares (PLS) regression method. Associations with a predictive value over 80% were found between the occurrence of mild to severe clinical signs and histopathological findings in the thymus, testes, epididymides and bone marrow. Piloerection, eyes half shut and slightly decreased motor activity were most strongly associated with the pathological findings. A 5% body weight loss was found to be a strong empirical predictor of pathological findings but could also be predicted accurately by clinical signs. Thus, we suggest using mild clinical signs and a 5% body weight loss as toxicity markers and as a non-invasive surveillance tool to monitor research animal welfare in toxicity testing. These clinical signs may also enable reduction of animal use due to their informative potential to support scientific decisions regarding drug candidate selection, dose setting, study design, and toxicity assessment.
Topics: Animal Experimentation; Animal Welfare; Animals; Rats; Toxicity Tests
PubMed: 33118607
DOI: 10.14573/altex.2003311 -
Pharmacokinetics and Efficacy of a Long-lasting, Highly Concentrated Buprenorphine Solution in Mice.Journal of the American Association For... Jan 2021Buprenorphine is a commonly used opioid for mitigating pain in laboratory mice after surgical procedures; however, the dosing interval necessary for standard...
Buprenorphine is a commonly used opioid for mitigating pain in laboratory mice after surgical procedures; however, the dosing interval necessary for standard buprenorphine may require treatment every 4 to 6 h to maintain an adequate plane of analgesia. An alternative formulation that provides prolonged plasma concentration with long-lasting effects would be beneficial in achieving steady-state analgesia. We evaluated a long-lasting and highly concentrated formulation of buprenorphine (Bup-LHC) in mice. Pharmacokinetic analysis was performed to assess plasma concentrations in male C57BL/6J (B6) and female CD1 mice after subcutaneous injection of 0.9 mg/kg. The Bup-LHC formulation provided plasma drug levels that exceeded the therapeutic level for at least 12 h in male B6 mice and was below therapeutic levels by 8 h in female CD1 mice. An experimental laparotomy model was used to assess analgesic efficacy. Female CD1 mice were treated with either Bup-LHC (0.9 mg/kg) or saline at 1 h before undergoing an ovariectomy via a ventral laparotomy. At 3, 6, 12, 24, and 48 h after surgery, pain was assessed based on the following behaviors: orbital tightness, grooming, wound licking, rearing, arched posture, ataxia, piloerection, nest building, and general activity. At 3 and 6 h after surgery, Bup-LHC-treated mice had significantly less wound licking and orbital tightness and considerably higher activity levels than did saline-treated mice. At 12 h, wound licking, orbital tightness and activity in Bup-LHC-treated mice were no longer significantly different from those of saline-treated mice. The results of this study suggest that Bup-LHC at 0.9 mg/kg provides sufficient plasma concentrations for analgesia in mice for 6 to 12 h after administration, as demonstrated behaviorally for at least 6 h after surgery.
Topics: Analgesics, Opioid; Animals; Buprenorphine; Female; Male; Mice; Mice, Inbred C57BL; Pain; Pain Measurement
PubMed: 32993847
DOI: 10.30802/AALAS-JAALAS-20-000049 -
Toxicon : Official Journal of the... Nov 2020Scorpion envenomations are a major public health problem in Brazil, and most medically important cases are attributable to the Tityus genus. The objective of this study...
Scorpion envenomations are a major public health problem in Brazil, and most medically important cases are attributable to the Tityus genus. The objective of this study is to describe the clinical and epidemiological aspects of a series of 151 cases of confirmed scorpion stings, which were treated at the hospitals of two cities in the Western Brazilian Amazon, between June 2014 and December 2019. This study shows that the genus Tityus was the most prevalent. Tityus (Atreus) metuendus (Pocock, 1897) was responsible for the greatest number of cases (68.2%), followed by Tityus (Archaeotityus) silvestris (Pocock, 1897) (14.6%). Most of the envenomations involved males (53.6%), and analysis showed a slight predominance in the group from 40 to 49 years (22.5%). The most affected body regions were feet (49.0%) and hands (31.8%). The time elapsed between the accident and medical care was ≤6 h in 92.1% of cases. Regarding clinical severity, classes I (80.8%) and II (15.9%) predominated. However, there were five (3.3%) class III cases; four for T. metuendus and one for T. silvestris. The most frequent local and systemic manifestations were, respectively, pain (84.1%), paresthesia (34.4%) and mild edema (25.8%), and nausea (9.3%) and myoclonia (8.6%). The clinical manifestations were similar among the patients stung by the different species of scorpions. There were no differences between the manifestations of envenomation caused by T. metuendus, T. silvestris and T. raquelae. For victims of T. apiacas, a higher frequency of piloerection and myoclonia was observed, and was described by the affected patients as a 'sensation of receiving an electric shock' throughout the body. No deaths were registered. The species of greatest epidemiological importance in Manaus is T. metuendus, a species that leads to clinical pictures that do not differ substantially from those observed in other Brazilian regions. T. apiacas causes neurological manifestations that differed from other Tityus species. Our findings suggest that the available antivenoms have little effectiveness when used in the treatment of envenomations by some Amazonian scorpions.
Topics: Adult; Animals; Antivenins; Brazil; Female; Humans; Male; Scorpion Stings; Scorpion Venoms; Scorpions; Species Specificity
PubMed: 32991937
DOI: 10.1016/j.toxicon.2020.09.012 -
Cell Aug 2020In the skin, sympathetic nerves, arrector pili muscles, and hair follicles form a tri-lineage unit to cause piloerection or goosebumps. In this issue of Cell, Schwartz...
In the skin, sympathetic nerves, arrector pili muscles, and hair follicles form a tri-lineage unit to cause piloerection or goosebumps. In this issue of Cell, Schwartz et al. report that, beyond goosebumps, muscle-anchored nerves form "synapse-like" connections with hair follicle stem cells to promote hair regeneration in response to cold.
Topics: Hair; Hair Follicle; Muscle, Smooth; Piloerection; Stem Cells
PubMed: 32763185
DOI: 10.1016/j.cell.2020.07.004 -
Cell Aug 2020Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study...
Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.
Topics: Accessory Nerve; Animals; Cell Cycle; Cold Temperature; Female; Fibroblast Growth Factors; Forkhead Transcription Factors; Gene Expression Profiling; Hair; Hair Follicle; Hedgehog Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Norepinephrine; Piloerection; RNA-Seq; Receptors, Adrenergic, beta-2; Repressor Proteins; Signal Transduction; Smoothened Receptor; Stem Cell Niche; Stem Cells; Sympathetic Nervous System; Synapses
PubMed: 32679029
DOI: 10.1016/j.cell.2020.06.031 -
Frontiers in Neuroscience 2020The volitional control of piloerection has been previously reported in a small subset of individuals. Although this ability may be useful to study the mechanism...
The volitional control of piloerection has been previously reported in a small subset of individuals. Although this ability may be useful to study the mechanism underlying piloerection, there is little existing research on this ability, neither objective evidence at a group-level, nor information about its stability under experimental constraints. The present study aimed to validate existing findings of voluntarily generated piloerection (VGP) and to examine its potential contribution to neuroscientific research based on objective evidence of this ability. In Study 1, to confirm the characteristics of VGP reported in previous studies and identify individuals with VGP capability, an online survey of VGP candidates was conducted. In Study 2, 18 VGP holders participated in a mail-based piloerection measurement experiment, and the nature of VGP was examined based on the objective data obtained by image-based analysis (GooseLab). Study 1 largely confirmed the characteristics of VGP reported in previous studies, and Study 2 demonstrated VGP at a group-level and provided information about the temporal characteristics of this ability, which supports the utility of VGP in neuroscientific research. For some participants, VGP appeared to be emotionally promoted, which suggests that VGP has some relationship with the emotional nature of involuntary piloerection. Although the studies did not tightly control the environment in which VGP was elicited, the findings nonetheless demonstrate the possible contribution of VGP to elucidating the mechanism of involuntary emotional piloerection and the neural basis of piloerection itself.
PubMed: 32581701
DOI: 10.3389/fnins.2020.00590 -
Brazilian Journal of Otorhinolaryngology 2022Considering that previous studies suggest that pesticides may cause hearing disorders in humans, as well as the lack of studies proving the specific mechanisms of injury...
INTRODUCTION
Considering that previous studies suggest that pesticides may cause hearing disorders in humans, as well as the lack of studies proving the specific mechanisms of injury and the difficulty of separating concomitant etiological factors of the hearing damage, such as noise and vibration, it is important to develop studies using animal models to elucidate the effects of exposure to those substances isolated from other hearing damage etiologies.
OBJECTIVE
To evaluate if the exposure to a dichlorvos based organophosphorus insecticide may induce ototoxicity.
METHODS
36 male Wistar rats were assigned to 3 groups (12 rats/group): control (exposed to water), positive control (treated with cisplatin to induce hearing damage) and experimental (exposed to dichlorvos based organophosphorus insecticide). The amplitude of distortion product otoacoustic emissions in the frequencies of 4, 6, 8, 10 and 12kHz was evaluated before and after exposure, as well as systemic toxicity signs, body mass gain and plasma cholinesterase. Open field and plus maze tests were performed in 24 rats: experimental (n=8), control (n=8) and positive control group (n=8 introduced new rats to induce anxiolytic activity) to evaluate the locomotor activity and anxiety, respectively.
RESULTS
There was no significant change in body mass gain and plasma cholinesterase in the dichlorvos based organophosphorus insecticide group, however, the animals showed transient piloerection, depression and dyspnea during exposure. The behavior was not affected in any group. The frequencies of 8 and 10kHz were significantly affected bilaterally in the insecticide group, which also showed a significant difference of the control in 10kHz on the right and 8 and 10kHz on the left ear.
CONCLUSION
Subchronic inhalation exposure to dichlorvos based organophosphorus insecticide induced ototoxicity in the cochlear function of rats without relevant systemic toxicity.
Topics: Animals; Dichlorvos; Inhalation Exposure; Insecticides; Male; Organophosphorus Compounds; Otoacoustic Emissions, Spontaneous; Rats; Rats, Wistar
PubMed: 32532628
DOI: 10.1016/j.bjorl.2020.04.005 -
Transplant International : Official... Oct 2020Intestinal passenger T leukocytes are responsible for graft-versus-host disease (GvHD) in intestinal transplantation (ITx). We hypothesized that ex vivo fludarabine...
Donor's graft ex vivo T-cell depletion with fludarabine reduces graft-versus-host disease signs and improves survival after intestinal transplantation - an experimental study.
Intestinal passenger T leukocytes are responsible for graft-versus-host disease (GvHD) in intestinal transplantation (ITx). We hypothesized that ex vivo fludarabine treatment of the bowel graft would diminish the risk of GvHD and improve overall survival post-transplant. We performed isolated heterotopic small bowel transplantations from Lewis (LEW) to Brown Norway (BN) rat strains, which generated GvHD signs from the fourth day post-transplant. These symptoms included rash, weight loss, piloerection, and diarrhea. The grafts of one of the experimental groups were immersed and sealed in cold Celsior preservation solution with 1000 µm fludarabine for 1 h, prior to its implantation into recipient animals. No histological signs of intestinal tissue alterations were observed after fludarabine treatment. Fludarabine-treated bowel recipients showed significantly later and milder clinical signs of GvHD and reduced total donor cell chimerism, as determined by flow cytometry using strain-specific anti-HLA antibodies. Additionally, fludarabine treatment prolonged recipients' overall survival (13.5 days ± 0.3 days vs. 9.2 days ± 0.5). We conclude that active modification of the intestinal leukocyte composition is advantageous in our ITx animal model. Immunosuppression with fludarabine during the surgical procedure, which could be translated directly to the clinic, protects bowel recipients from GvHD and improves overall post-transplant survival.
Topics: Animals; Graft vs Host Disease; Rats; Rats, Inbred Lew; T-Lymphocytes; Transplantation, Homologous; Vidarabine
PubMed: 32526809
DOI: 10.1111/tri.13672